SECTION 21 Disorders of the kidney and urinary tra

21.10.1 Diabetes mellitus andthe kidney

21.10.1 Diabetes mellitus andthe kidney

21.10.10 Atherosclerotic renovascular disease 5044

21.10.10 Atherosclerotic renovascular disease 5044 Philip A. Kalra and Diana Vassallo

21.10.2 The kidney in systemic vasculitis 4988 Dav

21.10.2 The kidney in systemic vasculitis 4988 David Jayne

21.10.3 The kidney in rheumatological disorders 50

21.10.3 The kidney in rheumatological disorders 5001 Liz Lightstone and Hannah Beckwith

21.10.3  The kidney in rheumatological disorders 5001 Yates M, et al. (2016). EULAR/​ERA-​EDTA recommendations for the management of ANCA-​associated vasculitis. Ann Rheum Dis, 75, 1583–​94. Zonozi R, Niles JL, Cortazar FB. (2018). Renal involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Rheum Dis Clin North Am, 44, 525–43. 21.10.3  The kidney in rheumatological disorders Liz Lightstone and Hannah Beckwith ESSENTIALS Many rheumatological conditions have systemic effects. Antibody production, complement activation, and protein deposition can all result in damage to the kidney, sometimes with devastating sequelae. Systemic lupus erythematosus Lupus nephritis is clinically evident in up to 75% of patients with systemic lupus erythematosus (SLE) and end stage renal disease (ESRD) occurs in 5 to 10% of patients at 10 years. Proteinuria is the most common clinical presentation, closely followed by nonvisible haematuria and tubular abnormalities. Patients with active lupus nephritis often have features of active SLE. The gold standard for lupus nephritis diagnosis is a renal biopsy, with treatment related to histopathological features observed. Class I (minimal mesangial) and II (mesangial proliferative) lesions are generally associated with a good prognosis; treatment is usually determined by extrarenal manifestations. First-​line renal treatment would be renin–​angiotensin system blockade to reduce proteinuria. Class III (focal proliferative) and IV (diffuse proliferative) lesions are the most common renal manifestations of SLE. Prior to modern immunotherapy, patient and kidney survival was poor. Treatment for these classes of lupus nephritis has induction and mainten- ance phases:  initially a rapid reduction in kidney inflammation is sought with intensive immunotherapy (often cyclophosphamide or mycophenolate mofetil (MMF) based). Once this has been attained, maintenance therapy is commenced (MMF/​azathioprine) with the aim of maintaining disease remission and minimizing treatment side effects. Class  V (membranous) lupus nephritis is associated with the
development of chronic kidney disease and ESRD, particularly if there is marked proteinuria. Treatment is generally as for class III and IV, although there is a less secure evidence base for this. Adjunctive immunosuppressive agents such as rituximab and tacrolimus are emerging as increasingly important lupus nephritis therapies. Systemic sclerosis Systemic sclerosis is a multiorgan connective tissue disease. Most renal manifestations are clinically silent. By contrast, the scleroderma renal crisis is characterized by accelerated-​phase hypertension and impaired renal function. It carries a high mortality risk. Rheumatoid arthritis Rheumatoid arthritis can affect the kidneys in many ways, most commonly by causing amyloid A amyloidosis. This presents with proteinuria, often severe enough to cause nephrotic syndrome, with 50% progressing to ESRD after 5 years (90% at 10 years). Renal vasculitis, mesangiocapillary glomerulonephritis, and mesangial IgA proliferative glomerulonephritis are also described. Gold and penicillamine (now rarely used) can cause proteinuria, sometimes with nephrotic syndrome. Sjögren’s syndrome Renal involvement in Sjögren’s syndrome is generally mild, but up to a quarter of patients develop acute or chronic kidney disease, typically with evidence of tubular dysfunction. Glomerular abnor- malities are rare and the most common histological abnormality is tubulointerstitial nephritis. Drug nephrotoxicity Conventional anti-rheumatics and over-​the-​counter nonsteroidal anti-​inflammatory drugs are used exceptionally widely in the com- munity and are nephrotoxic. Their almost ubiquitous use, especially during intercurrent illnesses, means they are frequent contributors to acute and chronic kidney damage. Systemic lupus erythematosus/​lupus nephritis Lupus nephritis is clinically evident in up to 75% of patients with systemic lupus erythematosus, a multisystem disease characterized by the presence of antinuclear autoantibodies (ANA) (see Chapter 19.11.2). Lupus nephritis ranges from mild, asymptomatic subclinical disease, to rapidly progressive nephritic and or/​nephrotic syndromes, with end stage renal disease (ESRD) seen in 5 to 10% of patients with systemic lupus erythematosus (SLE) at 10 years. The prognosis of lupus nephritis has improved considerably with the advent of effective antihypertensive medication, immunosuppression, antibiotics, dia- lysis and transplantation, but renal failure and cardiovascular dis- ease remain important determinants of morbidity and mortality. Pathophysiology Renal damage seen in lupus nephritis is multifactorial and involves both immune-​mediated and nonimmune-​mediated pathways. Defective clearance of apoptotic cells and autoreactive T cells results in persistent exposure of self-​antigens with subsequent development of autoimmunity. This loss of immunological tolerance then leads to increased production of autoreactive cells driving inflammation, either through direct infiltration (T cells, macrophages) and/​or through production of autoantibodies or cytokines, antibody depos- ition, cellular infiltration, and proliferation. Further stimulation of inflammatory, fibrogenic processes perpetuates disease progression, along with the presence of hypertension and proteinuria. Structural maladaptations that result from lupus nephritis can also cause glomerular hypertension, activation of the renin–​angiotensin–​ aldosterone system, and hyperlipidaemia. Subsequent upregulation

section 21  Disorders of the kidney and urinary tract 5002 of proinflammatory cytokines, progressive glomerulosclerosis, and interstitial fibrosis leads to a further reduction in functioning nephron mass, increasing the risk of further renal damage. Thus a vicious cycle of inflammation, destruction, and the development of disease is formed. Clinical presentations Most patients with SLE have evidence of renal involvement at pres- entation, usually in the form of asymptomatic proteinuria with or without nonvisible haematuria. Over time, the proportion with overt renal disease increases to approximately 60%, with higher rates in children. This is more common and generally more severe in nonwhite patients. Nearly 100% of patients with lupus nephritis have proteinuria, closely followed by nonvisible haematuria (80%) and tubular abnormalities (60–​80%). Other clinical findings in- clude nephrotic syndrome (45–​60%), hypertension (15–​50%), and granular casts (30%): rapidly declining renal function is much less common. Lupus nephritis may, however, be ‘clinically silent’, with no biochemical or urinary abnormalities. Patients with active lupus nephritis often have features of active extrarenal SLE, including serositis, a vasculitic rash, ulcers, fevers, or alopecia. However, although relatively rare, lupus nephritis can occur in isolation, and as a presenting feature of SLE. Investigations/​assessment All patients with SLE should have regular urinalysis (including urinary albumin-​to-​creatinine ratio or urinary protein-​to-​creatinine ratio quantification) and monitoring of their serum creatinine. Anti double-​stranded DNA and anti-​C1q antibodies are often abnormal in patients with lupus nephritis, their titres frequently correlating with disease activity. Decreasing serum third compo- nent of complement system (C3), particularly in conjunction with rising levels of anti double-​stranded DNA, correlates well with ac- tive lupus nephritis. Anti-​Sm antibody is also positive in up to 30% of black patients, but is not necessarily indicative of active disease. Rising antinucleosome antibodies may predict a renal flare. The gold standard for diagnosis of lupus nephritis remains a renal biopsy, enabling determination of lupus involvement and degree of activity or damage, and providing important prognostic indica- tors. This is justified when there is evidence of glomerular disease with renal impairment and/​or urinary sediment indicative of active nephritis: • Proteinuria (>100 mg/​24 h or protein:creatinine ratio >100 mg/​ mmol) • Haematuria (>10 dysmorphic red blood cells per high power field) • Casts of red and white blood cells Histopathology Various glomerular patterns of immune complex-​mediated injury are seen on biopsy and classification of lupus nephritis is based primarily on the location (mesangial, endothelial, and epithelial) and nature of lesions seen (active, chronic, focal, or diffuse) (Figs. 21.10.3.1–​21.10.3.3 and Table 21.10.3.1). Immunofluorescence microscopy of biopsies with lupus nephritis can show florid de- position (the classical ‘full-​house’ picture) of immunoglobu- lins, IgG, IgA, and IgM, as well as complement proteins, C3, C4, and C1q (Fig. 21.10.3.4). The 2003 International Society of Nephrology/​Renal Pathology Society (ISN/RPS) classification of Fig. 21.10.3.1  Lupus nephritis. The glomerulus has mild mesangial increase (ISN/RPS class II) (periodic acid–​methenamine silver staining, magnification ×50). Courtesy of Professor A.J. Howie. Fig. 21.10.3.2  Lupus nephritis. The glomerulus has marked mesangial increase with wire loops, a few doubled basement membranes, and segmental lesions (ISN/RPS class IV) (periodic acid–​methenamine silver staining, magnification ×40). By courtesy of Professor A.J. Howie. Fig. 21.10.3.3  Lupus nephritis. The glomerulus has marked swelling of the glomerular basement membrane (membranous lesions; ISN/RPS class V). Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

21.10.3  The kidney in rheumatological disorders 5003 lupus nephritis (Table 21.10.3.2 and Fig. 21.10.3.5) was developed to enable a more uniform description of histopathological lesions, promoting standardization of patient care and enabling improved comparison of outcomes between multinational centres. Inclusion of renal vascular lesions in the 2003 ISN/RPS classification system improves the prediction of renal outcomes. Treatment of lupus nephritis Decisions regarding treatment of patients with lupus nephritis are primarily dependent on histological lesions seen, but also reflect Table 21.10.3.1  Active and chronic glomerular lesions Active Chronic Endocapillary hypercellularity Glomerular sclerosis (segmental or global) Crescents—​cellular or fibrocellular Fibrous crescents Karyorrhexis Fibrous adhesions Fibrinoid necrosis Rupture of glomerular basement membrane Wire loops Hyaline thrombi Table 21.10.3.2  The 2003 International Society of Nephrology/​Renal Pathology Society classification of lupus nephritis (which is a modification of the 1995 WHO classification) Class I Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Class II Mesangial proliferative lupus nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy with mesangial immune deposits May be a few isolated subepithelial or subendothelial deposits visible by immunofluorescence or electron microscopy, but not by light microscopy (Fig. 21.10.3.1) Class III Focal lupus nephritis Active or inactive focal, segmental or global endo-​ or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations   Class III (A) Active lesions: focal proliferative lupus nephritis   Class III (A/​C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis   Class III (C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus nephritis Class IV Diffuse lupus nephritis Active or inactive diffuse, segmental or global endo-​ or extracapillary glomerulonephritis involving ≥ 50% of all glomeruli, typically with diffuse subendothelial immune deposits. The class is divided into diffuse segmental (IV-​S) lupus nephritis when ≥50% of the involved glomeruli have segmental lesions, and diffuse global (IV-​G) lupus nephritis when ≥50% of the involved glomeruli have global lesions (Fig. 21.10.3.2) Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation   Class IV-​S (A) Active lesions: diffuse segmental proliferative lupus nephritis   Class IV-​G (A) Active lesions: diffuse global proliferative lupus nephritis   Class IV-​S (A/​C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis   Class IV-​G (A/​C) Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis   Class IV-​S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus nephritis   Class IV-​G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Class V Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphological sequelae by light microscopy by immunofluorescence or electron microscopy with or without mesangial alterations (Fig. 21.10.3.3) Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed Class VI Advanced sclerotic lupus nephritis ≥90% of glomeruli globally sclerosed without residual activity A, active; C, chronic. Fig. 21.10.3.4  Lupus nephritis. IgG deposition within the glomerulus. Reproduced with permission from Condon M, Dodd P, Lightstone L. The patient with systemic lupus erythematosus: clinical features, investigations, and diagnosis. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 5004 the severity of clinical presentation (the degree of associated pro- teinuria, hypertension, and/​or extrarenal manifestations of SLE). Proliferative disease (class III and class IV lupus nephritis) is more aggressive than nonproliferative lupus nephritis and requires inten- sive immunosuppressive treatment to induce remission and prevent lasting kidney damage. Management of nonproliferative lupus nephritis Class I and class II ISN/RPS class I and class II lesions are associated with a better prognosis and consequently renal-​specific therapy is not indi- cated. Patients with class I lupus nephritis and class II with pro- teinuria less than 1 g/​day should have treatment dictated by the extrarenal manifestations of SLE. For those patients with class II lupus nephritis and proteinuria greater than 3 g/​day, treatment with corticosteroids or calcineurin inhibitors can be useful if proteinuria cannot be controlled by renin–​angiotensin system blockade alone. Class VI From a renal perspective, immunosuppression is not indicated in class VI lupus nephritis, which reflects chronic insult without ac- tive immune-​mediated injury. However, many patients with class VI lupus nephritis exhibit extrarenal manifestations of SLE necessitating immunosuppressive treatment. Class V (membranous nephropathy) Class V lupus nephritis, while generally regarded as a less aggres- sive form of lupus nephritis compared to types III and IV, is still associated with the development of chronic kidney disease and ESRD, particularly if there is marked proteinuria (even with normal baseline renal function). Given the adverse effects of subnephrotic proteinuria on kidneys, most nephrologists would treat these pa- tients with antiproteinuric and antihypertensive medications. Sustained heavy proteinuria (and associated hypercoagulable state) is associated with adverse cardiovascular effects, but there is only a limited evidence base looking at treatment of class V lupus neph- ritis. Steroids, ciclosporin, and cyclophosphamide treatment have been used, along with other immunosuppressive agents including mycophenolate mofetil (MMF), azathioprine, and tacrolimus. Appropriately sized randomized controlled trials would need to be undertaken before these immunosuppressive therapies can be un- equivocally recommended, and such trials are unlikely to be done. In a post hoc review of the outcomes of patients with ‘pure’ class V lupus nephritis in two trials, the combination of MMF and steroids was as effective as high-​dose cyclophosphamide and steroids. Management of proliferative lupus nephritis
(class III and class IV) Proliferative lupus nephritis is the most common renal manifest- ation of SLE. Prior to the advent of immunotherapy regimens, kidney survival and overall patient survival in diffuse prolifera- tive lupus nephritis was only 20 to 25%. While patient and kidney survival in class III and class IV lupus nephritis has markedly im- proved through intensive immunosuppression (current reviews suggest c.90% survival over 10 years, in those who achieve remis- sion), the response to treatment is often slow, and the risk of relapse remains high. Active or sclerotic lesions? YES YES YES YES YES YES NO NO NO NO NO NO Membranous change? Mesangial hypercellularity? Immune deposits on immunofluorescence? No lupus nephritis Class I Class II Class V 50% or more of glomeruli involved? Class III (A or A/C or C) Class IV (A or A/C or C) 50% or more of involved glomeruli have segmental lesions? Class IV-G Class IV-S Class VI if >90% global sclerosis without activity Fig. 21.10.3.5  Algorithm showing how the class of lupus nephritis is determined. In Class III or IV, A = active lesions only, A/C = active and chronic lesions, C = chronic lesions only, and if >50% glomeruli have >50% capillary walls with membranous change = Class III + V, or Class IV + V. See Table 21.10.3.1 for further explanation.

21.10.3  The kidney in rheumatological disorders 5005 The goal of treatment for active proliferative lupus nephritis is to induce a remission with intensive immunotherapy aimed at switching off the renal inflammation. Once this has been attained, maintenance therapy is commenced with the aim of continuing dis- ease remission, with minimal treatment side effects and ideally pre- vention of relapse. Induction regimens Traditionally, the mainstay of induction therapy in lupus nephritis has been corticosteroids plus cytotoxic agents. If disease is more severe, pulses of intravenous methylprednisolone are used prior to commencing oral corticosteroids. Since the early 1980s, cyclophos- phamide has dominated as the cytotoxic of choice, but concerns about the side effect profile, specifically risks of bladder toxicity, ovarian failure, leucopenia, and alopecia, have led to trials exam- ining reduced doses of cyclophosphamide and the introduction of MMF as an alternative immunosuppressant. The ‘Euro-​Lupus’ regimen compared a lower-​dose of cyclophos- phamide (500 mg intravenously every 2 weeks for 3 months) to the original ‘National Institutes of Health (NIH) regimen’ (0.5–​1 g/​m2 given monthly for 6 months). The trial demonstrated that the lower-​ dose regimen was as effective at inducing remission as the higher dose, but patients suffered fewer severe infections. The original study was in an exclusively northern European Caucasian popula- tion, but a more recent trial (the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) study) used Euro-​Lupus as the standard of care to which abatacept or placebo was added. There was no significant improvement gained by the addition of abatacept, but the trial demonstrated well that the Euro-​ Lupus regimen was effective in African American and Hispanic patients. The Aspreva Lupus Management Study (ALMS) was an inter- national trial designed to compare MMF to intravenous cyclophos- phamide (NIH regimen, plus standard glucocorticoid tapering) as induction therapy. The study was designed as a superiority study, with the aim of demonstrating that MMF would be superior at inducing complete remission at 6 months. It was not, but the rates were very similar for cyclophosphamide and MMF, with a similar incidence of adverse effects, serious infections, and deaths in both the MMF and cyclophosphamide arms. Post hoc analysis of the study suggested MMF was as efficacious as cyclophosphamide in the small group of patients with an estimated glomerular filtration rate of less than 30 ml/​min per 1.73 m2 at the outset and in those with class V lupus nephritis. All the recent guidelines on therapy suggest that induction for class III or IV lupus nephritis can be with cyclophosphamide-​ or MMF-​based regimens. They have suggested that in severe class III/​ IV lupus nephritis ‘a cyclophosphamide-​containing protocol for initial therapy may be preferred’, but it is worth noting that MMF may be more effective than cyclophosphamide in patients of African descent and Hispanic patients. A Cochrane review in 2012 system- atically analysed nine studies, concluding that MMF is as effective as cyclophosphamide, but with reduced side effects. A key factor in deciding which induction regimen to use is the importance of preserving fertility. Cyclophosphamide causes infertility in a dose-​ and age-​related manner that may be offset to a degree by the con- comitant use of ovarian protection regimens. By contrast, MMF does not cause infertility so may be preferable as a first-​line agent, although patients must be warned to avoid pregnancy while taking it as it is teratogenic. Regardless of initial therapy used, response needs to be assessed at 6 months to guide further management. There have been several analyses of very long-​term outcomes of the Euro-​Lupus trial and ALMS trial patients. These have clearly demonstrated that early re- duction in proteinuria predicts long-​term renal survival and that proteinuria of less than between 500 and 800 mg/​day at 1 year is associated with good long-​term outcomes. Maintenance therapy Following initial therapy to induce remission, the goal of treatment of lupus nephritis is to prevent systemic and lupus nephritis flares, and to preserve renal function while minimizing potential side ef- fects of long-​term therapy. Prolonged maintenance therapy after initial treatment is usually required as patients who receive only a short-​term (6 month) course of therapy have been shown to have an increased frequency of lupus nephritis relapse. Current options for maintenance therapy include azathioprine, MMF, cyclophospha- mide, and ciclosporin. When determining long-​term maintenance therapy options, patient-​specific factors, for example, tolerability of side effects, and desire for pregnancy should be considered. Initial studies in maintenance therapy for lupus nephritis com- pared cyclophosphamide pulses with maintenance azathioprine or MMF and demonstrated that patients treated with MMF or azathioprine were significantly less likely to develop chronic kidney disease. Mortality was similarly reduced compared to the cyclo- phosphamide group at 72 months. This has led to preferential use of MMF and azathioprine over cyclophosphamide. Trials to determine MMF or azathioprine superiority have yielded mixed results. Two key studies to date have been the ALMS trial ex- tension phase and the Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy of Lupus Nephritis Trial (MAINTAIN Nephritis Trial). In a Caucasian population, azathioprine appears to be equivalent to MMF, whereas MMF is the treatment of choice in a multiethnic population. Differences between the two drugs as maintenance therapy are small, and so if one drug is not tolerated, then the other should be tried. Similarly, patient circumstances may dictate the use of one drug over another: MMF is contraindicated in pregnancy, and azathioprine will be the preferred option in re- gions where cost or drug availability is an issue. The optimal time to remain on maintenance therapy has not been determined but in general is at least 2 to 3 years after remission induction. Novel therapies Some patients fail to respond to available treatment, and for others treatment-​associated side effects, particularly from corticosteroid therapy, limit patient adherence and subsequent treatment efficacy. Consequently, there is an urgent need to identify and develop new immunotherapies, enabling steroid-​sparing treatment regimens and to better manage refractory cases. Current lupus nephritis immunosuppressive therapies are anti-​ inflammatory, anti-complement and anti-cytokine in a relatively nonspecific manner. In recent years there has been an increased focus on targeting critical pathways in SLE pathogenesis with the aim of disrupting autoimmune mechanisms leading to kidney in- flammation and acute and chronic kidney injury (B-​ and T-​cell ac- tivity, costimulatory molecules, and antibody production). Sadly, all

section 21  Disorders of the kidney and urinary tract 5006 trials of new agents to date, all of which have been evaluated as ‘add-​ on’ therapies to standard of care, have not shown significant super- iority. The list of negative studies in lupus nephritis includes the use of rituximab, CTLA4-​Ig, and ocrelizumab. In each case, the trial has failed not necessarily due to lack of efficacy of the drug, but because the study was too small, or because of a finding of increased rates of infection (often attributable to higher doses of steroids). However, there remains optimism that better designed trials may translate into improvements in outcomes. Anti CD20 (rituximab) therapy Rituximab is a chimeric anti-​CD20 human/​mouse monoclonal antibody that has been used extensively in the treatment of non-​ Hodgkin’s lymphoma and has an excellent safety profile. Binding of rituximab to CD20+ cells results in both complement and FcγR-​ mediated cell killing, and clinically rituximab is an effective B-​cell depleter. B-​cell depletion ultimately might not only lead to reduction in autoantibodies (though note rituximab does not deplete plasma cells) but may also disrupt antigen presentation to T cells, critical for maintaining the autoimmune response, and markedly reduce cyto- kine production. A small subgroup of patients appear not to respond to rituximab, failing to deplete their B cells. The degree and duration of B-​cell depletion usually correlates with improvements in disease activity and scores. Prospective open-​label studies have reported widely on the efficacy of rituximab in both renal and non renal lupus, and rituximab has been found to be generally safe and well tolerated. However, the LUNAR study (Lupus Nephritis Assessment with Rituximab) and EXPLORER trial (Exploratory Phase II/​III SLE Evaluation of Rituximab)—​two large, prospective, placebo-​ controlled trials—​both failed to find a benefit of rituximab in renal or non renal lupus when added to standard-​of-​care treatment. Trial design has been implicated in the failure of these studies to meet their primary endpoints. In both studies participants were given high-​dose corticosteroids in addition to immunosuppressives such as MMF, which may have obscured the ability to discrim- inate between the rituximab and placebo arms. Efforts continue to try to find regimens using rituximab and MMF (and other agents) that would allow omission of oral steroids without compromising efficacy. Other targets in lupus nephritis As B cells are depleted in response to rituximab, levels of the B-​ lymphocyte-​stimulating factor (BlyS, also known as BAFF) increase, which may increase the generation of new autoreactive B cells. To counteract this potentially detrimental rise in BAFF, an anti-​BlyS monoclonal antibody, belimumab, has been trialled. A post hoc ana- lysis of phase III belimumab studies in non renal SLE patients exam- ined renal outcomes and demonstrated a reduction in the number of renal flares in belimumab-​treated patients. This is now being evalu- ated in an ongoing trial in lupus nephritis comparing belimumab and placebo in addition to the standard of care (ClinicalTrials.gov identifier: NCT01639339). Tacrolimus (FK506), a calcineurin inhibitor, has demonstrated similar efficacy to mycophenolate mofetil as induction therapy, and other studies include trials of an interferon-​α receptor blocker, an anti-​CD40, another anti-CD20 (obinutuzumab, a humanised monoclonal), a novel calcineurin inhibitor (voclosporin), as well as studies of small-​molecule inhibitors. It is a crowded area and the trials need to be smart to overcome the limitations of previous negative studies. Refractory lupus nephritis Up to 22% of patients with proliferative lupus nephritis are re- fractory to therapy with cyclophosphamide or MMF. If induction therapy fails, the general consensus is to switch and use the alterna- tive (MMF or intravenous cyclophosphamide). Rituximab is often added at this stage: although trial evidence is generally lacking, there have been reports of some promising results, for example, Jonsdottir and colleagues demonstrated that the addition of rituximab results in clinical and histological improvements in patients with refrac- tory lupus nephritis. The RING trial (ClinicalTrials.gov identi- fier: NCT01673295) was formally assessing whether the addition of rituximab in refractory lupus nephritis improved responses. Relapse of lupus nephritis Some patients have persistent relapses of lupus nephritis despite repeated treatment. It is important to recognize and treat relapses quickly, as with each relapse further renal damage is sustained. This is associated with both the development of chronic kidney disease and ESRD. Relapse is diagnosed clinically:  increasing proteinuria, rising serum creatinine level, and changes in urinary sediment should all alert clinicians. A reduction in serum complement levels and in- crease in anti-​double stranded DNA antibody titres may be seen prior to clinical relapse, and while these do not justify treatment per se, it is wise to see the patient more frequently in order to de- tect relapse early. If a renal relapse is suspected, then a renal biopsy may well be indicated to confirm the diagnosis and identify the class of lupus nephritis, which may transform spontaneously from one histological class to another and such changes cannot be predicted clinically with certainty. The most common transformations seen are from class III to class IV, or from a proliferative to nonproliferative class. Importantly, the development of increased proteinuria may represent chronic damage rather than acute inflammation, or a podocytopathy rather than proliferative or class V lupus nephritis. A definitive diagnosis requires a renal biopsy. Prognosis While the overall prognosis of patients with SLE and a proliferative glomerulonephritis has improved significantly with the judicious use of immunosuppressants, 5 to 10% of patients will have died after 10 years of treatment, and a further 5 to 15% will have devel- oped ESRD. The prognosis is poorer in African and Hispanic people (the reasons are unclear), and this needs to be remembered when interpreting results of randomized control trials. Proliferative glomerulonephritis (class III and IV) is associated with a worse outcome, along with the presence of chronic histo- logical changes on renal biopsy. Many patients with lupus nephritis (30–​50%) do not achieve complete remission and this is associated with a significantly increased risk of having further renal relapses, of developing ESRD and of dying. In patients who do achieve com- plete remission, relapses develop in 20–​40% over a follow-​up of about 10 years, and these are also associated with an increased risk

21.10.3  The kidney in rheumatological disorders 5007 of developing ESRD. Significant reduction in proteinuria at 3 and 6 months, and persistent reduction in proteinuria at 1 year, predicts better long-​term renal outcomes. Antiphospholipid antibody nephropathy in SLE Antiphospholipid antibodies are associated with a syndrome (antiphospholipid syndrome) characterized by arterial and venous thromboses and repeated miscarriages. These antibodies have reactivity against cardiolipin and the lupus anticoagulant and are found in 15 to 30% of patients with SLE. Antiphospholipid syndrome can be primary or associated with SLE. Renal mani- festations of antiphospholipid syndrome include thrombotic microangiopathy and chronic vascular lesions, superimposed on those of lupus nephritis. If there is evidence of extrarenal throm- bosis, oral anticoagulants should be commenced. Patients with lupus nephritis and antiphospholipid antibodies have a worse renal prognosis, presumably because of the superimposed renal vasculopathy. See Chapter 14.14 for further discussion. Long-​term outcome The main causes of death in lupus nephritis are treatment-​related sepsis (early) and cardiovascular causes (late). Renal failure can be treated with transplantation and dialysis; generally the activity of lupus nephritis reduces once dialysis is initiated. Overall survival on dialysis is approximately 75% at 10 years. Graft survival in pa- tients with SLE after kidney transplantation is similar to patients with other diseases, and recurrence of lupus nephritis is rare. Systemic sclerosis/​scleroderma Systemic sclerosis (SSc) is a multiorgan connective tissue disease of uncertain aetiology that is characterized by progressive inter- stitial and vascular fibrosis in the skin and other organs. There are three subtypes of SSc: limited cutaneous SSc (lcSSc) where cutaneous involvement is limited to the hands, forearms, face, and feet; diffuse cutaneous SSc (dcSSc) with proximal extension above the elbows or knees; and scleroderma sine scleroderma where skin involvement is absent and patients present only when end-​organ damage has occurred (see Chapter  19.11.3). Renal involvement in SSc can be acute or chronic and most renal manifestations are clinically silent, with autopsy studies detecting occult renal pathology in 60 to 80% of patients. By con- trast, scleroderma renal crisis demonstrates the acute effects of microvasculopathy in SSc. Scleroderma renal crisis Scleroderma renal crisis predominantly affects patients with dcSSC, occurring in 10 to 15% of patients with this disease. Mortality in scleroderma renal crisis remains high, particularly in patients who develop ESRD. Patients with early dcSSc are at greatest risk, and rapidly progressive skin disease or tendon fric- tion rubs are independent risk factors. Other studies have sug- gested that recent high-​dose corticosteroid use, the presence of anti-​RNA polymerase III antibodies, anaemia, and new-​onset cardiac failure are also risk factors for the development of sclero- derma renal crisis. Pathogenesis The pathogenesis of renal involvement in SSc is not fully under- stood. Acute vascular injury activates the coagulation and other inflammatory pathways, culminating in proliferative fibrovasculo­ pathy and thrombotic microangiopathy. Decreased renal perfusion from arterial constriction leads to hyperplasia of the juxtaglo- merular apparatus and hyperreninaemia, resulting in a hyperten- sive crisis and rapidly progressive renal injury. Pathology The smaller arcuate and interlobular arteries are predominantly involved in scleroderma renal crisis, showing intimal hyper- plasia with concentric mucoid intimal degeneration, but the in- ternal and external elastic laminae remain intact. The adventitia of interlobular arteries shows an abnormal degree of fibrosis. There is fibrinoid necrosis of afferent arterioles and glomeruli, and also glomerular thrombosis. Ischaemia of the glomerular tuft leads to wrinkling and thickening of the glomerular base- ment membrane and glomerular sclerosis (Fig. 21.10.3.6). These lesions resemble those seen in accelerated hypertension or the haemolytic uraemic syndrome, although the vessels involved tend to be larger and adventitial fibrosis is not seen in accelerated hypertension. Clinical presentation Mild proteinuria without loss of renal function is the most common presentation of SSc renal disease. An isolated reduction in glom- erular filtration rate is also in seen in patients with SSc and often follows a benign, non progressive course. By contrast, scleroderma renal crisis is characterized by new-​onset accelerated-​phase hyper- tension and a decrease in renal function of at least 30%. It is often associated with systemic symptoms including headache, visual dis- turbances, seizures, or encephalopathy. Flash pulmonary oedema can occur, and arrhythmias, myocarditis, and pericarditis are all associated with poorer prognosis. Fig. 21.10.3.6  Scleroderma kidney. A small artery has concentric mucoid intimal thickening, an arteriole has thrombosis and fibrinoid necrosis, and tubules and a glomerulus have ischaemic damage (periodic acid–​methenamine silver staining, magnification ×25). By courtesy of Professor A.J. Howie.

section 21  Disorders of the kidney and urinary tract 5008 Scleroderma renal crisis can (rarely) develop in individuals with a normal blood pressure. They are more likely to have a micro­ angiopathic haemolytic anaemia (90 vs 30%), thrombocytopenia (83 vs 21%), and pulmonary haemorrhage than patients with a hypertensive scleroderma renal crisis. Investigations/​assessment Autoantibodies (antinuclear antibodies (ANA)) are detectable in virtually all patients with SSc. A speckled ANA pattern is also seen in approximately 60% of patients with scleroderma renal crisis. Other autoantibodies associated with renal disease in SSc include anti-RNA polymerase III antibodies (ARA) and anti-fibrillarin antibodies (AFA, also known as anti-U3 RNP antibodies). In con- trast, SSc patients with anti-centromere or anti-topoisomerase 1 antibodies are less likely to develop renal disease. Renal function should be monitored and blood pressure checked at least monthly, with daily self-​monitoring introduced if hyper- tension develops. Urinalysis may reveal the presence of proteinuria (non-​nephrotic range) and nonvisible haematuria, with casts vis- ible on direct microscopy. Anaemia can be an early feature of scleroderma renal crisis. Thrombocytopenia and anaemia occur in up to 50 and 60% of cases respectively. Elevated levels of lactate dehydrogenase, low hapto- globin, and schistocytes in the peripheral blood smear may also be seen. Occasionally, disseminated intravascular coagulation can develop. Many clinical features of a scleroderma renal crisis are similar to those seen in thrombotic thrombocytopenic purpura. It is im- portant to differentiate the two because management varies mark- edly. Assays for plasma ADAMTS13 enzyme can be useful to exclude thrombotic thrombocytopenic purpura. Treatment Control of hypertension is fundamental in preventing irreversible vascular injury. A gradual decrease in blood pressure should be targeted because a rapid reduction can reduce renal perfusion and increase the risk of acute tubular necrosis. Angiotensin-​converting enzyme inhibitors are first-​line therapy and lead to regression of skin manifestations in some patients: they should be titrated up to maximum doses. In an acute crisis, continuous intravenous iloprost infusion can help reverse microvascular changes and con- trol blood pressure; if substantial thrombotic microangiopathy is present, plasma exchange can be used. Prognosis Approximately 25% of patients with scleroderma renal crisis re- quire dialysis at presentation, and 40 to 66% of these may not re- cover. Assessment of prognosis may be guided by renal biopsy, but clinical predictors of poor outcome include dcSSc, high skin scores (>20), older age, and evidence of cardiac involvement. Long-​term survival following scleroderma renal crisis is poor, especially for patients who do not recover renal function. Increased mortality is seen in males, those with normal blood pressure at presentation, and older patients. Scleroderma renal crisis is one of the few con- ditions where late recovery of renal function is sometimes seen as the inflammatory process resolves and blood pressure is tightly controlled. Rheumatoid arthritis Historically, the main causes of renal disease in rheumatoid arth- ritis have been secondary (amyloid A) amyloidosis and nephro- toxicity from drugs used in treatment (Box 21.10.3.1) (see Chapter  19.5). Renal vasculitis and glomerulonephritis are also described. However, the pattern of renal disease in rheumatoid arthritis is changing. Gold and penicillamine are now infrequently used, hence nephrotoxicity from these causes has become rare, and the incidences of amyloid A amyloidosis and rheumatoid vas- culitis have declined, probably as a result of early use of disease-​ modifying agents. Secondary amyloidosis Secondary amyloidosis results from deposition of fibrils containing amyloid A protein that is antigenically related to the acute-​phase reactant serum amyloid A (see Chapter 12.12.3). Rheumatoid arth- ritis is the commonest disease producing secondary amyloidosis in developed countries. Prevalence rates of 8 to 17% are reported in autopsy series and 5 to 10% in biopsy series, but the incidence has dropped dramatically due to much more aggressive therapy of rheumatoid disease, with fewer patients being left with a persistently active acute-​phase response. Cases of crescentic glomerulonephritis superimposed on renal amyloidosis in patients with rheumatoid arthritis have been described. Clinical features and diagnosis The presentation of renal amyloid is with proteinuria that is often severe enough to cause a nephrotic syndrome. Renal vein throm- bosis is particularly common. Diagnosis is established by renal bi- opsy (Fig. 21.10.3.7), where histological Congo red staining, which is birefringent in polarized light, is characteristic of amyloid. This staining is abolished by potassium permanganate in reactive amyl- oidosis but not in primary amyloidosis. Monoclonal and polyclonal antibodies that specifically bind amyloid A are available and of use for histological diagnosis. The diagnosis of amyloid is also aided by the availability of scans using radiolabelled serum amyloid P (SAP) Box 21.10.3.1  Renal disease in rheumatoid arthritis Consequences of rheumatoid arthritis • Amyloid A amyloidosis • Vasculitic glomerulonephritis • Mesangiocapillary glomerulonephritis • Mesangial IgA proliferative glomerulonephritis Drug nephrotoxicity Nonsteroidal anti-​inflammatory drugs • Reversible haemodynamically mediated renal impairment • Acute tubular necrosis • Acute interstitial nephritis with or without a nephrotic syndrome Gold and penicillamine • Proteinuria • Nephrotic syndrome • Membranous nephropathy • Rare reports of a crescentic glomerulonephritis

21.10.3  The kidney in rheumatological disorders 5009 protein, utilizing the strong calcium-​dependent affinity of SAP for amyloid fibrils of any protein type. Treatment and prognosis There is no specific therapy for amyloid A amyloidosis, the general principle being suppression of the underlying chronic inflamma- tion. Uncontrolled evidence suggests that aggressive treatment of rheumatoid arthritis may be effective in delaying the deterioration of renal function in patients with renal amyloid, and treatment with prednisolone and cyclophosphamide or methotrexate can induce remission of the nephrotic syndrome due to amyloid in patients with this condition. Treatment with antitumour necrosis factor-​α anti- bodies is also reported to lead to remission of renal disease due to amyloidosis. Renal amyloid leads to progressive renal failure; 50% of patients develop ESRD after 5 years, rising to 90% at 10 years, treatment of which is by dialysis and renal transplantation. Gold and penicillamine nephropathy Clinical features and diagnosis The most frequent presenting feature is proteinuria, which occurs in approximately 10% of patients receiving gold and up to 30% of those taking penicillamine. This progresses to the nephrotic syn- drome in 30 and 16%, respectively. Haematuria is uncommon, although it is seen more frequently with penicillamine, and still re- quires the exclusion of other causes when occurring in the context of therapy with these drugs. Renal function is usually normal. Gold and penicillamine are no longer widely used to treat patients with rheumatoid arthritis and nephrotoxicity from these agents is cor- respondingly uncommon. About 55 to 80% of patients who present with penicillamine-​ or gold-​induced proteinuria will have a membranous glomer- ulonephritis. Minimal-​change nephropathy is the next most frequently encountered histological lesion. Other less common renal lesions include mesangiocapillary glomerulonephritis and tubulointerstitial inflammation. Penicillamine may lead to the de- velopment of a rapidly progressive glomerulonephritis with cres- cents and pulmonary haemorrhage, resembling Goodpasture’s syndrome but without anti-glomerular basement membrane antibodies. Treatment and prognosis In general, gold and penicillamine should be discontinued when significant proteinuria develops (>0.5 g/​24 h). After cessation of the drug, proteinuria peaks at around 1 month then gradually disap- pears, and most patients will have clear urine by 1 year and almost all will achieve this by 2 years. Renal function does not deteriorate in uncomplicated cases. Glomerulonephritis The most commonly described glomerulonephritis in rheuma- toid arthritis that is not related to drug use is a mesangiocapillary glomerulonephritis, which in many cases is accompanied by IgA deposits (IgA nephropathy). Membranous nephropathy is also described. Renal vasculitis The clinical spectrum of rheumatoid arthritis includes a systemic necrotizing vasculitis with involvement of blood vessels ran- ging in size from capillaries to small and medium-​sized arteries. With more aggressive treatment of rheumatoid arthritis, vascu- litis from this cause is now uncommon. The clinical presentation includes nail-​fold infarcts, a leucocytoclastic vasculitis, a periph- eral neuropathy, pericarditis, gastrointestinal infarcts, and renal vasculitis. Renal abnormalities are found in about 25% of patients with rheumatoid vasculitis, usually nonvisible haematuria, proteinuria, and renal impairment. Renal histology shows a large-​vessel renal arteritis and a segmental necrotizing glomerulonephritis with crescent formation (vasculitic glomerulonephritis) (Fig. 21.10.3.8). Fig. 21.10.3.7  Amyloidosis in rheumatoid arthritis. Arterioles and glomeruli contain acellular masses of amyloid (periodic acid–​ methenamine silver staining, magnification ×40). By courtesy of Professor A.J. Howie. Fig. 21.10.3.8  Vasculitic glomerulonephritis in rheumatoid arthritis. Two glomeruli have sharply defined segmental lesions where there has been disruption of the tuft and partial obliteration of Bowman’s space (periodic acid–​methenamine silver staining, magnification ×32). By courtesy of Professor A.J. Howie.

section 21  Disorders of the kidney and urinary tract 5010 Treatment is with prednisolone and cyclophosphamide, usually leading to improvement of renal function. Renal disease in juvenile chronic arthritis Renal involvement in juvenile chronic arthritis is infrequent, but its presence is associated with a poor outcome. Proteinuria is found in 3 to 12% of patients and nonvisible haematuria in 3 to 8%. The renal lesions reported are usually complications of the underlying rheumatic disease, such as amyloidosis, or those arising as side effects of the drugs used. Cases of necrotizing crescentic glomer- ulonephritis, focal segmental glomerulosclerosis, and mesangial glomerulonephritis have all been described in children with the condition. Renal amyloid is found in 1.2 to 6.7% of patients with juvenile chronic arthritis, and affects patients with chronic and active dis- ease, with a predilection for systemic-​onset disease. It typically pre- sents with nephrotic-​range proteinuria. Aggressive treatment with chlorambucil has been shown to improve survival in patients with juvenile chronic arthritis and amyloid A amyloidosis. Sjögren’s syndrome Sjögren’s syndrome is an autoimmune condition in which there is inflammatory cellular infiltration of the exocrine glands (particu- larly the salivary and lacrimal glands) (see Chapter 19.11.4). The condition can occur in isolation (primary Sjögren’s syndrome) or in conjunction with other autoimmune diseases, usually lupus or mixed connective tissue disease (secondary Sjögren’s syndrome). Clinical features Dry mouth (xerostomia) and dry eyes (keratoconjunctivitis) are characteristic of Sjögren’s syndrome. Renal involvement is usually mild and often subclinical. Some patients present with distal tubular acidosis, impairment of urinary concentration, hypokalaemia, or rarely with Fanconi’s syndrome. Clinical manifestations of these renal tubular disorders include sterile pyuria, the development of renal calculi, polyuria, and (very rarely) the development of hypo- kalaemic periodic paralysis. Up to a quarter of patients can develop acute or chronic kidney disease. Investigation/​assessment Urine dip might reveal occasional leucocytes and moderate protein- uria. The most common histological abnormality is tubulointerstitial nephritis with predominantly T-​lymphocyte infiltrate, but various types of glomerulonephritis are also described. Glomerular abnor- malities are rare. Mixed connective tissue disease Mixed connective tissue disease is a rheumatological overlap syn- drome associated with anti-​U1-​RNP antibodies and clinical signs including synovitis, myositis, Raynaud’s phenomenon, acrocyan- osis, and hand oedema. Renal involvement occurs in up to one-​third of cases. Treatment has generally been with steroid therapy along with steroid-​sparing agents. Glomerular involvement will generally be treated in a similar manner to lupus nephritis, depending on the histology. Drug nephrotoxicity following treatment for rheumatic disorders Nonsteroidal anti-​inflammatory drugs The widespread use of nonsteroidal anti-​inflammatory drugs (NSAIDs) for the relief of pain and inflammation has meant that, although in any individual patient the risk of renal adverse events is small, renal complications are frequently seen. Non se- lective NSAIDs inhibit both constitutive cyclooxygenase (COX)-​1 and inducible COX-​2 enzymes involved in the prostaglandin and thromboxane A2 pathways responsible for the regulation of pain, renin release, and vascular tone. Since both COX-​1 and COX-​2 are expressed in the kidney, adverse effects are associated with both non selective and COX-​2 selective NSAIDs. Clinical syndromes as- sociated with NSAID use reflect either predictable abnormalities arising from their mode of action, especially in volume-​depleted individuals, or those with vascular impairment or idiosyncratic allergic responses. The clinical syndromes seen include ​acute tubular necrosis, acute tubulointerstitial nephritis, nephrotic syn- drome (minimal-​change disease or membranous nephropathy), and renal papillary necrosis. In addition, NSAID therapy may in- duce salt and water retention, hypertension, hyperkalaemia, and chronic kidney disease. In patients with chronic kidney disease or a functioning renal transplant, NSAIDs should not be used without careful consider- ation of the balance of benefit versus risk. Great care must be taken when prescribing NSAIDs to patients with volume depletion, and when using concomitant nephrotoxins. Chronic analgesic nephropathy Chronic analgesic nephropathy is characterized by renal pap- illary necrosis and chronic interstitial nephritis caused by prolonged and excessive consumption of analgesic mixtures. Compound analgesic mixtures are associated with the develop- ment of analgesic nephropathy, and classic radiographic find- ings (bilateral small kidneys, irregular contour, and renal papillar calcifications) are easily seen on CT. The course of the disease is dependent on severity of chronic damage at presentation, and unless analgesic consumption ceases, renal dysfunction will pro- gress. If analgesics are discontinued, renal function stabilizes or improves slightly in most patients, but there is an association with the later development of urinary tract malignancies in these patients. Renal toxicity of anti-rheumatic drugs Many conventional antirheumatic drugs are nephrotoxic, even in the absence of chronic kidney disease. Calcineurin inhibitors (ciclosporin and tacrolimus) are associated with significant renal toxicity. Acute renal impairment and hypertension are usually dose dependent and improve with dose reduction. Chronic renal dys- function is associated with characteristic histological changes (vas- cular hyalinosis, interstitial fibrosis, tubular atrophy, and glomerular

21.10.3  The kidney in rheumatological disorders 5011 sclerosis), is often progressive, and irreversible unless calcineurin inhibitors are stopped. The commonest manifestation of drug toxicity in the kidney is tubulointerstitial nephritis, often with an eosinophilic infiltrate. The presentation may be acute with systemic symptoms such as a drug rash and fever, and may be associated with systemic eosino- philia and hypocomplementaemia as well as acute kidney injury that can be severe. Patients usually have sterile pyuria, may have haematuria and can have nephrotic range proteinuria, though more commonly much lower levels of urinary protein loss. Some patients have a slower more insidious renal limited progression and the major finding will be unexplained chronic kidney dis- ease and sterile pyuria. Unless biopsied, the inflammation will be missed and these patients will present with irreversible advanced tubulointerstitial scarring. Nowadays the commonest drugs as- sociated with tubulointerstitial nephritis are penicillins, NSAIDs, proton pump inhibitors, furosemide, and sulphasalazine (which can also cause crystalluria and urinary stone formation)—​all used frequently in patients with rheumatic diseases. Treatment involves stopping the causative drug, if known, plus a course of oral steroids. Although there are no trials, a large retrospective study strongly suggested that those treated with steroids had better preservation of renal function than those who were not. In patients with pre-​existing chronic kidney disease, leflunomide is contraindicated (the active ingredient is renally excreted) and other medications including methotrexate, azathioprine, chlorambucil, and cyclophosphamide require reduced doses. Hydroxychloroquine is not reported to cause renal toxicity, but increased retinal monitoring should be undertaken in the pres- ence of renal impairment. At present, there has been no reported incidence of renal tox- icity in clinical trials of new biological therapies, but their use in patients with severe renal impairment has not been fully evaluated. Also of interest is the pharmacokinetics of these drugs in the face of severe nephrotic syndrome: are larger and/​or more frequent doses needed? FURTHER READING Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group (2012). KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl, 2, 139–​274. Rovin BH, et al. (2019). Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 95, 281–95. Lupus nephritis Almaani S, Meara A, Rovin BH (2017). Update on lupus nephritis. CJASN, 12, 825–35. Appel GB, et al. (2009). Mycophenolate mofetil versus cyclophospha- mide for induction treatment of lupus nephritis. J Am Soc Nephrol, 20, 1103–​12. Austin HA, et al. (1986). Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Eng J Med, 314, 614–​19. Austin HA, et al. (2009). Randomised controlled trial of prednisone, cyclophosphamide and cyclosporine in lupus membranous neph- ropathy. J Am Soc Nephrol, 20, 901–​11. Boumpas DT, et al. (1992). Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet, 340, 741–​5. Condon M, et al. (2013). Prospective observational single-​centre co- hort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis, 72, 1280–​6. Dooley MA, et al. (2011). Mycophenolate versus azathioprine as main- tenance therapy for lupus nephritis. N Engl J Med, 365, 1886–​95. Dooley M, et al. (2013). Effect of belimumab treatment on renal out- comes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus, 22, 63–​72. Gordon C, et al. (2018). The British Society for Rheumatology guide- line for the management of systemic lupus erythematosus in adults. Rheumatology, 57, e1–e45. Henderson L, et al. (2012). Treatment for lupus nephritis. Cochrane Database Syst Rev, 12, CD002922. Houssiau FA, et al. (2002). Immunosuppressive therapy in lupus neph- ritis: the Euro-​Lupus Trial, a randomised trial of low-​dose versus high dose intravenous cyclophosphamide. Arthritis Rheum, 46, 2121–​31. Houssiau FA, et al. (2010). Azathioprine versus mycophenolate mofetil for long term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis, 69, 2083–​9. Houssiau FA, et al. (2010). The 10-​year follow-​up data of the Euro-​ Lupus Nephritis Trial comparing low-​dose and high-​dose intra- venous cyclophosphamide. Ann Rheum Dis, 69, 61–​4. Jónsdóttir T, et  al. (2013). Long-​term follow-​up in lupus nephritis patients treated with rituximab—​clinical and histopathological re- sponse. Rheumatology (Oxford), 52, 847–​55. Korbet S, et al. (2000). Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaboration Study Group. Am J Kidney Dis, 35, 904–​14. Merrill J, et  al. (2010). Efficacy and safety of rituximab in subjects with moderately to severely active systemic lupus erythematosus (SLE): results from the randomised, double blind phase II/​III study EXPLORER. Arthritis Rheum, 58, 4029–​30. Mok C, et al. (2016). Tacrolimus versus mycophenolate mofetil for in- duction therapy of LN: a randomised controlled trial and long-​term follow-​up. Ann Rheum Dis, 75, 30–​6. Rovin B, et al. (2012). Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum, 64, 2515–​26. Rovin BH, et al. (2019). A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus neph- ritis. Kidney Int, 95, 219–31. Ruiz-​Irastorza G, Hunt B, Kahmashta M (2007). A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum, 57, 1487–​95. Sloan RP, et  al. (1996). Long-​term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J Am Soc Nephrol, 7, 299–​305. Weening JJ, et al. (2004). The classification of glomerulonephritis in sys- temic lupus erythematosus revisited J Am Soc Nephrol, 15, 241–​50. Wu L-H, et al. (2013). Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal out- come predictions. Kidney Int, 83, 715–23. Yo JH, Barbour TD, Nicholls K (2019). Management of refractory lupus nephritis: challenges and solutions. Open Access Rheumatol, 11, 179–88.

21.10.4 The kidney in sarcoidosis 5012 Ingeborg Hi

21.10.4 The kidney in sarcoidosis 5012 Ingeborg Hilderson and Jan Donck

21.10.6 Haemolytic uraemic syndrome 5027 Edwin K.S

21.10.6 Haemolytic uraemic syndrome 5027 Edwin K.S. Wong and David Kavanagh

21.10.6  Haemolytic uraemic syndrome 5027 D’Amico G (1998). Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int, 54, 650–​71. De Vita S, et al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Saadoun D, et  al. (2006). Antiviral therapy for hepatitis C virus-​ associated mixed cryoglobulinemia vasculitis. Arthritis Rheum, 54, 3696–​706. Saadoun D, et al. (2017). Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology, 153, 49–52.e5. Terrier B, et  al. (2012). Management of non infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Blood, 119, 5996–​6004. Renal involvement in Waldenström’s macroglobulinaemia Audard V, et al. (2008). Renal lesions associated with IgM-​secreting monoclonal proliferations: revisiting the disease spectrum. Clin J Am Soc Nephrol, 3, 1339–​49. Chauvet S, et al. (2015). Kidney disorders associated with monoclonal IgM-​secreting B-​cell lymphoproliferative disorders: a case series of 35 patients. Am J Kidney Dis, 66, 756–​67. C3 glomerulopathy and monoclonal gammopathy Bridoux F, et al. (2011). Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin J Am Soc Nephrol, 6, 2165–​74. Chauvet S, et al. (2017). Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood, 129, 1437–447. Chauvet S, et al. (2018). Both monoclonal and polyclonal immuno- globulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy. Front Immunol, 9, 2260. Ravindran A, et al. (2018). C3 glomerulopathy associated with mono- clonal Ig is a distinct subtype. Kidney Int, 94, 178–86. Zand L, et al. (2013). C3 glomerulonephritis associated with mono- clonal gammopathy: a case series. Am J Kidney Dis, 62, 506–​14. Renal involvement in lymphomas and leukaemias Moulin B, et al. (1992). Glomerulonephritis in chronic lymphocytic leukemia and related B-​cell lymphomas. Kidney Int, 42, 127–​35. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77. Renal involvement in POEMS syndrome Nakamoto Y, et al. (1999). A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. Nephrol Dial Transplant, 14, 2370–​8. Tumour lysis syndrome Coiffier B, et al. (2008). Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-​based review. J Clin Oncol, 26, 2667–​78. Cairo MS, et  al. (2010). Recommendations for the evaluation of
risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol, 149, 578–​86. Rampello E, et al. (2006). The management of tumor lysis syndrome. Nat Clin Pract Oncol, 3, 438–​47. 21.10.6  Haemolytic uraemic syndrome Edwin K.S. Wong and David Kavanagh ESSENTIALS Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. It is most often caused by Shiga toxin-​producing Escherichia coli (STEC-​HUS), and any HUS not caused by this is often termed atypical HUS (aHUS). aHUS may be caused by an underlying complement system abnormality (primary aHUS) or by a range of precipitating events, such as infections or drugs (secondary aHUS). Management of STEC-​HUS is supportive. In aHUS, plasma exchange is the initial treatment of choice until ADAMTS13 activity is available to exclude thrombotic thrombocytopenic purpura as a diagnosis. Once this has been done, eculizumab should be instigated as soon as possible. Introduction Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. HUS is broadly classified according to aetiology. The most common form of HUS is secondary to Shiga toxin-​producing Escherichia coli (STEC), STEC-​HUS. The term, atypical HUS (aHUS) has been used to classify any HUS not caused by Shiga toxin. With the discovery of the role of complement gene mutations in aHUS, primary aHUS has been used to refer to those cases with documented complement dysregulation. Many precipitating events, including infections, drugs, auto- immune conditions, transplants, pregnancy, and metabolic condi- tions have been associated with aHUS. These have frequently been called secondary aHUS. It is increasingly recognized that patients with an underlying complement system abnormality often require a secondary trigger for aHUS to manifest. Classifications describing both the genetic background and aetiological trigger are beginning to be introduced. Epidemiology The incidence of STEC-​HUS is approximately 20 per million popu- lation per year, but it is more common in children. An exception to this was in the 2011 E. coli 0104:H4 outbreak in Northern Europe where more than 800 cases of STEC-​HUS were reported, predomin- antly adults. The best estimate of aHUS incidence is 0.42 per million population per year in a British population. Pathology In the acute phase of disease, glomerular capillary wall thickening is seen as a result of endothelial cell swelling and accumulation of

section 21  Disorders of the kidney and urinary tract 5028 flocculent material between the endothelium and the underlying basement membrane (Fig. 21.10.6.1). Double contouring can be seen on silver staining. Collapsed capillary loops containing frag- mented red blood cells, fibrin, and platelet thrombi give the classical bloodless glomerular appearance. Fibrinoid necrosis of the afferent arteriole associated with thrombosis is also present. Mesangiolysis and development of aneurysmal dilatation of the capillaries may be seen. Subsequently, there is mucoid intimal hyperplasia with narrowing of the vessel lumen. With time, sclerotic and membranoproliferative changes may develop. Immunofluorescence demonstrates fibrin or fibrinogen in the glomeruli and vessel walls and nonspecific depos- ition of immunoglobulin and complement may be seen. There are no pathognomonic features to allow discrimination of STEC-​HUS from aHUS on histological grounds. Pathogenesis STEC-​HUS E.  coli O157:H7 is the most common strain causing STEC-​ HUS. Other serotypes of E. coli can also produce toxin, and the largest recorded outbreak of STEC-​HUS occurred in Northern Europe in 2011 due to infection with serotype O104:H4. In developing countries, Shigella dysenteriae type 1 is a common cause of HUS. STEC strains adhere to the gut and Shiga toxin is translocated through the intestinal epithelium. It has been suggested that Shiga toxin is then taken up by circulating leucocytes and transported to the kidney. Globotriaosylceramide (Gb3) is the receptor for Shiga toxin and mediates internalization, following which it is transported to the endoplasmic reticulum. The Shiga toxin complex is then cleaved to release the enzymatically active component that inacti- vates the ribosome, leading to inhibition of protein synthesis and cell death. It can also activate signalling pathways, inducing an inflamma- tory response in affected cells Atypical HUS Complement-​mediated aHUS A series of groundbreaking studies in the late 1990s established the role of complement overactivation in the pathogenesis of aHUS (Fig. 21.10.6.2). In patients with aHUS, loss-​of-​function mutations in complement regulators, activating mutations in complement components, and autoantibodies to complement regulatory compo- nents have been reported (Table 21.10.6.1). Loss-​of-​function mutations Mutations in the complement factor H gene (CFH) are the most common genetic predisposition to disease, accounting for around 25% of aHUS. The factor H protein (FH) is the major regulator of complement in the fluid phase. It functions by competing with factor B (FB) for C3b binding, decaying the complement compo- nent 3 (C3) convertase, and by acting as a cofactor for factor I (FI)-​ mediated C3b proteolysis. There is also a recognition domain at the C-​terminal end of FH that binds to C3b and glycosaminoglycans allowing FH to bind to and regulate complement on the glomerular endothelial surface. In aHUS, many of the mutations alter this re- gion and thus impair cell surface complement regulation. FI is a serum serine protease that cleaves C3b and C4b in the pres- ence of its cofactors (FH and CD46). Mutations in the complement factor I gene (CFI) are found in around 5 to 10% of aHUS, and de- fective regulation of complement has been demonstrated in func- tional analyses. CD46 is a cell surface-​bound complement regulator that acts as a cofactor for FI. Mutations in the CD46 gene account for approximately 10% of aHUS cases, with most mutations resulting in a quantitative deficiency. Activating mutations Activating mutations have been described in the genes encoding complement factor B (CFB) and C3 (C3). These are the complement components from which the amplifying C3 convertase is comprised. C3 mutations are found in around 2 to 10% of aHUS cases, whereas CFB mutations are rare. Mutations in both result in increased C3 convertase activity and consequently greater complement-​mediated damage to glomerular endothelium. Inhibitory autoantibodies Autoantibodies against FH have been identified in aHUS. These are usually shown to block the ability of FH to bind to C3b or glycosa- minoglycans and, therefore, inhibit complement regulation at the glomerular endothelium. Penetrance of disease Penetrance of disease is age related and has been reported to be as high as 64% by the age of 70 for individuals carrying a single genetic mutation. This suggests that additional disease risk modifiers are important. Around 3% of patients have one or more mutations, with increased penetrance per extra mutation. Together, these still do not explain why some patients develop disease until later in life. This is best explained by the need for an environmental trigger such as infection, drugs, or pregnancy (Box 21.10.6.1). Fig. 21.10.6.1  A glomerulus from a patient with HUS showing severe acute changes of congestion, intraluminal thrombi, red cell fragmentation, and endothelial cell swelling (haematoxylin and eosin, magnification ×400).

21.10.6  Haemolytic uraemic syndrome 5029 Other forms of aHUS Genetic Autosomal recessive defects in methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type (MMACHC) and diacylglycerol kinase-​ε (DGKE) have been shown to cause aHUS (Table 21.10.6.1). Combined methylmalonic aciduria and homocystinuria (cblC) is a disorder of cobalamin (vitamin B12) metabolism characterized by neurological, metabolic, and developmental symptoms. It is a het- erogeneous disorder and only some patients develop aHUS. The pathophysiological mechanism of HUS in the cblC defect is unclear, but the endothelial abnormalities on kidney biopsies are striking and suggest that endothelial cell dysfunction may be the precipitating event. Long-​term management of cblC disease is with cobalamin, folinic acid, and betaine. Mutations in DGKE have been reported to cause aHUS in the first year of life. DGK-​ε is part of an intracellular signalling cascade and Activation Amplification Loop C3 convertase C5 convertase C5 C5b Eculizumab MAC C5a C3b C3b C3b Bb — — Bb Ba B C3 FH FI CD46 C3b Terminal Pathway Classical Pathway Alternative Pathway Lectin Pathway Regulation Fig. 21.10.6.2  Complement cascade. Activation of the complement system occurs via one of three pathways, classical, alternative, or lectin, resulting in the cleavage of C3 into C3b. C3b then forms C3bBb, the C3 convertase of the alternative pathway, which in turn generates more C3b as part of a positive amplification loop. This then leads to the formation of C3bC3bBb, the C5 convertase, and activation of terminal pathway by cleaving C5 into C5a and C5b. C5a is an anaphylatoxin while C5b allows formation of membrane attack complex (MAC) generation and cell lysis. The regulatory proteins (FH, FI, and CD46) protect the host from complement overactivation by preventing persistent amplification of complement. Eculizumab prevents terminal pathway activation by inhibition of the cleavage of C5.

section 21  Disorders of the kidney and urinary tract 5030 although its role in the pathogenesis of aHUS has yet to be fully elu- cidated, it is not thought to participate in the complement system. In keeping with this, several individuals with mutations in DGKE have failed to respond to eculizumab. Noninherited Infection with neuraminidase-​producing Streptococcus pneumoniae accounts for approximately 5% of childhood HUS. The incidence is greatest in children younger than 2 years, most commonly in pa- tients with parapneumonic empyema. Neuraminidase cleaves sialic acid residues from the glycoproteins on the cell membrane of erythrocytes, platelets, and endothelium, exposing the normally hidden Thomsen–​Friedenreich antigen (T antigen). This then reacts with anti-​T IgM antibodies that are nor- mally present in plasma. It has been hypothesized that binding of anti-​T IgM to platelets and glomerular endothelium causes throm- botic microangiopathy by platelet aggregation and direct endo- thelial cell damage. Treatment is supportive with eradication of streptococcal infection. Many drugs have been reported to cause aHUS and this occurs by two main mechanisms:  immune-​mediated damage and direct toxicity. For example, quinine induces the development of autoanti- bodies reactive with either platelet glycoprotein Ib/​IX or IIb/​IIIa complexes, or both. In contrast, mitomycin C, an alkylating agent used to treat a variety of malignancies, is thought to cause aHUS by a direct toxic effect on endothelium. Pregnancy was historically cited as a cause of aHUS, but re- cent studies have suggested that over 80% of patients have a com- plement gene mutation and that pregnancy acts by unmasking complement-​mediated aHUS. Clinical features The diagnostic triad of acute kidney injury, microangiopathic haemolytic anaemia, and thrombocytopenia is common to both STEC-​HUS and aHUS. In cases of STEC-​HUS there is usually a prodromal phase. Around 3 days after ingestion of contaminated food, abdominal pain and bloody diarrhoea usually, although not invariably, occur. HUS de- velops in about 10% of patients after 3 to 4 days. In complement-​mediated aHUS, a triggering event is typically noted prior to presentation. Upper respiratory tract infections, fevers, pregnancy, and drugs have been suggested as potential trig- gers. Additionally, non-​STEC diarrhoea is a not uncommon trigger and clinicians should not assume diarrhoea equates to STEC-​HUS (Box 21.10.6.1). In pneumococcal-​associated aHUS, pneumonia or meningitis is usually present. Extrarenal manifestations, predominantly neurological, are re- ported in all types of HUS (Box 21.10.6.2). Laboratory investigations Once routine biochemical and haematological analyses have demonstrated a thrombotic microangiopathy, investigations are aimed at determining the underlying aetiology and excluding other differential diagnoses (Fig. 21.10.6.3). The most urgent test is an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay, deficiency of which is characteristic of thrombotic thrombocytopenic purpura. Diagnosis of STEC-​HUS To confirm the diagnosis of STEC-​HUS, stool samples should be sent for STEC culture in tellurite-​enriched sorbitol–​MacConkey agar. Samples may be negative, especially if sampling is late in the course of disease. Even following cessation of diarrhoea, rectal swabs or a faecal culture should be taken. Enzyme-​linked immunosorbent assay identification of Shiga toxins should be attempted from stool and stool cultures, as should polymerase chain reaction testing of stool for Shiga toxin genes. Serology identifying IgM against the commonly occurring STEC strains should also be performed. Box 21.10.6.1  Triggers of atypical HUS • Pregnancy • Respiratory infections: Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenza • Parasites: Plasmodium falciparum • Non-​STEC diarrhoeal illnesses: norovirus, Campylobacter upsaliensis, Clostridium difficile • Drugs:  alemtuzumab, cisplatin, gemcitabine, mitomycin, clopidogrel, quinine, interferon-​α, -​β, anti-​VEGF, ciclosporin, tacrolimus, ciprofloxacin, oral contraceptives, illicit drugs • Autoimmune:  anticardiolipin, C3 nephritic factor, systemic lupus erythematosus • Vaccination • Bone marrow transplantation • Malignancy: gastric, breast, prostate, lung, colon, ovarian, pancreatic, lymphoma Box 21.10.6.2  Extrarenal manifestations of HUS • Neurological involvement • Cerebral artery thrombosis/​stenosis • Digital gangrene • Extracerebral artery stenosis • Cardiac involvement/​myocardial infarction • Ocular involvement • Pulmonary involvement • Pancreatic involvement Table 21.10.6.1  Genetic causes of atypical HUS Gene name Gene symbol OMIM number Inheritance Complement factor H CFH 235400 AD/​AR Complement factor I CFI 612923 AD CD46 CD46 612922 AD/​AR Complement
component 3 C3 612925 AD Complement factor B CFB 612924 AD Diacylglycerol kinase-​ε DGKE 615008 AR Methylmalonic aciduria and homocystinuria, cobalamin C type MMACHC 277400 AR AD, autosomal dominant; AR, autosomal recessive.

21.10.6  Haemolytic uraemic syndrome 5031 Complement analysis in aHUS Before instigation of plasma exchange, serum levels of C3, C4, FH, and FI should be measured. Low C3 concentrations are suggestive but are not diagnostic of aHUS. CD46 surface expression should be evaluated by flow cytometry. Genetic screening and testing for auto- antibodies should be performed on all suspected cases. Treatment of STEC-​HUS There are no specific interventions shown to improve the outcome in STEC-​HUS and management is supportive care. Particular atten- tion should be paid to fluid and electrolyte replacement, blood pres- sure control, anaemia, renal support, and treatment of neurological manifestations. Antimotility agents should be avoided, and antibiotics are not currently recommended in the treatment of E. coli O157:H7 infec- tion due to a lack of evidence of efficacy and the potential to increase the risk of developing HUS. Studies have suggested that treatment with antibiotics causes increased toxin production and release. In contrast, a nonrandomized assessment from the 2011 E. coli O104:H4 outbreak suggested antibiotics reduced seizures and death. Unlike the O157:H7 strain, treatment of E. coli O104:H4 with anti- biotics did not increase quantities of Shiga toxin. Antibiotic treat- ment of S. dysenteriae does not increase the risk of HUS. There is no conclusive evidence to suggest plasma exchange is beneficial in STEC-​HUS and it is not routinely administered. The complement inhibitor eculizumab did not show any benefit when retrospective analysis of the Northern European STEC-​ HUS O104:H4 outbreak was performed. As STEC-​HUS is a self-​ limiting illness, only a randomized controlled trial will delineate any benefit. Treatment of aHUS Plasma exchange remains the initial treatment of choice until the ADAMTS13 activity is available to exclude thrombotic thrombocytopenic purpura as a diagnosis. It should be initiated as soon as the diagnosis of thrombotic microangiopathy is suspected. In addition to the replacement of faulty complement regulators and removal of FH autoantibodies and hyperfunctional comple- ment components in aHUS, plasma exchange will also remove ADAMTS13 autoantibodies and replace ADAMTS13 in throm- botic thrombocytopenic purpura. It should be performed daily and the dose titrated to control haemolysis. Once haemolysis has been controlled, plasma exchange can be withdrawn slowly, although individuals with genetic defects in the complement system are fre- quently plasma dependent and require long-​term plasma therapy (weekly/​biweekly) to maintain remission. Eculizumab The complement inhibitor, eculizumab, was first reported to be ef- ficacious in aHUS in 2009. It is a recombinant humanized mono- clonal antibody directed against C5 that blocks the cleavage of C5 into its effector components (Fig. 21.10.6.2). A nonrandomized, un- controlled, prospective study demonstrated efficacy in both plasma-​ resistant and plasma-​dependent aHUS. As with plasma exchange, the earlier eculizumab is commenced, the greater the conservation of renal function, and (if its great cost does not preclude) treatment with eculizumab should be instigated as soon as ADAMTS13 defi- ciency can be excluded. The current optimal duration of therapy is unclear, although re- cent reports have suggested that eculizumab may be safely discon- tinued in selected patients with appropriate clinical monitoring. A trial of intermittent disease-​driven versus continuous eculizumab therapy is required to define the optimal treatment strategy stratified by the underlying complement defect. Eculizumab has been used safely during pregnancy in patients with paroxysmal nocturnal haemoglobinuria. The terminal pathway of complement is critical in the immune response to encapsulated organisms and therefore vaccination with both a meningococcal group A, C, W, and Y conjugated vaccine and multicomponent meningococcal group B vaccine is mandatory prior to eculizumab treatment. Long-​term prophylactic antibiotic cover is also advisable. TMA TTP HUS aHUS STEC-HUS Pneumococcal aHUS Complement- mediated aHUS Other ADAMTS13 activity <5% Culture Shiga toxin detection Serology PCR Culture Serology T-antigen C3 C4 FI FH levels CD46 FACS Genetic Screening CFH CFI CFB C3 CD46 FH autoantibodies Genetic Screening DGKE, MMACHC Plasma homocysteine Urine organic acid chromatography Autoimmune screen ANA dsDNA Antiphospholipid Anti-Scl70 ↓Hb ↓Plts ↑LDH ↓Haptoglobin Fig. 21.10.6.3  Thrombotic microangiopathy diagnostic algorithm. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; C3, complement factor C3; C4, complement factor C4; CFB, complement factor B gene; CFH, complement factor H gene; CFI, complement factor I gene; DGKE, diacylglycerol kinase-​ε; FACS, fluorescence-​activated cell sorting; FI, factor I protein; FH, factor H protein; Hb, haemoglobin; LDH, lactate dehydrogenase; MMACHC, methylmalonic aciduria and homocystinuria, cblC type; plts, platelets; PCR, polymerase chain reaction; T-​antigen, Thomsen–​Friedenreich antigen; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

21.10.7 Sickle cell disease and the kidney 5032 Cl

21.10.7 Sickle cell disease and the kidney 5032 Claire C. Sharpe

section 21  Disorders of the kidney and urinary tract 5032 Renal transplantation in HUS STEC-​HUS Patients with STEC-​HUS normally recover renal function, although a few individuals will progress to endstage renal failure. Renal trans- plantation following STEC-​HUS is associated with a low recurrence rate, less than 1%, and the 10-​year graft survival is similar to those transplanted for dysplasia/​uropathies and significantly better than those transplanted for other renal conditions. Renal transplantation is therefore possible in these individuals, but it is advisable to under- take genetic screening first. There have been very occasional reports of individuals with confirmed STEC-​HUS having recurrent HUS following renal transplantation due to a coexistent genetic mutation. Atypical HUS In comparison, the transplant outcome for patients with aHUS was historically very poor, largely because of recurrence in the allograft. This outcome is predicted largely by the underlying genetic abnor- mality, with highest risk associated with CFH, CFB, and C3 muta- tions, and the lowest with CD46 mutations. Unlike the plasmas proteins FH, FI, C3, and FB, CD46 is mem- brane bound. As such, a renal allograft would be predicted to correct the underlying complement defect and protect against aHUS. It is because of this that the outcome is better with a recurrence rate of only approximately 20%. In those individuals with CD46 mutations in whom recurrence has occurred, additional genetic risk factors or endothelial microchimerism have been suggested to be the cause. It is perhaps not surprising that individuals with underlying gen- etic defects have a high recurrence rate because the post-​transplant milieu provides the necessary disease triggers (e.g. viral diseases, ischaemia reperfusion injury, donor-​specific antibodies, and im- munosuppressive drugs) to cause endothelial cell damage and acti- vation of the complement cascade. Although plasma exchange has a low success rate in rescuing recur- rent aHUS after renal transplantation, pre-​emptive plasma exchange has been associated with a trend to decrease recurrence. Rescue therapy or pre-​emptive treatment with eculizumab is successful and is now the treatment of choice in transplantation for aHUS. FURTHER READING Hanna RM, et al. (2019). Atypical hemolytic uremic syndrome and complement blockade: established and emerging uses of comple- ment inhibition. Curr Opin Nephrol Hypertens, 28, 278–87. Kavanagh D, Goodship TH, Richards A (2013). Atypical hemolytic uremic syndrome. Semin Nephrol, 33, 508–​30. Kavanagh D, Raman S, Sheerin NS (2014). Management of hemolytic uremic syndrome. F1000Prime Rep, 6, 119. Legendre CM, et  al. (2013). Terminal complement inhibitor eculizumab in atypical hemolytic-​uremic syndrome. N Engl J Med, 368, 2169–​81. Lemaire M, et al. (2013). Recessive mutations in DGKE cause atypical hemolytic-​uremic syndrome. Nat Genet, 45, 531–​6. Menne J, et  al. (2012). Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-​control study. BMJ, 345, e4565. Sheerin N, et al. (2016). A national specialised service in England for atypical haemolytic uraemic syndrome—​the first year’s experience. QJM, 109, 27–​33. Spinale JM, et  al. (2013). Update on Streptococcus pneumoniae associated hemolytic uremic syndrome. Curr Opin Pediatr, 25, 203–​8. 21.10.7  Sickle cell disease and the kidney Claire C. Sharpe ESSENTIALS About 60% of patients with sickle cell disease have sickle cell neph- ropathy. Clinical symptoms reflect medullary compromise, with polyuria, troublesome nocturia, enuresis, and dehydration being typical early manifestations. Haematuria, nonvisible and visible, is common. The prevalence of albuminuria rises with age, and those in whom this progresses rapidly are at greatest risk of developing endstage kidney disease, which eventually affects 10 to 15% of pa- tients with sickle cell nephropathy. Management of chronic kidney disease due to sickle cell nephrop- athy is along standard lines: no specific treatment has been shown to prevent the condition or retard its progression. Introduction Sickle cell disease (SCD) is endemic in malaria-​prevalent (or pre- viously prevalent) regions due to the protective nature of the car- rier state. It is most commonly found in sub-​Saharan Africa, India, Saudi Arabia, and the Mediterranean (Turkey, Greece, and Italy). The prevalence of the sickle cell trait (heterozygous carriers) ranges between 10 and 40% across equatorial Africa and decreases to be- tween 1 and 2% on the north African coast and less than 1% in South Africa. Renal involvement (sickle cell nephropathy (SCN)) affects approximately 60% of patients with SCD (homozygous haemo- globin S (HbSS) and HbSβ0 thalassaemia) at some point during their life, although only 10 to 15% of these patients develop endstage kidney disease. These figures are halved in individuals with the HbSC form of the disease, which is generally less se- vere. Heterozygous patients (HbSA) may develop some tubular defects later in life, but there is no evidence that they are at a greater risk of developing progressive chronic kidney disease. It is important to remember, however, that not all renal disease in patients with SCD is due to SCN. These patients may have other conditions, for example, lupus nephritis or glomerulo- nephritis secondary to blood-​borne viruses, and so microscopic

21.10.7  Sickle cell disease and the kidney 5033 haematuria, proteinuria, and renal dysfunction should always be investigated with this in mind. Pathophysiology A single point mutation on the β-​globin gene on the short arm of chromosome 11 results in the substitution of a valine residue for the usual glutamic acid at the seventh amino acid position (including the initial methionine) and is responsible for the formation of sickle haemoglobin (HbS). This substitution renders the haemoglobin molecule much less soluble under hypoxic and acidotic conditions and prone to polymerization. This process leads to the formation of rope-​like structures that span the cell and cause it to become mis- shapen and rigid. Although in health the kidneys receive approximately 25% of the cardiac output, the vessels (vasa recta) that supply the medulla of the kidney branch off early from the efferent arteriole, taking only a fraction of the total renal blood flow with them. Much of the blood that enters the renal cortex is therefore delivered back to the venous circulation without entering the medulla at all. The relatively sluggish but intricate circulation of the inner medulla is critical to maintaining the countercurrent multiplier system of the loop of Henle, which drives water and solute reabsorption and allows for effective urinary concentration. However, the resulting hypoxia (partial pressure of oxygen 10–​35 mmHg), acidosis, and hyperosmolarity make the inner medulla an ideal environment for the polymerization of deoxygenated HbS and subsequent sickling of red blood cells. Ultimately, this results in loss of vasa recta, im- paired renal medullary blood flow, microinfarcts, papillary ne- crosis, and loss of normal medullary function (Fig. 21.10.7.1). Alongside this, the persistent anaemia and a high cardiac output lead to a paradoxically increased blood flow to the renal cortex and raised glomerular filtration rate in children and young adults, resulting in glomerular hypertrophy and hyperfiltration. Over time, the persistent high pressure in the glomeruli can cause proteinuria and eventually glomerulosclerosis and renal impair- ment. Association studies have suggested that those patients who have the highest degrees of haemolysis are more likely to have a raised glomerular filtration rate and to develop the early manifest- ations of SCN. Clinical manifestations Tubular dysfunction Hyperfiltration alongside poor medullary perfusion causes hyposthenuria (inability to concentrate urine under water-​deprived conditions) in early childhood. Up to the age of 10 this is reversible with blood transfusions, but later in life this is irreversible, frequently leading to polyuria, troublesome nocturia, enuresis, and dehydra- tion. In addition, tubular dysfunction can be demonstrated in patients with SCN who often have a partial form of distal renal tubular acid- osis and a primary defect in the tubular secretion of potassium re- sulting in a hyperchloraemic metabolic acidosis and hyperkalaemia (Table 21.10.7.1). In contrast, proximal tubular function appears to be supranormal, associated with increased reabsorption of phosphate and β-​microglobulins and increased secretion of creatinine, making this molecule a poor surrogate marker of glomerular filtration rate. Haematuria Haematuria is common, both in SCD and sickle cell trait. It can range from nonvisible and painless, through visible and painless, to visible and painful. It is usually self-​limiting but can be severe enough to require transfusion. Small microinfarcts are often the cause of minor bleeding but full-​blown renal papillary necrosis with sloughing of the ischaemic papilla can cause severe haemorrhage and obstruction and may be complicated by superadded infection. Although most cases of haematuria are self-​limiting, it is important that they are in- vestigated to exclude more sinister underlying causes. One rare but devastating complication of both SCD and, more commonly, sickle cell trait is medullary carcinoma, a cancer specific to patients with (a) (b) (c) Fig. 21.10.7.1  Microangiograph of a pyramid from (a) a normal kidney (72 years); (b) a sickle cell haemoglobin C disease kidney (HbSC) (5 years); and (c) a homozygote sickle cell disease kidney (3 years). Reprinted from The Lancet, Vol. 295, Statius van Eps LW, Pinedo-​Veels C, de Vries GH, de Koning J, Nature of concentrating defect in sickle cell nephropathy microangiopathic studies, 450–​452, Copyright © 1970, with permission from Elsevier.

21.10.8 Infection- associated nephropathies 5034 A

21.10.8 Infection- associated nephropathies 5034 A. Neil Turner

section 21  Disorders of the kidney and urinary tract 5034 sickle haemoglobinopathies. This is highly aggressive, can occur in children as young as 2 years of age, and, so far, has proved to be uni- versally fatal within 2 years of presentation. Albuminuria and proteinuria The appearance of abnormal levels of albumin in the urine is an early manifestation of SCN. It is present in some teenage children but its prevalence increases with age, reaching approximately 60% in adults over 45 years. For many, the degree of albuminuria appears not to progress, but in others, nonselective proteinuria develops rapidly, and these are the patients most at risk of future renal impairment. Rarely, patients can develop full-​blown nephrotic syndrome, though this should always be investigated to rule out a second pathology. In particular, nephrotic syndrome has been reported in a number of pa- tients following infection with human parvovirus B19, in which case renal biopsy demonstrates the collapsing form of focal segmental glomerulosclerosis and (if taken early in the disease course) occasion- ally positive staining for the HPV B19 virus. In such cases the neph- rotic syndrome is usually self-​limiting, although a gradual decline in renal function often occurs in the months and years following the acute event. Treatment options Therapies to prevent progression of chronic kidney disease Treatment of patients with proteinuria with inhibitors of the renin–​ angiotensin system to reduce glomerular pressure and proteinuria has become accepted as standard practice in those who can tolerate it from a blood pressure and serum potassium perspective. Intermittent or regular blood transfusion is often used to manage the acute com- plications of SCD or for primary or secondary prevention of stroke, but there is little evidence for its use in the prevention or treatment of SCN. However, using blood transfusion to reduce the percentage of sickle haemoglobin in patients prior to surgery does have proven benefits and this is likely to be particularly important in those under- going renal transplantation. Hydroxycarbamide (hydroxyurea) therapy has clear clinical benefits for many patients with SCD, including a reduction in hospitalization episodes and painful crises. Although studies have failed to demonstrate any clear benefit of this treatment in the short term, it is likely that it helps maintain kidney health in those who respond well to this therapy in other respects. Haematopoietic cell transplantation is the only curative treatment currently available for SCD and is usually reserved for children with major complications such as stroke. Although it is probable that re- cipients of such transplants who have a good outcome are protected from developing SCN in future, most published studies exclude those with established renal disease from receiving this treatment and so its role in treating kidney dysfunction has not yet been studied. Treatment of endstage kidney disease Despite optimal treatment, some patients with SCD will develop progressive kidney failure that will eventually necessitate the need for renal replacement therapy. The prognosis for patients with SCD on dialysis is poor and the average lifespan after a diagnosis of endstage kidney disease is only 4 years. Kidney transplantation offers a better outcome and can increase life expectancy to 10 to 15 years in those who have a well-​functioning graft. Recurrent SCN can complicate the outcome following transplantation, although this can be mitigated by placing the patient on an exchange trans- fusion programme. FURTHER READING Alvarez O, et al. (2012). Effect of hydroxyurea treatment on renal func- tion parameters: results from the multi-​center placebo-​controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer, 59, 668–​74. Derebail VK, et al. (2019). Progressive Decline in Estimated GFR in Patients With Sickle Cell Disease: An Observational Cohort Study. Am J Kidney Dis, pii: S0272-6386(19)30007-1. doi: 10.1053/j. ajkd.2018.12.027. Nath KA, Hebbel RP (2015). Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol, 3, 161–​71. Sharpe CC, Thein SL (2014). How I treat renal complications in sickle cell disease. Blood, 24, 3720–​6. Thompson J, et al. (2007). Albuminuria and renal function in homo- zygous sickle cell disease: observations from a cohort study. Arch Intern Med, 167, 701–​8. 21.10.8  Infection-​associated nephropathies A. Neil Turner ESSENTIALS Infection may be a primary cause of renal disease (e.g. postinfectious glomerulonephritis) or affect the kidneys on a background of debilitating illnesses and previous medical interventions. Renal dis- ease may arise as a consequence of immune responses to a pathogen, direct invasion by the microorganism, or the effects of infection on the systemic or local circulations. Table 21.10.7.1  Signs and symptoms of renal involvement in sickle cell disease Initial changes (>80% patients) Early signs of renal damage (30–​60% of patients) Markers of progressive disease (10–​20% patients) Increased glomerular filtration rate Microalbuminuria Nonselective proteinuria Hyposthenuria Haematuria Falling glomerular filtration rate (>5 ml/​min per 1.73 m2 per year) Nocturia/​enuresis Tendency to hyperkalaemia Falling steady state haemoglobin concentrationa a Due to falling endogenous erythropoietin production as renal function declines.

21.10.8  Infection-associated nephropathies 5035 Glomerulonephritis—​associated with chronic and acute bacterial infections. Shunt nephritis follows colonization of a ventriculoatrial shunt, most commonly with Staphylococcus epidermidis, leading to constitutional symptoms, an acute inflammatory response, and (most characteristically) a type 1 mesangiocapillary glomeruloneph- ritis. Infective endocarditis and other deep-​seated bacterial infections may produce a similar renal picture, but they can also mimic vascu- litic syndromes and outcome is dependent on the response of the infection to treatment. Acute postinfectious glomerulonephritis—​see Chapter 21.8.5. Interstitial nephritis—​bacteria that can cause this include leptospira (Weil’s disease), Rickettsia rickettsii (Rocky Mountain spotted fever), legionella, and mycobacteria. Viral infections include hantaviruses (haemorrhagic fever with renal syndrome and nephropathia epidemica) and, almost exclusively following renal transplantation, cytomegalovirus and polyomavirus hominis type 1 (BK) virus. HIV-​associated renal disorders—​these include HIV nephropathy, which is a focal segmental glomerulosclerosis of ‘collapsing’ form, occurring almost exclusively in black patients. Other morpholo- gies are more common in other races, but interstitial disease is also common as a manifestation of infection or of drug toxicity. Hepatitis B virus—​chronic infection is strongly associated with membranous nephropathy; affected individuals are HBeAg and HBsAg positive, usually with coexistent hepatitis; seroconversion from HBeAg positive to HBeAb positive (naturally or induced by treatment) is associated with remission of the renal lesion. Hepatitis C virus—​chronic infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations; it is associated with membranoproliferative glomerulonephritis (MPGN, also described as MCGN), and reduction of viral replication has been associated with disease remission. Introduction Almost all renal lesions, particularly glomerular lesions, may be asso- ciated with infections. In the developed world, infection-​associated nephritis was once predominantly recognized during acute infec- tions occurring in apparently healthy individuals, and this is still the pattern in many countries. However, improvements in living con- ditions and health care reduce the numbers of healthy people suc- cumbing to complications of infection. Instead, infections occurring on a background of debilitating illnesses and previous medical inter- ventions become more common precipitants of renal disease. In this chapter, glomerular diseases and interstitial diseases as- sociated with infection are considered in turn. Particular attention is given to those glomerulopathies associated with bacterial endo- carditis and other chronic bacterial infections, and three viral in- fections of worldwide importance, HIV, hepatitis B, and hepatitis C. Pathogenesis Infection-​associated glomerular disease is usually attributed to trapping of circulating antigen–​antibody complexes in the glom- erulus, or to immune responses to pathogen-​derived antigens that become ‘planted’ in the glomerulus. The evidence for deposition of circulating immune complexes is strong for cryoglobulinaemia, and highly plausible for infections occurring within the vascular system such as bacterial endocarditis. In most other infections the evidence is less clear, and this is probably not a common mechanism of glomerular disease. A direct cytopathic effect on glomerular cells seems likely for some pathogens such as HIV and parvovirus, both of which infect glomerular podocytes and have been associated with ‘collapsing’ focal segmental glomerulosclerosis (FSGS). Interstitial renal disease is often blamed on direct invasion by the microorganism, and for some there is evidence that this is true. The pathogen may cause injury directly, or indirectly by causing cells to express foreign antigens which generate an immune response. More speculatively, an immune response generated to an organism may cross-​react with a remote self-​antigen, triggering autoimmunity through molecular mimicry, but there are no unequivocal examples of this. Infection may also involve the kidney by interfering with the cir- culation either generally (septic shock) or locally (e.g. by causing thrombotic microangiopathy, as for Escherichia coli O157 or Capnocytophaga canimorsus (previously DF-​2)). Occasionally, toxins may be released that harm the kidney directly (e.g. haemo- globin in malaria). Medically administered toxins include anti- microbial agents that impair renal function by crystallization (e.g. aciclovir, indinavir) or by predictable toxicity (e.g. aminoglycosides, amphotericin, and tenofovir), or by idiosyncratic reactions such as acute interstitial nephritis (e.g. penicillins). Glomerulonephritis associated with chronic
and acute bacterial infections Classic acute postinfectious glomerulonephritis is considered in Chapter  21.8.5. This account considers subacute or chronic dis- eases, although other causes of a ‘classic’ picture are mentioned. Shunt nephritis was first recognized in the 1960s, and it remains the archetype of an immune complex nephritis. The glomerulonephritis occurring in association with infective endocarditis is very similar. Both are caused by subacute infection within the bloodstream, with constant shedding of antigen and formation of antigen–​antibody complexes. Other bacterial infections may cause similar pictures. Shunt nephritis and similar syndromes of intravascular infection In shunt nephritis, a ventriculoatrial shunt implanted for hydro- cephalus becomes colonized by bacteria, usually of low pathogen- icity. More common modern equivalents are infected long-​term central venous catheters and other intravascular devices. The syn- drome does not occur with ventriculoperitoneal shunts, which are therefore now the preferred neurosurgical option, making shunts now a rare cause of the syndrome. Although Staphylococcus epi- dermidis has been most commonly implicated in these infections, Propionibacterium acnes or other organisms are sometimes in- volved. Typically the diagnosis is only appreciated after weeks to months of symptoms of mild to moderate pyrexia and malaise as- sociated with haematuria and proteinuria and progressive renal impairment. Fevers have often been attributed to urinary infec- tion in patients with neurogenic bladders. There may be moderate splenomegaly. Investigations show complement consumption and

section 21  Disorders of the kidney and urinary tract 5036 an acute-​phase response with normochromic normocytic anaemia, and variable renal impairment. The renal lesion is characteristically a type 1 membranoproliferative (mesangiocapillary) glomeruloneph- ritis with deposition of multiple immunoglobulins and complement components beneath the endothelium, the classic appearance of a circulating immune complex nephritis. Sometimes the picture is more severe, showing a diffuse proliferative lesion, occasionally with crescents. In other cases, the histological appearances are less pro- nounced with focal proliferative changes. Antibiotic treatment alone is almost never adequate to cure these infections, which require removal of the intravascular device, fol- lowed by its replacement after an interval if it is still required. Delayed diagnosis and delayed removal may lead to more severe and irreversible renal damage, and sometimes to endstage renal failure, but some degree of recovery can follow successful treatment. Infective endocarditis A similar syndrome can occur in infective endocarditis, as part of which minor degrees of glomerular disease are probably extremely common. In truly subacute endocarditis, symptoms and signs are as seen in shunt nephritis. Typical streptococcal infections are well represented in case reports, but there have been multiple reports involving ‘slow’ infections such as Q fever (Coxiella burnetii), and more unusual causes including chlamydia and fungi. Typical patients in developed countries have shifted from being young patients with rheumatic heart disease, to being elderly with comorbid conditions, long-​term vascular access devices, pace- makers, etc. Infection of prosthetic or native heart valves may be implicated. Right-​sided endocarditis occurring in intravenous drug abusers may be particularly likely to present as nephritis, because the diagnosis is often delayed. Depletion of serum complement is again diagnostically useful, but, as for shunt nephritis, most other serological and haemato- logical changes are nonspecific. Partial treatment with antibiotics makes diagnosis and management more difficult, as positive blood cultures are usually a key part of proving the diagnosis and selecting appropriate therapy. The pathological lesion is typically similar to that of shunt neph- ritis, but forms of endocarditis that are acute, rather than subacute (e.g. that associated with Staphylococcus aureus), are more likely to cause glomerulonephritis in a diffuse proliferative pattern, some- times with crescent formation. Focal changes that are indistinguish- able from antineutrophil cytoplasmic antibody (ANCA)-​associated vasculitis have been reported in the literature, and ANCA are de- tected in some patients. There may be a florid purpuric cutaneous vasculitis (as in Fig. 21.10.8.1), but there may be few or no other signs of vasculitis elsewhere. However, immune deposits are usually pre- sent in glomeruli, in contrast to the primary small-​vessel vasculitides. In most cases, the outcome is dependent on the response of the endocarditis to treatment, but renal involvement is a poor prog- nostic factor for survival, which may be simply because it reflects long-​lasting infection, although recovery from dialysis dependence may occur. Patients with endocarditis are also prone to two other renal le- sions: interstitial nephritis related to antibiotics and, in those with disease on the left side of the heart or with right–​left shunts, renal emboli, although glomerulonephritis is a more common cause of urinary abnormalities. Deep-​seated bacterial infections Amyloidosis is a well-​recognized consequence of very chronic bac- terial (including mycobacterial) and other infections, and is de- scribed in Chapters 12.12.3 and 21.10.5. As in reactive amyloidosis of other aetiologies, progression of the renal lesion may be prevented or even partially reversed by treatment of the cause. Deep-​seated infections, particularly abscesses, may also be asso- ciated with glomerulonephritis. Although the mechanisms involved are presumably similar to those of shunt nephritis and nephritis as- sociated with endocarditis, blood cultures have often been negative in reported cases. Staphylococcus aureus is the most frequently impli- cated organism. A wide variety of renal lesions have been described, usually inflammatory/​proliferative and with immunoglobulin de- position. Unsuspected abscesses or other deep-​seated infections are occasionally found only after the renal biopsy appearances trigger a search. Such hidden abscesses are more likely in obese or older people, and in those on corticosteroids or who are immunosup- pressed by other means or by disease. Acute glomerulonephritis and other infections Acute glomerulonephritis resembling poststreptococcal neph- ritis has been reported in association with a large number of other organisms, including current (as opposed to recent) infection with staphylococci, streptococci, and other bacteria, and with acute viral infections that are usually self-​limiting. These include Epstein–​Barr virus, cytomegalovirus, varicella, measles, mumps, parvovirus, and coxsackieviruses. Some may cause a clinical syn- drome that is very similar to poststreptococcal nephritis, while others typically cause a less florid ‘nephritic’ or mixed ‘nephritic/​ nephrotic’ picture. Staphylococcus aureus is particularly asso- ciated with a variant of postinfectious glomerulonephritis with prominent nephrotic features and dominant IgA deposition in glomeruli. Diagnostic difficulties in bacterial infection-​related glomerulonephritis Infection-​related nephritis may present in a very similar manner to nephritis associated with other systemic diseases, notably microscopic polyangiitis and other small-​vessel vasculitides (see Fig. 21.10.8.1  Cutaneous vasculitis in a patient with Staphylococcus aureus endocarditis.

21.10.8  Infection-associated nephropathies 5037 Chapter 21.10.2). As both types of disease process may be associated with fever, a systemic illness, and an acute-​phase response, it is im- portant to consider the possibility of infection in all patients thought to have systemic vasculitis. Blood cultures should be routine. ANCA assays are extremely useful, but it is important to note that ANCA positivity has been recorded in many infections, both by fluorescence and by solid-​phase assays: ANCA are not diagnostic of small-​vessel vasculitides. Renal biopsy is often the most discriminating investi- gation. Infection-​associated glomerulonephritis is usually (but not invariably) associated with plentiful immunoglobulin deposition, whereas small-​vessel vasculitis is characteristically pauci-​immune. Nonglomerular causes of renal impairment (interstitial nephritis, acute tubular necrosis) are also distinguished by renal biopsy. Interstitial nephritis associated with infections Bacterial infections Acute bacterial pyelonephritis is usually a florid and painful dis- order associated with symptoms of urinary tract infection, as de- scribed in Chapter 21.13. Substantial renal impairment is usual only if a single functioning kidney is affected. Occasionally, however, the diagnosis is masked by immunosuppression (e.g. in a transplanted kidney), age, or other factors, and the diagnosis is made by the renal biopsy appearances of neutrophils in the interstitium and in tubules, which are rarely found in any other renal lesions. Acute interstitial nephritis is a key feature of Weil’s disease, a se- vere form of leptospirosis (see Chapter 8.6.35). Jaundice and renal failure follow a febrile illness caused by infection with Leptospira interrogans. The renal lesion comprises interstitial oedema with pre- dominantly mononuclear infiltrates and foci of tubular necrosis. Renal failure is usually oliguric but may be polyuric. Dialysis may be required for days to weeks, and renal recovery may sometimes be incomplete. Other bacterial infections that may cause a similar pathological picture include Rocky Mountain spotted fever (Rickettsia rickettsii), in which there may be an interstitial nephritis with foci of haemor- rhage, and acute Yersinia pseudotuberculosis infection, in which an acute lymphocytic interstitial nephritis has been described in sev- eral patients. Legionnaires’ disease (Legionella pneumophila) has been reported to be associated with renal impairment, also with an interstitial nephritis, but in some instances may show a picture of acute tubular necrosis. The same is probably true of other severe pneumonias. Mycobacteria can cause a chronic granulomatous interstitial nephritis (discussed in ‘Mycobacteria’). Viral infections Hantaviruses Hantaviruses are carried by small rodents, and have been associ- ated with a range of human syndromes that involve the kidneys with varying severity. ‘Haemorrhagic fever with renal syndrome’ (HFRS) is characterized by oliguric renal failure, associated histologically with lymphocytic interstitial nephritis that may be haemorrhagic in severe cases, reflecting the systemic bleeding diathesis. Some pa- tients have been reported to have persistent renal impairment after recovery. HFRS was originally associated with Hantaan strains of hanta- virus in Korea, while milder disease, with less frequent and usually less severe renal impairment and without haemorrhagic diathesis, was associated with the Seoul strain. Milder disease (nephropathia epidemica) recognized in northern Europe and subsequently more widely was associated with the Puumula strain. However, it has be- come apparent that there are many more subtypes of hantavirus, and the association of a serotype with a particular clinical picture is not rigid. Severe disease with shock, variable haemorrhage, and some- times pulmonary impairment has been encountered in the Balkans and Greece. Disease with predominantly pulmonary manifestations and shock has been recognized, particularly in North America, al- though these geographical variations in clinical picture are no more rigid than the strain variations. Ribavirin is active against hantaviruses in vitro, and therapy with ribavirin was found to be effective in HFRS caused by the classic Hantaan strain in China and confirmed in Korea, but there are likely to be strain differences as no benefit could be demonstrated in trials in the pulmonary syndrome in North America, and evidence for value more widely seems weak. Cytomegalovirus, polyomaviruses, and other viruses Cytomegalovirus (CMV) may lie dormant in renal tubular cells, and during new or reactivated infection causes characteristic in- clusion bodies. This rarely has a significant impact on renal func- tion outside the setting of renal transplantation, where CMV infection commonly occurs concurrently with acute rejection. Although there is evidence that CMV infection may precipitate rejection, it is also clear that the risk of CMV infection is greatly increased by most types of antirejection therapy. CMV may also rarely cause a florid glomerular lesion characterized by gross endo- thelial cell damage and swelling, resembling pre-​eclampsia. This has again been recognized almost exclusively in renal transplants, where some believe that the appearances are due to, or complicated by, vascular rejection. Human polyomaviruses (BK and JC) were previously believed to be benign passenger viruses which replicated without causing damage during immunosuppression. However, BK virus has been increasingly recognized as a cause of impaired renal transplant function, usually many months after transplantation. The histo- logical changes of tubulitis closely resemble acute cellular rejection, but further immunosuppression favours further infective damage. Observation of typical inclusion bodies and immunohistochemical studies prove the true cause of the tubulitis, and renal function may improve after reduction of immunosuppressive agents, al- though renal outcome is often poor despite this. Polymerase chain reaction-​based screening has been introduced in many centres in attempts to make an earlier diagnosis, but there is still no proven antiviral therapy and reduction of immunosuppression is not without risk. A strategy of combining leflunomide (as a replace- ment for azathioprine or mycophenolate mofetil), intravenous immunoglobulin, and ciprofloxacin has been tried, but shown no benefit. Polyomavirus renal disease seems to be less common in pa- tients immunosuppressed for reasons other than renal transplant- ation, but it is being increasingly recognized. A wide range of other viruses and microorganisms have been less regularly associated with interstitial lesions. HIV (considered in the following section) may cause an interstitial nephritis. Another

section 21  Disorders of the kidney and urinary tract 5038 condition that is likely to be infective in origin, Kawasaki’s disease, is associated with interstitial nephritis, although glomerular lesions have also been described occasionally. HIV and renal disease Renal impairment is commonly encountered at some stage of HIV infection. The largest single cause of serious renal disease in this group is the distinct entity of HIV nephropathy. However, this gen- eralization is misleading as this specific diagnosis is largely restricted to black patients, and there are many other causes of renal disease in patients with HIV infection. FSGS associated with HIV infection (HIV nephropathy) HIV nephropathy is characterized by heavy proteinuria and renal impairment. It is an important cause of endstage renal failure in Africa, but also significant in black adults of working age in the United States of America. Although it has often been described as an initial manifestation of HIV infection, in these circum- stances the infection is advanced, with high viral loads and low CD4 counts. Histologically, the appearances are of FSGS of the ‘collapsing’ form, with injury and hypertrophy of glomerular epithelial cells accompanied by variable interstitial inflamma- tion with oedema and microtubular dilatation (Fig 21.10.8.2). The racial (black African) restriction of susceptibility to HIV nephropathy and increased risk of other types of FSGS is due to variants in the APOL1 gene which convey resistance to trypano- somiasis. How they produce their disadvantageous renal effects is not yet known. Without therapy the condition progresses to endstage renal failure rapidly, over weeks to months. Perhaps because it is associated with low CD4 counts, the medium-​term prognosis in the past was poor despite renal replacement therapy, but effective antiviral therapy can alter this. Non-​FSGS nephropathies in HIV infection FSGS accounts for a minority of HIV-​associated renal disease in most populations. An HIV immune complex glomerulonephritis (HIVICK) has been described, but so have other specific types of renal disease, encompassing almost all types of glomerular le- sion, interstitial nephritis, cryoglobulinaemia, and thrombotic microangiopathy. IgA nephropathy has been frequently recorded. Some of these lesions may be directly caused by HIV infection, while others are related to concurrent infections with other microorganisms, and some may be related to therapy. The occur- rence of autoimmune phenomena in HIV infection may also be accompanied by an increase in immune-​mediated primary renal diseases of many types. Interstitial nephritis is often but not always related to anti-​HIV drugs. Tenofovir in particular may cause tubular injury with renal impairment and sometimes Fanconi’s syndrome. Aciclovir and indinavir have replaced sulphonamides as common causes of crystal nephropathy. Adjusting the doses of these and other drugs in the setting of renal impairment is prob- lematic. Patients with HIV infection receive many other drugs with predictable nephrotoxicity, and polypharmacy also puts them at risk of allergic reactions. Highly active antiretroviral therapy and
other therapies Highly active antiretroviral therapy (HAART), when instituted early, may arrest the progression of FSGS as well as lowering the mortality of patients with endstage renal failure. Severity of chronic damage on biopsy may be a better prediction of prognosis than serum creatinine. Its effect on non-​FSGS nephropathies may also be beneficial. Patients with any diseases associated with proteinuria should be treated with angiotensin-​converting enzyme inhibitors. Treatment with corticosteroids should probably be considered in patients with HIV-​FSGS who progress despite effective HAART and intensive renoprotective therapy with angiotensin-​converting enzyme inhibi- tors and blood pressure control. Patients with good control of HIV do well on renal replacement therapies, and several national guidelines now allow and recom- mend transplantation for patients whose prognosis is of many years. In high-​incidence regions, transplantation of kidneys from HIV-​ positive donors improves organ supply. Nephropathy associated with hepatitis B virus Chronic infection with hepatitis B virus (HBV) (see Chapter 8.5.21) is strongly associated with membranous nephropathy, and it is an important secondary cause of the lesion. A less clear relationship holds with membranoproliferative glomerulonephritis (MPGN, also known as MCGN), while for hepatitis C virus (HCV) the con- verse is true. Chronic HBV infection is much more common in some regions and racial groups, and the distribution of HBV-​related nephropathy closely follows this distribution. The clinical picture may be compli- cated by the concurrence of HBV infection by infection with HCV, HIV, or with other organisms, or by the coincidence of significant renal and hepatic disease. HBV membranous nephropathy has a Fig. 21.10.8.2  Histology of HIV-​associated nephropathy showing glomerular collapse with a focal sclerosing lesion, microcystic tubular dilatation, and interstitial inflammation (magnification ×200). Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand.

21.10.8  Infection-associated nephropathies 5039 close relationship with virus multiplication, so affected individuals are usually HBeAg and HBsAg positive, with evidence of hepatitis, although this may be minor. Membranous nephropathy is a more common complication of HBV infection in children, but it is also more benign in this group. The lesion may be static, or in some cases (particularly in adults) associated with progressive deterioration to endstage renal failure. Histopathology is typical of membranous nephropathy, and HBV antigens may be detectable in glomerular deposits. Idiopathic membranous nephropathy is caused by autoantibodies to podocyte surface proteins, usually to the phospholipase A2 (PLA2) receptor, but these are not typically identified in patients with secondary membranous nephropathy, including that associated with HBV. The target in these circumstances may be viral, but it has not been identified. Seroconversion from HBeAg positive to HBeAb positive is asso- ciated with remission of the renal lesion, whether the conversion oc- curs naturally or is induced by treatment. Spontaneous remission of the renal lesion is more likely in children. Antiviral treatment is the appropriate therapy when required, as immunosuppression may increase viral burden. Recently acquired (within months) HBV infection has been asso- ciated with classic polyarteritis nodosa (PAN) in some populations, such as in France and North America, but even in these areas HBV-​ PAN is uncommon and apparently decreasing. Furthermore, the as- sociation of the two diseases is rare in some countries with low (e.g. the United Kingdom) and with high (e.g. Thailand) rates of HBV carriage, suggesting the involvement of a cofactor. Clinically, the disease is typical of PAN, affecting medium and somewhat smaller vessels but not capillaries, and therefore not usually associated with focal necrotizing or crescentic nephritis. ANCA are not usually detected. Treatment is difficult to balance as immunosuppression (usually with corticosteroids alone) is often indicated, but favours viral replication and exacerbation of liver disease, while remission is associated with seroconversion from HBeAg positivity to HBeAb positivity. Nephropathy associated with hepatitis C virus Chronic HCV (see Chapter 8.5.22) infection is the commonest cause of mixed essential (type II) cryoglobulinaemia in most populations, and an important cause of MPGN without overt cryoglobulinaemia. The clinical picture includes cutaneous vasculitis, glomerular path- ology (mesangiocapillary glomerulonephritis, MCGN), and other manifestations. Cryoglobulins contain quantities of HCV antigens and bound antibody, in addition to monoclonal IgM rheumatoid factors. HCV may also be associated with MCGN in the absence of detectable cryoglobulins. A relationship with membranous neph- ropathy is also possible, but not proven. As for HBV, reduction of viral replication has been associated with disease remission. Immunosuppression with corticosteroids and some- times other agents may be required to control disease manifestations caused by vasculitis. B-​cell depletion with anti-​CD20 monoclonal anti- bodies may help to control the disease if antiviral therapy does not. Renal sequelae of other chronic infections Amyloidosis Amyloidosis (see Chapter 12.12.3) may be a consequence of all sorts of chronic infection, but of the ‘tropical’ infections is most frequently associated with schistosomiasis, filariasis, or leishmaniasis. Mycobacteria Mycobacterial infections (see Chapter 8.6.26) cause a chronic granu- lomatous interstitial nephritis that is characteristically associated with inflammatory and fibrotic abnormalities in the ureters and lower (a) (b) (c) Fig. 21.10.8.3  Radiological appearances in urinary schistosomiasis. (a) Plain radiograph showing linear bladder calcification. (b) Retrograde urogram showing contracted bladder with reflux into extremely dilated ureter, and hydronephrosis. (c) Cystogram showing large irregular filling defect in the bladder caused by a tumour. Reproduced with permission from Barsoum RS. Schistosomiasis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 5040 urinary tract. Symptoms often relate to lower tract involvement, but the disease may be asymptomatic, and in the earliest stages involvement is presumed to be restricted to the kidneys, with subsequent spread to the lower tract. Sterile pyuria is the rule, and impaired renal function is common at presentation. Imaging by intravenous urography or other techniques will show blunting of calyces, progressing to changes typ- ical of pyelonephritis or papillary necrosis, along with lower tract ab- normalities such as ureteric strictures and scarring and contraction of the bladder. Amyloidosis is a well-​recognized secondary complication of mycobacterial infections. Idiosyncratic reactions to antituberculous drugs are another common cause of late renal dysfunction. Syphilis Congenital syphilis (see Chapter 8.6.37) may cause severe nephrotic syndrome with the histological pattern of membranous nephropathy. This is also the usual pattern when secondary syphilis rarely causes nephrotic syndrome. Both respond to antispirochaetal treatment. Malaria Plasmodium falciparum infections (see Chapter  8.8.2) are an ex- tremely important cause of acute kidney injury worldwide. This oc- curs in 1 to 5% of infected patients native to a malarial area, but a higher proportion of nonimmune visitors, and is associated with high mortality (15–​45%). Series from Africa have cast doubt on the existence of a specific chronic malarial nephropathy that was described in earlier litera- ture. Biopsy studies have shown a high incidence of infection-​related glomerulonephritis and of FSGS, but have found little evidence of a distinct malarial disease. Schistosomiasis Schistosomiasis (Fig. 21.8.10.3; see Chapter 8.11.1) is best recog- nized for causing disease of the lower urinary tract, but chronic in- fections associated with hepatosplenomegaly may be associated with glomerular disease after many years. In Schistosoma haematobium infection this is often due to secondary infections with Salmonella spp. rather than directly associated with schistosomal infection. In Schistosoma mansoni infection the relationship is probably usually directly causal, typically causing MPGN. Filariasis Longstanding filariasis (see Chapter 8.9.2) may also be associated with glomerular lesions. An acute syndrome with tubulointerstitial nephritis has also been described in association with the presence of microfilariae in renal capillaries. FURTHER READING Arendse CG, et al. (2010). The acute, the chronic and the news of HIV-​ related renal disease in Africa. Kidney Int, 78, 239–​45. Bigé N, et al. (2012). Presentation of HIV-​associated nephropathy and out- come in HAART-​treated patients. Nephrol Dial Transplant, 27, 1114–​21. Bonarek H, et al. (1999). Reversal of c-​ANCA positive mesangiocapillary glomerulonephritis after removal of an infected cysto-​atrial shunt. Nephrol Dial Transplant, 14, 1771–​3. Clementi A, et al. (2011). Renal involvement in leishmaniasis: a review of the literature. Nephrol Dial Transplant Plus, 4, 147–​52. Conlon PJ, et al. (1998). Predictors of prognosis and risk of acute renal failure in bacterial endocarditis. Clin Nephrol, 49, 96–​101. Daugas E, Rougier JP, Hill G (2005). HAART-​related nephropathies in HIV-​infected patients. Kidney Int, 67, 393–​403. De Vita S, et al. (2012). A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum, 64, 843–​53. Doe JY, et al. (2006). Nephrotic syndrome in African children: lack of evidence for ‘tropical nephrotic syndrome’? Nephrol Dial Transplant, 21, 672–​6. Elsheikha HM, Sheashaa HA (2007). Epidemiology, pathophysiology, management and outcome of renal dysfunction associated with plasmodium infection. Parasitol Res, 101, 1183–​90. Fabian J, et al. (2013). The clinical and histological response of HIV-​ associated kidney disease to antiretroviral therapy in South Africans. Nephrol Dial Transplant, 28, 1543–​54. Genovese G, et al. (2010). Association of trypanolytic ApoL1 variants with kidney disease in African-​Americans. Science, 329, 841–​5. Haffner D, et  al. (1997). The clinical spectrum of shunt nephritis. Nephrol Dial Transplant, 12, 1143–​8. Krautkrämer E, Zeier M, Plyusnin A (2013). Hantavirus infection:  an emerging infectious disease causing acute renal failure. Kidney Int, 83, 23–​7. Lai AS, Lai KN (2006). Viral nephropathy. Nat Clin Pract Nephrol, 2, 254–​62. Majumdar A, et al. (2000). Renal pathological findings in infective endocarditis. Nephrol Dial Transplant, 15, 1782–​7. Montseny JJ, et al. (1995). The current spectrum of infectious glom- erulonephritis: experience with 76 patients and review of the litera- ture. Medicine (Baltimore), 74, 63–​73. Moudgil A, et al. (2001). Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney Int, 59, 2126–​33. Muller E, Kahn D, Mendelson M (2010). Renal transplantation between HIV-​positive donors and recipients. N Engl J Med, 362, 2336–​7. Naqvi R, et al. (2003). Outcome in severe acute renal failure associated with malaria. Nephrol Dial Transplant, 18, 1820–​3. Nasr SH, et al. (2008). Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore) 87, 21–​32 Neugarten J, Baldwin DS (1984). Glomerulonephritis in bacterial endocarditis. Am J Med, 77, 297–​304. Nickeleit V, Mihatsch MJ (2006). Polyomavirus nephropathy in na- tive kidneys and renal allografts: an update on an escalating threat. Transpl Int, 19, 960–​73. Perico N, et al. (2009). Hepatitis C infection and chronic renal diseases. Clin J Am Soc Nephrol, 4, 207–​20. Peters CJ, Simpson GL, Levy H (1999). Spectrum of hantavirus infec- tion: hemorrhagic fever with renal syndrome and hantavirus pul- monary syndrome. Ann Rev Med, 50, 531–​45. Post FA, et al. (2008). Predictors of outcome in HIV-​associated neph- ropathy. Clin Infect Dis, 15, 1282–​9. Sneller M, Hu Z, Langford C (2012). A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-​ associated cryoglobulinemic vasculitis. Arthritis Rheum, 64, 835–​42. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Chapters 183–​198 and 284. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham. Wearne N, et  al. (2012). The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant, 27, 4109–​18.

21.10.9 Malignancy- associated renal disease 5041

21.10.9 Malignancy- associated renal disease 5041

21.10.9  Malignancy-associated renal disease 5041 21.10.9  Malignancy-​associated renal disease A. Neil Turner ESSENTIALS Malignancies can affect the kidneys by direct invasion, meta- bolic and remote effects of tumour products, deposition of tu- mour products, triggering of immune reactions, and effects of treatment. Particular malignancy-​associated renal diseases include the following: Thrombotic microangiopathy—​particularly reported for malignan- cies of the stomach, pancreas, and prostate, and also with certain chemotherapeutic agents. Minimal-​change nephrotic syndrome—​rarely caused by lymphoma. Membranous nephropathy—​associated with malignancy, usually of solid organs, in 5 to 11% of cases. Malignant disease is typic- ally advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. Very few treatable and otherwise sub- clinical tumours are uncovered by investigation in routine clinical practice. Focal necrotizing and crescentic nephritis—​may rarely be associated with malignancy, when they are usually antineutrophil cytoplasmic antibody negative. Proteinuria—​may be caused by agents that modulate interferons or vascular endothelial growth factors. Introduction Malignant disease may affect the kidney and urinary tract by five broad mechanisms (see Table 21.10.9.1). Acute kidney injury is common in patients with malignancy: in many instances the cause is not specifically related to the malignancy, but it can be, and in many instances several factors combine (Fig. 21.10.9.1). Direct involvement of the urinary tract Solitary kidney tumours in adults are usually caused by renal cell carcinoma (hypernephroma). Bilateral tumours may occur, but multicentric tumours or bilateral tumours in young patients should lead to suspicion of an inherited disorder, particularly von Hippel–​ Lindau syndrome (see Chapter 21.12; cystic and solid lesions, some malignant) or tuberous sclerosis (see Chapter 21.12; benign lesions), both having autosomal dominant inheritance. Lymphoma and leu- kaemia may occasionally invade the renal substance on a sufficient scale to cause renal impairment, but it is rare for other tumours to do so. A rare and aggressive renal medullary tumour has been described in young patients with sickle cell trait or disease. These are easily confused with tumours of the collecting system and carry a poor prognosis. The collecting system and lower urinary tract may be affected by transitional cell tumours or by malignancies that may invade the tract bilaterally or below the bladder. Transitional cell tumours af- fecting the bladder are common, and sometimes cause renal mani- festations if extensive. Lesions in the ureters and collecting system are less common. They occur multifocally in association with anal- gesic nephropathy and two conditions caused by aristolochic acid- (‘Chinese herb’) nephropathy and Balkan endemic nephropathy (see Chapter 21.9.2). Metabolic effects of malignancies on the kidney Hypercalcaemia is a feature of many malignancies, both with and without metastasis. Its renal effects are discussed in Chapter 21.14. Hypokalaemia may be a consequence of acute leukaemias or rectal tumours, and may occasionally be severe enough to cause renal dys- function (see Chapter 21.2.2). Severe hyperuricaemia (>900 µmol/​litre) is characteristically as- sociated with massive cell death occurring following chemotherapy of haematological or solid tumours (tumour lysis syndrome), when it is usually accompanied by marked hyperphosphataemia and often by hypocalcaemia. High serum lactate dehydrogenase levels may also be diagnostically useful. Similar gross hyperuricaemia may be seen following radiotherapy of radiosensitive tumours, or may occur without therapy in malignancies with a very high rate of cell turn- over, particularly acute lymphocytic or acute myeloid leukaemia, or poorly differentiated solid tumours. Uric acid levels this high can lead to precipitation within renal tubules and acute kidney injury. Prevention and treatment of tumour lysis syndrome is discussed in Chapter 21.10.5. Table 21.10.9.1  How malignant disease affects the kidney and urinary tract Mode of involvement Examples Direct Tumours of the renal substance Lymphoma, leukaemia deposits Remote metastases from solid tumours Tumours of the urinary tract, prostate gland, etc. Local invasion (cervix, colon) Metabolic and remote effects Hypercalcaemia Hypokalaemia Hyperuricaemia Thrombotic microangiopathy (tumour-​associated thrombotic thrombocytopenic purpura) Deposition of tumour products Myeloma kidney (precipitation in tubules) Immunoglobulin deposition diseases Immune reaction Minimal-​change disease (particularly with lymphomas) Membranous nephropathy (particularly with solid tumours) Rapidly progressive glomerulonephritis and small-​vessel vasculitis Effect of treatment Tumour lysis syndrome Direct toxicity of drugs Idiosyncratic (e.g. immune) response

section 21  Disorders of the kidney and urinary tract 5042 Remote effects of malignant tumours on the kidney Thrombotic microangiopathy Thrombotic microangiopathy occurring in association with ma- lignant disease (also known as malignancy-​associated thrombotic thrombocytopenic purpura; see Chapters 22.7.3 and 22.7.5) is often attributed to chemotherapy. It is particularly associated with certain agents (e.g. bleomycin, mitomycin), although isolated reports im- plicate others. However, in some instances the classic presentation with thrombocytopenia, microangiopathic haemolytic anaemia, and renal failure occurs in association with primary tumours. This has been particularly reported for malignancies of the stomach, pan- creas, and prostate. The syndrome is occasionally the presenting sign of malignancy but often occurs in a patient known to have a tumour. In the absence of specific evidence, tumour-​related thrombotic microangiopathy is usually treated in the same way as throm- botic microangiopathy of other types, by plasma exchange for fresh frozen plasma. If the tumour itself is responsive to treatment, microangiopathy generally subsides too. Renal function may be re- coverable if the process is halted rapidly, an outcome that is most likely in prostatic carcinoma. Deposition of tumour products The protean effects of monoclonal overproduction of immuno- globulins, or their component parts, are considered elsewhere (see Chapter 21.10.5). The tubulotoxic effects of freely filtered im- munoglobulin light chains may be amplified by hypercalcaemia in myeloma, or by concurrent administration of other nephrotoxins, notably intravenous radiological contrast media or possibly loop diuretics. AL amyloidosis (see Chapters 12.12.3 and 21.10.5) is an- other possible consequence of monoclonal proliferation of B cells, devastating enough on its own, but it may be associated with mye- loma or progress to overt myeloma. A variety of other renal con- sequences may occur in B-​cell disorders with overproduction of immunoglobulin fragments, notably the light-​chain (and rarer heavy-​chain) deposition disorders. Immune reactions Malignant diseases are common, hence on occasions cancer will be associated with nephropathies by chance. There are many case re- ports in the literature, but some associations have been reported Causes of AKI in a patient with Malignancies Prerenal Causes • NSAIDS • Contrast • Sepsis • Hypotension • Diarrhea • N/V Renal Vein Thrombosis Renal Arterial Occlusion Artery Stenosis • Lymphadenopathy • Blood Clots • Tumor infiltration & Encasement, Fibrosis • Capillary Leak Syndrome lgM Thrombi, (Waldenstrom's Cryoglobulinaemia), Light Chain Deposition Disease Amyloidosis Drug Crystals ATI from Tubulotoxins Cast Nephrophathy Infiltration in plasma cell leukaemia or lymphoma Nephron Artery Vein Kidney Ureter lntrarenal Causes Bladder Urethra Post-renal Causes Fig. 21.10.9.1  Summary of causes of acute kidney injury (AKI) in patients with cancer. ATI, acute tubular injury; NSAIDs, nonsteroidal anti-​ inflammatory drugs; N/​V, nausea and vomiting. Reproduced with permission from Moeckel GW, Manjunath V, and Perazella MA. Acute kidney injury in the cancer patient. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

21.10.9  Malignancy-associated renal disease 5043 consistently and are beyond doubt. The best-​supported linkages between malignancies and intrinsic renal diseases are for minimal-​ change disease and membranous nephropathy, glomerular condi- tions that are (membranous) or are believed to be (minimal-​change) immunologically mediated. There is also a frequently reported asso- ciation of malignancy with various types of vasculitis, particularly small-​vessel vasculitis, which—​as with glomerulonephritis—​is usually believed to be immunologically mediated, both because of the typical contexts in which it occurs and because of its usual response to immunosuppressive agents. By contrast, there is little evidence for association of malignancies with primary interstitial renal diseases. Some malignancies are particularly likely to be associated with renal disease. Chronic lymphocytic leukaemia and similar low-​ grade B-​cell tumours are associated with a variety of types of glomerulopathy. Thymomas have frequently been associated with glomerular lesions, usually causing nephrotic syndrome with various histological patterns reported. Minimal-​change nephrotic syndrome Lymphomas, usually Hodgkin’s disease, are rarely associated with minimal-​change nephropathy. The renal lesion is typical in patho- logical characteristics, and usually also in response to cortico- steroid treatment. In exceptional cases, this is the presenting sign of the lymphoma, and it may also herald relapse. More so than with other renal lesions that are putatively associated with ma- lignancy, there is often a close temporal relationship between the occurrence of nephrotic syndrome and the presentation of the tu- mour. However, there is no way of proving the association in an individual patient, or of suspecting an underlying lymphoma in patients who present with nephrotic syndrome without systemic symptoms. As the association is very rare in comparison to the number of young patients with minimal-​change disease, screening other than by clinical examination and simple investigations is not justified. Less commonly, minimal-​change disease has been associated with solid tumours, and particularly with malignant and benign thymomas. Membranous nephropathy Membranous nephropathy is caused by antibody (autoanti- body) formation to any of several molecules on the surface of the podocyte. It has often been associated with malignancies, but mem- branous nephropathy is not rare and occurs in older patients who are at relatively high risk of malignancy simply on account of their age. Series have shown rates of malignancy from 5 to 11%, although the risk is greater in older patients. However, variation in reporting practice makes published figures difficult to interpret, for example, if tumours that are recognized long after the renal diagnosis are in- cluded. Most reported tumours are of solid organs, including al- most all types, but haematological malignancies are also implicated. Very often the disease is advanced and obvious when nephrotic syndrome or heavy proteinuria is recognized. In some cases, the nephrotic syndrome or proteinuria lessens after effective treatment of the malignancy. The use of alkylating agents or corticosteroids as treatment for the membranous nephropathy is not recommended in this setting, unless this would be appropriate for treatment of the malignancy itself. There is controversy about the value of screening for malig- nancy in patients presenting with membranous nephropathy when malignancy is not apparent from initial investigations. Aside from routine haematological and biochemical investi- gations, chest radiography, and renal ultrasonography that are needed in all cases of nephrotic syndrome, in older patients it is appropriate to perform careful breast and rectal examination, faecal occult blood screening, and possibly mammography and sigmoidoscopy or colonoscopy. However, in clinical practice, the number of treatable and otherwise subclinical tumours un- covered in this way is low. Systemic vasculitis Focal necrotizing and crescentic nephritis, with or without evi- dence of small-​vessel vasculitis affecting other organs, may occur in association with malignancy. Some cases may be chance asso- ciations of malignancy with typical small-​vessel vasculitis that is not uncommon in older people, but there are sufficient reports of unusual associations to strongly suggest that there is sometimes a causal relationship. As well as true vasculitis, cancer-​related thrombotic microangiopathy and thrombotic events compli- cating disseminated intravascular coagulation in association with cancer may resemble systemic vasculitis and lead to diagnostic confusion. The most common type of vasculitis to be associated with ma- lignancy is small-​vessel cutaneous vasculitis. In other cases, bowel and other organs including the kidney have been involved by a small-​ to medium-​vessel systemic vasculitis, which is usually antineutrophil cytoplasmic antibody (ANCA) negative. However, more typical ANCA-​associated vasculitis has also been associated with malignancy, and there may be a particular relationship between granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis) and renal cell carcinoma. Usually the kidney is not involved in cancer-​associated systemic vasculitis, but when it is, the appearances are indistinguishable from those of small-​vessel vascu- litis of other aetiologies. Immune deposits in glomeruli are not usual (pauci-​immune). Atrial myomas have been associated with lesions of larger and smaller vessels, and it appears that embolization is not always the explanation for this. Effects of treatment for malignancy These include the tumour lysis syndrome (discussed earlier and in Chapter 21.10.5), as well as idiosyncratic or predictable reactions to therapeutic agents. On occasions, minimal-​change disease or other proteinuria-​ causing lesions have been associated with treatment with inter- ferons and with drugs that target vascular endothelial growth factor (VEGF) or its signalling. Anti-​VEGF therapy may also cause thrombotic microangiopathy. The bisphosphonate pamidronate has caused proteinuria and focal segmental glomerulosclerosis, usually when given at high doses in myeloma. Cisplatin may cause tubular damage, predominantly to proximal tubules, and is characteristically associated with features of a renal Fanconi syndrome (see Chapter 21.16), although there can also be significant loss of glomerular filtration rate when severe. Ifosfamide,

section 21  Disorders of the kidney and urinary tract 5044 but not cyclophosphamide, is also prone to cause permanent tubular damage. High-​dose methotrexate and pemetrexed may cause tubular damage. Radiation nephropathy develops slowly and is termed acute if it occurs within 6 months of exposure. Hypertension is usually a prominent feature, and there may be accompanying thrombotic microangiopathy. Chronic radiation nephropathy appears from 1 to 20 years after exposure and typically presents indolently with chronic kidney disease, with imaging revealing small kidneys. FURTHER READING Bacchetta J, et al. (2008). Paraneoplastic glomerular diseases and ma- lignancies. Crit Rev Oncol Haematol, 70, 39–​58. Biava CG, et al. (1984). Crescentic glomerulonephritis associated with nonrenal malignancies. Am J Nephrol, 4, 208–​14. Dabbs DJ, et al. (1986). Glomerular lesions in lymphomas and leuke- mias. Am J Med, 80, 63–​70. Goel A, et  al. Renal medullary carcinoma. Radiopaedia. http://​ radiopaedia.org/​articles/​renal-​medullary-​carcinoma Gordon LI, et al. (1999). Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/​hemolytic uremic syndrome in the cancer patient. Semin Thromb Hemost, 25, 217–​21. Gupta R, Billis A, Shah RB (2012). Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell car- cinoma with a focus on their interrelationship. Am J Surg Pathol, 36, 1265–​78. Gurevich F, Perazella MA (2009). Renal effects of anti-​angiogenesis therapy: update for the internist. Am J Med, 122, 322–​8. Izzedine H, et al. (2006). Drug-​induced glomerulopathies. Exp Opin Drug Saf, 5, 95–​106. Izzedine H, et al. (2010). VEGF signalling inhibition-​induced protein- uria: mechanisms, significance and management. Eur J Cancer, 46, 439–​48. Kurzrock R, Cohen PR, Markowitz A (1994). Clinical manifestations of vasculitis in patients with solid tumors. A case report and review of the literature. Arch Intern Med, 154, 334–​40. Maher ER (2011). Genetics of familial renal cancers. Nephron Exp Nephrol, 118, e21–​6. Markowitz GS, et  al. (2001). Collapsing focal segmental glomerulosclerosis following treatment with high-​dose pamidronate. J Am Soc Nephrol, 12, 1164–​72. Markowitz GS, Bomback AS, Perazella MA (2015). Drug-​induced glomerular disease: direct cellular injury. Clin J Am Soc Nephrol, 10, 1291–​9. O’Callaghan CA, et  al. (2002). Characteristics and outcome of membranous nephropathy in older patients. Int Urol Nephrol, 33, 157–​65. Pabla N, Dong Z (2008). Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int, 73, 994–​1007. Ronco PM (1999). Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int, 56, 355–​77. Turner AN, et al. (eds) (2015). Oxford textbook of clinical nephrology, 4th edition. Oxford University Press, Oxford. Watts RA, Scott DG, Mukhtyar C (2015). Secondary vasculitis. In: Vasculitis in clinical practice, pp. 173–​84. Springer International Publishing AG, Cham. 21.10.10  Atherosclerotic renovascular disease Philip A. Kalra and Diana Vassallo ESSENTIALS Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing of one or both renal arteries and frequently coexists with atherosclerotic disease in other vascular beds. Patients with this con- dition are at high risk of adverse cardiovascular events, with mortality around 8% per year. Many patients with ARVD have chronic kidney disease, but only a minority progress to endstage kidney disease, suggesting that pre-​existing hypertensive and/​or ischaemic renal parenchymal injury is the usual cause of renal dysfunction. Many patients with ARVD are asymptomatic, but there can be important complications such as uncontrolled hypertension, rapid decline in kidney function, and recurrent acute heart failure (flash pulmonary oedema). Management—​patients with ARVD should receive medical vas- cular protective therapy just like other patients with atheromatous disease. This involves antiplatelet agents such as aspirin, statins, antihypertensive agents (angiotensin-​converting enzyme inhibi- tors or angiotensin receptor blockers are the drugs of choice), opti- mization of glycaemic control in diabetic patients, and advice/​help to stop smoking. On the basis of randomized controlled trial data, the majority of patients should not be offered revascularization by angioplasty/​stenting for the purpose of improving blood pressure control or stabilizing/​improving renal function. However, there is evidence that a subgroup of patients with specific complications of ARVD (as previously mentioned) may benefit from revascularization. Introduction Atheromatous disease is common, indeed almost universal in elderly individuals, and it is a multiorgan disease process. Atherosclerotic renovascular disease (ARVD) refers to atheromatous narrowing or occlusion of one or both renal arteries and as expected, occurs more frequently with increasing age and in the presence of cardiovascular risk factors such as diabetes, smoking, and hypertension. Although ARVD is very often asymptomatic and usually discovered inciden- tally during investigation for extrarenal atherosclerotic disease, haemodynamically significant stenosis in certain patients can lead to important complications such as uncontrolled hypertension, pro- gressive decline in kidney function, and recurrent episodes of acute heart failure (flash pulmonary oedema). The heterogeneous nature of ARVD poses a significant diag- nostic and management dilemma to the physician. Despite signifi- cant progress in imaging techniques, accurate determination of the haemodynamic significance of a stenosis remains difficult. In addition, percutaneous revascularization carries a risk of complica- tions and does not guarantee improved outcomes. This is probably due to irreversible renal parenchymal damage in the poststenotic kidney, a product of both local (e.g. oxidative stress) and systemic

21.10.10  Atherosclerotic renovascular disease 5045 (e.g. longstanding hypertension, diabetes) insults. This would ex- plain the neutral results of recent large prospective trials in ARVD, which have shown that revascularization does not confer any added benefit to optimal medical therapy in unselected populations. However, there is evidence that subgroups of patients with a ‘high-​ risk’ phenotype, for example, patients with recurrent flash pul- monary oedema, or refractory hypertension in conjunction with rapidly declining renal function, do benefit from revascularization. Identifying these patients in a timely manner remains a consider- able challenge. The issue of investigation and treatment of renal artery stenosis (RAS) in the context of the patient presenting with hypertension is discussed in Chapter 16.17.3. This brief chapter focuses more on pa- tients with impairment of renal excretory function (chronic kidney disease) with reduced (and falling) estimated glomerular filtration rate (eGFR) in association with ARVD. The underlying aetiology, genetics, pathogenesis, and histopath- ology of the major macrovascular RAS lesions in ARVD are broadly as for atherosclerotic disease in general (see Chapter  16.13.1). However, as already mentioned, histopathological changes in the kidneys of patients with chronic kidney disease associated with ARVD can include hypertensive and ischaemic injury, as well as atheroembolic disease. The latter is a recognized cause of acute kidney injury occurring after revascularization. Epidemiology It is difficult to state the true incidence and prevalence of ARVD because of variability in both the definition and in the enthusiasm with which the diagnosis is pursued. There is no uniform agreement about the precise degree of RAS which constitutes a haemodynam- ically significant lesion. However, in the context of the patient with gradually failing renal function, in which the causal mechanism might be ‘ischaemic renovascular disease’ (ischaemic nephropathy), many consider that the presence of significant high-​grade RAS (>70% narrowing of both renal arteries, or of the artery to a single functioning kidney) is necessary to make the diagnosis. Most ARVD epidemiological studies have been performed in populations with known atherosclerosis or cardiovascular risk factors, hence leading to selection bias. A  study of administra- tive claims data from the United States Medicare population over 67 years of age gave an incidence of 3.7/​1000 patient years. The overall prevalence in such patients is around 0.5%. Another study in which healthy individuals over 65 years of age living in the United States of America were screened for ARVD by means of a dop- pler ultrasound scan reported an incidence of 6.8%. However, the prevalence of ARVD in populations with significant comorbidities is much higher—​unsuspected ARVD has been found in around 25% of patients with peripheral vascular disease and in up to 50% of patients with congestive heart failure. In various studies RAS has been demonstrated in 5 to 22% of patients with endstage renal dis- ease aged over 50 years, but the presence of ARVD here does not al- ways imply causality of the renal dysfunction. Conversely, patients with ARVD usually have evidence of other macrovascular disease such as coronary (67%), peripheral arterial (56%), and cerebrovas- cular (37%) atherosclerotic disease. Some atherosclerotic RAS lesions become worse with time, but this is not inevitable, especially since the advent of modern, multitargeted medical management of atherosclerosis, which in- cludes statins and tight risk factor control. Serial imaging studies performed in the pre-​statin era reported a rate of progression to occlusion of up to about 40% over 12 months’ follow-​up, leading to loss of renal function and renal atrophy. However, nowadays, progression to total occlusion occurs much less commonly, and later studies have reported a rate of occlusion of 3% over 3 years. Clinical features The diagnosis of ARVD should be suspected in any patient with other manifestations of atherosclerosis who presents with stable chronic kidney disease or progressive impairment of renal func- tion, especially in the presence of hypertension that is particularly severe or difficult to control. Other clinical pointers are the pres- ence of abdominal or iliofemoral bruits, significant deterioration in renal function after initiation of treatment with an angiotensin-​ converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), and asymmetry of renal size on imaging (>1.5 cm difference in length of the two kidneys). Flash pulmonary oedema is a well-​described and ‘classic’ manifestation of ARVD, but pul- monary oedema in a patient with ARVD is more usually attrib- utable to concurrent ischaemic cardiac disease. ARVD is now increasingly recognized in association with congestive cardiac failure. Clinical investigations ARVD can only be confirmed by some form of imaging and the main techniques used include duplex Doppler ultrasonography (very operator dependent) (Figs. 21.10.10.1 and 21.10.10.2), mag- netic resonance angiography (either contrast free or with gado- linium, although the latter is contraindicated in patients with an eGFR <30 ml/​min per 1.73 m2; see Chapter 21.4), CT angiography (which requires administration of nephrotoxic contrast media) (Fig. 21.10.10.2), and digital subtraction angiography (which requires ar- terial puncture/​instrumentation and administration of nephrotoxic contrast media). The investigative approach will be determined by local availability and expertise. Note that, with the exception of high-​quality arterial Doppler studies, none of the above-​mentioned tests assess functional significance of the RAS lesion, which remains a major deficiency in the investigation and management of patients with ARVD. The urine may contain some protein (albumin:creatinine ratio uncommonly >50 mg/​mmol), but is bland, without red cells or casts. Management All patients with ARVD should receive interventions appropriate for any patient with known atherosclerotic disease, including encouragement of and assistance with smoking cessation, aspirin

section 21  Disorders of the kidney and urinary tract 5046 (or other antiplatelet agents), statin therapy, blood pressure control, and in patients with diabetes, optimization of glycaemic control. Early studies discouraged the use of ACE inhibitors or ARBs in patients with RAS as they were thought to decrease perfusion pres- sure across a stenosis and exacerbate renal injury, but subsequent studies confirmed that renin–​angiotensin blockade can both miti- gate the intrarenal parenchymal injury that leads to chronic kidney disease in ARVD and improve overall survival by optimizing cardiac status. In view of this, ACE inhibitors and ARBs are now considered the antihypertensive agents of choice in patients with ARVD. Nonetheless, a minority of patients with bilateral RAS or severe RAS affecting a solitary functioning kidney are at risk of acute kidney injury with such therapy, hence close monitoring of kidney func- tion after initiation of an ACE inhibitor or ARB is essential. Blood pressure and renal chemistry should be checked within 2 weeks of starting renin–​angiotensin blockade in any patient, and especially in those with RAS. Renal function should then be rechecked on a 6-​monthly basis once the patient is receiving a stable maintenance dose, and more frequent monitoring may be required in patients who are on concurrent diuretic therapy or aldosterone antagonists. If, following initiation of an ACE inhibitor or ARB, serum creatinine concentration increases by more than 30% or eGFR declines by more than 25%, and there is no other apparent precipitating cause of acute kidney injury such as dehydration or concurrent nephro- toxic medication (e.g. nonsteroidal anti-​inflammatory agents), the dose of the ACE inhibitor or ARB may need to be reduced to a previously tolerated level or stopped altogether. Hypotension may cause an acute decline in GFR due to impaired autoregulation in patients with chronic kidney disease or in those with critical RAS receiving an ACE inhibitor or ARB. In the event of an intercurrent illness which can cause hypotension, such as diarrhoea, vomiting, or sepsis, it should be recommended that the ACE inhibitor or ARB are temporarily stopped until the patient has recovered. Such advice is now part of ‘Sick Day rules’ programmes for prevention of acute kidney injury. A key management question concerns whether renal revasculari­ zation with renal artery angioplasty/​stenting is warranted. While there is no doubt that such interventional procedures can produce ‘anatomical cure’ of RAS (Fig. 21.10.10.3), there is a small chance (approximately 3%) of major debilitating complications including groin haematoma, acute kidney injury, cholesterol embolization, arterial dissection, and renal infarction. Fig 21.10.10.1  Normal right renal artery as assessed by colour Doppler ultrasound. Spectral analysis (bottom of image) shows low resistance waveform in the artery. From https://​www.med-​ed.virginia.edu/​courses/​rad/​gu/​anatomy/​kidneys.html. (a) (b) Fig 21.10.10.2  Panel (a) shows a CT angiogram with the red arrow indicating significant stenosis in the right renal artery. Panel (b) shows the colour Doppler ultrasound appearance compatible with the angiographic findings. An elevated peak systolic velocity of 246.6 cm/​s is noted at the area of stenosis. (a) From http://​www.radblazer.com/​renal-​artery-​stenosis-​angiogram/​. (b) From https://​iame.com/​online/​duplex_​and_​color_​doppler_​of_​the_​kidney/​content.php.

21.10.10  Atherosclerotic renovascular disease 5047 A number of studies have been carried out over the past two decades to determine whether anatomical improvement trans- lates into clinically useful outcomes for patients, and to assess how revascularization compares with modern multitargeted medical management. Results from small randomized controlled trials showed no clear evidence of benefit for revascularization over con- servative medical management. The largest and most recent ran- domized controlled trials, the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) studies, provide the most robust data regarding the role of revascularization in the management of patients with ARVD. The United Kingdom-​based ASTRAL trial randomized 806 patients with ARVD to either medical therapy alone or medical therapy with revascularization. The primary endpoint was change in renal function from baseline and after a median follow-​up of 34 months. Results showed that revascularization had no impact on decline in renal function or on blood pressure control, incidence of cardiovascular events, or mortality (secondary endpoints), and there was a significant complication rate of 7% associated with the procedure. The CORAL study was based in the United States of America (although around 50% of patients were from the rest of the world), and is the largest study in ARVD to date; 947 patients were random- ized to stenting and best medical therapy or best medical therapy alone. The primary endpoint was a composite of major cardiovas- cular events, progressive deterioration in renal function, and death from cardiovascular or renal causes. Again, after a median follow-​up of 43 months, revascularization did not confer any clinical benefit over medical therapy on its own. However, a major criticism of these ARVD trials is the fact that these results may not be entirely generalizable as patients with ‘high-​ risk’ features (e.g. uncontrolled hypertension, rapidly deteriorating renal function, or unstable cardiac status) were specifically excluded. A  recent single-​centre retrospective study looked at 237 patients with at least 50% RAS and one or more ‘high-​risk’ features. Around one-​quarter (24%) of these patients underwent revascularization and their outcomes were compared with those of patients who were treated exclusively medically. Revascularization led to improved clinical outcomes in patients with either flash pulmonary oedema or a combination of rapidly declining kidney function and uncon- trolled hypertension. Our recommendation is that there is no benefit in screening asymptomatic patients with chronic kidney disease and/​or hyper- tension for ARVD, and that most patients found to have ARVD should generally not be referred for revascularization for the purpose of improving blood pressure control or stabilizing/​ improving renal function. There is, however, some evidence that revascularization may play a role in the management of an im- portant subset of patients with certain ‘high-​risk’ features who have not been well-​represented in clinical trials. These include patients with severe RAS and with otherwise unexplained rapid decline in renal function, those with recurrent episodes of flash pulmonary oedema (not explained by cardiac disease), and per- haps those with severe hypertension not adequately controlled by multiple drug treatments (or in whom reduction in arterial pres- sure leads to significant decline in eGFR). Another subgroup who (a) (b) (c) Fig 21.10.10.3  An intra-​arterial digital subtraction angiography series showing left renal angioplasty and stent placement. (a) Flush aortogram showing severe (>95%) left renal artery stenosis (arrow); the more distal circulation beyond the stenosis is just visible. (b) The angioplasty catheter (arrow) has traversed the renal artery stenosis. (c) A stent has been deployed (arrow). Courtesy of Professor J. Moss, Gartnavel Hospital, Glasgow.

section 21  Disorders of the kidney and urinary tract 5048 could justifiably be treated with revascularization are those who require ACE inhibitors or ARBs because of concomitant heart disease and/​or renal parenchymal injury, but show intolerance of these drugs as manifest by acute kidney injury. Prognosis Patients with ARVD are at a higher risk of cardiovascular events and death than the general population due to their significant athero- sclerotic burden. However, renal function tends to remain stable and only rarely do patients with ARVD require renal replacement therapy due to ARVD progression. Indeed, in the Medicare popu- lation in the United States of America, the risk of mortality during follow-​up was almost six times that of requiring renal replacement therapy. Recent trials in ARVD have shed light on the heterogeneous nature of this condition and how prognosis may be quite vari- able. This is illustrated by the different baseline characteristics of patients enrolled into the ASTRAL and CORAL trials and their slightly divergent outcomes; the average eGFR for ASTRAL was 40 ml/​min per 1.73 m2 whereas that for CORAL was higher, approxi- mately 58 ml/​min per 1.73 m2. As a result, mortality was around 8% per year for ASTRAL, compared to around 4% per year for CORAL, whereas the incidence of endstage kidney disease was 2% per year for ASTRAL and 0.5% per year for CORAL. Nonetheless, the results of both of these trials highlight the steady improve- ment in the prognosis of ARVD that has occurred over the past few decades, a testament to the reno-​ and cardioprotective effects of modern medical therapy. Future developments Timely identification of individuals who may gain benefit from revascularization remains a very important challenge to clinicians, and recent progress in imaging and diagnostic technology may help address this issue. Novel functional magnetic resonance imaging (MRI) techniques such as blood oxygen level-​dependent (BOLD)-​ MRI may estimate the degree of intrarenal hypoxia and thus help identify critically ischaemic kidneys. MRI has also been used to measure single-​kidney GFR and other perfusion parameters that may correspond to the functional status of the kidney. Indeed, a high single-​kidney GFR-​to-​parenchymal volume ratio has been shown to identify kidneys that may be salvaged by revascularization because they retain viable or ‘hibernating parenchyma’. Progress in biomarker technology over the past decade has stimulated interest in the identification of serum or urine biomarkers, such as neutro- phil gelatinase-​associated lipocalin (NGAL), tubular kidney injury molecule-​1 (KIM-​1), or brain natriuretic peptide (BNP), which can help predict outcomes post revascularization. However, these novel techniques have only been studied under experimental conditions and more research is required to determine whether they can be ap- plied to clinical practice. Increased understanding of the complex pathogenesis of renal parenchymal injury in ARVD has paved the way for novel thera- peutic strategies. Cell-​based therapies have been proposed to counteract the inflammatory milieu and oxidative stress typically found in the poststenotic kidney. These might prevent irreversible loss of renal microvascular architecture and help improve clinical outcomes. FURTHER READING Bax L, et al. (2009). Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function:  a randomized trial. Ann Intern Med, 150, 840–​8. Cheung CM, et al. (2006). MR-​derived renal morphology and renal function in patients with atherosclerotic renovascular disease. Kidney Int, 69, 715–​22. Cooper CJ, et al. (2014). Stenting and medical therapy for atheroscler- otic renal-​artery stenosis. N Engl J Med, 370, 13–​22. Chrysochou C, et al. (2012). BOLD imaging: a potential predictive biomarker of renal functional outcome following revascularization in atheromatous renovascular disease. Nephrol Dial Transplant, 27, 1013–​19. Eirin A, Textor SC, Lerman LO (2019). Novel therapeutic strategies for renovascular disease. Curr Opin Nephrol Hypertens, 28, 383–9. Herrmann SMS, Saad A, Textor SC (2014). Management of athero- sclerotic renovascular disease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant, 30, 366–​75. Kalra PA, et al. (2005). Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int, 68, 293–​301. National Institute for Health and Care Excellence (2013). Acute kidney injury:  prevention, detection and management. Clinical guideline [CG169]. National Institute for Health and Care Excellence, London. National Institute for Health and Care Excellence (2014). Chronic kidney disease: in adults: assessment and management. Clinical guide- line [CG182]. National Institute for Health and Care Excellence, London. Ritchie J, et al. (2014). High-​risk clinical presentations in atheroscler- otic renovascular disease: prognosis and response to renal artery revascularization. Am J Kidney Dis, 63, 186–​97. Saad A, et al. (2013). Stent revascularization restores cortical blood flow and reverses tissue hypoxia in atherosclerotic renal artery sten- osis but fails to reverse inflammatory pathways or glomerular filtra- tion rate. Circ Cardiovasc Interv, 6, 428–​35. The ASTRAL Investigators (2009). Revascularisation versus medical therapy for renal-​artery stenosis. N Engl J Med, 361, 1953–​62.

ESSENTIALS Kidney diseases encountered in tropical areas are a mix of conditions that have a worldwide distribution and those that are secondary to factors unique to the tropics, for example, climatic conditions, infec- tious agents, nephrotoxic plants, envenomations, and chemical toxins. Cultural factors, illiteracy, superstitions, living conditions, level of access to health care, and nutritional status also affect the nature and course of disease. Knowledge of such conditions and issues is important for medical professionals in all parts of the globe, as ease of travel means that individuals and practices are exported with increasing frequency. Glomerular diseases—​there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of in- jury dependent upon the nature of the prevalent endemic infection in that region. Important infection-​related glomerulopathies include quartan malarial, schistosomal, and filarial nephropathies. Once es- tablished, the course of disease is rarely modified by treatment of underlying infection. Acute kidney injury (AKI)—​there is a higher prevalence of community-​acquired AKI in the tropics than elsewhere. Medical causes predominate, with diarrhoeal diseases, intravascular haem- olysis due to glucose-​6-​phosphate dehydrogenase deficiency, inges- tion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries. Falciparum malaria and leptospirosis are the most important infectious aetiologies. Use of in- digenous herbs and chemicals by traditional healers (‘witch doctors’) are the most important toxic causes of AKI in sub-​Saharan Africa. Chronic kidney disease (CKD)—​although the contributions of dia- betes and hypertension are growing, many cases are secondary to glomerular diseases, likely infection related, or have CKD of undeter- mined aetiology. Many of the latter are agriculture or farm workers presenting with chronic tubulointerstitial nephritis of unknown cause. Introduction Approximately 40% of the world’s population live in the tropics, geographically defined as the area between the latitudes 23° north to 23° south. Kidney diseases in tropical areas are a variable mix of globally encountered conditions and those specific to the geopolit- ical characteristics of the region. Tropical ecobiology strongly influences the pattern and presen- tation of kidney diseases encountered. Tropics are characterized by high ambient temperature; some regions receive heavy rains, while other areas are arid, with little precipitation. Extreme heat and hu- midity can lead to unrecognized fluid losses, especially among those engaged in manual labour. Studies have demonstrated that people can lose up to 5 kg of weight during the course of a day and show features of subclinical rhabdomyolysis, both of which can lead to kidney injury. Rains force leaching of minerals and organic compounds from the fragile tropical soil into flowing water, which can leading to waterlogging and contamination of fields with potentially toxic metals. The combination of high temperatures, wet weather, and sal- inity support growth of a variety of flora and fauna, including poten- tially nephrotoxic plants, pathogenic microorganisms, and animals that can serve as disease vectors and intermediate hosts. The end re- sult is a high prevalence of water­borne and infectious diseases, many of which are associated with kidney injury. Rains cause a spike in the incidence of nephrotoxic snake bites, since flooding of snake bur- rows forces their inhabitants to come to the surface. Population migration over millennia has led to accumulation of certain genetic traits that increase kidney disease risk in the tropics. These include glucose-​6-​phosphate dehydrogenase (G6PD) deficiency giving rise to intravascular haemolysis and pigment-​ induced acute kidney injury (AKI); progressive kidney disease in haemoglobinopathies such as sickle cell anaemia and thalassaemias; MYH9 and APOL1 alleles predisposing to HIV-​associated kidney disease; and hypokalaemia, hypercalcaemia, hypocitraturia, and renal tubular acidosis due to inherited defects in tubular transport. Compared to countries in temperate regions, tropical countries are disadvantaged in socioeconomic terms. Except for two small countries (Singapore and Hong Kong), all tropical countries are classified in low-​ or middle-​income categories. Poorly developed healthcare systems reduce access of large populations to medical services. Traditional health systems that rely on unproven and po- tentially harmful therapies flourish in the tropics, some of which are associated with practices that increase kidney disease risk. 21.11 Renal diseases in the tropics Vivekanand Jha

section 21  Disorders of the kidney and urinary tract 5050 Cultural factors, illiteracy, superstitions, poor living conditions, and nutritional status also affect the nature, presentation, and course of kidney disease. Delayed diagnosis leads to extreme presentations that have been (almost) eliminated in the developed world. For ex- ample, it is not uncommon for children with distal renal tubular acidosis to present with marked skeletal deformities and severe growth retardation, or those with posterior urethral valves to go un- diagnosed until they are several years old. Acute renal cortical ne- crosis following septic abortion and placental abruption continues to be seen regularly. Malnutrition exaggerates the impact of kidney disease; a lower degree of protein loss leads to more severe periph- eral oedema and serous effusions. Delayed and suboptimal treat- ment leads to loss of opportunities to implement preventive and/​ or curative therapies, thereby increasing morbidity and mortality. Economic considerations also prevent the implementation of more refined technological solutions. For example, continuous renal replacement therapy is eschewed in favour of cheaper and less com- plex peritoneal dialysis. In an era of easy transcontinental movement of people, organ- isms, and materials, all physicians and nephrologists need, more than ever before, to be aware of tropical renal diseases. People who have migrated from the tropics may continue to engage in habits that predispose to kidney disease, even in their new location. Slowly pro- gressive diseases due to past exposures in the tropics may produce delayed clinical manifestations. This chapter highlights the important differences between dif- ferent syndromes of kidney disease in the tropics and the rest of the world, and discusses some specific renal diseases unique to the trop- ical regions. Types of renal disease Glomerular diseases The overall prevalence of glomerulonephritis is reported to be higher in tropical countries than in temperate regions. Surveys from hos- pitals in sub-​Saharan Africa show that nephrotic syndrome accounts for 0.2 to 4% of all admissions. Primary glomerular diseases account for the majority, but secondary causes are responsible in 40 to 55% of patients in Zimbabwe and Jamaica. There is variation in the epidemiology, aetiology, clinical presen- tation, and natural history of glomerulonephritis between different tropical countries (Figs. 21.11.1 and 21.11.2). In general, there is a high prevalence of infection-​related glomerulonephritis throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Minimal-​change disease is as frequent in Asia and North Africa as in the developed world, but is less common in the rest of Africa. In a study from South Africa, minimal-​change disease was respon- sible for nephrotic syndrome in 75% of children of Indian ancestry, whereas only 13.5% of black children showed this lesion. A high frequency of proliferative glomerulopathies and steroid resistance is described in paediatric patients from the Democratic Republic of Congo, Zimbabwe, Malawi, Nigeria, Kenya, and Uganda. Membranous nephropathy is seen with a high frequency among children with nephrotic syndrome in countries with a high hepatitis B virus (HBV) carrier rate, and in some areas HBV-​related disease accounts for up to 15% of all membranous nephropathy cases. By contrast, mesangial proliferative forms with IgA deposits seem to be more common in adults with HBV infection. A strong (and likely causal) association has been described between chronic hepatitis C virus (HCV) infection and several chronic glomerular diseases. An autopsy study revealed glomerular lesions in 55% of HCV-​infected individuals, including mesangial proliferative glomerulonephritis (17.6%), membranoproliferative glomerulonephritis (11.2%), and membranous nephropathy (2.7%). Recent population-​based studies have shown a link between the prevalence of HCV infection and proteinuria. The introduction of new treatments for HCV is likely to reduce the prevalence of HCV-​related glomerulonephritis. Postinfectious glomerulonephritis continues to be encountered in high frequency throughout the tropics. In studies from north Africa and the Middle-​East, about 15 to 20% of all paediatric biopsies show diffuse proliferative glomerulonephritis, likely postinfectious. The prevalence of poststreptococcal glomerulonephritis in the Goajiro Jamaica Ghana Sudan South Africa Pakistan Papua New Guinea Singapore North India Europe 0% 20% 40% 60% 80% 100% Minimal change Diffuse proliferative Membranous Mesangiocapillary Mesangioproliferative FSGS Others Fig. 21.11.1  Prevalence of different types of glomerular lesions in adults with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis. United Kingdom South Africa (Blacks) Zimbabwe South India Nigeria North India South Africa (Indians) Papua New Guinea 0% 20% 40% 60% 80% 100% Minimal change Diffuse proliferative Membranous Mesangiocapillary Mesangioproliferative FSGS Others Fig. 21.11.2  Prevalence of different types of glomerular lesions in children with nephrotic syndrome in different parts of the world. FSGS, focal segmental glomerulosclerosis.

21.11  Renal diseases in the tropics 5051 Indian community of Venezuela was twice that seen in other parts of the Goajira state. Acute kidney injury Community-​acquired AKI is the commonest nephrological emer- gency encountered in the tropics, and referral patterns to dialysis units suggest a higher prevalence of community-​acquired AKI in the tropics than elsewhere. In a large referral hospital in North India, 1.5% of all hospital ad- missions were referred to the nephrology service for management of moderate to severe AKI. Medical causes predominate, with diar- rhoeal diseases, intravascular haemolysis due to G6PD deficiency, ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases, although obstetric causes remain common in some tropical countries (Figs. 21.11.3 and 21.11.4). In a recent global study conducted by the International Society of Nephrology, AKI patients in low-​ and low–​middle-​income coun- tries of the tropics were younger than those from rest of the world, although the extent to which this is explained by ascertainment bias remains uncertain. In a study from India, the average age of patients dialysed for AKI was 34.3 years. Dehydration was the most common cause of AKI, followed by infections, pregnancy-​related AKI, and animal envenomation. Fig. 21.11.3  Map showing areas with a high prevalence of community-​acquired AKI. Areas with a high prevalence of malaria-​associated AKI are shown in maroon, and with intermediate prevalence in yellow; orange indicates areas with a high prevalence of both leptospiral and malarial AKI; textured fill in countries of sub-​Saharan Africa indicates a high prevalence of malarial and herbal remedy-​induced AKI; green indicates AKI of other causes. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% North India South India Sri Lanka Thailand Nigeria S Africa Ghana Argentina Medical Surgical Obstetric Fig. 21.11.4  Causes of AKI in different tropical countries. Modified from Chugh, Satprija and Jha, Oxford Textbook of Clinical Nephrology, Oxford University Press, Oxford 2005.

section 21  Disorders of the kidney and urinary tract 5052 In contrast to patients with hospital-​acquired AKI seen in tem- perate countries, the kidney is the sole affected organ in more than 50% of cases at diagnosis. However, when tropical AKI is seen as part of an undifferentiated illness that includes AKI, liver failure, respiratory failure, neurological dysfunction, disseminated intra- vascular coagulation, and metabolic acidosis, then establishing the cause can be impossible in the absence of specialized facilities. Lack of resources forces a significant proportion of patients with AKI in tropical low-​income countries to go untreated, but the pro- portion of those receiving treatment who recover is greater than in the developed world, reflecting the relatively young age and absence of any pre-​existing disease in the affected individuals. Saving Young Lives, a collaborative project between the International Society of Nephrology, International Paediatric Nephrology Association, International Society for Peritoneal Dialysis, and Sustainable Kidney Care Foundation, is developing a sustainable programme to treat AKI using peritoneal dialysis in sev- eral countries of sub-​Saharan Africa and Southeast Asia. Chronic kidney disease There are several notable differences in the pattern of chronic kidney disease (CKD) in topical populations compared to those in temperate zones. Tropical patients with endstage renal disease are significantly younger. Although the contribution of diabetes and hypertension to the overall CKD burden in the tropics is growing, a significant proportion develop CKD secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many patients come to medical attention for the first time with advanced renal failure and few prior symptoms. Most often, these are individuals from poor socioeconomic background and are agri- culture or farm workers who work long hours in hot and humid environments. Investigations reveal minimal proteinuria, bland urinary sediment, and smooth contracted kidneys. Kidney biop- sies in a few cases have shown bland tubulointerstitial nephritis. ‘Mini-​epidemics’ of such cases has been reported from several trop- ical regions in central America (Costa Rica, Guatemala, Nicaragua, El-​Salvador, Mexico), north America (California), South and Southeast Asia (India, Sri Lanka, Thailand), Middle-​East (Saudi Arabia, Qatar), and Africa (Egypt, Sudan) (Fig. 21.11.5). Dubbed variously CKD of uncertain aetiology (CKDu), chronic interstitial nephritis in agricultural communities (CINAC) and other terms (e.g. mesoamerican nephropathy), the aetiology of this condition has been a subject of intense speculation. The currently favoured postulations include recurrent heat stress with episodes of dehy- dration and/or rhabdomyolysis, and exposure to agrochemicals, particularly pesticides. Other hypotheses are heavy metals (con- taminating drinking water, rice and edible fish), fluoride, tropical infections, dietary peculiarities, consumption of herbal medicines, and abuse of over-​the-​counter medications. See Chapter 21.9.2 for further discussion. Obstructive nephropathy due to urolithiasis is common in Pakistan, Thailand, and parts of India known as ‘stone belts’. Kidney diseases specific to the tropics In addition to nephropathies that have a worldwide distribution, some renal lesions have been described solely in residents of trop- ical countries. These can be broadly grouped under infectious and toxic categories. Causal relationships are suggested by epidemio- logical studies, demonstration of a temporal relationship between the inciting event (infection, environmental insult, or toxin exposure) and the development of renal manifestations, and by resolution following treatment of the infection or withdrawal of the insult. Improved diagnostic techniques and appropriately designed experi- mental studies have provided concrete evidence of a cause-​and-​effect relationship in some instances. Examples include establishment of aristolochic acid as the cause of Balkan endemic nephropathy, and identification of specific infections (e.g. scrub typhus, dengue, and leptospirosis) as the cause of undifferentiated febrile syndromes with Fig. 21.11.5  Tropical countries from where hot spots of chronic kidney disease of undetermined aetiology have been reported (red: definite; yellow: probable).

21.11  Renal diseases in the tropics 5053 AKI. Confirmation has been obtained by the demonstration of either the organism or microbial antigens in the renal lesions, and elution of specific antibodies in the case of infections, and toxic compounds in the case of plant and animal toxins. In some cases, animal models have provided insight into the genesis of the lesions. Infectious causes of renal disease in the tropics Table 21.11.1 shows the various tropical infections that can cause kidney injury. Malarial renal diseases Malaria, caused by members of the protozoan Plasmodium genus, is endemic in the Indian subcontinent, Middle East, East Asia, sub-​Saharan Africa, and Central America. Of the five species patho- genic to humans, renal lesions have been described following in- fections with Plasmodium falciparum, P.  vivax, P.  knowlesi, and P. malariae, but not after P. ovale. Glomerulonephritis is the chief complication of P. malariae infection, whereas the others primarily present with AKI. Malarial AKI Less than 1% of all patients with P. falciparum and P. knowlesi infec- tion develop AKI, but the prevalence increases to 60% in those with severe infection. Nonimmune visitors to an endemic area are more likely to develop severe infection than local residents. Malarial AKI has been reported from the Indian subcontinent, Thailand, Malaysia, and Africa. In recent years, AKI has been encountered in association with P. vivax infection, in particular from the Indian subcontinent. Molecular methods have permitted identification of human infec- tion with P. knowlesi, earlier thought to be limited to macaques in Malaysia, Thailand, Vietnam, Myanmar, and Philippines. Clinical features The initial symptoms are nonspecific and consist of malaise, headache, fatigue, muscle aches, fever, and chills. Nausea, vomiting, and hypo- tension are frequent in nonimmune individuals. Encephalopathy, acute respiratory distress syndrome, and disseminated intravascular coagulation indicate severe infection. AKI is usually seen by the end of the first week and is nonoliguric in 50 to 75% of cases. Haemolytic anaemia and cholestatic jaundice are frequent accompaniments. The so-​called blackwater fever has seen a resurgence among nonimmune European expatriates, probably due to the reintroduction of quinine and mefloquine into the treatment regimen. Individuals with G6PD deficiency can develop severe haemolysis. Renal failure lasts from a few days to several weeks, with an average of 2 weeks. Investigations show azotaemia, hyponatraemia, hyperkalaemia, and lactic acidosis. Diagnosis requires the demonstration of asexual forms of the parasite in peripheral blood smears stained with Giemsa stain or acridine orange. Morphological features of P.  knowlesi infection resemble those of P. falciparum in the early and P. malariae in the late stages, and accurate identification requires the use of molecular techniques. Test kits for rapid diagnosis of malaria on finger-​prick blood samples are commercially available. These depend upon immunochromatographic detection of malaria antigens such as histidine-​rich protein 2 (PfHRP2), lactate dehydrogenase (pLDH) or aldolase (pAldo). Useful in the field, these tests are relatively in- sensitive at low levels of parasitaemia and for nonimmune popula- tions. Other problems include false positivity and cross-​reactivity between Plasmodium species. Pathology Acute tubular necrosis, characterized by cloudy swelling and degen- eration of tubular cells and casts loaded with malarial pigment, is the most prominent finding. Tubular cells contain haemosiderin gran- ules. Varying degrees of interstitial oedema and mononuclear cell infiltrate are also seen. Pathogenesis Kidney injury is attributed to haemorheological changes induced by the parasite that lead to renal ischaemia. P. falciparum merozoites consume and degrade erythrocyte proteins and alter the red cell Table 21.11.1  Tropical infections associated with kidney injury Class Organism Nature of renal lesion Protozoal Plasmodium malariae Glomerulonephritis Plasmodium falciparum AKI, TMA Plasmodium vivax and knowlesi AKI Schistosoma mansoni Glomerulonephritis Wuchereria bancrofti Glomerulonephritis Loa loa Glomerulonephritis Onchocerca volvulus Glomerulonephritis Bacterial Mycobacterium leprae Glomerulonephritis, amyloidosis Mycobacterium tuberculosis Glomerulonephritis, interstitial nephritis, destructive inflammation, amyloidosis Salmonella typhi and paratyphi Glomerulonephritis Shigella dystenteriae AKI, TMA Brucella abortus AKI Burkholderia pseudomallei AKI Vibrio cholera and vulnificus AKI Orient tsutsugamushi AKI Campylobacter jejuni AKI Viral Dengue haemorrhagic fever Glomerulonephritis, AKI Hantaan virus AKI Rift valley fever AKI Yellow fever Glomerulonephritis, AKI Spotted fever AKI HIV Glomerulonephritis, AKI, TMA Hepatitis B and C Glomerulonephritis Rotavirus, Norwalk agent AKI Spirochete Leptospira icterohaemorrhagica AKI, AIN, CKD Fungus Zygomycetes spp. AKI, renal infarction AIN, acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease; TMA, thrombotic microangiopathy.

section 21  Disorders of the kidney and urinary tract 5054 membrane, making the erythrocytes more spherical and less de- formable. Cup-​shaped, electron-​dense structures that overlie accre- tions of histidine-​rich P. falciparum erythrocyte membrane protein and extrude an adhesive protein of high molecular weight are ex- pressed on the erythrocyte membrane and mediate attachment to endothelial cells, causing a phenomenon called ‘cytoadherence’. Infected erythrocytes adhere to uninfected red cells, platelets, monocytes, and lymphocytes. P.  falciparum can also activate the alternate complement pathway and intrinsic coagulation cascade. Increased production of endothelin-​1, increased plasma viscosity secondary to an increase in plasma fibrinogen, and rhabdomyolysis also contribute to the AKI. Contributory factors include volume depletion secondary to capillary leak and haemolysis. Studies from Thailand indicate that prior infestation with helminths protects against malarial AKI. Management Severe falciparum malaria requires supportive care in combin- ation with specific antimalarial treatment (see Chapter  8.8.2). Combination therapies, including artemisinin derivatives, are the norm. Careful fluid management is needed in patients with pul- monary oedema. Prognosis The mortality of malarial AKI is 10 to 40%. Late referral, high para- sitaemia, multiorgan involvement, and infection in previously unimmunized subjects portend a poor prognosis. Malarial glomerulopathy Before 1980, nephrotic syndrome was encountered during periods of intense transmission of P.  malariae infection among children in western Nigeria, Uganda, Kenya, Côte d’Ivoire, Sumatra, New Guinea, and Yemen, with plasmodium positivity in 40 to 75% of cases. The prevalence of such quartan malarial nephropathy (the term quartan is used because the fever tends to return at 3-​day inter- vals) has shown a sharp decline with the eradication of malaria, and the entity does not find a mention in recent reports. Clinical features The nephrotic syndrome develops several weeks after the onset of fever. Nonvisible haematuria is noted in about one-​third of cases. Hypertension develops along with decline in renal function. Hypoalbuminaemia is profound, with values commonly less than 1 g/​dl. The serum cholesterol level tends to be normal or low, re- flecting low dietary intake. Serum creatinine is usually normal at presentation. Glomerulonephritis in other malaria infections is usually clin- ically silent, but nonselective proteinuria, nonvisible haematuria, and casts are noted in 20 to 50% of cases with falciparum malaria. Glomerular lesions are seen at autopsy in about 18% of cases who die with P. falciparum and P. knowlesi infections. Pathology and pathogenesis The morphological appearance of quartan malarial nephropathy is of a mesangiocapillary pattern. Demonstration of malarial antigen in the deposits and binding of specific antibody to circulating mal- arial antigens suggest an immunological basis for the condition. Experimental studies also support this hypothesis. Environmental factors such as malnutrition or coinfection with Epstein–​Barr virus may be permissive. The liver may act as a source of continuous antigen supply. Mild endocapillary glomerulonephritis has been de- scribed in falciparum malaria. Management Once established, quartan malarial nephropathy follows an inex- orably progressive course, culminating in renal failure within 2 to 4 years. Antimalarials and steroids have proved ineffective in ar- resting progression of kidney disease. Remission has been reported occasionally with cyclophosphamide, but there is no improvement in survival. By contrast, glomerulonephritis associated with falcip- arum malaria resolves within a few weeks of eradication of infection. Renal disease in schistosomal infections Schistosomiasis is a chronic infection caused by trematodes (blood flukes) and affects over 300 million people in Asia, Africa, and South America. Of the seven species pathogenic to humans, the most prevalent are Schistosoma haematobium (Africa and the Middle East), S. mansoni (South America and Africa), and S. japonicum (China and the Far East). S. haematobium primarily involves the lower urinary tract, whereas S. mansoni involves the gastrointes- tinal tract and portal system, leading to hepatic fibrosis and portal hypertension. Schistosomal glomerulopathy Glomerulonephritis has been described in association with hepatosplenic schistosomiasis produced by S.  mansoni. Reports from autopsy series in Brazil during the 1960s were followed by clin- ical observations from endemic areas of Africa, Saudi Arabia, and Yemen. Proteinuria has been reported in 1 to 22% of patients in- fected with S. mansoni and 2 to 5% with S. haematobium infection. Subclinical glomerular lesions were found in about 40% of patients with hepatosplenic schistosomiasis. Clinical features Though described at all ages, glomerulonephritis is most frequent in young adults with overt hepatosplenic disease. Males are affected twice as frequently as females. Peripheral oedema and ascites are the hallmarks; hypertension is seen in 50% of cases, appearing late in the disease. Proteinuria is poorly selective and haematuria uncommon. Complement levels are usually low. Nonspecific antibody produc- tion is demonstrated by false-​positive rheumatoid factor or the VDRL (Venereal Disease Research Laboratory) tests. It is important to exclude other causes of nephrotic syndrome before attributing the lesions to schistosomiasis. Diagnosis is confirmed by demonstrating viable eggs in the stool or egg-​containing granulomas in rectal or liver biopsies. Pathology Five patterns of glomerular pathology have been described (Table 21.11.2). The class I lesion is the earliest and most frequent, and is the principal lesion in renal allografts with recurrent schistosomal nephropathy. Class  II lesions are more frequent in patients with concomitant salmonella infection. The frequency of class  III le- sions varies from 20% in asymptomatic patients to over 80% in those with overt renal disease. The class IV lesion, seen in 15 to 40% of cases, cannot be distinguished from idiopathic focal segmental

21.11  Renal diseases in the tropics 5055 glomerulosclerosis on the basis of light microscopy, but immuno- fluorescence reveals IgA deposition. Class  III and IV lesions are seen in patients with fibrotic livers and associated with severe hypocomplementaemia. Class V prevalence varies from 15 to 40%, with a higher frequency in African patients. This form is not usually affected by hepatic fibrosis. Pathogenesis The glomerulopathy is caused by the immunological reaction to specific schistosomal antigens. Antigens have been demonstrated in the glomeruli of baboons infected with S. mansoni, and circu- lating immune complexes have been documented in experimental animals and humans with hepatosplenic disease. Circulating com- plexes localize in mesangial and subendothelial locations, whereas the extramembranous deposits form in situ. Portocaval shunting prevents hepatic processing of worm antigen and delivers it directly into the systemic circulation. IgM anti- bodies are seen in most patients with hepatosplenic schistosomiasis alone, but circulating mononuclear IgA-​bearing cells and IgA anti- bodies predominate in those with glomerular involvement. An iso- tope switch from IgM-​ to IgA-​producing B cells is believed to be responsible for this alteration. An aberrant Th2 cytokine response contributes to organ damage. Genetic factors are thought to play a role; polymorphisms in IL13 and STAT6 genes have been associated with disease severity. The immune reaction may be modified by con- comitant infection with salmonella, hepatitis viruses, staphylococci, and mycobacteria. Epidemiological studies have shown clearance of urinary abnormalities following therapy for salmonella alone, sug- gesting a permissive role of this infection. Management Treatment of schistosomal glomerulopathy is disappointing. Antischistosomal drugs (see Chapter 8.11.1) do not alter the clin- ical course, which is one of inexorable progression to renal failure. Steroids or cytotoxic agents are similarly ineffective. Salmonella in- fection should be looked for and treated in all patients. Schistosomiasis involving the lower urinary tract The adult S. hematobium worm resides and lays eggs in the perivesical venous plexus, where they get trapped in the urinary tract mucosa and incite granuloma formation. Clinical manifestations appear when they coalesce into larger granulomata or polyps that ulcerate and bleed. Over time, fibrosis and calcification set in. The presenting feature is painful haematuria, and characteristic ova with terminal spikes may be seen on urinary examination. Later stages are characterized by symptoms related to reduced bladder volume, obstruction to urine flow at the level of bladder outlet or ureterovesical junction, vesicoureteric reflux, or urinary tract infec- tion. Plain radiology may reveal linear or irregular calcification in the bladder wall, ureter, or seminal vesicles (Fig. 21.11.6). Bladder cancer is a complication of chronic schistosomal cystitis, and develops two to three decades after the initial infection in about 5% of all infected individuals. In Egypt, schistosomal eggs are dem- onstrated in over 85% of resected bladder cancer specimens. Long-​standing obstruction leads to progressive loss of kidney function; 7 to 20% of the endstage renal disease population in Egypt is secondary to lower tract schistosomiasis. Renal disease in filarial infection Filarial worms are nematodes transmitted to humans through arthropod bites. Clinical manifestations depend upon the location of microfilariae and adult worms in the tissues. Of the eight filarial species that infect humans, Loa loa, Onchocerca volvulus, Wuchereria bacrofti, and Brugia malayi are associated with kidney disease. Loiasis is prevalent in West and Central Africa and manifests with localized allergic inflammation and swelling. Onchocerciasis (river blindness) is characterized by subcutaneous nodules, a pruritic skin rash, sclerosing lymphadenitis, and ocular lesions. Bancroftian and Table 21.11.2  Clinicopathological classification of schistosomal glomerulopathy Class I II III A IIIB IV V Light microscopic pattern Mesangioproliferative Exudative Mesangiocapillary type I Mesangiocapillary
type II Focal and segmental glomerulosclerosis Amyloidosis (a) ‘Minimal lesion’ (b) Focal proliferative (c) Diffuse proliferative Immunofluorescence Mesangial IgM and C3. Schistosomal gut antigens Endocapillary C3 Schistosomal
antigens Mesangial IgG, IgA, and C3, schistosomal gut antigen Mesangial and subepithelial IgG and C3, schistosomal gut antigen (early), IgA
(late) Mesangial IgG, IgM, and IgA Mesangial IgG Asymptomatic
proteinuria +++ –​ + + + + Nephrotic syndrome + +++ ++ +++ +++ +++ Hypertension ± –​ ++ + +++ ± Progression to endstage renal disease ± ± ++ ++ +++ +++ Response to treatment ± +++ –​ –​ –​ –​ Modified with permission from Barsoum R, Kidney Int 1993.

section 21  Disorders of the kidney and urinary tract 5056 brugia infections cause febrile episodes associated with acute lymph- angitis and lymphadenitis, leading to lymphoedema manifesting as hydrocele and elephantiasis. This form of filariasis is endemic in Africa and South and South-​East Asia. Filarial nephropathy Clinical features Urinary abnormalities have been described in 11 to 25% of cases of loiasis and onchocerciasis, with nephrotic syndrome in 3 to 5%. In a survey in an endemic area, proteinuria was detected in over 50% of patients with lymphatic filariasis, with 25% showing a glomerular pattern of protein loss. The frequencies of proteinuria, nonvisible haematuria, and hypertension are significantly higher in patients with chronic sclerosing filariasis than in those with an acute febrile illness or microfilaraemia. False-​positive rheumatoid factor and anti-​DNA and antiphospholipid antibodies have been described. Pathology Light microscopy reveals a gamut of lesions, including minimal-​ change disease and focal segmental glomerulosclerosis, and mesangial proliferative, mesangiocapillary, and chronic sclerosing glomerulonephritis. Diffuse basement membrane thickening with endocapillary proliferation is the commonest finding. Mononuclear interstitial infiltration and microinfarcts around blood vessels have been demonstrated in patients with loiasis. Microfilariae may be found in the glomerular capillary lumina (Fig. 21.11.7), tu- bules, and interstitium. Electron microscopy shows widely spaced subepithelial, subendothelial, and intramembranous deposits and spikes. O. volvulus and B. malayi antigens, along with IgM, IgG, and C3 have been demonstrated. Pathogenesis Glomerulonephritis is likely immune complex mediated. The levels of circulating immune complexes correlate with the adult worm burden. Dogs infected with Dirofilaria immitis develop glomerular lesions similar to human filariasis: glomerular lesions developed after selective catheterization and infusion of D. immitis into one renal artery; the contralateral kidney either remained un- involved or showed minor lesions, suggesting in situ immune com- plex formation. Diethylcarbamazine treatment, by killing the parasite, may lead to antigen release into the circulation, thus exacerbating the immune process. A temporal relationship between the administration of this agent and the development of proteinuria has been noted. Management Good response to antifilarial therapy with diethylcarbamazine is ob- served in patients with non-​nephrotic proteinuria and/​or haema- turia. The response is inconsistent in those with nephrotic syndrome, when deterioration of renal function may continue despite clearance of microfilariae. Chyluria Lymphatic filariasis secondary to W. bancrofti or B. malayi infec- tions leads to fibrosis of lymph glands and dilatation of draining lacteals. Under pressure, the dilated retroperitoneal lacteals rup- ture into the low-​pressure urinary system, leading to leakage of lymph in urine. The presentation is characterized by passage of milky white urine (Fig. 21.11.8), with or without haematuria. Patients complain of backache, probably caused by distended vessels. Formation of chylous clots may result in acute urinary retention. Prolonged chyluria results in the loss of protein, fat, and lympho- cytes in the urine, leading to hypoproteinaemia and lymphopenia. Urinalysis shows proteinuria, and—​if the history of change in urine colour is not elicited—​an erroneous diagnosis of nephrotic syn- drome might be made, prompting an unnecessary kidney biopsy. About 80% of cases respond to treatment with diethylcarbamazine and dietary modification. Sclerotherapy using local instillation of povidone iodine, hypertonic dextrose, or silver nitrate is required for resistant cases (or less commonly surgery). Fig. 21.11.6  Plain radiograph of a patient with S. haematobium infection showing calcification of bladder wall. Courtesy of Professor R. Barsoum. Fig. 21.11.7  Photomicrograph of a kidney biopsy showing microfilariae with parallel-​arranged nuclei throughout their length and covered by a sheath on their external aspect in the glomerular capillary lumen in a patient with lymphatic filariasis (arrows) (periodic acid–​Schiff stain, magnification ×100).

21.11  Renal diseases in the tropics 5057 Renal disease in leprosy Leprosy is a chronic granulomatous disorder caused by the acid-​fast bacillus Mycobacterium leprae. Nephritis was an important cause of death until the 1950s, but is now rare. The main renal lesions en- countered are glomerulonephritis, secondary amyloidosis, and tubulointerstitial nephritis. Glomerulonephritis The incidence of glomerulonephritis in leprosy is now less than 2%, but old autopsy series showed lesions in over 50% of cases. Most cases are seen in patients with multibacillary disease and during epi- sodes of erythema nodosum leprosum. Clinical presentation may be as nephrotic syndrome, acute nephritic syndrome, or rapidly pro- gressive renal failure. Hypocomplementaemia is common, and cir- culating cryoglobulins may be present. Mesangial proliferative and diffuse proliferative glomeruloneph- ritis are the commonest histological lesions. Electron microscopy reveals electron-​dense deposits in the mesangial and subendothelial regions, focal foot-​process widening, glomerular capillary basement membrane reduplication with mesangial interposition, and endothe- lial cytoplasmic vacuolation. Immunofluorescence reveals granular IgG and C3 deposits in the mesangium and along capillary walls. Circulating immune complexes can be detected in 30 to 75% of patients, and can be of mycobacterial origin or dapsone:antidapsone antibodies. Alternate pathway complement activation by cryopre- cipitates can also contribute. Steroids or antileprosy drugs have no effect on the course of glomerular disease. Prednisolone may hasten the recovery of renal function in patients with renal failure during episodes of erythema nodosum leprosum. Amyloidosis Amyloid was documented in 55% of cases in older autopsy and bi- opsy studies in leprosy cases from the United States of America, 31% from Brazil, and less than 10% from Mexico, Africa, and India. The amyloid is of AA type and is far more frequent in lepromatous than nonlepromatous leprosy. Erythema nodosum leprosum further in- creases the risk as each episode is associated with a marked elevation of serum amyloid A protein. Patients with tuberculoid leprosy who have long-​standing and infected trophic ulcers can also develop this complication. Renal disease in tuberculosis Tuberculosis is endemic throughout the tropics. Concerted efforts to contain the disease have been thwarted by the HIV epidemic and treatment default, leading to a rise in drug-​resistant disease. Seen in less than 10% of all cases with tuberculosis, urinary tract involve- ment is a relatively late manifestation of disease. Common presenting features are irritative lower urinary symp- toms suggestive of infection as a result of ureteric and bladder in- volvement secondary to seeding of M. tuberculosis into the urine. Urinalysis shows pus cells, but cultures are repeatedly sterile. The presence of sterile pyuria or failure of symptoms to respond to conventional antibacterial treatment should raise the possibility of urinary tract tuberculosis. Systemic symptoms like fever, night sweats, and weight loss are helpful diagnostic clues when present. Only about one-​third of patients show simultaneous pulmonary involvement. Involvement of renal parenchyma takes the form of granuloma- tous interstitial nephritis and caseous destruction, culminating in small nonfunctioning and often calcified kidneys. An association with glomerulonephritis was postulated in the pre-​antibiotic era, but only occasional recent reports have described immune com- plex glomerulonephritis and dense-​deposit disease in tuberculosis. A well-​known complication, however, is amyloidosis, which is still seen in a significant proportion of patients in poor countries where the disease remains untreated for long periods. Once established, the course of amyloidosis is unaffected by treatment of the underlying tuberculosis. Imaging (Fig. 21.11.9) provides important diagnostic clues, with about 30% showing dystrophic calcification of the urinary tract (bladder and ureteric walls, or—​less commonly—​renal paren- chyma). Involvement of the excretory system is delineated better by intravenous urography, CT, or magnetic resonance imaging which shows thickening, irregularity or narrowing of involved segments, and cavities or mass effects secondary to necrosis. Fibrosis and (a) (b) Fig. 21.11.8  Panel (a) shows milky white urine in a patient with chyluria secondary to lymphatic filariasis and panel (b) shows filling up of ruptured lacteals on retrograde pyelogram.

section 21  Disorders of the kidney and urinary tract 5058 contraction of the bladder gives rise to reduction in capacity—​the classical ‘thimble bladder’. Extrarenal spread can also be identified on imaging. Patients with advanced and bilateral disease have a reduced glom- erular filtration rate due to generalized destruction of the paren- chyma, but a more common cause for renal failure is urinary tract obstruction due to scarring of the lower tract. Management requires institution of antitubercular therapy ac- cording to local guidelines. Obstructive lesions that fail to respond to therapy require surgical correction, including urinary diversion and bladder augmentation surgery. Renal disease caused by leptospirosis Leptospirosis, the most widespread zoonosis in the world, is an occupational hazard in fishermen, coal miners, and sewage, ab- attoir, and farm workers throughout the tropics. The pathogenic Leptospira interrogates complex has 30 serogroups and 240 sero- types. Leptospira are shed in the urine by the animal hosts (rats, mice, gerbils, hedgehogs, foxes, dogs, cattle, sheep, pigs, and rabbits) and survive for several weeks in a moist environment. Human infec- tion occurs upon exposure of abraded skin and exposed mucosae to contaminated water, soil, or vegetation. Clinical features Leptospirosis occurs in both sexes and in all age groups. The inci- dence peaks during or soon after the rainy season, especially fol- lowing floods. The disease starts with fever, chills, headache, severe muscle aches and tenderness, and dry cough, which terminate with defervescence after 4 to 10 days. Organ involvement is seen in the second phase and takes the form of AKI, cholestatic jaundice, and haemorrhagic manifestations (Weil’s syndrome). AKI occurs in 20 to 85% of cases and is oliguric in 40 to 60%. It is typically mild and nonoliguric in anicteric patients. Renal magne- sium and phosphate wasting is common. Diuresis ensues by the end of the second week, and may last longer than that associated with other causes of AKI. Recent studies suggest that leptospiral infection can persist in hu- mans and may have long-​term adverse effects on kidney function. Molecular techniques have shown asymptomatic urinary shedding of leptospira in areas of high disease transmission, including in those without serological evidence of recent infection. In a recent population-​based study, individuals with previous leptospira ex- posure had a higher prevalence of CKD stages 3 to 5. Further, those with a higher antibody titre showed a greater decline in estimated glomerular filtration rate on follow-​up. Diagnosis Diagnosis is based on culture or serology. The organisms can be grown on Fletcher’s or Stuart’s semisolid media from blood during the first phase, and later from urine. Antileptospiral antibodies are detectable in the second phase. A single titre of greater than 1:400 or a fourfold increase is taken as significant. A macroscopic agglutination test or a slide test can be used to screen patients, but these are not specific. The gold standard is the complex microscopic agglutination test that requires maintenance of live leptospira cultures. Other tests include an IgM-​specific dot enzyme-​linked immunosorbent assay (ELISA), complement fixation, serum and salivary ELISA, rapid IgM dipstick ELISA, and gold immunoblot tests. Lately, nucleic acid-​based testing has allowed identification of greater number of cases. Pathology Grossly, the kidneys are swollen and bile stained. The main light-​ microscopic lesion is a tubulointerstitial nephritis, with mono- nuclear cells and eosinophilic infiltration. Mild and transient mesangial proliferative glomerulonephritis with C3 and IgM depos- ition is occasionally noted. Pathogenesis Renal involvement results from direct invasion of the renal tissue by the organism and liberation of bacterial enzymes, metabol- ites, and endotoxins. Addition of leptospira endotoxin to human macrophages induces release of tumour necrosis factor-​α (TNFα). Proximal convoluted tubules show a decrease in expression of so- dium/​hydrogen exchanger isoform 3, aquaporin 1, and α-​Na+,K+-​ ATPase. The glycoprotein component of the endotoxin inhibits the renal Na+,K+-​ATPase and apical Na+–​K+–​Cl− cotransporter, leading to potassium wasting. Leptospiral outer membrane proteins have been localized to the proximal tubules and interstitium of infected animals. Recent studies have suggested the involvement of Toll-​like receptor, leading to activation of NF-​κB and mitogen-​activated pro- tein kinases, and enhanced message for inducible nitric oxide syn- thase, monocyte chemoattractant protein-​1 and TNFα. Leptospiral outer membrane proteins may also induce activation of the trans- forming growth factor-​β/​SMAD-​associated fibrosis pathway, leading to accumulation of extracellular matrix. Management Leptospirosis is a self-​limiting disease, and mild cases recover spon- taneously. The emphasis is on symptomatic measures, together with correction of hypotension and fluid and electrolyte imbalance. Antibiotic therapy can shorten the duration of fever and hasten amelioration of leptospiruria. Adverse prognostic factors include Fig. 21.11.9  Intravenous pyelogram in a patient with renal tuberculosis. The left kidney is hydronephrotic and the right kidney is nonfunctioning and shows punctuate calcification of the dilated pelvicalyceal system. Courtesy of Professor John Eastwood.

21.11  Renal diseases in the tropics 5059 advanced age, pulmonary complications, hyperbilirubinaemia, diarrhoea, hyperkalaemia, and the presence of other infections. Kidney injury in scrub typhus Scrub typhus, caused by Orientia tsutsugamushi, a Gram-​negative α-​proteobacterium of family Rickettsiaceae, is endemic in Asia, with an estimated 1 million cases occurring annually. The infection is maintained in nature by transovarian transmission in trombiculid mites. Human involvement occurs when people get bitten by in- fected larvae, leading to inoculation of organisms into the skin. The World Health Organization identifies scrub typhus as a re-​ emerging disease in South-​East Asia and the South-​Western Pacific region, with a fatality rate of 30% in untreated cases. Until recently, renal involvement due to scrub typhus had not received much at- tention, and a recent systematic review could only find a few case reports specifically describing AKI. However, recent studies from India have shown renal abnormalities in 70 to 80% of cases, and about 50% exhibit AKI, which is an independent predictor of mor- tality. Vascular endothelial cell injury is thought to be the pre- dominant mechanism. Renal biopsies have shown mild mesangial hyperplasia, acute tubular necrosis, or tubulointerstitial nephritis. Other infective causes of renal disease Zygomycosis Zygomycosis (syn. mucormycosis) is an opportunistic infection caused by the saprophytic fungi of the order Mucorales and genera Rhizopus, Absidia, and Rhizomucor. The spores gain entry into the body through inhalation or cutaneous breach. The fungus primarily spreads through vascular route, leading to thrombosis of large and small arteries and infarction and necrosis of the affected organ. Primary renal zygomycosis has been described from several tropical countries. Patients present with high fever, lumbar pain, pyuria, and oliguric AKI. The initial route of entry of the organism is often uncertain. Diagnosis requires a high index of suspicion and use of imaging. Ultrasonography reveals enlarged kidneys. CT scan appearance is often diagnostic and shows large kidneys with perinephric stranding, large nonenhancing areas indicating infarction (Fig. 21.11.10), along with perirenal and/​or intrarenal abscesses. Characteristic broad, aseptate hyphae can be demon- strated in material obtained by needle aspiration or biopsy. The only definitive treatment is extensive debridement of affected tissue, which may include bilateral nephrectomy and systemic amphotericin B therapy. This condition carries an extremely poor prognosis. HIV infection Most individuals affected with HIV infection live in the tropical countries of Africa and South Asia. The frequency of renal involve- ment varies widely in different geographic areas and races, with less than 5% in Asia and Latin America and 25 to 50% in Africa. Renal lesions can be as a direct result of the HIV infection, or indirectly secondary to treatment or associated conditions (Table 21.11.3 and Fig. 21.11.11). Fig. 21.11.10  Contrast-​enhanced CT of the abdomen showing almost complete nonenhancement of the left and minimal patchy contrast enhancement of the right renal parenchyma (suggesting infarction), along with bilateral perinephric stranding (arrows) in a patient with AKI due to bilateral mucormycosis. Table 21.11.3  Renal manifestations in of HIV infection Direct renal effects associated with HIV infection Acute kidney injury • Volume loss (e.g. gastroenteritis, pancreatitis) • Infections • Myocardial dysfunction (e.g. cardiomyopathy) • Liver failure (HIV cholangiopathy or coinfection with hepatitis B and/​or C); hepatorenal syndrome Chronic kidney disease • HIV-​associated nephropathy (HIVAN) • HIV immune complex glomerulonephritis Electrolyte and acid–​base disorders • Hyponatraemia (related to SIADH, volume depletion, and adrenal insufficiency) • Hypernatraemia (related to dehydration) • Hyperkalaemia (related to renal dysfunction, trimethoprim, or IVI pentamidine use and
adrenal insufficiency) • Hypokalaemia (related to diarrhoea and amphotericin B therapy) • Metabolic acidosis (lactic acidosis secondary to tissue hypoperfusion, stavudine use or liver disease or kidney failure) Indirect renal involvement Acute kidney injury • Toxins, especially traditional herbal medications • Analgesics, especially nonsteroidal
anti-​inflammatory drugs • Antiretroviral agents, especially tenofovir (tubular toxicity), ritonavir (exacerbates tenofovir nephrotoxicity), indinavir (crystal
formation and obstruction), and stavudine (lactic acidosis and/​or pancreatitis) Chronic kidney disease • Metabolic syndrome associated with
antiretroviral drug use • Other chronic kidney disease with incidental HIV infection IVI, intravenous infusion; SIADH, syndrome of inappropriate antidiuretic hormone secretion. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 5060 The presentation of renal disease in HIV infection is the re- sult of a complex interplay between the pheno-​ and/​or genotypic variants of the virus, the genetic make-​up of the host, and envir- onmental factors. The viral genes nef and var increase podocyte proliferation and dedifferentiation, and alter podocyte protein expression. HIV-​1 infection induces tubular injury by triggering an apoptotic pathway involving caspase activation and FAS up-​ regulation. Release of a variety of cytokines also affects podocytes and tubular cells. HIV-​associated nephropathy also shows a strong genetic pre- dilection: people of African ancestry exhibit a 20-​fold increase in relative risk compared with individuals of Caucasian descent. The differential risk has been traced to the presence of pathogenic vari- ants of MYH9 and APOL1 gene variants in this population. A number of studies have shown a direct link between the viral load and development as well as progression of kidney disease. Use of highly active retroviral therapy has had a favourable effect on dis- ease course. Toxic causes of renal disease in the tropics Snake venoms Most of the 450 venomous snake species are found in the tropical and subtropical regions. Renal lesions have been reported following bites by snakes belonging to classes Viperidae (Russell’s viper, saw-​ scaled viper, puff adder, pit viper, and rattlesnakes), Colubridae (boomslang, Bothrops jararaca, gwardar, dugite, and Cryptophis nigrescens), and Hydrophidae (sea snakes). AKI is the most fre- quent and clinically important effect of envenomation on the kid- neys, with most cases seen following viper and sea snake bites. In India, about 13 to 32% of those bitten by Echis carinatus (Russell’s viper) develop AKI. The reported incidence from other countries varies between 1 and 27%. Clinical features The initial symptoms are pain and swelling of the bitten part, fol- lowed by blister formation and ecchymosis. Bleeding—​as ooze from fang marks, haematemesis, melaena, or haematuria—​is seen in 65% of cases. Sea-​snake bites cause myonecrosis, which manifests as muscle pains and weakness. Renal failure sets in from within a few hours to as late as 4 days after the bite, and is usually oliguric. A history of passage of ‘Coca-​ Cola’-​coloured urine, indicating intravascular haemolysis, is obtained in about one-​half of cases, and over 90% show oliguria. Life-​threatening hyperkalaemia may develop in patients with haem- olysis or myonecrosis. With effective management, oliguria resolves in 5 to 21 days; persistence indicates the likelihood of renal cortical necrosis (Fig. 21.11.12). Pathology Grossly, the kidney are swollen and exhibit petechial haemorrhages. Light microscopy shows acute tubular necrosis in 70 to 80% of cases. Interstitial oedema, inflammatory cell infiltration, and scat- tered haemorrhages may be seen. Electron microscopy reveals dense intracytoplasmic bodies in the proximal tubules representing degen- erated organelles. Other lesions include acute interstitial nephritis, thrombotic microangiopathy, necrotizing arteritis, and crescentic glomerulonephritis. Acute cortical necrosis is seen in 20 to 25% of cases. Pathogenesis Renal damage is a cumulative effect of direct nephrotoxicity of venom, hypovolaemia, haemolysis, myoglobinuria, and dissemin- ated intravascular coagulation. Injection of snake venom leads to increased excretion of tubular enzymes in rats. Administration of Russell’s viper venom led to a dose-​dependent decrease in inulin clearance in isolated perfused rat kidney. Destruction of the glom- erular filter, lysis of vessel walls, mesangiolysis, and tubular injury have been shown in experimental models. A vasculotoxic factor has been isolated from the venoms of several snakes. Similarities have been noted between the structure of the potent vasoconstrictor endothelin-​1 and the venom of the Israeli burrowing asp. Fig. 21.11.11  Photomicrograph of a patient with HIV-​associated nephropathy showing glomerular collapse, focal sclerosis, and microcytic dilatation of tubules. Reproduced with permission from Naicker S, Paget G. HIV and renal disease. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Courtesy of Prof Stewart Goetsch, University of the Witwatersrand. Fig. 21.11.12  Contrast-​enhanced CT of the abdomen in a patient with AKI following an Echis carinatus bite showing acute cortical necrosis. The nonenhancing zone of necrotic cortex is limited by the enhancing subcortical rim on the outside (arrows) and the medulla on the inside (arrowheads).

21.11  Renal diseases in the tropics 5061 Hypotension and circulatory collapse can result from blood loss, release of kinins, or depression of the medullary vasomotor centre or myocardium. Kininogenases are present in crotalid venom. Viper palastinae venom produces depression of the medul- lary vasomotor centre, whereas Bitis arietans venom causes myo- cardial depression, arteriolar dilatation, and increased vascular permeability. Phospholipase A  and a basic protein called ‘direct lytic factor’ present in Russell’s viper and E. carinatus venoms cause intravas- cular haemolysis and disseminated intravascular coagulation. Microangiopathic haemolytic anaemia can develop following A. rhodostoma, Russell’s viper, E. carinatus, puff adder, and guarder bites. Viper venom activates the coagulation cascade at several levels, leading to rapid thrombin formation. Management The mainstay of management is prompt antivenom administration to cases with evidence of systemic envenomation or local inflam- mation involving more than 50% of the limb circumference. There is no agreement on the exact dose needed, or duration of therapy. A rule of thumb is to continue administration until the effects of systemic envenoming disappear as shown by normalization of the whole-​blood clotting time. Concomitant measures include re- placement of lost blood, maintenance of electrolyte balance, ad- ministration of tetanus immunoglobulin, and adequate treatment of pyogenic infection. Maintenance of a high urinary output, as well as alkalinizing the urine, may attenuate renal damage in those with haemolysis. Other animal toxins Bee, wasp, and hornet stings Stinging insects belonging to the order Hymenoptera, such as honeybees, yellow jackets, hornets, and paper wasps, are found in most tropical countries. Systemic symptoms develop when an in- dividual is attacked by a swarm of insects and receives a large dose of venom. Manifestations include vomiting, diarrhoea, hypotension, and loss of consciousness. AKI is secondary to haemolysis, rhabdo- myolysis, or both. Haemolysis results from the action of a basic pro- tein fraction, melittin, and phospholipase A. Rhabdomyolysis has been attributed to polypeptides, histamine, serotonin, and acetyl- choline. Experimental studies have suggested a direct nephrotoxic role of venom components. Renal biopsy invariably reveals acute tubular necrosis. Carp and sheep bile Acute hepatic and renal failure have been reported following con- sumption of the raw gallbladder or bile of freshwater and grass carps (Ctenophryngodon idellus, Cyprus cardio, Hypophythalmichthys molitrixn, Mylopharyngodon pisces, and Aristichthys nobles) in Taiwan, South China, Hong Kong, Japan, India, and South Korea, and sheep bile in the Middle East. Initial symptoms include abdom- inal pain, nausea, vomiting, and watery diarrhoea. Hepatocellular jaundice and AKI occur 48 h after ingestion. Haematuria is noted in 75% of cases. The duration of renal failure ranges from 2 to 3 weeks. Manifestations vary depending upon the varieties of carp and amount of bile ingested. Histology reveals acute tubular necrosis and interstitial oedema. Other conditions AKI has been reported following stings by scorpion, jellyfish, and giant centipede. Scorpion stings result in disseminated intravascular coagulation and internal bleeding, and these can give rise to intra- vascular haemolysis. Plant toxins Tropical communities consume products derived from locally grown plants, either as food or as medicines, and many of these con- tain nephrotoxic substances. Exposure may be accidental, when a toxic plant is mistaken for an edible one. The insult can be identified quickly when the presentation is acute, but the cause–​effect rela- tionship may be harder to establish in the case of slowly progressive kidney disease. Traditional medicines constitute a special class of nephrotoxins among poor populations in tropical Africa and Asia. In African hos- pitals, more than 75% of all deaths from acute poisoning and 25 to 60% of all AKI from medical causes are due to traditional medicines. These agents are obtained from traditional healers (‘witch-​doctors’), who wield considerable power. Administration is either by the oral route or as enemas, the latter consisting of mixtures of herbs, barks, roots, leaves, and bulbs, administered through a truncated cow’s horn or hollow reed. Increasing urbanization and industrialization have introduced potent chemicals (e.g. paint thinners, turpentine, chloroxylenol, ginger, pepper, soap, vinegar, copper sulphate, and potassium permanganate) into their armamentarium. AKI has been reported following the use of such enemas: detailed studies are not available, but histology usually shows acute tubular necrosis. Callilepis laureola (impila) poisoning C. laureola, a herb with a tuberous rootstock, grows in several coun- tries in sub-​Saharan Africa. An extract of the tubers is taken orally or as an enema as a traditional remedy, and is a common cause of AKI in the black South African population. Symptoms appear within 24 h in 40% and within 4 days in 70% of patients. Children and older people show earlier and more severe abnormalities. Abdominal pain and vomiting are followed by hypoglycaemia, convulsions, and jaundice. Histology shows acute tubular necrosis and/​or interstitial infiltration. Atractyloside, an alkaloid in the tuber of the plant, in- hibits ATP synthesis and is believed to have nephrotoxic and hypo- glycaemic effects. Gastrointestinal fluid loss contributes to the renal dysfunction. Treatment is supportive and includes correction of hypoglycaemia and volume and electrolyte replacement. The mor- tality rate is over 50%. Djenkol bean poisoning Djenkol beans (Pithecolobium lobatum and P.  jiringa, family Mimosaceae) are considered a delicacy in Indonesia, Malaysia, southern Thailand, and Myanmar (Burma). AKI can occur when raw beans are consumed in large amounts with low fluid intake, and nephrotoxicity has been reported most commonly in the rainy season from Malaysia and Indonesia. Symptoms include dysuria, lumbar pain, hypertension, haematuria, and oligoanuria. The breath and urine emit a characteristic sulphuric odour. Urinalysis shows needle-​like crystals of djenkolic acid, a sulphur-​rich cysteine thioacetal of formaldehyde that forms in the concentrated acidic urine of the distal tubules. Individual susceptibility to the toxic

section 21  Disorders of the kidney and urinary tract 5062 effects is variable, possibly related to hydration status or variability in activity of metabolizing enzymes. High fluid intake and urinary alkalinization helps in dissolving the crystals. Most victims recover within a few days. Chronic ingestion can lead to development of djenkolic acid stones. Mushroom poisoning Less than 1% of all mushrooms are toxic. AKI has been observed following the ingestion of mushrooms of the genera Amanita, Galleria, Cortinarius, and Inocybe. Amanita phalloides (death cap) and A. virus (destroying angel) grow commonly in lawns, pastures, on living trees, in basements, plasterboard walls, and flower pots, and may be picked and ingested by inexperienced collectors and children. Initial symptoms are related to the gastrointestinal tract and may result in dehydration and hypotension. The toxic com- pounds (phallotoxin, amatoxin) inhibit RNA polymerase. Hepatic and renal failure develops after a couple of days. Renal histology shows acute tubular necrosis. Management is supportive; charcoal haemoperfusion is effective in clearing α-​amanitin from circulation and may improve outcome. Overall mortality is over 50%, and ex- ceeds 70% in children. Long-​term ingestion of cortinarius mushrooms has been impli- cated in chronic renal failure. Details of other toxic plants that have been associated with development of kidney diseases are described in Table 21.11.4. Chemical nephrotoxins Increasing industrialization has facilitated the access of the poor and poorly educated populations of tropical countries to a variety of chemicals. Poisonings have been reported after accidental inges- tion or following attempted suicide or homicide. AKI is a manifest- ation of toxicity of many of these agents, such as copper sulphate, ethylene glycol, paraphenylenediamine (PPD), paraquat, ethylene dibromide, and hexavalent chromium compounds. Ethylene glycol Ethylene glycol is used as an organic solvent, antifreeze, preservative, and glycerine substitute. It is metabolized in the liver to glyoxylic acid and oxalate, which combines with calcium and gets deposited in the acid milieu of renal tubules as calcium oxalate crystals, leading to AKI. Epidemics of ethylene glycol poisoning in children as a result of substitution of nontoxic propylene glycol with toxic di-​ and poly- ethylene glycols as a vehicle in paediatric syrup preparations have been reported from tropical countries including India, Bangladesh, Nigeria, South Africa, and Haiti. The mortality is high due to underlying diseases and delayed diagnosis:  236 deaths were re- corded among 339 children with AKI in Bangladesh during one such epidemic. Paraphenylenediamine PPD is a widely used chemical in Africa, Middle East, and Indian subcontinent as a textile, fur, or hair dye, to colour cosmetics, for temporary tattoos, photographic development, and in gasoline. It is a well-​known skin irritant and may be absorbed from the skin. Being cheap and widely available, it is also used for suicidal pur- poses. Clinical manifestations include cervicofacial oedema, chocolate brown-​coloured urine, oliguria, muscular oedema, and shock. The most common renal presentation is as oliguric AKI, perhaps secondary to direct toxicity, rhabdomyolysis, and hypovol- aemia, and PPD toxicity is a common cause of AKI in parts of the Indian subcontinent and Africa. Treatment is mostly supportive. Antihistamines and steroids are used in the management of airway oedema. Alkaline diuresis is tried in those with myoglobinuria. PPD is not dialysable. Copper sulphate Copper sulphate is commonly used as a pesticide, in the leather in- dustry, and in making home-​made glue. Its blue colour makes it at- tractive to children, with risk of inadvertent poisoning, and it is used for suicidal purposes in the Indian subcontinent. Initial symptoms of copper sulphate poisoning consist of a metallic taste, increased salivation, burning retrosternal pain, nausea, vomiting, diarrhoea, haematemesis, and melaena. Jaundice, hypotension, convulsions, and coma indicate severe poisoning. Acute pancreatitis, myoglobinuria, and methaemo- globinaemia have also been reported. Oliguric AKI develops in 20 to 25% of cases and is frequently associated with passage of dark (Coca-​Cola)-​coloured urine, indicating intravascular haemolysis, the risk of which is increased in genetic G6PD defi- ciency. Renal histology shows acute tubular necrosis with abun- dant pigmented haemoglobin casts indicating haemoglobinuria. Acute cortical necrosis occurs rarely. Dialysis may be required for renal failure, but is ineffective in clearing copper from the body. Future challenges In the coming years, tropical societies will face major impacts of climate change and water scarcity on kidney health. Changes in air and ocean temperature will make their impact felt in the tropics during the course of next 10 years, long before changes are noted in the temperate regions. Temperatures in excess of 50°C are already being recorded regularly in the tropics. The number of tropical cyclones is rising year on year. According to the United Kingdom-​based risk analysis firm Maplecroft, the top 10 countries at ‘extreme risk’ from climate change are all tropical countries. The kidneys are particularly vulnerable to the effects of climate change. Dehydration secondary to heat stress will increase the risk of acute as well as chronic kidney injury. Unpredictable rainfall, as seen in the Indian state of Tamil Nadu in 2015, is likely to lead to the re-​emergence of water-​borne and vector-​borne infectious diseases, nullifying the past gains made in infection control. Changes in climate and biodiversity have been linked to increases in zoonotic and vector-​borne disease outbreaks. Changes in vector ecology and water quality will increase the risk of the re-​emergence of previously contained infections or of the emergence of new in- fections in the tropics. Potential changes in the virulence of organ- isms is also a possibility, as shown by the emergence of kidney injury in vivax malaria, once considered benign, and of kidney injury in scrub typhus. Degradation of the ecosystem, with air and water pol- lution, will increase the risk of exposure to environmental toxins.

21.11  Renal diseases in the tropics 5063 A decreased ability to excrete, secondary to dehydration, will lead to higher concentrations of such toxins in the kidney, with adverse consequences on kidney health. Combating these challenges will require concerted action on medical as well as societal and political fronts. Anticipating the upcoming challenges and fortifying the health system to address these in a timely manner is a challenge that needs to be tacked urgently. FURTHER READING Araujo ER, et  al. (2010). Acute kidney injury in human leptospir- osis: an immunohistochemical study with pathophysiological cor- relation. Virchow Arch, 456, 367–​75. Barber BE, et al. (2013). A prospective comparative study of knowlesi, falciparum, and vivid malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium Table 21.11.4  Plant nephrotoxins in the tropics Plant Reported from Active molecule Renal manifestations Other manifestations Averrhoa bilimbi (irumban puli) South India Oxalic acid Intratubular obstruction Averrhoa carambola (star fruit) Hong Kong, Taiwan Oxalate Intratubular precipitation of oxalate crystals Vomiting Callilepis laureola (impila) Sub-​Saharan Africa Atractyloside ATN Abdominal pain, diarrhoea, vomiting, jaundice, seizures, and coma Catha edulis (khat leaf) East Africa, Arab peninsula S-​cathione, ephedrine ATN Hepatotoxicity Cleistanthus collinus (oduvan) India Cleistanthin A and B, collinusin, diphylline AKI Hypotension, hypokalaemia, arrhythmia Colchicum autumnale (meadow saffron) Turkey Colchicine ATN Haemorrhagic gastroenteritis, muscle paralysis, respiratory failure Crotalaria laburnifolia (bird flower) Zimbabwe, Sri Lanka Pyrrolizidine alkaloids ATN, HRS Hepatic veno-​occlusive disease,
pulmonary injury, thrombocytopenia Cupressus funebris Endl (mourning cypress) Taiwan Flavonoid ATN, AIN AHF, haemolytic anaemia, thrombocytopenia Dioscorea quartiniana and D. quinqueloba (yam) Africa, Asia Dioscorine, dioscin ATN Convulsions, encephalopathy Dodonaea angustifolia (sand olive) South Africa Unknown AIN Pulmonary embolism Euphorbia metabelensis, E. paralias (spurge) Zimbabwe Irritant chemicals in plant latex ATN Thrombocytopenia Glycyrrhiza glabrata (liquorice) Several countries Glycyrrhizic acid ATN Rhabdomyolysis, hypokalaemia,
hypertension, cardiac arrhythmia Larrea tridentate (chaparral) Chile, South Africa Nordihydroguaiaretic acid, s-​quinone Renal cysts, renal cell carcinoma Hepatic failure Lawsonia alba (henna) Middle east, North Africa, Pakistan 2-​hydroxy-​1,4-​ naphthoquinone ATN Haemolysis Pithecolobium lobatum and Pithecolobium jiringa (djenkol) beans South East Asia Djenkolic acid Intratubular obstruction and ATN Lumbar and lower abdominal pain, hypertension Propolis Brazil, Taiwan Unknown AIN Contact dermatitis Rhizoma rhei Hong Kong Anthraquinones (emodin, aloe-​emodin) AIN None Securidacea longepedunculata (violet tree, wild wisteria) Congo, Zambia, Zimbabwe Methylsalicylate, securinine, saponins ATN Vomiting, diarrhoea Sutherlandia frufesces (cancer brush), Dodonaea angustifolia South Africa Unknown AIN Pulmonary embolism Takeout roumia Morocco, Sudan Paraphenylenediamine ATN Rhabdomyolysis Taxus celebia (Chinese yew) Asia Flavonoid ATN, AIN Hepatitis, haemolysis, DIC Thevetia peruviana (yellow
oleander) India, Sri Lanka Cardiac glycosides ATN, mesangiolysis Liver failure, cardiac arrhythmias Tribulus terrestris USA, Iran Unknown ATN, AIN Liver failure, encephalopathy Tripterygium wilfordii Hook F
(thunder god vine) Taiwan Triptolide ATN Diarrhoea, shock Uncara tomentosa (cat’s claw) Peru Alkaloids, flavonols AIN Diarrhoea, hypotension, bruising, bleeding gums AHF, acute hepatic failure; AIN, acute interstitial nephritis, AKI, acute kidney injury; ATN, acute tubular necrosis, DIC, disseminated intravascular coagulation; GI, gastrointestinal; HRS, hepatorenal syndrome.

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ESSENTIALS There are more than 200 inherited disorders in which the kidney is affected. Many are single gene diseases that affect children, but cases are not restricted to paediatrics and diagnosis is often made in adults. They display a wide range of renal features: cystic, glomerular, tubulointerstitial, vascular, malformative, tumoural, and urolithiasis. Autosomal dominant polycystic kidney disease—​affects about
1/​1000 individuals and accounts for 7% of cases of endstage renal failure in Western countries. Inheritance is autosomal dominant, with mutations in polycystin 1 responsible for 75% of cases and mutations in polycystin 2 accounting for most of the remainder. May present with renal pain, haematuria, urinary tract infection, or hypertension, or be discovered incidentally on physical examination or abdom- inal imaging, or by family screening, or after routine measurement of renal function. Commonly progresses to endstage renal failure be- tween 40 and 80 years of age. Main extrarenal manifestations are intracranial aneurysms, liver cysts, and mitral valve prolapse. Alport’s syndrome—​X-​linked dominant inheritance in 85% of kindreds, with molecular defects involving the gene encoding the α-​5 chain of the type IV collagen molecule. Males typically pre- sent with visible haematuria in childhood, followed by permanent nonvisible haematuria, and later by proteinuria and renal failure. Extrarenal manifestations include perceptive deafness of variable se- verity and ocular abnormalities (bilateral anterior lenticonus is path- ognomonic). Carrier women often have slight or intermittent urinary abnormalities, but may develop mild impairment of renal function late in life, and a few develop endstage renal disease. In the auto- somal recessive form of Alport’s syndrome, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both af- fected men and women. Hereditary tubulointerstitial nephritis—​nephronophthisis is the most common genetic cause of endstage renal disease in chil- dren and young adults, and is a group of autosomal recessive tubulointerstitial nephropathies with multiple, small medullary cysts that appear late in the course of the disease. Eighty per cent of cases are caused by homozygous deletions of the NPH1 gene, which codes for nephrocystin. It presents with polyuria, polydipsia, and growth retardation in early childhood, progressing to endstage renal disease at a mean age of 14 years. In adults, autosomal dominant tubulointerstitial nephritis, sometimes with gout and medullary cysts, is related to mutations in various genes (UMOD, MUC1, REN, TCF2). Hereditary tumours—​in von Hippel–​Lindau disease, due to mu- tations in the tumour suppressor gene VHL, renal cysts and bilat- eral multifocal renal cell carcinomas are found in 70% of cases. Carcinomas are often asymptomatic, should be screened for regu- larly, and occur at a mean age of 45 years. In tuberous sclerosis, due to mutations in genes encoding hamartin (TSC1) or tuberin (TSC2), multiple and bilateral renal angiomyolipomas may bleed, or induce progressive renal impairment. Autosomal dominant polycystic kidney disease and other cystic diseases of the kidneys An overview of the most frequent causes of cystic kidney diseases, genetic and nongenetic, is shown in Table 21.12.1. Autosomal dominant polycystic kidney disease Autosomal dominant polycystic kidney disease (ADPKD) is by far the most frequent inherited kidney disorder, accounting for approxi- mately 7% of cases of endstage renal failure in Western countries. It is one of the most frequent human inherited monogenic diseases (c.1 in 1000 individuals). Diagnosis The diagnosis of ADPKD is mainly based on renal imaging. Ultrasonography, inexpensive and safe, remains the imaging mo- dality of choice to make the diagnosis. One must take into account the presence or absence of a family history of ADPKD, the patient’s age, the number of observed cysts, and their localization and morph- ology. If unsure, a genetic diagnosis is sometimes offered and differ- ential diagnoses must be explored. Positive diagnosis in a subject at risk of ADPKD This follows screening, usually of asymptomatic children and/​or siblings of an affected individual who have a 50% risk of having inherited ADPKD. Paediatric complications of ADPKD are ex- ceptional and there is no proven benefit to screen for ADPKD in 21.12 Renal involvement in genetic disease D. Joly and J.P. Grünfeld

section 21  Disorders of the kidney and urinary tract 5066 children, and the psychological consequences of a positive diagnosis in children or adolescents are unknown. Thus, most nephrologists recommend checking blood pressure annually, but do not propose screening before 18 to 20 years of age. In relatives of a case, the diag- nosis of ADPKD is based on the presence of cysts on the kidney ultrasound. However, ‘simple’ renal cysts are not rare in the general population, and their prevalence increases with age. For the age group 15 to 39 years, an ADPKD diagnosis is made if there are three or more cysts (unilateral or bilateral), and between 40 and 59 years, at least two cysts on either side. ADPKD cannot be formally excluded before 40 years of age. These criteria ensure a positive and negative predictive value of 100% and are applicable to all patients regardless of ADPKD genotype. In the absence of these criteria, the presence of cysts is most often associated with banal multicystic kidney disease. Exclusion of diagnosis of ADPKD In a person at risk for ADPKD who wants to give a kidney to a relative or loved one, it is essential to rule out the diagnosis with certainty. Two tests may be applied: (1) genetic testing to be com- pared with the known family anomaly, and (2) a magnetic resonance imaging (MRI) scan, knowing that the negative predictive value of this test (no renal cyst) is almost perfect from the age of 16, at least to exclude PKD1-related disease. Absence of family history of ADPKD About 10 to 15% of patients with ADPKD have a negative family history. When ultrasound examination of one of the parents of the patient is positive, it is most often a late diagnosis of a mild form (a PKD2 gene mutation or a not truncating mutation of the PKD1 gene). If ultrasound examination of both parents is negative, a de novo mutation (about 5% of cases) is possible, as well as somatic mosaicism. Several elements plead in favour of ADPKD: • Negative differential diagnosis of other renal cystic disease (Table 21.12.2 and Figure 21.12.1) • Kidneys are increased in size with countless cortical and me- dullary cysts • Extrarenal cross-​sectional (CT or MRI) imaging:  presence of cysts in the liver, eventually the pancreas or spleen • Genetic testing (see Table 21.12.2) Renal ultrasonography in ADPKD See Fig. 21.12.1. Symptoms Renal manifestations In some patients, ADPKD is asymptomatic and discovered during family investigation, or by chance on abdominal ultrasonography. In most cases, however, there are symptoms and patients complain of one or more of the following at some time during their life: renal pain due to cyst development, or stone or blood clot migration; bleeding within a cyst, leading to flank pain, with the hyperdense Fig. 21.12.1  Typical ultrasonographic appearances of ADPKD. The kidney is enlarged and contains multiple cysts of different sizes. Reproduced with permission from Sandford R. Autosomal dominant polycystic kidney disease: diagnosis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press. Table 21.12.1  Conditions causing cystic kidney diseases Condition Characteristics Autosomal dominant diseases Autosomal dominant polycystic kidney disease Large kidneys (often), numerous diffuse renal cysts, hepatic cysts Von Hippel–​Lindau (VHL) disease Large kidneys (often), cysts, solid lesions Tuberous sclerosis Large kidneys (often), cysts, angiomyolipomas TCF2 mutation (renal cysts and diabetes syndrome) Medullary cysts; cystic dysplasia ± urinary malformations ± diabetes (MODY type 5) UMOD, REN, MUC1 mutations Medullary cysts ± gout Medullary cysts TCF2, UMOD, REN mutations Autosomal dominant inheritance Recessive polycystic kidney disease, nephronophthisis Autosomal recessive inheritance Frequent nonhereditary multicystic diseases Renal multicystic disease Less than 5 simple cysts without kidney enlargement Tubulointerstitial nephritis Small medullary cysts (mostly seen on MRI) if impaired renal function Acquired cystic disease Patients with impaired renal function, often on dialysis Medullary sponge kidney (Cacchi—​Ricci) Urolithiasis, nephrocalcinosis Parapelvic cysts Cysts limited to renal sinus Table 21.12.2  Diagnostic tests for ADPKD Test Age
(years) To affirm
ADPKD To exclude ADPKD Renal ultrasonography 15–​39 ≥3 cysts (total) Impossible 40–​59 ≥2 cysts in each kidney 0 or 1 cyst in each kidney Renal MRI

16 ≥10 cysts (total) <5 cysts Genetic testing (Adults) PKD1 or PKD2 mutation No PKD1/​PKD2 mutation May be negative (somatic mosaicism?)

21.12  Renal involvement in genetic disease 5067 cyst fluid then being visualized by CT; bleeding into the urinary tract, with visible haematuria occurring in approximately 30% of cases; or fever due to upper urinary tract infection, which is more frequent in women, or to cyst fluid infection. Renal stones, pre- dominantly uric acid (for unknown reasons), develop in about 20% of the patients. Hypertension is a common and early finding in ADPKD, occurring in about 30 to 50% of patients with normal renal func- tion. Subsequently, with the development of renal failure, up to 80% of patients become hypertensive. Why hypertension develops is not known: it has been ascribed to compression and ischaemia of the normal renal parenchyma by cysts. Renal failure is also a common finding in ADPKD. When it occurs, it usually progresses to endstage at between 40 and 60 years of age. However, in 30% of cases it reaches endstage later, and in 5% earlier, including very rare instances when it develops in the first years of life. Recent epidemiological studies have indicated that ADPKD may have a much more indolent course in a substantial number of cases: 25 to 50% of affected subjects are not in endstage renal failure by 70 years of age, and some patients may reach 80 or 90 years without the need for renal replacement therapy. This information is crucial for genetic counselling. Genetic factors are major determinants of renal prog- nosis: the renal disease progresses more slowly in families with PKD2 disease (mean age at endstage renal disease 55 years in PKD1 disease, compared with >75 years in PKD2 disease). PKD1 disease progresses more slowly in women than in men. Control of hypertension may slightly reduce the rate of progression. Extrarenal manifestations Liver cysts develop in 70% of patients, usually later in life than renal cysts. They are more frequent and more diffuse in women than in men. They are usually asymptomatic but may be clinically palpable, and are typically detected by ultrasonography. Liver function tests are usually normal. Liver cyst infection may occur, particularly in patients on dialysis or in transplant recipients. Massive liver involve- ment can cause severe discomfort in some cases, mostly in women. Cardiovascular abnormalities include intracranial aneurysms and mitral valve prolapse. Subarachnoid haemorrhage or intracerebral bleeding due to rupture of intracranial aneurysm are among the most severe complications of ADPKD and occur in approximately 1 to 2% of patients. Rapid diagnosis and urgent neurosurgical opinion are required. Diagnosis should be suspected early, before complete rupture, in patients with ADPKD with recent and severe headache, or with any transient focal neurological deficit. In cross-​sectional studies performed using noninvasive screening methods such as high-​resolution CT or magnetic resonance angi- ography, intracranial aneurysms have been found in 7 to 8% of asymptomatic middle-​aged patients with ADPKD. The prevalence is higher in those with a family history of intracranial aneurysm. The risk of rupture is largely dependent on aneurysm size. Routine screening by noninvasive methods is not indicated for all asymp- tomatic patients with ADPKD, but it seems reasonable in certain subgroups, in particular those with a family history of intracranial aneurysm or subarachnoid haemorrhage, those who have already bled from an aneurysm (since recurrent aneurysm is possible), and possibly those who are to undergo major elective surgery. In high-​ risk groups, screening should be repeated every 5 to 10 years since the cerebral vascular disease is progressive. Mitral valve prolapse is discovered in 20% of patients with ADPKD by echocardiography, whereas it is found in only 2 to 3% of the general population. Other cardiac valve abnormalities and occa- sionally artery dissection or aneurysm may also be detected. Other extrarenal abnormalities observed in ADPKD include pes excavatum, colonic diverticula, and abdominal hernias. Pathogenesis Cysts develop only in a few nephrons and only focally, whereas all nephron cells carry the mutated gene. This has been explained by a two-​hit phenomenon which postulates that renal tubular (or liver bil- iary) cells that are at the origin of cysts bear first the germinal PKD gene mutation, and then acquire a somatic PKD gene mutation involving the other allele, this event occurring at random in a limited number of cells. This explanation does not exclude other mechanisms. The link be- tween the genetic event(s) and cystic fluid accumulation is not known. The disease has an autosomal dominant mode of inheritance, so that the risk of any child of an affected parent carrying the abnormal gene is one in two, new mutations being rare. Mutations affecting polycystin 1 (from the PKD1 gene on the short arm of chromosome 16) are responsible for 75% of cases in the most recent series, with mu- tations affecting polycystin 2 (from the PKD2 gene on the long arm of chromosome 4) accounting for most of the remainder. Polycystin 1 and polycystin 2 are transmembrane proteins that are able to interact, function together as a nonselective cation channel, and also induce several distinct transduction pathways. The ‘polycystin complex’ may have three different subcellular localizations and associated putative functions: at lateral membranes of the cells (with a role in cell–​cell interaction), at the basal pole of the cell (with a role in cell–​ extracellular matrix interaction), and at the apical primary cilia of the cells (with a role in mechanotransduction of the urinary flux). Treatment—​general and symptomatic High fluid intake and regular follow-​up of blood pressure and renal function are indicated in all patients with ADPKD. The control of hypertension is an essential part of management, achieved with standard antihypertensive agents. Haematuria should be managed conservatively if possible, although bleeding may sometimes be pro- longed over several days and even weeks. The relief of pain or abdominal discomfort can be difficult. In add- ition to symptomatic treatment, surgical renal cyst decompression should be restricted to very selected cases. Surgery is rarely needed in the management of renal stones. Liver cyst aspirations by needle under CT guidance, fenestration, or resection may be needed when massive involvement gives rise to pain; and in very rare cases such patients have come to liver transplantation. Kidney infection requires administration of antimicrobials appro- priate for upper urinary tract infection (see Chapter 21.13). In some cases, control of infection is not obtained, most probably because agents penetrate some infected cyst fluids poorly and do not achieve adequate concentration. Lipophilic drugs such as trimethoprim–​ sulphamethoxazole and fluoroquinolones have the best penetration into cyst fluid. Liver cyst infection also requires antimicrobials and drainage if infection is not controlled. Standard medical management of chronic renal failure is indi- cated, as are renal replacement therapy and kidney transplantation when the patient reaches endstage, the results being similar to those obtained in other renal diseases.

section 21  Disorders of the kidney and urinary tract 5068 Treatment—​specific Identification of polycystins and their downstream intracellular dysregulated signalling pathways has provided clues to how the disease develops and thereby to the possibility of specific inter- ventions. Among various molecules, V2 receptor antagonists (tolvaptan), somatostatin analogues (octreotide), and mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus) have been tested and shown promise in animal models. A  ran- domized trial of tolvaptan in patients aged 18 to 50 years, with an estimated glomerular filtration rate greater than 60 ml/​min and total kidney volume greater than 750 mL, demonstrated a reduced rate of annual increase in total kidney volume (2.8% vs 5.5%), a reduced annual rate of decline of renal function (−3.0 µmol/​L vs −4.3 µmol/​L), and reduced rate of reaching a composite endpoint comprising measures of clinical progression and rate of kidney function decline (44 vs 50 events per 100 patient-​years of follow-​ up). Patients who took tolvaptan had a higher rate of adverse events related to aquaresis, but a lower frequency of adverse events re- lated to ADPKD. Elevation of serum alanine aminotransferase to more than 2.5 times normal occurred in 4.9% of patients taking tolvaptan (vs 1.2% controls), and the United States Food and Drug Administration has subsequently issued a safety warning about the possibility of irreversible liver injury associated with the use of the drug. In the United Kingdom the National Institute for Health Care and Excellence have recommended Tolvapatan as an option to slow progression of cyst development and renal failure in patients with CKD stages 2 or 3 who have evidence of rapidly progressing disease, subject to the medication being provided at an agreed discount. Clinical trials of octreotide have shown a tendency for reduction in increase in renal size and decline in glomerular filtration rate, but without the reductions reaching statistical significance and with a suggestion that beneficial effects may be attenuated after 2 years. Clinical trials of everolimus and sirolimus have not shown signifi- cant clinical benefit, and these agents have a formidable side effect profile. Genetic counselling The pattern of inheritance of ADPKD means that the offspring of an affected subject each have a 50% risk of having the disease. The dis- ease has a highly variable clinical course, even within a given family. Prenatal diagnosis by gene linkage studies using material derived from chorionic villus sampling has been performed and can be con- sidered if required and if adequate family information is available, but the demand for such prenatal diagnosis has been very low in Western countries. This is explained by the late onset and the vari- able clinical course of the disease, often relatively benign, which cannot yet be predicted by DNA analysis. Ultrasonography may occasionally show renal cysts in the fetus, but late in pregnancy. Obviously, due to the slow and late develop- ment of macrocysts, negative ultrasonography in the fetus (as well as in a child) does not rule out the disease. Autosomal recessive polycystic kidney disease Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease (c.1 in 40  000 individuals), the first manifest- ations of which appear early in childhood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1, located on chromosome 6), are responsible for all typical forms of ARPKD. The PKDH1 gene product, fibrocystin, is a transmembrane protein local- ized to the cell primary cilia. Three clinical features characterize this disease: • Its recessive nature:  both heterozygous parents are unaffected, with normal renal ultrasonography; parental consanguinity is found in some families. • Renal cysts derive from the collecting ducts, accounting for the striations in the dilated collecting system seen on MRI. • The renal disease is in most cases associated with congenital hepatic fibrosis: this may be responsible for portal hypertension due to presinusoidal block, or for bacterial angiocholitis due to intrahepatic bile duct dilatation. In children, ARPKD should be differentiated from ADPKD, which can be detected in childhood, even in neonates. Family history and renal ultrasonography in parents are decisive for correct diagnosis. In very rare families with PKD1 disease, renal involvement may be revealed in neonates and may progress to endstage within the first year of life. The diagnosis of ARPKD may be made before birth by ante- natal ultrasonography, showing renal enlargement and increased echogenicity (as well as oligohydramnios). However, prenatal diag- nosis may be uncertain and, since cystic changes occur in well-​ developed collecting ducts, these are detected only in the second half of pregnancy. When there is huge renal enlargement, pulmonary hypoplasia and respiratory distress may lead to death within hours after birth. With prolonged survival, liver and renal involvement becomes prominent. Gastrointestinal bleeding due to portal hyper- tension may be life-​threatening and necessitate surgical portocaval shunt. Systemic hypertension is a frequent finding in the first year of life but, surprisingly, it may regress in subsequent years. Urinary tract infection is common. The rate of progression of renal failure is variable: of those who survive the neonatal period, about 50% reach endstage in childhood, whilst this occurs in adulthood in the remainder. TCF2 mutation; renal cysts and diabetes syndrome (RCAD) Heterozygous mutations in the TCF2 gene encoding hepatocyte nuclear factor (HNF)-​1β, a DNA transcription factor, were initially described as one of the main molecular causes of maturity-​onset dia- betes of the young (MODY) type 5. It now appears that renal anom- alies are the key feature of HNF1β mutation phenotype and often precede the onset of diabetes. Renal cysts and progressive renal failure are frequent; glomerulocystic kidney disease and renal hypoplasia have been reported. Abnormal liver function tests, hyperuricaemia, hypomagnesaemia, pancreatic hypoplasia, and urogenital malforma- tions have also been related to HNF1β mutations. Other hereditary cystic kidney diseases Renal cysts may be found in other autosomal dominant diseases, such as von Hippel–​Lindau disease, tuberous sclerosis, as well as in three recently identified major causes of familial tubulointerstitial nephritis (UMOD, REN, and MUC1 gene mutations) with frequent medullary cysts. Most of these rare condition progress to endstage renal failure. Renal medullary cysts are also found in juvenile nephronophthisis, but not early in the course.

21.12  Renal involvement in genetic disease 5069 Genetic glomerular diseases Glomerular structural diseases In glomerular structural diseases, proteins of podocytes or base- ment membrane are mutated (Table 21.12.3). X-​linked Alport’s syndrome Basement membranes of glomeruli may be altered by type IV col- lagen mutations. Six α chains of type IV collagen have been iden- tified so far, with each molecule of type IV collagen being made up of three of these chains, differently associated in various basement membranes. In X-​linked Alport’s syndrome, mutations have been identified in the gene encoding the α-​5 chain that maps to the long arm of the X chromosome. X-​linked Alport’s syndrome is characterized by the association of progressive haematuric hereditary nephritis and bilateral sensorineural hearing loss. Its prevalence is approximately 1 in 5000 individuals. The first renal manifestation is typically visible haematuria, occurring sometimes in the first year of life, recurring during childhood, and followed by permanent nonvisible haematuria. Proteinuria appears later. A nephrotic syndrome, usually moderate, develops in 30 to 40% of patients. In other cases, moderate protein- uria and nonvisible haematuria are the presenting symptoms in adulthood. By electron microscopy, the basement membrane can be abnormally thickened with splitting of the lamina densa, thinned with focal thickening, or diffusely thin. The disease is progressive, leading to renal failure in all affected males, but the rate of progres- sion is heterogeneous from one family to another, although usually homogeneous within a given family. In some, endstage is reached at or before 30 years of age, sometimes in childhood; in others, renal failure progresses to endstage between the ages of 30 and 60 years. Carrier females of X-​linked Alport’s syndrome often have slight or intermittent urinary abnormalities. Some may develop impairment of renal function late in life. The hearing defect may lead to severe perceptive deafness, but it is often moderate or slight, only detected by audiometric testing. The hearing loss labels a given family, but is not found in all patients with renal disease. Eye abnormalities are detected in 30 to 40% of cases. These include bilateral anterior lenticonus detected by slit-​lamp examination—​a pathognomonic abnormality—​and perimacular or macular retinal flecks that are seen by fundoscopic examination and do not alter visual acuity. Recurrent corneal erosions occur in some patients. Genetic counselling first requires the correct identification of the mode of inheritance. If X-​linked dominant inheritance is docu- mented, affected men will not transmit the disease to their sons, whereas all their daughters will carry the mutant gene; affected women will transmit the mutant gene to 50% of either sons or daughters. DNA analysis may be helpful for genetic counselling in these families. Treatment of hypertension and supportive management of renal failure are indicated in patients with progressive disease. The re- sults of kidney transplantation are similar to those obtained in other renal diseases, but in rare cases antiglomerular basement membrane crescentic glomerulonephritis develops in the graft. It is assumed that this complication is related to alloimmunization to the ‘missing antigen’ introduced by the transplant. Autosomal Alport’s syndromes In the autosomal recessive form, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women. The genes encoding α-​3 or α-​4 chains are mu- tated. Affected subjects are homozygotes in consanguineous fam- ilies, or compound heterozygotes in other cases. In families with leiomyomatosis, α-​5 and α-​6 genes, located contiguously on the X chromosome, are both involved in a large deletion. In some families, macrothrombocytopenia is associated with nephritis and hearing defects: mutations involve the MYH9 gene, encoding the nonmuscle myosin heavy chain IIA. Table 21.12.3  Genetic glomerular structural diseases Disease Gene (OMIM) Inheritance Renal phenotype Extrarenal phenotype X linked Alport’s
syndrome COL4A5 (301050) XL Nonvisible haematuria (constant) ± episodes of visible haematuria; increasing proteinuria ± nephrotic range, progressive renal failure. Early endstage renal disease (ESRD) in most males Sensorineural hearing loss; anterior lenticonus and other eye anomalies Myosin heavy chain 9 (MYH9) MYH9 AD Nonvisible haematuria, proteinuria, progressive renal failure Macrothrombocytopenia Leucocyte inclusions Sensorineural hearing loss Cataract Nail patella syndrome (osteo-​onychodysplasia) LMX1B (161200) AD Focal and segmental glomerulosclerosis with specific ultrastructural changes of the glomerular basement membrane, in 30% of patients, may progress to ESRD in some Inconstant. Absence, dysplasia, or hypoplasia of the nails and patella; elbow dysplasia; bilateral iliac horns arising from the anterosuperior iliac crest; eye disease and sensorineural hearing loss possible Congenital nephrotic
syndrome of the Finnish
type Nephrin AR Massive proteinuria occurs in utero and persists in infancy. Intense therapy needed: nutritional support to compensate for protein loss; prevention of infection and thrombosis; bilateral nephrectomy; continuous peritoneal dialysis, and finally kidney transplantation None Familial focal segmental glomerulosclerosis Various (see text) AR or AD Progressive proteinuria, sometimes nephrotic. May progress to ESRD None AD, autosomal dominant; AR, autosomal recessive; XR, X-​linked.

section 21  Disorders of the kidney and urinary tract 5070 Benign familial haematuria This condition is characterized by isolated nonvisible haema- turia, without proteinuria or progression to renal failure, in both men and women. Renal biopsy usually shows a thin glomerular basement membrane (hence the alternative name thin basement membrane nephropathy) and immunofluorescence studies are negative. The mode of transmission is compatible with auto- somal dominant inheritance of mutations involving the α-​3 or α-​4 chain gene. Familial focal segmental glomerulosclerosis Familial focal segmental glomerulosclerosis with either autosomal dominant or autosomal recessive inheritance has been well charac- terized. Mutation of the NPHS2 gene, which encodes podocin, and mutations of PLCE may cause recessive steroid-​resistant nephrotic syndrome in some families, which can be of early or late onset. Mutations in ACTN4, which encodes α-​actinin-​4, mutations of TRPC6, and mutations of INF2 (which encodes formin) may cause autosomal dominant focal segmental glomerulosclerosis. All these proteins are synthesized and secreted by the podocytes, and interact and regulate plasticity and slit diaphragm permselectivity with other podocyte proteins. Mutations (especially podocin mu- tations) may be detected in some cases of sporadic steroid-​resistant nephrotic syndrome. Nephrin is localized at the slit diaphragm be- tween podocyte foot processes (which are both absent in affected subjects), and plays a key role in the normal glomerular filtration barrier. Mutations of nephrin are responsible for autosomal reces- sive congenital nephrotic syndrome. Familial IgA nephropathy For most types of other primary glomerulonephritis, familial cases have been anecdotally reported. The most frequent form, albeit rare, is probably familial IgA nephropathy, either primary (Berger’s dis- ease) or associated with Henoch–​Schönlein purpura. Metabolic diseases with glomerular involvement In metabolic diseases with glomerular involvement, a defect in an enzyme or its cofactor leads to accumulation or deficiency of a specific metabolite. Fabry disease’s, mitochondrial cytopathy, lecithin-​cholesterol acyl transferase (LCAT) deficiency, hepatorenal glycogenosis (glucose-​6-​phosphatase deficiency), and glycogen storage disease type I are the most important diseases in this group (Table 21.12.4). Fabry’s disease Fabry’s disease, a rare X-​linked lysosomal storage disease, results from α-​galactosidase A  deficiency. Glycosphingolipid deposition mainly occurs in the cardiovascular and renal system. Hemizygotes males are more severely affected than heterozygote females. The first manifestations are painful acroparaesthesias, appearing in child- hood and often prevented by administration of carbamazepine or phenytoin. Angiokeratomas, anhidrosis, and corneal deposits de- velop subsequently. Ischaemic cerebrovascular complications, car- diac valve abnormalities, myocardial deposition of glycolipids, and coronary events are the most severe manifestations, along with renal involvement. In the kidney, glycolipid deposition involves glomerular epithe- lial cells, tubular cells, and endothelial and smooth muscle cells of intrarenal arteries. The latter changes are responsible for progressive renal ischaemia. Renal disease is revealed by proteinuria at around 20 years, and then progresses to endstage between 40 and 60 years of age, necessitating regular dialysis and/​or kidney transplantation. Glycolipid deposition does not recur in the renal graft that contains normal α-​galactosidase activity. Diagnosis is based on symptoms, familial history, measurement of α galactosidase activity in leucocytes, demonstration of typical inclusions on a tissue biopsy, and genetic analysis. Two different re- combinant enzyme treatments (agalsidase α and agalsidase β) have been available since 2001. Enzyme replacement therapy promotes Table 21.12.4  Genetic glomerular metabolic diseases Disease Gene (OMIM) Inheritance Renal phenotype Extrarenal phenotype Fabry’s disease GLA (301500) XL Mostly in men: proteinuria, progressive kidney failure; sometimes tubular dysfunction (polyuria, Fanconi’s syndrome) and renal parapyelic cysts. Glycolipids accumulation observed on light and electron microscopy Pain (acromelalgia), skin (angiokeratomas, anhidrosis), eye (cornea verticillata), heart (left ventricular hypertrophy, conduction anomalies, valve anomalies, angina), strokes (hearing loss, ataxia, vascular dementia) Mitochondrial cytopathy, MIDD type MT-​TL1 (520000) Mitochondrial Proteinuria, progressive renal failure (focal segmental glomerular sclerosis, tubulointerstitial nephritis) Sensorineural hearing loss and diabetes in adults (seek for maternal inheritance); pigmentary retinopathy, ptosis, cardiomyopathy, myopathy, neuropsychiatric symptoms Lecithin-​cholesterol acyl transferase (LCAT) deficiency LCAT (245900) AR Lipid accumulation occurs in glomerular mesangial cells and progresses to endstage renal disease. Lipid deposition recurs slowly in kidney transplants Lipid accumulation occurs in the eyes (causing corneal deposits), erythrocyte membranes (leading to low-​grade haemolytic anaemia), arterial walls (contributing to premature atherosclerosis) Hepatorenal glycogenosis (glucose-​6-​ phosphatase deficiency; glycogen storage disease type I; von Gierke) G6PC (type a 232200) SLC37A4 (type b 232220) AR Early enlarged kidneys Late glomerular hyperfiltration proteinuria, progressive renal failure Early hypoglycaemia, intolerance to fasting, hepatomegaly, growth retardation, osteopenia, round face, platelet ± neutrophil dysfunction, enteropathy Late hepatic adenomas and carcinomas AR, autosomal recessive; XR, X-​linked.

21.12  Renal involvement in genetic disease 5071 cell clearance of substrate and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on car- diac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria >1 g/​day and/​or estimated glomerular filtration rate <60 ml/​min per 1.73 m2). Genetic diseases with renal tumours Renal cell carcinomas occur in both sporadic and heritable forms. Four major autosomal dominantly inherited renal cell carcinoma syndromes have been identified:  von Hippel–​Lindau syndrome, Birt–​Hogg–​Dubé syndrome, hereditary leiomyomatosis and renal cell cancer, and hereditary papillary renal cancer (Table 21.12.5). Heritable renal cell carcinoma should be suspected in various situ- ations:  young age, bilateral lesions, positive family history, and extrarenal phenotype. The VHL gene mutated in von Hippel–​Lindau syndrome is a tu- mour suppressor gene: two mutations (‘two-​hit’ phenomenon) are required to trigger tumour formation, the first one being germinal (inherited) and the second one somatic. Renal cysts and bilateral multifocal renal cell carcinomas are found in 70% of the patients. Carcinomas are often asymptomatic, should be screened for regularly (Fig. 21.12.2), and occur at a mean age of 45 years. Nephron-​sparing surgery (tumourectomy) or percutaneous radiological interventions (radiofrequency ablation or cryoablation) are advocated when tech- nically feasible. Early treatment of multiple and recurrent renal cell carcinomas prevents metastatic disease, spares nephrons, and is asso- ciated with a significant improvement of renal prognosis. Angiomyolipoma, a benign and frequent sporadic renal tumour, is the most typical renal lesion encountered in tuberous sclerosis, where it is usually multiple, bilateral, and associated with extrarenal manifestations. Two genes are identified in tuberous sclerosis: TSC1 on chromosome 9q, encoding hamartin, and TSC2 on chromo- some 16p, encoding tuberin. By ultrasonography, angiomyolipomas are hyperechogenic, and by CT they are characterized by their high fat content (Fig. 21.12.3). Bleeding is the main complication of renal angiomyolipoma. Multiple angiomyolipomas may also severely reduce renal mass and lead to renal failure. The develop- ment of segmental glomerulosclerosis may accelerate the progres- sion to endstage. Renal cysts may also be found in TSC2 forms, and the incidence of renal cell carcinoma is slightly higher than in the general population. Everolimus inhibits the mTOR complex 1 pathway and reduces the size of angiomyolipomas in patients with tuberous sclerosis; its use is approved for asymptomatic, growing, Fig. 21.12.2  CT of the kidneys in a patient with von Hippel–​Lindau disease. In the right kidney, a solid tumour is found as well as cystic changes. In the left kidney, a voluminous multilocular tumour is detected with thick walls, corresponding to renal clear cell carcinoma, associated with other cystic lesions. Table 21.12.5  Genetic diseases causing renal tumours Disease Gene (OMIM) Inheritance Renal phenotype Extrarenal phenotype Von Hippel–​Lindau disease VHL (193300) AD Renal cysts and cancers (clear cells renal carcinomas) Haemangioblastoma of the cerebellum, brain stem, spinal cord, and retina; phaeochromocytoma; pancreatic cysts and carcinoma; epididymal cystadenoma Birt–​Hogg–​Dubé syndrome BHD (135150) AD Hybrid (chromophobe, ococytoma, renal cell carcinoma) Fibrofolliculomas, pulmonary cysts, pneumothorax, colorectal polyps Hereditary leiomyomatosis and renal cell cancer (HLRCC) FH (150800) AD Papillary carcinoma, type 2 (bilateral, multifocal) Skin leiomyoma, uterine leiomyoma Hereditary papillary renal cancer (HPRC) MET (179755) AD Papillary carcinoma, type 1 (bilateral, multifocal) None Tuberous sclerosis STB1 (191100) STB2 (613254) AD Multiple and bilateral angiomyolipomas and renal cysts; focal and segmental glomerulosclerosis Epilepsy, intellectual disability (central nervous system cortical tubers); astrocytomas; retinal hamartomas; skin lesions (facial angiofibromas, hypopigmented spots, Koenen tumours, café-​au-​lait spots, shagreen patch); cardiac rhabdomyoma; in women, pulmonary lymphangiomyomatosis AD, autosomal dominant.

section 21  Disorders of the kidney and urinary tract 5072 TSC-​related angiomyolipomas greater than 3  cm in diameter. Selected angiomyolipomas may also be treated by renal selective embolization, surgical tumorectomy, or microablative techniques such as radiofrequency ablation or cryoablation. Congenital anomalies of the kidney and urinary tract More than 20 single gene mutations may result in a wide range of congenital anomalies of the kidney and urinary tract, including renal agenesis, renal hypodysplasia, multicystic dysplastic kidney, hydronephrosis, ureteropelvic junction obstruction, megaureter, ureter duplex, vesicoureteral reflux, and posterior urethral valves. These anomalies may be associated with extrarenal symptoms. Congenital anomalies account for 40 to 50% of children with chronic kidney disease: Table 21.12.6 describes on the four main causes. Genetic disorders with nephrolithiasis Pertinent clinical data on these disorders are summarized in Table 21.12.7. Additional information can be found in Chapters 21.14, 21.15, and 21.16. Other genetic diseases with kidney involvement Cystinosis Cystinosis (which is to be clearly distinguished from cystinuria that is due to defective reabsorption of cystine in the proximal tubule; see Chapter 21.14) is a rare (1 in 200 000 live-​born babies), autosomal recessive condition that results from defective carrier-​mediated transport of cystine through the lysosomal membrane due to mu- tations in the gene encoding cystinosin (CTNS). The diagnosis is based on the findings of cystine crystals in tissues, such as the eyes, and on the elevated cystine content in leucocytes. The clinical manifestations are due to progressive intralysosomal accumulation of cystine. In the infantile form, the first symptoms are related to the clinical consequences of Fanconi’s syndrome (salt and water depletion, hypokalaemia, acidosis, and rickets) appearing be- fore 6 months of age. Renal failure develops later, reaching endstage generally before 12 years. In addition to symptomatic management, cysteamine has proved to be effective in cystinosis. It accumulates within lysosomes, pro- motes cystine outflow, and thus reduces tissue cystine content. Administration of this drug should be started as soon as the diag- nosis is made. It may slow the rate of progression of renal failure and prevent most extrarenal complications. However, despite recent progress, tolerance of the drug is not good because of its offensive taste and odour, so compliance may be poor. Topical cysteamine prevents corneal crystal deposition. Fig. 21.12.3  Multiple bilateral renal angiomyolipomas in a patient with tuberous sclerosis (CT scan). Note the voluminous angiomyolipoma (with high content of fat that is black) at the periphery of the right kidney. Table 21.12.6  Congenital anomalies of the kidney and urinary tract Disease Gene (OMIM) Inheritance Renal phenotype Extrarenal phenotype HNF1β disease (renal cysts
and diabetes syndrome; MODY type 5 diabetes) TCF2 (137920) AD Renal cysts, renal dysplasia, renal hypoplasia, single kidney, horseshoe kidney Diabetes mellitus (MODY type 5) Hyperuricaemia, hypomagnesaemia, elevated SGOT, SGPT Renal coloboma syndrome PAX2 (120330) AD Renal hypoplasia, vesicoureteral reflux, oligomeganephronia Optic nerve coloboma Branchio-​oto-​ renal (BOR) syndrome EYA1 (113650) SIX1 (610896) AD Hypoplasia, dysplasia, aplasia (uni-​ or bilateral), Various collecting system anomalies Laterocervical fistulas or cysts, outer, middle and inner ear anomalies Bardet–​Biedl syndrome BBS1–​17 (209900) AR ± oligogenic Hypertension, tubular dysfunction (diabetes insipidus, acidosis), abnormal calyces, communicating cysts, fetal lobulation, interstitial nephritis, glomerular scarring, renal failure Retinal degeneration, polydactyly, obesity, short stature, mental retardation, hypogonadism AD, autosomal dominant; AR, autosomal recessive.

21.12  Renal involvement in genetic disease 5073 FURTHER READING Autosomal dominant polycystic kidney disease Chapman AB, et  al. (2015). Autosomal-​dominant polycystic kidney disease (ADPKD):  executive summary from a Kidney Disease:  Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 88, 17–​27. Cornec-​Le Gall E, et al. (2019). Autosomal dominant polycystic kidney disease. Lancet, 393, 919–35. National Institute for Health Care and Excellence (2015). Tolvaptan for treating autosomal dominant polycystic kidney disease. https:// www.nice.org.uk/guidance/ta358 Torres VE, et al. (2012). Tolvaptan in patients with autosomal dom- inant polycystic kidney disease. N Engl J Med, 367, 2407–​18 Inherited diseases with glomerular involvement Deltas C, Pierides A, Voskarides K (2013). Molecular genetics of familial hematuric diseases. Nephrol Dial Transplant, 28, 2946–​60. Eckardt K-​U, et  al. (2015). Autosomal dominant tubulointerstitial kidney disease:  diagnosis, classification, and management  –​ a KDIGO consensus report. Kidney Int, 88, 676–​83. Eng CM, et al. (2006). Fabry disease. Genet Med, 8, 539–​48. Joly D, Béroud C, Grünfeld J-​P (2015). Rare inherited disorders with renal involvement-​approach to the patient. Kidney Int, 87, 901–​8. Rombach SM, et al. (2013). Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis, 8, 47. Terryn W, et al. (2013). Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice. Nephrol Dial Transplant, 28, 505–​17. Inherited tubulointestinal disorders Devuyst O, et al. (2019). Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers, 5(1), 60. doi: 10.1038/s41572-019-0109-9. Eckardt K-​U, et  al. (2015). Autosomal dominant tubulointerstitial kidney disease:  diagnosis, classification, and management—a KDIGO consensus report. Kidney Int, 88, 676–​83. Hildebrandt F, Airik R, Sayer JA (2013). Nephronophthisis—me- dullary cystic kidney disease. In: Schrier RW, et al. (ed.) Schrier’s Diseases of the kidney (9th edn), pp. 501–​18. Lippincott, Williams and Wilkins, Philadelphia. Inherited disorders with renal tumours Bissler JJ, et al. (2013). Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-​2):  a multicentre, randomised, double-​blind, placebo-​ controlled trial. Lancet, 381, 817–​24. Bissler JJ, Christopher Kingswood J (2018). Renal manifestation of tuberous sclerosis complex. Am J Med Genet Semin Med Genet, 178, 338–47. Joly D, et al. (2011). Progress in nephron sparing therapy for renal cell carcinoma and von Hippel-​Lindau disease. JURO, 185, 2056–​60. Genetic diseases with urolithiasis Cochat P, Rumsby G (2013). Primary hyperoxaluria. N Engl J Med, 369, 649–​58. Genetic diseases with kidney involvement Hildebrandt F (2010). Genetic kidney diseases. Lancet, 375, 1287–​95. Joly D, Béroud C, Grünfeld J-​P (2015). Rare inherited disorders with renal involvement-​approach to the patient. Kidney Int, 87, 901–​8. Remuzzi G, et al. (2014). Rare inherited kidney diseases: challenges, opportunities, and perspectives. Lancet, 383, 1844–​59. Table 21.12.7  The main inherited disorders associated with nephrolithiasis Disease Mode of transmission Type of stone Chronic renal failure Specific treatment Cystinuria AR Cystine No Urine alkalinization d-​penicillamine or other chelators Idiopathic hypercalciuria Unknown Calcium No Diet (normal sodium and protein intake) Thiazide Primary hyperoxaluria type I AR Monohydrated calcium Yes (nephrocalcinosis) Vitamin B6 Oxalate Liver transplantation Dent’s disease XR Calcium Yes (nephrocalcinosis) Distal tubular acidosis AR/​AD Calcium No Potassium citrate or bicarbonate HPRT deficiency (Lesch–​Nyhan syndrome) XR Uric acid Yes Urine alkalinization Allopurinol APRT deficiency AR 2,8-​dihydroxyadenine Yes (rarely) Allopurinol Xanthinuria AR Xanthine No AD, autosomal dominant; APRT, adenine phosphoribosyl transferase; AR, autosomal recessive; HPRT, hypoxanthine-​guanine phosphoribosyl transferase; XR, X-​linked.

ESSENTIALS Urinary tract infection (UTI) is a common condition, accounting for 1 to 3% of all primary care consultations in the United Kingdom. It affects patients of both sexes and all ages. The commonest or- ganism causing uncomplicated community-​acquired bacterial UTI is Escherichia coli. Aetiology and pathogenesis The occurrence and course of a UTI is influenced by the integrity of the host defence and by bacterial virulence factors. Disruption of the highly specialized transitional cell epithelium which lines the urinary tract, incomplete bladder emptying, anatomical abnormalities, and the presence of a foreign body, such as a urinary catheter, can all con- tribute to disruption of the host defence and increase the likelihood of infection. Sexual intercourse and use of spermicides increase the risk, and genetic factors influence the susceptibility of some people. Bacterial characteristics that determine their ability to cause infection include specific mechanisms to adhere to the uroepithelium (‘pili’ or ‘fimbriae’ in the case of certain E. coli), or adaptations allowing them to colonize foreign surfaces, such as a urinary catheter (proteus), and subsequently cause infection. Clinical features and diagnosis Presentation—​cystitis commonly presents with some combination of dysuria, urgency, frequency, polyuria, suprapubic tenderness, and haematuria. Patients with pyelonephritis often have loin pain and other systemic symptoms, with or without symptoms of cystitis. Asymptomatic infection is common, especially in older people, but it is not justified to send a urine sample from an asymptomatic patient for culture, with the notable exceptions of pregnant women, when treatment is mandatory, and prior to invasive urological surgery, when treatment prior to surgery can reduce the risk of postoperative sepsis. Diagnosis—​acute uncomplicated UTI can often be diagnosed on symptoms alone, with urinalysis increasing diagnostic accuracy. Submission of a sample for microbiological testing is unnecessary in most cases (exceptions to this rule include pregnancy, recurrent infection, and those patients with abnormal host defences). Current United Kingdom and European guidelines on the level of bacterial counts required to diagnose ‘significant’ infection are variable and should not be used as the sole determinant of whether antibiotic treatment should be initiated. Differential diagnoses (‘culture-​negative syndromes’)—​these include (1)  chlamydial infection, which must be identified and treated to avoid long-​term complications such as infertility; also (2) urethral syndrome and (3)  painful bladder syndrome (interstitial cystitis), which significantly affect a patient’s quality of life and for which treat- ment is often unsuccessful. Investigation—​beyond microbiological testing, further investiga- tion of women with uncomplicated UTI is seldom justified. In men, and those women with features indicating complicated infection, in- vestigation for an underlying cause should be considered: diabetes must be excluded, and anatomical or functional abnormality of the urinary tract sought, as appropriate, by imaging, cystoscopy, and urinary flow studies. Management Antibiotics—​trimethoprim and nitrofurantoin remain the first choice for community-​acquired UTI in the United Kingdom. Complicated UTI is caused by a wider spectrum of organisms, and recommenda- tions for treatment differ. Guidelines on specific antibiotic treatment and duration of treatment are available, but with increasing antibiotic resistance (including of E. coli to trimethoprim), local microbiological advice should be taken into account. Prevention of recurrent uncomplicated UTI—​many clinicians advise patients with such recurrence to take measures to improve perineal hygiene, to empty the bladder after sexual intercourse, to maintain a high fluid intake, and (if vesicoureteric reflux is suspected) to practise double voiding, but the evidence that these measures are effective is weak. Long-​term antibiotic prophylaxis reduces the rate of recur- rent UTI, but at the risk of adverse effects. Nightly, thrice weekly, and postcoital prophylaxis have all been shown to be of benefit, but there is no evidence to support the use of rotating antibiotic prophylaxis. Cranberry extract and methenamine hippurate are effective in some patients and have the advantage of not increasing the risk of anti- biotic resistance. Oestrogens are not recommended for the routine prevention of recurrent infection in postmenopausal women, but may be of benefit in those with marked atrophic vaginitis. 21.13 Urinary tract infection Charles Tomson and Neil Sheerin

21.13  Urinary tract infection 5075 Complicated urinary tract infections Complicated UTIs are those occurring in a patient with abnormal host defences. It is uncommon for any man with an anatomically normal urinary tract to suffer a UTI. Urethral catheterization—​UTI occurs after 2% of in/​out urethral catheterizations and after 10 to 30% of 5-​day indwelling catheter- ization, and is nearly inevitable in patients with long-​term indwelling catheters. This is an important cause of hospital-​acquired infec- tion, significantly increasing the risk of Gram-​negative septicaemia and mortality. However, management of patients unable to empty their bladder fully for reasons such as prostatic outflow obstruction or neurogenic bladder dysfunction because of spinal cord injury is often difficult without medium-​ or long-​term urinary catheterization. Use of prophylactic antibiotics to cover short-​term catheter insertion may be justified, but this is not the case in patients with long-​term catheters, although regular bladder washouts and methenamine may be of some benefit. Treatment of asymptomatic bacteriuria in patients with anatomically abnormal urinary tracts or with indwelling urinary catheters is unjustified and likely only to lead to the emer- gence of antibiotic-​resistant urinary infection. Clean, intermittent self-​catheterization should be considered as an alternative where possible. Urinary tract stones—​these are an important cause of recurrent and relapsing UTIs that are difficult or impossible to treat with antibiotic therapy alone, repeated courses of which often encourage the de- velopment of resistant organisms. Removal of stones is often difficult and requires repeated interventions. Identification of the stone type and prevention of formation of further stones is an important part of any treatment plan. Anatomically abnormal kidneys—​inherited renal abnormalities such as polycystic kidneys are often complicated by UTI, which can be difficult to treat if the infection involves a cyst. Renal transplant recipients are at an increased risk of UTI due to a variety of factors, including the anatomy of the transplant kidney, postoperative cath- eterization, and immunosuppressive medication. Unusual viral or- ganisms such as polyoma (BK) virus may cause infection in this group of patients. Vesicoureteric reflux—​the normal bladder prevents reflux of urine into the ureters during micturition. Congenital abnormalities of the vesicoureteric junction can allow this to occur, as can acquired ab- normalities such as bladder outflow obstruction, which disrupts normal host defence against ascending infection and thus makes children (particularly girls) more prone to ascending UTI. Cortical defects (‘scars’) in the upper and lower poles of the kidneys are fre- quently found in such children. These may be caused by ascending infection causing acute pyelonephritis, but similar appearances can occur in the absence of UTI and are likely due to renal dysplasia, in- herited along with abnormal insertion of the ureters into the bladder. Progressive kidney failure may occur in such patients, but it is more likely that this is due to the late effects of renal dysplasia and con- genital reduction in renal mass, rather than to the effects of scarring caused by ascending infection. Clinical trials comparing long-​term prophylactic antibiotics for the first 5 years of life versus surgical ur- eteric reimplantation have shown a similar incidence of symptom- atic UTI in both treatment groups; whether either treatment reduces the risk of the development of new scars or of progressive kidney failure remains uncertain. Pregnancy—​there is a significantly increased risk of acute pyelonephritis in pregnant women with untreated bacteriuria, many of whom will be asymptomatic. Late pyelonephritis is associated with an increased incidence of preterm delivery and low birth weight, hence the need in pregnancy to screen for and treat UTI promptly with antibiotics. Ascending UTI is rarely complicated by unusual conditions such as acute papillary necrosis or perinephric abscess. These can lead to destruction of renal parenchymal tissue and chronic kidney dis- ease, usually in the context of abnormal host defence such as dia- betes or urinary tract obstruction. Malakoplakia is an extremely rare complication of bacterial UTI, characterized by destructive tu- mour-​like granulomatous infiltrates in the urinary bladder, kidneys, and (occasionally) other organs. Other causes of UTI may need to be considered depending on the patient’s ethnic background and medical and travel history (e.g. fungal infections, tuberculosis, and schistosomiasis). Introduction ‘Urinary tract infection’ (UTI) refers to bacterial, viral, or fungal in- fection of the kidneys, renal pelvis, ureters, or bladder. Infections primarily involving the urethra are nearly always sexually acquired and are dealt with elsewhere (see Section 9). ‘Pyelonephritis’ refers to infection primarily involving the kidneys and collecting sys- tems. ‘Cystitis’ refers to infections localized to the urinary bladder. ‘Recurrent’ UTIs are due to repeated reinfection, whether by similar organisms on each occasion or by different species; ‘relapsing’ and ‘persistent’ infections are due to the continued presence of the same organism, suppressed or not suppressed during antibiotic therapy. ‘Uncomplicated’ UTIs occur in an anatomically and functionally normal urinary tract; ‘complicated’ infection refers to all infections occurring in patients either with impaired host defence (e.g. dia- betes), with abnormal urinary tract function (e.g. pregnancy), or ab- normal urinary tract anatomy (e.g. urinary tract obstruction). Infection of the urinary tract is important for different reasons in different age groups. In infants and children, ascending infection is thought to be a preventable cause of renal parenchymal scarring and eventual renal failure, although it is controversial how frequently this occurs. In adult women, recurrent lower UTI (‘cystitis’) is a common cause of time off work. In all age groups, persistent or relapsing infec- tion is an important indicator of abnormal host defences, usually due to abnormal anatomy or function of the urinary tract, and may re- sult in irreversible renal damage unless the underlying cause is dealt with. UTI are the cause of over 50% of Gram-​negative septicaemic episodes. In older people, nonspecific symptoms including toxic confusional states are often due to occult UTI. Epidemiology Symptomatic bacterial UTI is one of the commonest bacterial in- fections. Around 1% of boys and 3% of girls will develop a UTI during childhood, and 50% of women will be treated for at least one UTI during their lifetime, with recurrent infections in a signifi- cant minority. UTI is rare in men until after the age of 60, when

section 21  Disorders of the kidney and urinary tract 5076 the rising prevalence of impaired bladder emptying leads to an in- creased incidence of infection. Asymptomatic bacteriuria is found in about 10% of elderly men and in 20% of elderly women. UTI is one of the commonest bacterial infections managed in primary care, and is the cause of 1 to 3% of all primary care consultations in the United Kingdom. UTI is responsible for over 25% of all community-​ acquired bacteraemias, more than any other source of infection. The Nosocomial Infection National Surveillance System reported that in England (2011), 17.2% of all healthcare-​associated infections were due to UTI, and 7.5% of hospital-​acquired bacteraemias were due to catheter-​associated UTI. Aetiology The commonest causative organisms in uncomplicated bacterial UTI are Gram-​negative gut organisms, particularly Escherichia coli (Box 21.13.1). This reflects the fact that most infections reach the urinary tract via the urethra from the perineum. However, as dis- cussed later, only some subtypes of E. coli and only some of the other species of gut organisms have the necessary virulence characteristics to enable infection of the normal urinary tract. E. coli is the third most common organism causing hospital-​acquired bacteraemia. Complicated UTIs are caused by a broader spectrum of bacteria, including Gram-​positive in addition to Gram-​negative organisms and those with multiple resistance to antibiotics. Pathophysiology The occurrence and course of UTIs are influenced by the integrity of the host defence and bacterial virulence factors. Host defence Most UTIs are acquired by ascent of the infecting organism up the urethra; only a very few result from haematogenous spread or—​even less commonly—​from vesicoenteric fistulas. The renal pelvis, ure- ters, bladder, and urethra possess a highly specialized transitional cell epithelium, which normally maintains complete impermeability to all components of urine, including toxins and water. This is main- tained by tight junctions between the surface layers of epithelial cells, with a very high transepithelial electrical resistance. In the bladder, this impermeability has to be maintained despite repeated large changes in surface area as the bladder fills and empties. This is maintained by unfolding and refolding of the large, highly folded ‘umbrella’ cells that form the uppermost layer of the epithelium, to- gether with insertion and endocytosis of vesicles, ready-​lined with uroplakin, a hexagonal transmembrane protein found only on the surface of umbrella cells. Ascending infection takes place in a series of steps, at each of which defective host defence increases the chance of successful es- tablishment of infection (Fig. 21.13.1). Frequency and completeness of bladder emptying For an ascending infection to become established in the bladder, the number of organisms needs to reach a critical mass. The chance of this happening is reduced by increased urine flow rate, causing dilution of organisms within the bladder, and by frequent voiding, which also flushes the urethra and helps to prevent ascent of or- ganisms into the bladder. This is termed ‘hydrokinetic’ defence. Habitual infrequent voiding is thought to be a risk factor for re- current UTIs for this reason. Patients with recurrent UTIs are rou- tinely advised to increase fluid intake and frequency of voiding, and some women report that a high fluid intake alone is enough to clear symptomatic infection. Incomplete voiding, which may be present in both sexes and is not necessarily due to outflow obstruction (Box 21.13.2), is an important cause of increased susceptibility to urine infection. Vesicoureteric reflux During normal micturition, urine is expelled into the urethra while retrograde flow (‘reflux’) of urine into the ureters is prevented be- cause muscular contraction of the bladder wall results in closure of the vesicoureteric junctions. Reflux of urine into the ureters can occur if this mechanism is defective, followed by return to the Box 21.13.1  Organisms commonly causing uncomplicated UTI • Escherichia coli • Klebsiella pneumoniae • Proteus • Pseudomonas • Enterococcus • Staphylococcus saprophyticus (in sexually active females) Entry into renal parenchyma

21.13  Urinary tract infection 5077 bladder once bladder contraction has finished. The most common cause of reflux is abnormal insertion of the ureters into the bladder, which occurs as a relatively frequent developmental anomaly. The other major cause is abnormally high intravesical pressure, for ex- ample, in high-​pressure chronic retention of urine due to bladder outflow obstruction, or in neurogenic bladder in patients with par- tial spinal cord lesions. Whatever the cause, reflux of urine results in failure to expel all bladder urine during micturition and therefore significantly impairs host defence against infection, as well as being associated with a greatly increased risk of infection ascending to the kidneys and causing acute pyelonephritis. Vesicoureteric reflux is frequently found in children with UTIs. The question of whether as- cending infection is a cause of renal damage in children with reflux is discussed later in this chapter. Foreign bodies, stones, and privileged sites The presence of a foreign body, such as a urinary catheter or ureteric stent, or a stone within the urinary tract, creates a protected site where uropathogenic organisms can adhere and multiply, relatively protected from both hydrokinetic and mucosal defence mechan- isms. In this situation, it is often impossible to eradicate urine in- fection unless the foreign body or stone is removed, and prolonged use of antibiotics often results in the acquisition of resistance by the infecting organism. Urinary infection is nearly inevitable after a few weeks of bladder catheterization. Other ‘privileged’ sites in- clude renal cysts (as in polycystic kidney disease, discussed later) and bladder diverticula. Sexual activity Many women first experience acute cystitis shortly after becoming sexually active. Most women have transient bacteriuria after sexual intercourse, which develops into symptomatic cystitis only in a mi- nority. In case–​control studies of young women, the risk of UTI was associated with vaginal intercourse, and increased further by condom use. These findings are explained by the mechanical effect of intercourse encouraging ascent of organisms up the urethra, an effect that may be exacerbated by condom use, particularly without lubri- cants. The risk of UTI is also increased by a change in sexual partner, which may reflect male-​to-​female transmission of uropathogens. Use of spermicides as an adjunct to barrier contraceptive methods is also associated with an increased rate of periurethral colonization with E. coli and other uropathogens and with an increased risk of symptomatic UTI, probably because the active component in sper- micides (nonoxynol-​9) is bactericidal against lactobacilli. The pro- tective effect of micturition soon after intercourse, based on the supposition that washout of recently introduced bacteria will pre- vent establishment of infection, remains unproven. Vaginal and periurethral flora Vaginal secretions are normally colonized by lactobacilli that ap- pear to protect against colonization by uropathogenic bacteria such as E. coli. The mechanism of this protection is uncertain, but may in part be related to the maintenance of an acidic pH, which sup- presses growth of some uropathogenic bacteria. Suppression of this normal vaginal colonization by antibiotic treatment or by spermi- cide use increases the risk of colonization of the periurethral mucosa by uropathogenic bacteria and subsequent ascending UTI. In add- ition, atrophic vaginitis caused by oestrogen deficiency is associated with the absence of lactobacillus colonization, which may be part of the reason for the increased risk of UTI in postmenopausal women. Genetic factors In laboratory studies, adherence of E. coli to both vaginal and buccal cells is greater in cells taken from women with recurrent UTIs than in cells from healthy controls, and women with recurrent UTIs more frequently have gut colonization by uropathogenic strains of E. coli, suggesting that they experience more frequent UTIs because they are more susceptible to colonization of the periurethral area by uropathogenic bacteria. It appears that this difference in suscepti- bility to colonization and infection, especially in patients in whom there is no other defect of host defence (such as vesicoureteric re- flux), is due to genetically determined differences in the extracellular antigens to which bacteria adhere, in particular in the expression of blood group antigens. The density of glycosphingolipids is higher in patients with the P1 blood group than those with the P2 blood group, and the P1 blood group is a risk factor for acute pyelonephritis among girls without vesicoureteric reflux. Expression of the large oligosaccharide A, B, H blood-​group antigens on the cell surface partially or completely ob- scures the smaller glycosphingolipids, preventing them from being bound by type P fimbriae, which is why women with the secretor phenotype, in which these antigens are both expressed on the cell surface and secreted, are less prone to most E. coli infections than nonsecretors. Nonsecretors also have an increased inflammatory re- sponse (fever and acute-​phase response) to urinary infection com- pared with secretors, and nonsecretors are over-​represented among patients with urographic evidence of reflux nephropathy. However, some E. coli strains only bind to cells from subjects who are secretor-​ positive blood group A. Local immunity Another aspect of host defence is the local production of antimicro- bial peptides, secreted by uroepithelial cells into the urine, and the secretion of IgA into the urine. However, there is little convincing evidence that impaired local IgA secretion is responsible for in- creased susceptibility to UTI. Patients with defects in systemic im- munity, whether cellular or humoral, do not appear to be at a greatly increased risk of UTI; the risk of UTI with AIDS is only increased in men practising unprotected anal intercourse. Bacterial virulence factors The ability of a bacterium to colonize the gut and periurethral mucosa, and subsequently to adhere to the uroepithelium, is a major determinant of its ability to cause clinical infection, particularly if other host defences are intact. This ability to adhere is governed by a specific interaction between bacterial adhesins, located on the tips of thin filaments (‘pili’ or ‘fimbriae’), with genetically determined Box 21.13.2  Some causes of incomplete bladder emptying • Bladder outflow obstruction: —​  Benign prostatic hypertrophy —​  Prostate cancer —​  Strictures—​bladder neck, urethral —​  Uterine prolapse • Detrusor underactivity • Abnormal bladder innervation: —​  Spinal cord injury —​  Autonomic neuropathy (e.g. diabetes)

section 21  Disorders of the kidney and urinary tract 5078 glycoproteins on the cell surface of the host cell. Type 1 fimbriae bind to mannose-​containing glycoproteins (uroplakins) that are present on the surface of uroepithelial cells, but also to Tamm–​ Horsfall protein, which is present in urine and can competitively inhibit binding of bacteria to cell surface glycoproteins. Type P pili bind the α-​galactosyl-​1,4-​β-​galactose disaccharide sequence pre- sent in some glycoproteins and glycosphingolipids, including the human P blood-​group antigen system, and also on the cell surface of uroepithelial cells as well as red cells. Some uropathogens are particularly adapted to colonizing for- eign surfaces, particularly those coated by biofilm or mucin; for example, proteus are able to transform into a swarming phenotype with massive flagellas, organize into rafts, and move very rapidly against the flow of urine—​they are therefore important causes of in- fection in patients with indwelling urinary catheters and those with ileal conduits. Staphylococcus saprophyticus, an important cause of UTI in sexually active young women, is probably better able to cause UTI than S. aureus or S. epidermidis because of its possession of a lactosamine adhesin, permitting adherence to uroepithelial cells. Following adherence, fimbriae appear to retract, drawing the or- ganism closer to the surface of the uroepithelial cell. Adherence is followed by apoptosis, exfoliation, and excretion of infected super- ficial cells and replacement by less differentiated cells, a process that may also contribute to host defence. Some bacteria may also intern- alize into urothelial cells, allowing persistence within the urinary tract and occupation of a site inaccessible to water-​soluble anti- biotics. Uropathogenic bacteria also possess other virulence factors including toxin production, resistance to complement-​mediated lysis, and metal ion-​chelating proteins. Clinical features of UTI Cystitis The commonest presentation of UTIs is with ‘cystitis’, a symptom complex associated with lower UTI in which many of the symptoms are directly attributable to increased bladder irritability caused by local infection, without systemic symptoms. Typical symptoms—​ not all of which are specific for lower UTI—​are listed in Box 21.13.3. Dysuria may be due to urethritis or vaginitis, but these are usually not associated with urinary frequency, and may be associated with vaginal discharge or itching and with specific findings on vaginal examination. There is considerable overlap between the symptoms of UTI, idiopathic overactive bladder (dysuria and haematuria are uncommon), painful bladder syndrome and chemical, drug or radi- ation induced cystitis. Asymptomatic bacteriuria By definition, this is an incidental finding in patients whose urine is cultured despite the absence of urinary tract symptoms. It is seldom justified to send a urine sample from an asymptomatic patient for cul- ture, so this diagnosis should only rarely be made in clinical practice. Two important exceptions are during pregnancy and prior to invasive urological surgery (discussed later). Elderly patients with asymptom- atic bacteriuria are also at increased risk of death, but this is probably because bacteriuria is a marker of poorer general health: antibacterial treatment has not been shown to improve survival in this situation. Acute pyelonephritis The term ‘acute pyelonephritis’ denotes infection within the renal pelvis, with or without active infection within the renal paren- chyma. The diagnosis is usually made on the basis of the presence of flank pain (usually unilateral), fever, rigors, raised C-​reactive protein (or erythrocyte sedimentation rate or plasma viscosity), neutrophilia, and evidence of urine infection on culture of a mid- stream urine sample. Although localization studies show a poor cor- relation between the site of infection and the presence or absence of systemic symptoms, the clinical syndromes of ‘cystitis’ and ‘acute pyelonephritis’ are a robust means of deciding on treatment. Diagnosis Inspection and dipstick testing When typical symptoms are present (more than three of those listed in Box 21.13.3) or if fewer symptoms are present but the urine is cloudy and dipstick urinalysis is positive for nitrite and leucocyte esterase, a diagnosis of UTI likely. In this situation, it is reasonable to make a diagnosis of UTI without further delay and to institute empirical treatment if required. Whether a midstream urine sample should also be sent to the laboratory for confirmation and identifi- cation of the causative organism depends on the clinical situation, as discussed in ‘Laboratory diagnosis and culture of urine’. However, in many situations the diagnosis is not so obvious, and the diagnostic accuracy of inspection and dipstick testing less good. Cloudy urine may be caused by bacteria and pyuria, but may also be caused by amorphous phosphate crystals that form in normal urine as it cools. Low concentrations of bacteria and white cells will not cause sufficient turbidity to be detected on visual inspection. An offensive, fishy smell is highly suggestive of UTI, but relatively infrequent. Visible haematuria can certainly occur as a result of severe cyst- itis, but is frequently absent in isolated UTI and is more often due to glomerular bleeding or urothelial bleeding as a result of tumours or stones. Dipstick detection of haematuria is neither sensitive nor specific for the detection of UTI. Proteinuria can occur in UTI as a result of the release of proteins from white cells, but is neither spe- cific nor sensitive; albumin excretion remains normal unless there is a systemic inflammatory response. Box 21.13.3  Common symptoms of lower UTI • Severe dysuria, often described as ‘scorching’ or ‘like peeing barbed wire’, worse towards the end of or immediately after micturition • Increased urinary frequency • Urgency—​the sensation of a strong desire to pass urine • Strangury—​the feeling of needing to pass urine despite just having done so • Offensive-​smelling urine, often described as ‘strong’ or ‘fishy’ • Visible haematuria • Urge incontinence—​leakage of urine associated with the desire to pass urine • Constant lower abdominal aching, not just in the genital area but also in the back, flanks, and lower abdomen • Nonspecific malaise, aching all over, nausea, tiredness, irritability, and cold sweats

21.13  Urinary tract infection 5079 Leucocyte esterase is an enzyme released by white cells and a reliable test for pyuria, which is in most situations a major diag- nostic criterion for UTI, as discussed in the next section. A posi- tive test indicates 10 white cells/​ml. Note, however, that transport of urine samples in containers containing boric acid can result in false-​negative leucocyte esterase tests, as the boric acid inhibits the enzyme. Nitrite is produced by most uropathogens, which reduce urinary nitrate to nitrite, but not by Gram-​positive organisms. A positive test for nitrite is highly suggestive of UTI. False-​negative tests can be seen in patients with low dietary nitrate and in those taking high-​ dose ascorbic acid. The diagnosis of acute uncomplicated UTI is highly likely with a history of two urinary symptoms, and a positive nitrite test. A combination of visual inspection and dipstick testing is a rea- sonable screening test for patients in whom uncomplicated UTI is suspected on clinical grounds: in this situation, crystal-​clear urine and negative dipsticks for nitrite and leucocyte esterase make the diagnosis of UTI very unlikely (Table 21.13.1). The worst that is likely to happen if the diagnosis is missed is that the patient will rep- resent with more obvious abnormalities due to progression of the UTI to a more severe stage. However, in situations in which it would be important not to miss the opportunity to start treatment early, for example, in patients with known abnormalities of host defence, pregnancy, or previous acute pyelonephritis, or in suspected atypical infections, formal microscopy and culture of the urine is required. An algorithm for diagnosis of suspected uncomplicated UTI in adult women is shown in Fig. 21.13.2. Laboratory diagnosis and culture of urine The diagnosis of bacterial infection in the urinary tract might appear straightforward, relying on culture of freshly voided urine. However, urine samples are very easily contaminated during voiding by bac- teria from the perineal skin (or, to a lesser extent, the foreskin in males), resulting in false-​positive results. The only certain way to circumvent this problem is to take urine directly from the bladder, either by suprapubic needle aspiration of urine from the bladder, which is invasive and seldom performed in clinical practice, or by urethral catheterization, which carries a 1 to 2% risk of introducing infection into the bladder. In men, contamination of the voided urine sample can largely be avoided by retraction of the foreskin prior to voiding. In women, the reliability of urine culture can be improved by instructing women to part the labia with one hand and Table 21.13.1  Usefulness of inspection and dipstick testing in the diagnosis of UTI Test Utility False positive False negative Cloudy appearance Suggestive Phosphate crystals Common Haematuria Unreliable Renal disease, stones, tumours Common Proteinuria Unreliable Renal disease Common Leucocyte esterase Highly suggestive Some antibiotics Boric acid Nitrite Highly suggestive Few Gram +ve infection   Severe or ≥ 3 symptoms of UTI Dysuria Urgency Frequency Polyuria Haematuria AND NO vaginal discharge or irritation 90% culture positive Give empirical antibiotic treatment Consider other diagnosis Urine NOT cloudy 97% NPV Obtain urine specimen Positive nitrite, and leucocytes and blood 92% PPV or Positive nitrite alone Probable UTI Treat with first line agents on local or HPA Guidance Negative nitrite Positive leucocyte Negative nitrite, leucocytes and blood 76% NPV or negative nitrite and leucocyte positive blood or protein Laboratory microscopy for red cells is less sensitive than dipstick UTI Unlikely Consider other diagnosis Reassure and give advice on management of symptoms UTI or other diagnosis equally likely Review time of specimen (morning is most reliable) Treat if severe symptoms or consider delayed antibiotic prescription and send urine for culture Mild or ≤ 2 symptoms of UTI (as above) Perform urine dipstick test with nitrite When reading test WAIT for the time recommended by the manufacturer URINE CLOUDY Suprapubic tenderness URINARY SYMPTOMS IN ADULT WOMEN <65 DO NOT CULTURE ROUTINELY In sexually active young men and women with urinary symptoms consider Chlamydia trachomatis Fig. 21.13.2  Algorithm for diagnosis of suspected acute uncomplicated UTI in adult women. Reproduced with permission from https://​www.gov.uk/​government/​publications/​urinary-​tract-​infection-​diagnosis.

section 21  Disorders of the kidney and urinary tract 5080 ensuring collection of a midstream sample, without either the ini- tial portion or the ‘afterdrip’, but is not improved further by perineal washing or antiseptic use. These precautions only reduce the risk of contamination, rather than abolishing it altogether. Microscopy and flow cytometry analysis of urine samples allows quantification of pyuria—​the presence of white blood cells in the urine. However, the methodologies used to report pyuria vary enormously. Significant pyuria is usually defined as a urinary white cell count of more than 10 leucocytes/​µl of unspun urine. Bacterial UTI is by far the commonest cause of pyuria, and symptomatic patients with pyuria whose urine cultures are reported as showing no significant pathogens should be suspected either of having ‘low-​count’ bacteriuria due to early infection, or infection with a slow-​growing organism, chlamydial infection, or one of the causes of sterile pyuria (Box 21.13.4). However, vaginal leucorrhoea can also result in ‘false-​positive’ pyuria. Once a urine sample is obtained, the conditions under which it is cultured determine whether any organisms present grow. Standard laboratory culture conditions are designed to encourage the growth of recognized urinary pathogens (if present), but may not be optimal for the growth of atypical organisms or of those not usually recog- nized as urinary pathogens. Because small numbers of organisms are frequently cultured from urine as a result of contamination, growth of an organism is conventionally reported as a ‘significant growth’ if it meets several criteria. These are summarized in Box 21.13.5. Although the number of bacteria per millilitre of urine to diagnose UTI is frequently quoted at greater than 105 cfu/​ml, this threshold will miss many cases of UTI. Lower thresholds are therefore applied in some countries (see later in this section). Identification of multiple organisms is often regarded as a sign of contamination. However, genuine mixed growth of two or more bacteria may occur in complicated UTI (Box 21.13.6), as may the growth of an organism not usually associated with the urinary tract. In addition, the spectrum of organisms recognized as capable of causing genuine UTI is widening. S. saprophyticus was only fairly recently recognized as a cause of UTI in sexually active women, and it is possible that other true urinary pathogens are yet to be iden- tified, perhaps accounting for some cases of the so-​called urethral syndrome (see ‘Urethral syndrome and chlamydial urethritis’). ‘Low-​count’ bacteriuria may reflect genuine bladder infection, particularly in early UTIs, and may occur in patients who have in- creased their fluid intake and are ‘diluting’ their bacterial counts by generating a high urinary output; also in patients infected with slow-​ growing organisms such as S. saprophyticus. The criterion of 105 cfu/​ml was originally validated in asymp- tomatic women, but subsequent studies showed that nearly 50% of women presenting with frequency and dysuria had genuine bladder infection but with counts between 102 and 105 cfu/​ml on culture of a midstream urine sample. If symptomatic women with counts of be- tween 102 and 104 cfu/​ml are left untreated, most will have persistent symptoms and counts of more than 105 cfu/​ml 2 days later. Current European guidelines advise that the number of colony counts that should be considered to indicate UTI should vary according to the clinical context, for example, with lower counts being accepted as indicative of infection in the presence of symptoms. In the United Kingdom, greater than 104 cfu/​ml of a single organism, or greater than 103 cfu/​ml of E. coli or S. saprophyticus is regarded as signifi- cant. However, implementation of these criteria by laboratories would require high-​quality clinical details to be provided at the time of submission of the urine sample, and most laboratories adhere to the 105 criterion. In men, bacterial counts of 103 cfu/​ml or more are very likely to reflect significant infection, as the potential for signifi- cant contamination is lower. The presence of pyuria further increases the likelihood that low counts are significant, although pyuria is not always present in proven bladder infection, particularly if the sample is taken early after the onset. The traditional method of expressing urinary white cell counts as cells per high-​power field is very poorly reproducible, as the volume in a high-​power field is extremely variable. If accur- ately quantified, the criterion of 10 white cells/​mm3 separates pa- tients with genuine bacteriuria from those without. Localization to upper or lower urinary tract Tests to discover whether infection is confined to the bladder or whether it has spread to involve one or both kidneys are very seldom necessary, but may be required if, for example, surgical removal of a kidney because of recurrent infection is contemplated. The ‘gold standard’ for diagnosis of upper UTI is culture of urine obtained from each ureter by direct catheterization during cystoscopy, but Box 21.13.4  Causes of ‘sterile pyuria’ • Partially treated bacterial UTI • Bacterial UTI with a ‘fastidious’ organism • Chlamydial urethritis • ‘False-​negative’ urine cultures due to contamination of midstream urine sample with antiseptic • Contamination by vaginal leucocytes • Chronic interstitial nephritis: —​  Analgesic nephropathy —​  Sarcoidosis (urinary white cells may be lymphocytes, not neutrophils) • Urinary tract stones • Acute interstitial nephritis, such as allergic interstitial nephritis (urinary white cells may be eosinophils) • Papillary necrosis: —​  Diabetes —​  Sickle cell disease • Renal tract tuberculosis • Fever Box 21.13.5  Criteria for the diagnosis of UTI • There is a pure growth (i.e. of a single organism) • The organism grown is a ‘recognized’ urinary pathogen • Quantitative urine culture results in greater than 105 cfu/​ml • There is significant pyuria on urine microscopy, and few if any squamous cells Box 21.13.6  Conditions in which genuine mixed-​growth UTI may occur • Ileal conduits • Neurogenic bladder • Vesicocolic fistula • Urinary tract stones • Renal abscesses • Long-​term indwelling urinary catheters or stents

21.13  Urinary tract infection 5081 such an invasive procedure can only be justified in exceptional cir- cumstances, and even then may be difficult to interpret due to con- tamination of ureteric samples by bladder urine during passage of the catheters. This test is seldom used in modern practice. Renal excretory function usually remains unchanged during acute pyelonephritis unless obstruction is present, but acute kidney injury is occasionally seen, often associated with coincident use of nonsteroidal anti-​inflammatory drugs (NSAIDs), diuretics, and angiotensin-​converting enzyme inhibitors or angiotensin II re- ceptor blockers. Imaging to diagnose pyelonephritis is rarely indi- cated in adults. Abnormal appearances on contrast CT scanning and/​or dimercaptosuccinic acid (DMSA) scanning have been re- ported, including generalized renal swelling, focal areas of decreased parenchymal enhancement, and perirenal abscess formation, with the development of cortical scars and calyceal diverticula if imaging is repeated on follow-​up. In general, the more severe the infection is clinically (assessed by acute-​phase response, duration of fever, etc.), the more marked the radiological abnormality. However, significant loss of renal excretory function following acute pyelonephritis in patients without diabetes, obstruction, or pre-​existing reflux neph- ropathy/​dysplasia, is remarkably uncommon even on long-​term follow-​up, and the significance of such scars is therefore uncertain. Differential diagnosis of UTI Occasionally patients may present with symptoms and signs highly suggestive of UTI, with or without pyuria, but with negative urine cultures. These patients may have ‘false-​negative’ urine cultures, for example, a low growth of a genuine pathogen; infection with a ‘fas- tidious’ organism, the presence of which is not detected by routine laboratory cultures; or they may have a noninfectious cause. It is dangerous to label symptoms in such patients as psychogenic; pro- longed symptoms combined with numerous unsuccessful trials of antibacterials, or with different explanations from different doctors, may result in psychological stress, which in turn may amplify symp- toms, but there is little evidence that psychological disease is the pri- mary problem, even in a subgroup. Urethral syndrome and chlamydial urethritis The term ‘urethral syndrome’ was used in the past as a synonym for the typical symptoms of cystitis, namely frequency, urgency, and dysuria. More recently it has been applied to the subgroup of women with typical symptoms but in whom a recognized urinary pathogen cannot be cultured from the urine. Some of these patients, particu- larly those with pyuria, have chlamydial urethritis. Chlamydial infection can be confirmed by culture of a urethral swab, or by detection of chlamydia antigens on an endocervical or urethral swab or first-​pass urine specimen by nucleic acid ampli- fication techniques. It can be treated with tetracyclines, but as the infection may be sexually transmitted it is also important to treat the patient’s sexual partner(s), who may be asymptomatic. Patients with confirmed chlamydial infection should also be tested for gonorrhoea. Other patients with urethral syndrome have ‘low-​count’ infection with a true bacterial urinary pathogen. Vaginal infection or atrophy should be excluded, as these can cause similar symptoms. The pathogenesis and optimal management of the remaining pa- tients with frequency and dysuria, but with no identifiable bacterial infection, remains controversial. There is controversy over the role of ‘fastidious bacteria’ that are difficult to grow in the laboratory, par- ticularly lactobacilli. Empirical antibiotic treatment is equally suc- cessful in eradicating symptoms in women presenting to primary care whether or not urinary pathogens are found on urine culture, suggesting that the syndrome is frequently due to bacterial infection that is not detected by routine laboratory urine culture. However, a few women with persistent symptoms do not respond to antibiotics, and in these women repeated courses of antibiotics are likely to lead to the emergence of antibiotic-​resistant organisms, which may later cause true infection that is difficult to treat. Psychological distress is common in patients with persistent lower urinary tract symptoms, but the prevalence of emotional or psychiatric disorders is no higher in women presenting to general practitioners with dysuria and fre- quency whose urine cultures are negative than in those with proven cystitis. Urologists often offer such women urethral dilatation on the assumption that the symptoms are due to urethral spasm or stric- ture, but there is minimal evidence beyond clinical anecdote that this procedure is of any benefit; one randomized controlled trial showed no difference in outcome between urethral dilatation and cystoscopy alone. Women with recurrent episodes of frequency and dysuria, with or without pyuria, whose urine cultures remain sterile should be carefully evaluated for the presence of vaginitis (either infective or atrophic). It is justified in this situation to obtain urine direct from the bladder during an episode, preferably by suprapubic aspiration or alternatively by urethral catheterization, and ensure that this is cultured in conditions permitting the identification of fastidious or low-​growing organisms. In urine obtained direct from the bladder, any growth of organisms is clinically significant. Any infection so detected should be treated, preferably with a prolonged course of an appropriate antibiotic to ensure complete eradication. If no infec- tion can be detected, cystoscopy is required to exclude noninfective causes of cystitis. Painful bladder syndrome/​interstitial cystitis Painful bladder syndrome/​interstitial cystitis is a chronic bladder syndrome of unknown aetiology. It is characterized by bladder pain (which classically worsens on bladder filling and diminishes with bladder emptying), urgency, frequency, and nocturia, despite—​by definition—​sterile urine. The syndrome often coexists with other conditions, particularly irritable bowel syndrome. Urine microscopy shows pyuria. Cystoscopy shows variable inflammation, sometimes with ulceration (Hunner’s ulcers, first described in 1914). Bladder biopsies show a chronic inflammatory infiltrate; mast cell infiltra- tion is common, but is also seen in infective cystitis. The condition may progress to cause contracture of the bladder. Many of these features would be explained by an acquired defect in the barrier function of the uroepithelium, but the cause of such a de- fect remains unclear. It remains possible that infection by a fastidious organism is responsible for initiating the disease in some patients. Numerous therapies have been tried, including dietary restriction (citrus fruits, caffeine, alcohol, and carbonate drinks may worsen symp- toms); various oral drugs (pentosan polysulphate sodium, hydroxyzine, amitriptyline, antibiotics, ciclosporin, gabapentin); instillation of intravesical agents including heparin, glycosaminoglycans and bacille Calmette–​Guérin (BCG); and most commonly hydrodistension. In severe cases, where all other therapeutic options have failed, bladder augmentation or cystectomy with urinary diversion may be necessary.

section 21  Disorders of the kidney and urinary tract 5082 Drug-​induced cystitis This presents similarly, although often more acutely and with visible haematuria. It may be caused by acrolein (a metabolite of cyclophospha- mide), ifosfamide, NSAIDs (particularly tiaprofenic acid), and danazol. Ketamine-​induced cystitis Ketamine abuse can result in severe inflammation of the urothelium, associated with decreased bladder compliance and high-​pressure vesicoureteric reflux, sometimes resulting in obstructive kidney damage. The syndrome typically presents with severe lower urinary tract symptoms, with urinary frequency, urgency, dysuria, urge in- continence, with or without painful haematuria. On cystoscopy the macroscopic appearances can be mistaken for interstitial cystitis. The histological appearances mimic carcinoma in situ. The natural history remains uncertain, and no treatment has yet been shown to be effective. Radiation-​induced cystitis Radiation-​induced cystitis is seen in patients who have been treated for bladder or gynaecological malignancy. Clinical investigation—​distinction between uncomplicated and complicated UTI The clinical approach to investigation and treatment of patients with UTI—​including whether to send a urine sample for culture, how long to treat for, and whether to send a repeat sample to confirm eradication of infection—​depends on making a distinction between ‘uncomplicated’ and ‘complicated’ UTI. Although this is sometimes straightforward—​for instance, UTIs in pregnant women and in catheterized patients are, by definition, ‘complicated’—​sometimes the decision on whether to investigate for an underlying cause of ‘complicated’ UTI depends solely on the presenting features. Most women with uncomplicated cystitis do not require inves- tigation and may be treated empirically. The yield in such women of investigation with cystoscopy and/​or intravenous urography is low. Because minor abnormalities such as duplex collecting sys- tems are common in the general population, these will often be found in women presenting with cystitis, but detection of such ab- normalities does not lead to any change in treatment. Investigation of women should therefore be reserved for those with atypical fea- tures (Box 21.13.7). In men, UTI is associated with an underlying abnormality of host defence in 80% of cases (usually bladder outflow obstruction). Men with proven UTI should therefore be offered investigation, par- ticularly if symptoms do not settle, infection recurs, or haematuria persists. Table 21.13.2 shows the important abnormalities that need to be excluded if investigation is thought to be necessary. Whether adults should be investigated for vesicoureteric reflux is open to doubt, as there is no good evidence that antireflux surgery (e.g. ureteric reimplantation, injection of Teflon around the ureteric orifice) is of benefit in preventing either ascending infection or renal damage. Treatment Uncomplicated asymptomatic bacteriuria The only situations in which treatment of asymptomatic bacteriuria is recommended are during pregnancy and prior to invasive uro- logical surgery; these situations are discussed in later sections. Uncomplicated cystitis Patients with symptomatic lower UTI should be offered symp- tomatic treatment initially with paracetamol, and—​if this does not provide symptomatic relief—​with an NSAID. The two main aims of antibiotic treatment in UTI are to achieve rapid resolution of symptoms, and to prevent recurrent episodes of infection in the in- dividual patient to minimize the emergence of antibiotic resistance of organisms. Rational treatment of UTI requires the physician to balance the costs and dangers of treatment (including cost of the drug, risk of unwanted side effects, and the induction of resistance) with benefit. Is treatment necessary at all? Many women with recurrent uncom- plicated cystitis report that they can clear their own infections by increased fluid intake and frequent voiding. Many buy alkalinizing agents (e.g. potassium citrate) to ameliorate the symptoms, which work by reducing bladder irritability. Placebo-​controlled studies and studies comparing NSAIDs with antibiotics have confirmed that uncomplicated infections in women will usually clear spontan- eously. Antibiotics reduce the duration of symptoms by 1 to 2 days. Antibiotics could therefore be avoided in patients with mild symp- toms, and reserved for those with more severe symptoms and those who express a strong preference for antibiotic treatment. An alter- native approach is to delay the introduction of antibiotics for 48 h Box 21.13.7  Indications for further investigation in females with UTI • Genuine mixed growth • Failure of standard antibiotic treatment to eradicate infection • Relapsing infection (repeated detection of the same organism, as iden- tified by antibiotic sensitivity pattern, or more detailed typing) • Confirmed infection with organisms not usually recognized as uropathogens • Infection with Proteus spp. • Marked acute-​phase response (or symptoms of ‘acute pyelonephritis’), suggesting tissue invasion • Persistent haematuria after treatment of infection Table 21.13.2  Clinical investigation of UTI Abnormality to be excluded Investigation Diabetes Blood test Urinary tract stones Ultrasonography as first-​line imaging and plain radiography (KUB), intravenous urography, CT urography if indicated Anatomical abnormalities of the upper tract (e.g. papillary necrosis, reflux nephropathy) Urinary tract obstruction Bladder diverticula Cystoscopy Impaired bladder emptying Urinary flow studies KUB, kidneys–​ureters–​bladder.

21.13  Urinary tract infection 5083 to allow the infection to clear spontaneously, a strategy that—​when offered—​is chosen by a high proportion of patients. Choice of antibiotic It is usually impracticable to await the results of culture and sen- sitivity testing, and in most cases such tests are not justified. The choice of antibiotic is therefore usually empirical, based on the likeli- hood that the drug will clear the infection (efficacy), cost, side effect profile, and the risk of selection of resistant organisms, both in the patient being treated and in the community. The efficacy of antibiotics is not fully predictable from in vitro sen- sitivity testing, which is probably part of the reason why trimetho- prim (with or without sulphamethoxazole) remains the first-​line choice in many areas, despite an upward trend in resistance rates. This is at least in part because many antibiotics are concentrated in the urine to levels far greater than those found in tissues, and at these concentrations may remain active against organisms that are reported to be resistant to the concentrations found in tissues, which are usually used to define resistance in vitro. Trimethoprim is also concentrated in vaginal secretions by ‘ion trapping’. However, increasing resistance in vitro to trimethoprim is sure to lead sooner or later to increased clinical failure rates, as has already been ob- served for β-​lactam antibiotics. Some of the clinical properties of the most commonly used antibiotics are reviewed in Table 21.13.3, with the target and mechanisms of actions of different antibiotic agents shown in Fig. 21.13.3. The 2018 recommendations of the National Institute for Health and Care Excellence (NICE) for treatment of UTI are summarized in Table 21.13.4. Duration of treatment Although a single high dose of an antibiotic will cure many women with uncomplicated lower UTI, cure rates are higher with 3-​day courses and higher still with 7-​day courses. However, the risk of ad- verse effects is also related to the duration of treatment. Alternatives to antibiotic therapy Cranberry juice and tablets, methenamine hippurate, and treatment of atrophic vaginitis with topical oestrogens have all been used in the prevention of UTI (see later sections), but there is no proven role for any of these interventions in the treatment of an established UTI. Uncomplicated ‘acute pyelonephritis’ Choice of antibiotic The antibiotic chosen in this situation needs good tissue penetration as well as high urinary excretion, and must be fully active against the infecting organism at typical serum concentrations. It is there- fore much more important to identify the infecting organism and its antibiotic sensitivity pattern by sending urine (or blood from pa- tients in hospital) for culture. However, empirical treatment must be started while awaiting culture and sensitivity results, as acute pyelonephritis can evolve rapidly into a life-​threatening illness. Oral therapy with a quinolone antibiotic (ciprofloxacin, ofloxacin, norfloxacin) is probably the best choice, although treatment with co-​ amoxiclav (or trimethoprim or trimethoprim–​sulphamethoxazole if local resistance rates are low) are alternatives. Treatment with a β-​ lactam antibiotic alone, even if the infecting organism is fully sensitive in vitro, is associated with a high rate of recurrence compared with treat- ment by other agents. Patients with septicaemia should receive a quin- olone (for which oral administration is as effective as intravenous) or Cell wall synthesis Pencillins Daptomycin Cephalosporins Carbapenems Glycopeptides MurA inhibitors Siderophore – β- lactam antibiotics Cell wall PABA Efflux pump inhibitors DNA Gyrase/Topoisomerase Quinolone Folic-acid- metabolism Dihydrofolate- reductase- inhibitors Trimethoprim Sulfonamides 50S Inhibitors Linezolid Nitrofurantoin 30S Inhibitors Tetracyclines Tigecycline Aminoglycosides Nitrofurantoin Cell membrane DNA DHFA THFA Ribosome Fig. 21.13.3  Targets and mechanisms of actions of different antibiotic agents used in the treatment of UTI. DHFA, dihydrofolic acid; PABA, p-​ aminobenzoic acid; THFA, tetrahydrofolic acid. Reprinted from European Urology, 49(2), 235–​44, Wagenlehner FME and Naber KG, Treatment of Bacterial Urinary Tract Infections: Presence and Future. Copyright © 2005, with permission from Elsevier. Table 21.13.3  Clinical properties of antibiotics commonly used for UTIs Antibiotic Advantages Disadvantages Trimethoprim Cheap Well tolerated High concentrations in vaginal and periurethral fluid Increasing rates of in vitro resistance Trimethoprim–​ sulphamethoxazole As for trimethoprim Possible reduced risk of emergence of resistant strains Increasing rates of resistance Adverse reactions (e.g. rash) to sulphonamide component Not licensed for the treatment of UTI in some countries β-​Lactams (e.g. amoxicillin, cephalosporins) Cheap Well tolerated High rates of resistance Less effective than trimethoprim in 3-​day or single-​day regimens Allergic reactions High risk of Clostridium difficile colitis β-​Lactams with β-​ lactamase inhibitor (e.g. co-​amoxiclav) As for β-​lactams Low rates of resistance Cost Risk of selection of resistant strains Allergic reactions High risk of Clostridium difficile colitis Nitrofurantoin Cheap Does not induce resistance in bowel organisms Nausea and vomiting (less with macrocrystalline preparations) Hepatic, neurological, haematological, and pulmonary toxicity (mostly seen with prolonged treatment) Less effective in patients with low glomerular filtration rates Quinolones, e.g. ciprofloxacin Well tolerated Broad antibacterial spectrum including many uropathogens Cost High risk of Clostridium difficile colitis Achilles tendon damage

section 21  Disorders of the kidney and urinary tract 5084 a combination of an aminoglycoside with ampicillin plus β-​lactamase inhibitor, or an extended-​spectrum cephalosporin with or without an aminoglycoside. Once-​daily administration of aminoglycosides is as effective as thrice-​daily and reduces the risk of toxicity. Duration of therapy It is widely recommended that acute pyelonephritis is treated with a significantly longer course of antibiotics than acute cystitis (Table 21.13.4). It is therefore reasonable to suggest that in a patient with systemic symptoms (including flank pain) and fever; or leuco- cytosis, or a raised C-​reactive protein; antibiotic treatment should be continued until these abnormalities have disappeared. A 7-​day course of a quinolone antibiotic should be sufficient for most pa- tients, but longer courses of antibiotic treatment may be required for other antibiotics or if symptoms persist. . Prevention of recurrent uncomplicated UTI Advice about personal hygiene and other matters It is common practice to advise women with UTIs to void after inter- course, practise double micturition, wipe themselves from front to back after micturition, and increase their fluid intake. A systematic review concluded that the evidence for such advice was not based on good evidence, and stated ‘routine advice about adopting or discontinuing any particular lifestyle factors should not be offered to patients with bacterial UTI’. However, absence of evidence of benefit is not the same as evidence of absence of benefit, and for individuals with recurrent and/​or complicated UTI, individualized advice along these lines is reasonable. Long-​term prophylactic antibiotics Some women with recurrent cystitis choose to have antibiotic treat- ment for each infection as it arises, particularly if they are allowed to self-​administer treatment as soon as symptoms start. Others may opt for prophylactic treatment. Long-​term, low-​dose antibiotic treat- ment is effective in reducing the rate of infection in such women, al- though not to zero, and with a significant risk of adverse effects (e.g. gastrointestinal symptoms, rash, vaginal irritation). Prophylactic treatment should be considered in women with at least two symp- tomatic infections per year and probably works by preventing colon- ization of periurethral tissues by uropathogens. Trimethoprim (100 mg at night) is widely used for prophylaxis be- cause it achieves very high concentrations in vaginal fluid and may therefore remain active against organisms that are resistant to the concentrations used in in vitro sensitivity testing. Nitrofurantoin (100 mg at night) has also been widely used, and may be more ef- fective, but can cause rare but serious adverse effects (pulmonary and hepatic toxicity) with long-​term therapy, making regular moni- toring of liver enzymes and lung function tests necessary. Because both are well absorbed they do not reach high concentrations in the colon, hence emergence of resistant strains in colonic flora is un- common, whereas this problem does arise with long-​term use of β-​ lactam antibiotics. Long-​term use of quinolones is associated with a significant risk of selection of resistant strains, and also carries a risk of Achilles tendon rupture. A number of dosage regimens have been used, including nightly treatment, thrice-​weekly treatment, and postcoital treatment, with no convincing evidence of the superiority of one regimen over another. There is no evidence to support the use of ‘rotating’ antibiotic prophylaxis. Table 21.13.4  NICE recommendations for the treatment of symptomatic lower UTI in the community Uncomplicated UTI in women, i.e. no fever or flank pain Use urine dipstick to exclude UTI –​ve nitrite and leucocyte 95% negative predictive value There is less relapse with trimethoprim than cephalosporins or pivmecillinam. Community multiresistant E. coli with extended-​spectrum
β-​lactamase enzymes (ESBLs) are increasing so perform culture in all treatment failures. ESBLs are multiresistant but remain sensitive to nitrofurantoin Trimethoprim OR nitrofurantoin 200 mg BD 100 mg (modified release) BD 3 days Second choice—​depends on susceptibility of organism isolated, e.g. nitrofurantoin, pivmecillinam, fosfomycin UTI in pregnancy Send MSU for culture. Avoid use of nitrofurantoin at term because of risk of neonatal haemolysis Nitrofurantoin Second choice: Cefalexin OR amoxicillin 50–​100 mg QDS 500 mg BD 500 mg TDS 7 days 7 days 7 days UTI in men Send MSU for culture Timethoprim OR nitrofurantoin 200 mg BD 100 mg (modified release) BD 7 days 7 days Second choice—depends on susceptibility of organism isolated, e.g. cefalexin, co-amoxiclav, trimethoprim, ciprofloxacin Children Send MSU for culture and susceptibility Waiting 24 h for results is not detrimental to outcome Trimethoprim OR nitrofurantoin Second choice: Nitrofurantoin, amoxicillin (if susceptible), cefalexin See BNF for dosage 3 days Acute
pyelonephritis Send MSU for culture. A recent randomized controlled trial showed 7 days ciprofloxacin was as good as 14 days co-​trimoxazole If no response within 24 h—​admit to hospital Cephalexin recommended in pregnancy Ciprofloxacin OR co-​amoxiclav
(if susceptible) OR trimethoprim
(if susceptible) 500 mg BD 500/​125 mg TDS 200 mg BD 7 days 7–10 days 14 days Recurrent UTI in women Post coital prophylaxis is as effective as prophylaxis taken nightly. Nitrofurantoin OR trimethoprim 50–100 mg at night or 100 mg post coital 100 mg at night or 200 mg post coital BD, twice daily; BNF, British National Formulary; MSU, midstream urine; QDS, four times daily; TDS, three times daily.

21.13  Urinary tract infection 5085 Box 21.13.8  Possible causes of UTI in men • Bacterial prostatitis and prostatic calcification • Lack of circumcision • Impaired bladder emptying (particularly if this has resulted in bladder catheterization or instrumentation) • Anal intercourse • Urinary tract stones • Reflux nephropathy Other treatments Cranberry juice or tablets  Cranberry juice contains proanthocyanidin, which inhibits adher- ence of P-​fimbriated E. coli. Cranberry products are not regulated and the concentration of the active ingredient varies considerably. To date, the clinical evidence that regular ingestion of cranberry juice or tablets can prevent UTIs remains unconvincing. Methenamine hippurate Methenamine is hydrolysed in acid urine to produce formaldehyde, a powerful antiseptic. Use of this drug is not associated with the emergence of antibiotic resistance. Its effectiveness may be enhanced by urine acidification, achieved for instance by coprescribing high-​ dose ascorbic acid. A 2012 Cochrane review found that the evidence base was limited, but that methenamine reduced the risk of UTIs among women with anatomically normal urinary tracts (relative risk of symptomatic UTI 0.24, 95% confidence interval 0.07–​0.89), but not among patients with known urinary tract abnormalities. Treatment of atrophic vaginitis There is significant heterogeneity in the results of trials examining the effects of topical oestrogens on prevention of recurrent UTIs. This may be due to differences in inclusion criteria. Oestrogens are not recommended for the routine prevention of recurrent UTIs in postmenopausal women, but they may be of benefit in individuals with marked atrophic vaginitis. Vaginal oestrogens can cause side effects including breast tenderness and vaginal bleeding, discharge, and irritation. Probiotics Attempts to prevent recurrent urinary infection by re-​establishing colonization by lactobacilli have so far not yielded convincing evi- dence of benefit. Vaccines Vaccination is an attractive option for the prevention of UTI. There is evidence from preclinical studies that vaccination can reduce in- fection rates, but there is no convincing evidence that it does so in humans. UTI in particular circumstances UTI in men UTI in men is uncommon, as the length of the urethra and the fact that the penile mucosa is seldom colonized with faecal organisms including uropathogens confer major protection against ascending infection. The occurrence of UTI in a man therefore suggests an ab- normality of host defence, which may predispose to more severe in- fection and should be investigated unless the cause is immediately obvious (e.g. the presence of a urinary catheter). Risk factors that may be identified by investigation are listed in Box 21.13.8. Prostatitis Prostatitis is a common cause of visits in primary care and of uro- logical referrals. It can cause considerable morbidity, and patients may remain symptomatic for years. The National Institutes of Health consensus classification of prostatitis syndromes is summarized in Box 21.13.9. Acute bacterial prostatitis Acute bacterial prostatitis causes fever, rigors, backache, and dys- uria, and may result in acute urinary retention. Symptoms and signs of epididymitis may also be present. Rectal examination reveals an enlarged, tender prostate. Bacteriuria and pyuria are frequently pre- sent. Untreated, acute prostatitis may culminate in prostatic abscess formation, so ultrasonography of the prostate should be requested in patients who do not respond promptly to antibiotic treatment. The causative organism (commonly E.  coli) can be identified on urine culture. An antibiotic that has good tissue penetration (e.g. trimethoprim, a tetracycline, or a quinolone) should be used and continued for 4 weeks, as it is thought that this reduces the risk of chronic prostatitis. Chronic bacterial prostatitis This is an uncommon syndrome caused by the persistence of a uropathogen (usually Gram-​negative organisms or enterococcus) within the prostate, with repeated episodes of acute infection caused by the same organism on each occasion, and few if any symptoms between episodes. Obtaining bacteriological proof that the infecting organism is ‘hiding’ in the prostate gland between acute episodes is difficult. The ‘textbook’ method described by Stamey and Mears involves culture of four specimens obtained during voiding of the bladder:  the first 10 ml voided and a midstream sample are col- lected; the patient then interrupts the flow of urine, bends forward, and digital prostatic massage is performed, resulting (sometimes) in the collection of a few drops of ‘expressed prostatic secretions’; fi- nally, voiding is completed and a fourth sample collected. Prostatitis is diagnosed when bacterial counts are highest in the expressed prostatic secretions and the final voided urine sample; urethritis, by contrast, results in high counts in the first sample. Because of its complexity and the unpleasantness of performing digital prostatic Box 21.13.9  National Institutes of Health classification of prostatitis syndromes • Acute bacterial prostatitis • Chronic bacterial prostatitis • Chronic prostatitis/​chronic pelvic pain syndrome: A Inflammatory B Noninflammatory • Asymptomatic inflammatory prostatitis Adapted from National Institutes of Health classification of prostatitis syn- dromes, with permission.

section 21  Disorders of the kidney and urinary tract 5086 massage per rectum during interrupted micturition, this test is very rarely performed in practice, and many patients are simply treated with a prolonged course of a quinolone antibiotic. α-​Blockers have been shown to reduce recurrence rate, possibly by reducing reflux of urine into prostatic ducts during micturition. Acute and chronic bacterial prostatitis are the best understood but least common of the prostatitis syndromes. More than 90% of symptomatic patients have chronic prostatitis/​chronic pelvic pain syndrome. Chronic prostatitis/​chronic pelvic pain syndrome Chronic urological pain is the primary component of this disorder. Patients may also complain of dysuria, strangury, urinary frequency, and pain during sexual intercourse, but have no evidence of bacterial infection on cultures of prostatic secretions, semen, or post-​massage urine specimens. Certain conditions must be excluded, including active urethritis, urological cancer, significant urethral stricture, or neurological disease affecting the bladder. Patients with this symptom complex may be further subclassified as having inflammatory or noninflammatory pelvic pain syn- drome according to the presence or absence of leucocytes in semen. Occasionally, patients are found to have evidence of prostatic in- flammation on biopsy, or to have leucocytes in prostatic fluid in the absence of symptoms, in which case they are regarded as having asymptomatic inflammatory prostatitis. Treatment There is no gold standard for diagnosis, nor a clear understanding of the pathophysiology, no correlation between symptoms and pros- tatic histology, and no satisfactory treatment for this ill-​understood group of conditions. As in the urethral syndrome in women, some cases may be caused by persistent infection by fastidious bacteria, such as chlamydia or mycoplasma; a prolonged trial of a tetracyc- line is therefore often used. Other treatments include regular pros- tatic massage, NSAIDs, α-​blockers, and 5-​α reductase inhibitors. α-​Blockers have been shown to be of some benefit in all types of symptomatic chronic prostatitis in one randomized study. Urethral catheterization UTI occurs after 2% of in/​out urethral catheterizations, after 10 to 30% of 5-​day indwelling catheterization, and is nearly inevitable in patients with long-​term indwelling catheters. It is an important cause of hospital-​acquired infection, increasing the risk of Gram-​ negative septicaemia fivefold and carrying a threefold increase in mortality after adjustment for age, severity and type of underlying illness, duration of catheterization, and renal function. Organisms enter the bladder either by migration between the catheter and the urethral mucosa or by ascent up the column of urine in the lumen after entry into the drainage system following contamination at dis- connection or drainage points. Although most infections are prob- ably caused by ascent of the patient’s own faecal flora, investigation of clusters of infections by highly antibiotic-​resistant organisms showed that inadequate hand-​washing by hospital staff may also cause some infections. A sample obtained directly from the catheter (not from the drainage bag) represents bladder urine, when any bacterial growth should be considered as evidence of UTI; low-​count infection (e.g. <102 cfu/​ml) usually progresses within days to higher counts. Mixed growths are common in patients with long-​term catheterization and may be associated with mixed-​growth bacteraemia. Risk factors for the acquisition of infection include increasing duration of catheterization, increasing age, female sex, renal im- pairment, diabetes mellitus, and the nature of the underlying illness. Use of prophylactic antibiotics is associated with a delay in the onset of infection and may be justified in high-​risk patients re- quiring catheterization for at least 24 h and up to 14 days, whereas in those with long-​term catheters, use of prophylactic antibiotic simply increases the risk of emergence of antibiotic-​resistant patho- gens without any benefit. Use of silver alloy-​coated catheters, or use of antibiotic-​impregnated catheters, also reduces the risk of infec- tion in the short term, but not in long-​term catheterization, and may be justified in high-​risk patients; no direct comparisons of these two interventions have been performed; both are more ex- pensive than standard catheters, and the balance of cost and benefit remains uncertain. Progress is being made in the development of new catheter materials that may provide further resistance against colonization by microorganisms. Urethral catheters should not be inserted unless absolutely neces- sary (is knowledge of hourly urinary output really going to change your management?). Early removal of urethral catheters reduces the risk of symptomatic UTI. Suprapubic catheters are associated with lower risks of UTI and a lower rate of recatheterization in postsurgical patients, but their use may be associated with a higher risk of com- plications. If a urethral catheter is used, catheter care should follow appropriate guidelines (e.g. as provided by the National Institute for Health and Care Excellence in the United Kingdom). There is some evidence that antibiotic prophylaxis at the time of catheter removal can reduce the risk of subsequent symptomatic UTI. Clean intermittent self-​catheterization should be considered as an alternative to long-​term urethral catheterization. Whether prophy- lactic antibiotics further reduce the risk of UTI among patients undertaking intermittent self-​catheterization remains uncertain. Condom drainage should be used as an alternative to urethral catheterization for incontinence in men unless there is obstructive nephropathy; this form of bladder drainage reduces the risk of UTI fivefold and is better tolerated. Treatment of asymptomatic bacteriuria in patients with anatom- ically abnormal urinary tracts or with indwelling urinary catheters is unjustified and is likely only to lead to the emergence of antibiotic-​ resistant urinary infection. Abnormal bladder emptying Incomplete bladder emptying, removing the ‘washout’ part of host defence, greatly increases the risk of UTI, as in patients with prostatic bladder outflow obstruction and those with neurogenic bladder due to spinal cord injury. Long-​term catheterization only increases these risks. Where possible, the cause of incomplete bladder emptying should be treated. However, patients shown on urodynamic study to have underactive detrusor activity will not benefit from pros- tatectomy or α-​blockade and may require long-​term intermittent self-​catheterization. Bladder dysfunction in patients with neurogenic bladder (e.g. due to spina bifida or spinal cord injury) depends on the level of injury. Patients with lesions above T11 have hyperreflexic bladder activity, often with sphincter dyssynergia (failure of the sphincter to relax during detrusor contraction), resulting in a high-​pressure system,

21.13  Urinary tract infection 5087 often with high-​pressure reflux, combined with impaired emptying. In combination with UTI, this frequently results in progressive renal damage. Those with lesions below L1 have decreased detrusor ac- tivity with large amounts of residual urine, which also increases the risk of UTI. Diabetic neuropathy may also cause decreased de- trusor activity. The aim of treatment in both situations is to achieve a low-​pressure bladder with low residual volumes. This may involve teaching patients to utilize reflexes to induce bladder contraction and sphincter relaxation, condom drainage for incontinence, anticholin- ergics to reduce detrusor overactivity, sphincterotomy, augmenta- tion cystoplasty, and intermittent self-​catheterization. Long-​term urethral catheterization should be avoided wherever possible. There is no evidence that regular use of antiseptics to wash the perineum and urethral meatus are of benefit. Bladder washouts with saline or boiled (and then cooled to body temperature) water may be of benefit in eliminating mucus in patients with augmentation cystoplasties. Antiseptic bladder washouts are of minimal value in prevention, probably because uropathogens become embedded in a biofilm adherent to the bladder wall. Treatment of UTI in patients with abnormal bladder emptying should be reserved for those with evidence of invasive infection. The diagnosis is obvious in those with cloudy urine combined with fever, rigors, and flank pain, but it is important to remember that symptoms and signs—​particularly flank pain, dysuria, urgency, and frequency—​may be absent in those with neurological dysfunction. Urological surgery Patients with asymptomatic bacteriuria who undergo invasive uro- logical procedures that are associated with mucosal bleeding are at high risk of postprocedure bacteraemia and clinical sepsis syn- dromes, and there is evidence that preoperative antibiotic treatment of asymptomatic bacteriuria (ideally, the night before the procedure, continued until completion or removal of an indwelling catheter, whichever is the later) reduces these risks. Urinary diversion Ileal or colonic conduits have been used for many years in patients requiring cystectomy for malignancy, and occasionally (although increasingly less frequently) for nonmalignant conditions such as neurogenic bladder. Such conduits are frequently complicated by urine infection, as the bowel mucosa and the mucus it produces readily permits adherence of uropathogens. Upper urinary tract dilatation is common, irrespective of whether the ureteric anasto- moses are designed to be nonrefluxing or not, and there is a high incidence of recurrent ‘acute pyelonephritis’ with flank pain, fever, and rigors. Diagnosis of UTI in patients with a conduit requires insertion of a catheter to the far end of the conduit and collec- tion of urine via the catheter, rather than culture of urine collected from the conduit bag. Preventive measures include ensuring that the ileal segment is as short as possible at the time of surgery and ensuring a high fluid intake. The belief that cranberry juice reduces the incidence of UTI by reducing bacterial adherence is as yet un- proven, although it seems probable that treatments designed to interfere with bacterial adherence or with mucin production are more likely than antibiotic treatment to help prevent symptomatic infection in these patients. Urinary tract stones Urinary tract stones are an important cause of persistent or relapsing UTI, as they provide a ‘hiding place’ in which organisms are protected from antibiotics. Management of such patients is complicated, as it may be impossible to eradicate infection without aggressive stone management (which may involve extracorporeal shock-​wave litho- tripsy, percutaneous and ureteroscopic stone removal). Attempts at stone removal may be complicated by septicaemia unless combined with antibiotic treatment, yet prolonged antibiotic therapy may en- courage the emergence of resistance in the infecting organism. Infection stones are caused by chronic infection with urease-​ producing organisms, usually Proteus mirabilis, and account for around 5% of urinary tract stones. These stones are made of struvite (MgNH4PO4.6H2O), which forms as a result of the action of the al- kaline pH caused by the production of ammonium and hydroxyl ions from the breakdown of urea by urease. Pure struvite stones may result from de novo UTI by a urease-​producing organism, and are commoner in women and (probably) in patients with pre-​existing anatomical abnormalities of the upper urinary tract such as reflux nephropathy, pelviureteric junction obstruction, or urinary diver- sion. They may also form as a secondary complication of metabolic stones. Struvite stones often expand to fill the entire renal pelvis, forming ‘staghorn’ calculi, but such calculi should not be assumed to be due to infection (rather than a metabolic cause) without demon- stration of chronic infection by a urease-​producing organism and/​or biochemical analysis showing that the stone is made of struvite. The usual presentation is with symptomatic ‘acute pyelonephritis’ and al- kaline urine; renal colic is unusual due to the large size of the stones. Treatment is with a combination of antibiotics and stone removal, which is imperative to prevent stone recurrence. Urease inhibitors (acetohydroxamic acid, propionhydroxamic acid) may reduce stone recurrence but are too toxic for clinical use. See Chapter 21.14 for further discussion. Autosomal dominant polycystic kidney disease Cystitis is common in women with polycystic kidney disease, and in 20% it is the presenting clinical finding, but there is no evidence that host defence in the lower urinary tract is abnormal. However, the risk of upper UTI is increased, and its diagnosis and treat- ment complicated. Acute parenchymal infection presents as acute pyelonephritis with flank pain, fever, and infected bladder urine, and usually responds to conventional therapy. Infection of cysts is more difficult to diagnose:  the urine may be sterile and there may be no pyuria if the infected cyst does not communicate with the urinary space. Presentation is with fever and a discrete area of tenderness in the affected kidney. Blood cultures are the most re- liable way of making a bacteriological diagnosis. Imaging studies, looking for cysts with increased fluid density, septations, and thick walls, are seldom conclusive, as similar appearances may occur normally or after previous cyst haemorrhage. The spectrum of causative organisms suggests that ascending infection rather than haematogenous spread is the usual route of infection. Hydrophilic antibiotics, including aminoglycosides and β-​lactam antibiotics, penetrate poorly into those cysts that maintain large ionic gradients, whereas quinolones, trimethoprim–​sulphamethoxazole, doxycyc- line, and clindamycin achieve better penetration. Prolonged courses

section 21  Disorders of the kidney and urinary tract 5088 of antibiotics are usually needed to eradicate infection, with surgical resection a last resort. Renal transplantation UTI is the commonest bacterial infection after renal transplant- ation. Risk factors include urethral catheterization in the early postoperative period, the use of ureteric stents, pre-​existing abnor- malities of bladder emptying (such as diabetic autonomic neur- opathy, previous bladder outflow obstruction, and small contracted bladders in anuric patients on dialysis), anatomical abnormalities in the upper urinary tract (such as reflux nephropathy), contam- ination of the transplanted organ during retrieval and storage, abnormal drainage of urine from the transplanted kidney, vesico- ureteric reflux into the transplant, areas of renal infarction, and immunosuppression. The commonest causative bacteria are those found in the general population with UTI, but many organisms not usually considered as urinary tract pathogens may also cause significant infection in these patients. Many infections are asymp- tomatic. Prophylactic antibiotics may reduce the early postoperative risk and many centres use co-​trimoxazole as it also reduces the risk of pneumocystis pneumonia. Antibiotic treatment must be chosen with care because of the risk of interactions with immunosuppres- sive treatment and of nephrotoxicity. The impact of isolated lower UTIs in transplant recipients is dif- ficult to quantify because there may be coexisting upper tract in- fection. Many transplant recipients (7–​40%) with symptoms of cystitis go on to develop graft pyelonephritis, which is an inde- pendent risk marker for subsequent reduced graft function, graft loss, and increased mortality. In transplant recipients, asymptom- atic bacteriuria is common and associated with an increased risk of developing graft pyelonephritis. Although treatment of asymptom- atic bacteriuria in transplant recipients appears to reduce the risk of graft pyelonephritis, there is no evidence that treatment improves transplant outcome. Although screening, treatment of asymptom- atic patients, and long-​term antibiotics are strategies used post transplantation, more research is required to determine whether this has any positive effect on long-​term outcomes. Infection with Corynebacterium urealyticum can cause ‘en- crusted pyelitis’ in transplant kidneys, in which the pelvis of the transplant kidney becomes encrusted with calcified material, which can cause obstruction and thus transplant dysfunction. The CT appearances are characteristic (Fig. 21.13.4). The calcification comprises struvite (magnesium ammonium phosphate), as in in- fection stones. Management is difficult, and comprises prolonged antibiotic therapy and surgical excision of the calcified material, if possible. Infection with BK virus (a polyoma virus) may cause cystitis, ur- eteric stenosis, and interstitial nephritis (easily mistaken for acute rejection) in renal transplant recipients. The diagnosis may be sug- gested by recognition of infected transitional uroepithelial cells on urine cytology (‘decoy’ cells), quantitative polymerase chain reac- tion of blood and urine for BK virus, and confirmed by histological recognition of inclusion bodies and immunostaining for the BK virus (or SV40) large T antigen on renal biopsy. Treatment is by re- duction of immunosuppression, but this is often complicated by fur- ther rejection. Pregnancy Asymptomatic bacteriuria early in pregnancy is associated with the development of acute pyelonephritis in up to 30% of patients (20–​ 30 times the risk in women without bacteriuria) if left untreated. It is commoner in women of lower socioeconomic status and is as- sociated with an increased incidence of preterm delivery and low birth weight, particularly if the pregnancy is complicated by acute pyelonephritis towards term. The increased risk of pyelonephritis is attributed to ureteric dilatation caused primarily by progesterone-​ induced smooth muscle relaxation. Antibiotic treatment of asymptomatic infection reduces the risk of acute pyelonephritis and of preterm delivery and low birth weight. Similar benefit is seen from a short course of treatment and from continued antibiotic prophylaxis. The choice of initial anti- biotic should be based on local resistance patterns. Nitrofurantoin has the best safety record in pregnancy: alternatives are shown in Table 21.13.4. Current guidelines support the use of a 7-​day course of antibiotics in symptomatic UTI in pregnancy. Follow-​up urine cultures at each antenatal visit should be performed to ensure that bacteriological cure has been achieved. (See Chapter 14.5 for further discussion.) Reflux nephropathy Vesicoureteric reflux (retrograde flow of urine up into the ureters and, in severe cases, as far as the renal pelvis and kidney) is often found in children with recurrent UTI. At the time of first diagnosis of UTI or subsequently, a few such children are found to have a characteristic pattern of renal parenchymal scarring at the upper and lower poles, with underlying clubbing and distortion of calyces. This pattern of scarring has become known by a variety of terms, including ‘reflux nephropathy’ and ‘chronic pyelonephritis’. Patients with reflux neph- ropathy have an increased risk of recurrent UTI, may develop stones, and some develop hypertension, proteinuria, and progressive renal impairment with an inexorable progression to endstage renal failure. Under the age of 1 year, when only relatively severe cases come to clinical attention, slightly more boys than girls are affected; in older Fig. 21.13.4  CT scan of transplant kidney with calcification of the renal pelvis (arrows) due to encrusting pyelitis.

21.13  Urinary tract infection 5089 children, the disease is diagnosed up to five times more frequently in girls, possibly because the disease is often discovered during investi- gation of UTI, which is commoner in females. Reflux nephropathy is commonly familial, best modelled by an autosomal dominant pat- tern of inheritance with variable penetrance. The diagnosis of reflux nephropathy is conventionally made in adults by intravenous urography or CT urography, which permits the detection both of focal parenchymal scarring and the underlying calyceal abnormality (Fig. 21.13.5). Ultrasound scanning can show focal scarring but does not allow visualization of the calyces. DMSA isotope scanning is the most sensitive test for the detection of paren- chymal scars, and is widely used in children, as there are few alterna- tive causes of focal scarring in this age group. Lateral displacement of the ureteric orifices can be demonstrated by Doppler ultrasonog- raphy in most patients with reflux nephropathy. Demonstration of vesicoureteric reflux by direct or isotopic micturating cystography is commonly used to confirm the diagnosis in children, but is rarely justified in adults, as the absence of reflux could be due to spontan- eous resolution of reflux with age (it often resolves in childhood), and its presence seldom justifies a change in clinical management. The histological appearances of ‘chronic pyelonephritis’ are well de- scribed and may occasionally be seen in patients with no scarring on urography or even DMSA scanning, probably because the scars are too small in these patients to be detected radiologically. The conventional view is that reflux nephropathy is ‘postinfectious focal renal scarring’ and caused by the ascent of infected urine into the renal pelvis and then into the collecting ducts and renal paren- chyma via compound papillas (papillas in which more than one col- lecting duct opens into the pelvis). These are found at the upper and lower poles, but not in the middle calyces—​explaining the polar dis- tribution of scars. Sequential radiological imaging studies in children with UTIs appear to support this theory, with the emergence of new scars up until the age of around 5 years, after which it is thought that maturation of the papillas prevents entry of infected urine into the renal parenchyma. Experimental infection in pigs causes a pattern of scarring very similar to that seen in human reflux nephropathy. An alternative hypothesis is that at least some children with the radiological diagnosis of reflux nephropathy have congenital renal dysplasia, caused by abnormal nephrogenesis in utero, and as- sociated abnormal embryogenesis of the ureterovesical junction leading to vesicoureteric reflux. Vesicoureteric reflux is often found in various genetic syndromes that include renal dysplasia, and in nonsyndromic renal dysplasia or aplasia, vesicoureteric reflux in the contralateral ureter is commonly seen. This theory would explain the presence of classic reflux nephropathy in neonates and in chil- dren with no documented history of UTI. Even the emergence of new scars during the first 5 years of life could be due to differen- tial growth around areas of renal dysplasia. The rarity with which acute pyelonephritis in adults results in renal impairment, even in the presence of radiological evidence of scar formation, is perhaps further evidence that progressive loss of renal function is more likely to be due to ‘remnant nephropathy’ in dysplastic kidneys rather than the result of postinfectious scarring alone. These two hypotheses have different implications for the preven- tion of reflux nephropathy. Proponents of the ‘postinfectious focal renal scarring’ theory believe that diagnosis in infancy and treat- ment to prevent the ascent of infected urine into the renal pelvis until at least the age of 5 years should prevent the emergence of renal scarring and the later sequelae of hypertension, proteinuria, and progressive renal failure; by contrast, such treatment will not prevent these sequelae if reflux nephropathy is a disease of em- bryogenesis. Of course, the two theories are not mutually exclu- sive: in an individual patient, reflux nephropathy may be due to the interaction of dysplasia and ascending infection during infancy. Antireflux surgery (ureteric reimplantation) and long-​term prophy- lactic antibiotic treatment have been compared in several large ran- domized trials. Surgery is more effective at preventing episodes of acute pyelonephritis than medical treatment, but no other major differences in outcome were observed, and potential complica- tions of antireflux surgery include ureteric obstruction, itself a po- tent cause of renal parenchymal damage. In modern practice, open surgical ureteric reimplantation is now seldom performed, having been replaced by endoscopic techniques involving subureteric or intraureteric injection of dextranomer/​hyaluronic acid copolymer. However, this form of antireflux surgery has not been tested in large randomized controlled trials. A randomized comparison of antibiotic prophylaxis with placebo (the RIVUR trial) showed a reduction in symptomatic infections, but no difference in the development of new scars, with antibiotic prophylaxis. Eradication of asymptomatic infection in children with or without proven vesicoureteric reflux used to be widely practised in the hope that it would prevent ascending infection and renal damage. However, prophylactic treatment for 2 years of covert bacteriuria in schoolgirls without renal scarring has no effect on glomerular filtra- tion rate at age 18, but was associated with lower fractional reabsorp- tion of glucose and with a smaller increment in glomerular filtration rate and greater degrees of glycosuria during subsequent pregnancy. Screening for asymptomatic bacteriuria with the aim of preventing these minor abnormalities is not currently thought justified. Pooled analysis of recent trials that have included a placebo arm show no clear evidence of benefit from long-​term prophylaxis, either in terms of reduction of symptomatic UTIs or in reduction of the acquisition of new cortical scars. Fig. 21.13.5  Reflux nephropathy on intravenous urography, more marked on the right side than the left. Several focal scars (arrowed) involving the full thickness of the renal parenchyma and associated with calyceal clubbing are most obvious in the polar regions. Reproduced with permission from Bailey RR (1993). Vesicoureteric reflux and reflux nephropathy. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney, 5th edn,
pp 689–​727. Little, Brown, Boston. Copyright © 1993 Lippincott, Williams & Wilkins.

section 21  Disorders of the kidney and urinary tract 5090 Whatever the cause of reflux nephropathy, there is little doubt that women with it are more prone to recurrent acute pyelonephritis than those with anatomically normal upper urinary tracts, particu- larly during pregnancy. Invasive/​destructive renal parenchymal infection As discussed previously, ascending infection may cause the clinical syndrome of ‘acute pyelonephritis’ but seldom causes significant renal parenchymal damage. However, this is not the case if there is further impairment of host defence against infection, particularly by diabetes or urinary tract obstruction. Acute papillary necrosis This is an unusual complication of acute pyelonephritis, but more likely to occur in older people and especially those with diabetes. It should be suspected, as should urinary stones, in the patient with symptoms and signs of acute pyelonephritis who also has pain sug- gesting renal colic. This situation requires immediate imaging, usu- ally with ultrasonography, to exclude urinary obstruction, and if obstruction is present then it must be relieved urgently, most often by antegrade nephrostomy. The use of NSAIDs is associated with an increased incidence of chronic renal papillary necrosis, perhaps because they compromise the renal medullary circulation. It therefore seems reasonable to say that these agents should be discontinued, at least temporarily, in the presence of acute pyelonephritis. Renal carbuncle or abscess Renal carbuncle is the formation of renal cortical abscesses, often only in one kidney, caused by blood-​borne infection, usually asso- ciated with untreated S. aureus septicaemia. It is most commonly seen in intravenous drug abusers and patients with diabetes. There is usually a significant time delay between the initial infection and presentation with renal carbuncle, typically 6 to 8 weeks. Presenting symptoms include fever, malaise, and abdominal or flank pain, and are often nonspecific. Because the infection is limited to the renal cortex and does not communicate with the collecting system, the urine is sterile and acellular. Blood cultures are usually negative. Radiological studies show a semisolid, thick-​walled mass, percutan- eous aspiration of which yields pus. Pyonephrosis Pyonephrosis is a bacterial infection within a completely obstructed collecting system, for instance, due to an obstructing ureteric stone. Patients usually present with fever, rigors, and flank pain, and have a marked neutrophilia and acute-​phase response. Radiological differ- entiation from hydronephrosis relies on the presence of echogenic material and/​or septa in the pelvicalyceal system, and confirmation is by percutaneous aspiration; as with other localized UTIs, the voided bladder urine may be sterile. Untreated pyonephrosis rapidly results in complete destruction of the renal parenchyma, followed by death from complications of sepsis if nephrectomy is not per- formed; correction of obstruction and aggressive intravenous anti- biotic therapy may prevent this if instituted soon enough. Perinephric abscess Perinephric abscess may complicate renal carbuncle or, more com- monly, acute pyelonephritis—​particularly if complicated by an anatomical or functional abnormality of the urinary tract. Typical presenting symptoms are those of acute pyelonephritis, with flank pain, fever, and rigors. If the abscess does not communicate with the collecting system (e.g. in abscesses caused by haematogenous spread or complicating obstruction or renal cysts), there may be no lower urinary tract symptoms, no pyuria, and the urine may be sterile. Response to antibiotic treatment is much less rapid than in patients with uncomplicated acute pyelonephritis. Diagnosis is by ultra- sonography, urography, or CT, followed by percutaneous (or occa- sionally surgical) aspiration, drainage, and culture of the aspirate. Prolonged antibiotic treatment of the organism identified is needed, stopping only when there is evidence that the infection has resolved, based on resolution of fever and of the acute-​phase response, and re- peated radiological studies. This may take as long as 8 weeks. Xanthogranulomatous pyelonephritis Xanthogranulomatous pyelonephritis is an atypical form of chronic infection of the renal parenchyma in which bacterial infection, usu- ally in the presence of obstruction or staghorn calculi, results in for- mation of granulomas with the accumulation of lipid-​rich foamy macrophages. The process may be multifocal and can be complicated by extension into the perinephric fat, causing perinephric abscess. Patients are typically febrile and ill, with a history of progressive weight loss, anaemia, and malaise, without lower urinary tract symp- toms, and have a mass in the flank on examination. Radiologically, the multifocal mass crossing tissue planes may be indistinguishable from a renal cell carcinoma, which may also cause systemic symp- toms such as fever, anaemia, and weight loss. Although both require surgical excision, radical surgery can be avoided if the diagnosis is made preoperatively. Emphysematous pyelonephritis Emphysematous pyelonephritis is a rare and life-​threatening form of acute pyelonephritis in which there is tissue necrosis together with formation of hydrogen and CO2, which accumulate in pockets in the renal parenchyma, perinephric space, and collecting systems—​ ‘gas gangrene of the kidney’ (Fig. 21.13.6). The typical patient is an Fig. 21.13.6  Gas-​forming infection, seen as the three black holes in the single remaining (right) kidney of a patient with diabetes. The left kidney had been removed 2 years earlier for a similar gas-​forming infection. This infection was successfully treated by intravenous antibiotics and percutaneous drainage.

21.10The kidney in systemic disease

21.10The kidney in systemic disease

21.13 Urinary tract infection 5074 Charles Tomson

21.13 Urinary tract infection 5074 Charles Tomson and Neil Sheerin

21.15 The renal tubular acidoses 5104 John A. Saye

21.15 The renal tubular acidoses 5104 John A. Sayer and Fiona E. Karet

21.2 Electrolyte disorders 4729 21.2.1 Disorders o

21.2 Electrolyte disorders 4729 21.2.1 Disorders of water and sodium homeostasis Michael L. Moritz and Juan Carlos Ayus

21.2.2 Disorders of potassium homeostasis 4748 Joh

21.2.2 Disorders of potassium homeostasis 4748 John D. Firth

CONTENTS 21.2.1 Disorders of water and sodium homeostasis  4729 Michael L. Moritz and Juan Carlos Ayus 21.2.2 Disorders of potassium homeostasis  4748 John D. Firth 21.2.1  Disorders of water and sodium homeostasis Michael L. Moritz and Juan Carlos Ayus ESSENTIALS Regulation of water balance and sodium disorders Water intake and the excretion of water are tightly regulated processes that are able to maintain a near-​constant serum osmolality. Sodium disorders (dysnatraemias—​hyponatraemia or hypernatraemia) are almost always due to an imbalance between water intake and water excretion. Understanding the aetiology of sodium disorders depends on under- standing the concept of electrolyte-​free water clearance—​this is a con- ceptual amount of water that represents the volume that would need to be subtracted (if electrolyte-​free water clearance is positive) or added (if negative) to the measured urinary volume to make the electrolytes contained within the urine have the same tonicity as the plasma electrolytes. It is the concentration of the electrolytes in the urine, not the osmolality of the urine, which ultimately determines the net excretion of water. Hyponatraemia Hyponatraemia, defined as a serum sodium concentration of less than 135 mmol/​litre, is a common electrolyte disorder. It is al- most invariably due to impaired water excretion, often in states where antidiuretic hormone release is (1) a normal response to a physiological stimulus such as pain, nausea, volume depletion, postoperative state, or congestive heart failure; or (2)  a patho- physiological response as occurs with thiazide diuretics, other types of medications, or in the syndrome of inappropriate diuresis; with both often exacerbated in hospital by (3) inappropriate iatrogenic administration of hypotonic fluids. Clinical features—​these can range from the patient who is en- tirely asymptomatic at one end of the spectrum to hyponatraemic encephalopathy—​most commonly manifesting with nausea, vomiting, and headache—​at the other. Cerebral demyelination is a serious complication associated with hyponatraemia and its treat- ment, at its worst manifesting as pseudocoma with a ‘locked in’ state. Children and premenopausal women are at particular risk of poor outcomes, as are those who are hypoxic at presentation. It is now recognized that even mild chronic hyponatraemia is as- sociated with subtle neurological impairment, leading to falls and associated bone fractures in the elderly, and is an independent risk factor for mortality in both ambulatory and hospital settings. Management approach—​the first priority is to exclude a hyperosmolar state and verify whether the patient is hypotonic, by (when possible) measuring the serum osmolality. The diagnostic approach is further based on the history, clinical assessment of the patient’s volume status, and estimation of urinary electrolytes. Key issues are to recognize that (1) hyponatraemic encephalopathy is a medical emergency that should be diagnosed and treated promptly with hypertonic saline to prevent death or devastating neurological complications; but also (2) that patients who are asymptomatic do not require immediate treatment with hypertonic saline, whatever their level of serum sodium. Precipitating causes (e.g. thiazide diur- etics) should be withdrawn when possible. Practical management—​algorithms, even if complex, cannot ac- curately predict a patient’s response to treatment of hyponatraemia: close monitoring of serum sodium is essential. Patients with sus- pected hyponatraemic encephalopathy, with either mild or advanced symptoms, children or adults, should receive a 2 ml/​kg bolus of 3% NaCl with a maximum volume of 100 ml. A single bolus would result in at most a 2 mmol/​litre acute rise in serum sodium, which would quickly reduce brain oedema. The bolus could be repeated one or two times if symptoms persist. The advantage of this approach over a continuous infusion of 3% NaCl is that there is a controlled and immediate rise in serum sodium and there is little or no risk of inad- vertent overcorrection, as can occur if a 3% NaCl infusion runs at an excessive rate or for too long. Cerebral demyelination—​this is a serious complication that has been associated with the correction of severe and chronic hyponatraemia, hence all patients receiving an infusion of 3% saline
21.2 Electrolyte disorders

section 21  Disorders of the kidney and urinary tract 4730 should have their serum sodium measured at least every 2 h until they are clinically stable and the serum sodium values are stable, with appropriate modification of treatment in response to the measure- ments. Failure to do so, and reliance on a calculated infusion rate, can lead to significant patient injury from an excessive increase in serum sodium. Prevention—​hyponatraemia is usually iatrogenic and can be avoided or detected as follows: (1) hypotonic fluids should never be administered following surgery unless used to correct a free-​water deficit—​0.9% (normal) saline (NaCl) should be given postoperatively if parenteral fluids are indicated; (2) all hospitalized patients should be considered at risk for the development of hyponatraemia and should not be given hypotonic fluids unless a free-​water deficit is present or if ongoing free-​water losses are being replaced; and (3) patients taking thiazide diuretics, especially older people, should be weighed before and after starting therapy and serum electrolytes monitored to detect water retention and the development of hyponatraemia. Hypernatraemia Hypernatraemia, defined as a serum sodium concentration greater than 145 mmol/​litre, is a common electrolyte disorder that occurs when water intake is inadequate to keep up with water losses. Since the thirst mechanism is such a powerful stimulus, hypernatraemia almost invariably occurs in the context of an illness and care that re- stricts the patient’s access to water. Clinical features—​these are mainly related to central nervous system dysfunction caused by cerebral dehydration and cell shrinkage. Management approach—​the first step in evaluation is to take a de- tailed history focusing on fluid intake and losses. To assess urinary water losses, it is necessary to measure the urinary cationic electro- lytes (sodium and potassium) and the urinary osmolality, remem- bering that the urinary osmolality alone cannot always determine the presence or absence of electrolyte-​free water losses in the urine, the reason being that water can be excreted with nonelectrolyte osmoles or with electrolyte osmoles. Practical management—​needs to be guided by the following principles: (1) correction of underlying deficits in circulatory blood volume by infusion of 0.9% saline; (2) correction of chronic hypernatraemia at a pace that avoids therapy-​induced cerebral oe- dema, which requires an understanding of both the initial water deficit and of ongoing water losses if the patient is polyuric; (3) ad- ministration of water by drinking or feeding tube is preferable to treatment with intravenous fluids if possible; (4) glucose-​containing solutions should be avoided if possible; (5) as for the treatment of hyponatraemia, algorithms cannot accurately predict the response to treatment of hypernatraemia, hence regular monitoring of serum sodium with appropriate adjustment of treatment in response to the values obtained is mandatory; (6) patient should be corrected to high normal or mildly hypernatraemic values to prevent cerebral oedema from overcorrection. Prevention—​(1) patients with impaired access to water (e.g. infants, elderly, and hospitalized patients) should be considered at risk for the development of hypernatraemia, and their serum sodium should be monitored; (2) urinary electrolytes should be measured in conjunc- tion with urinary osmolality in patients with polyuria to assess water losses in the urine and urinary concentrating ability; and (3) adequate free water should be provided to prevent hypernatraemia. Disorders of water metabolism Hyponatraemia and hypernatraemia occur when there is a break- down of the normal homeostatic mechanisms that keep water in- take and excretion precisely balanced to prevent the development of disturbances in the serum sodium. There are numerous causes of impairment in this homeostatic function, such as renal failure, use of diuretics, and nonosmotic release of antidiuretic hormone (ADH) due to nausea, pain, or other stimuli. Poor outcomes are still common among patients with hypernatraemia and hyponatraemia, in many cases due to failure to promptly recognize a life-​threatening condition and initiate appropriate treatment. In this chapter, the pathophysiology of sodium disturbances is addressed, with a focus on understanding clinical presentations of the diseases. Regulation of water balance Dysnatraemias (hyponatraemia or hypernatraemia) occur when there is an imbalance between water intake and water excretion. Extracellular fluid tonicity is reflected by the concentration of the serum sodium. Nearly all cell membranes are permeable to water, hence water will equilibrate between the intracellular space and the extracellular space to maintain the same osmolality in both compartments, and intra- cellular electrolyte concentrations will approximate the extracellular electrolyte concentrations. This means that the serum sodium concen- tration (Nase) is proportional to the total body exchangeable sodium (Nae) plus the total body exchangeable potassium (Ke): Na + K / total body water Na e e se ( ) ∝

(Equation 21.2.1.1) Water intake and the excretion of water are tightly regulated pro- cesses and therefore a near-​constant serum osmolality is maintained (Fig. 21.2.1.1). Because of this tight regulation, disturbances in serum sodium are nearly always caused by perturbations in water balance, not of electrolytes. Renal water handling It is through the actions of ADH (also known as arginine vaso- pressin) that the kidney regulates water excretion. The normal kidney has the ability to vary urinary concentration significantly, from as low as 50 mOsm/​kg to as high as 1200 mOsm/​kg when ADH activity is maximal, although when there is renal insufficiency (especially tubulointerstitial disease) this range is much more re- stricted. This means that the kidney can either excrete a large water load in very dilute urine or conserve water significantly. A math- ematical illustration can make this clear. If a daily solute load is taken to be 800 mOsm (mainly electrolytes and urea, the latter due to protein catabolism), then this amount must be excreted in 24 h in order to maintain solute balance. Under conditions of maximal urinary concentration, this could be excreted in approximately 667 ml of urine ([800 mOsm/​1200 mOsm] × kg−1), which would be the expected response to a hypernatraemic state. Conversely, under conditions of maximal urinary dilution, this osmolar load would be excreted in 16 litres of urine ([800 mOsm/​50 mOsm] × kg−1), which would be an expected response to water intoxication or could occur in the setting of diabetes insipidus. Therefore, the body has the ability, under normal conditions, to achieve water balance across a very wide range of water intake. Disorders in water balance usually

21.2.1  Disorders of water and sodium homeostasis 4731 occur when there is a disruption in these processes that allow water intake and water excretion to be exquisitely matched. The concept of electrolyte-​free water The concept of electrolyte-​free water is a good approach to under- standing patients with disturbances in water balance. The electrolyte-​ free water clearance is a conceptual amount of a fluid that represents the volume that would need to be subtracted (if electrolyte-​free water clearance is positive) or added (if negative) to the measured urinary volume to make the electrolytes contained within the urine have the same tonicity as the serum electrolytes (Fig. 21.2.1.2): [1 ([Na ] [K ] / Na [K ] volume of urine ml
) ([ ] )] ( ) u u se se − + + × + + + + = electrolyte free water clearance −

(Equation 21.2.1.2) where [Na+]u is urinary sodium concentration, [K+]u is urinary po- tassium concentration, [Na+]se is serum sodium concentration, and [K+]se is serum potassium concentration. The electrolyte-​free water represents the amount of water lost in excess of electrolytes and which would therefore—​if not replaced—​ have an effect on serum osmolality. A few key points must be made about the electrolyte-​free water. First, it is truly a conceptual volume because, as can be seen in Equation 21.2.1.2, it can take on a negative value, which occurs when the electrolyte concentration in the urine exceeds that in the serum: when the electrolyte-​free water clearance is negative, there is net retention of electrolyte-​free water. Second, the concept of electrolyte-​free water clearance highlights the fact that it is the concentration of the electrolytes in the urine, not the osmolality of the urine, which ultimately determines the net excre- tion of water. In other words, the urine osmolality may be high but, if the urine contains mainly urea and very few electrolytes, there will still be a net loss of water. Electrolyte-​free water clearance can there- fore be calculated as shown in Equation 21.2.1.2 as a convenient clin- ical tool for assessing water need in a patient. Clinical utility of electrolyte-​free water clearance A critical point to understand is that the urine electrolytes and not the urine osmolality determine the amount of free water excreted in the urine. Typically, if the relationship between the serum elec- trolytes and the urine electrolytes is understood, it is not necessary to calculate a value for the electrolyte-​free water clearance. In the case where the concentration of electrolytes in the urine exceeds the concentration of electrolytes in the serum, then free water is not being excreted in the urine. Conversely, when the concentra- tion of electrolytes in the urine is less than that in the serum, then free water is being excreted in the urine. Figure 21.2.1.3 illustrates this relationship: much can be learned regarding water excretion by simply examining the concentration of the electrolytes in the urine. Hyponatraemia Hyponatraemia is defined as a serum sodium concentration lower than 135 mmol/​litre, which is a common condition in hospital set- tings and increasingly recognized in outpatients. Hyponatraemia can be asymptomatic, although careful neurological evaluation has de- tected subtle abnormalities in patients with chronic hyponatraemia ADH suppressed Dilute urine (free-water excretion) ADH release stimulated Concentrated urine (free-water retention) Thirst stimulated Increased water intake Free-water retention Free-water excretion Free-water intake = free-water excretion Hyponatraemia Hypernatraemia Normonatraemia Fig. 21.2.1.1  Regulation of water intake and excretion to maintain normonatraemia. Reproduced with permission from Achinger SG, Ayus JC. Fluid and Electrolytes. In Civetta, Taylor, and Kirby’s Critical Care, 4th edition. Volume of electrolytes isotonic to serum Volume of electrolyte-free water (urea, glucose, and ketones) Volume of urine containing electrolytes and nonelectrolytes (urea, glucose, and ketones) Fig. 21.2.1.2  Resolution of urinary volume into a proportion of electrolytes isotonic to serum, with the remainder as ‘electrolyte-​free water’.

section 21  Disorders of the kidney and urinary tract 4732 and serum sodium as high as 132 mmol/​litre, which can lead to falls and fractures in the elderly. There is increasing evidence that hyponatraemia is an independent risk factor for mortality, particu- larly in patients with endstage liver disease, congestive heart failure, pneumonia, and endstage renal disease. Hyponatraemia is a signifi- cant healthcare burden, resulting in increased medical costs and length of hospital stay. The most serious complication of hyponatraemia is hyponatraemic encephalopathy (central nervous system symptoms secondary to cerebral oedema), which is a medical emergency that must be diag- nosed promptly and treated quickly, or death or devastating neuro- logical complications can result. It is critical to differentiate between symptomatic and asymptomatic hyponatraemia as the management is much different. It is recognized that risk factors for hyponatraemic encephalopathy play a critical role in determining whether or not patients are likely to develop this condition as a consequence of hyponatraemia:  those of young age, premenopausal women, and those with hypoxia are at increased risk of a poor outcome. Prevention Most cases of hospital-​acquired hyponatraemia can be prevented by avoiding hypotonic intravenous fluids and administering 0.9% NaCl when indicated. Significant morbidity and mortality from hyponatraemic encephalopathy has occurred in hospital- ized patients receiving hypotonic intravenous fluids, in particular postoperative patients. In 2003, we proposed that 0.9% NaCl (Na 154  mmol/​litre) be administered for the prevention of hospital-​ acquired hyponatraemia in patients at risk for ADH excess, and that the routine practice of administration of hypotonic and near isotonic intravenous fluids (Na ≤130  mmol/​litre) be aban- doned. Hospitalized patients are at high risk for hospital-​acquired hyponatraemia from numerous physiological stimuli for ADH production, such as nausea, vomiting, pain, stress, volume deple- tion, and disease states associated with high ADH production such as respiratory illnesses, central nervous system disease, and the postoperative state. There have been numerous prospective studies demonstrating that hypotonic fluids result in a high incidence of hospital-​acquired hyponatraemia, whereas 0.9% NaCl effectively prevents the development of hyponatraemia without resulting in fluid-​related complications such as hypernatraemia or fluid over- load. We recommended that hypotonic fluids be restricted in their use to patients with either hypernatraemia (Na >145 mmol/​litre), or ongoing urinary or extrarenal free water losses. Isotonic fluids are incapable of producing hypernatraemia in the absence of a renal concentrating defect or large extrarenal free water losses, as a normal functioning kidney can generate free water by excreting hypertonic urine. Pathogenesis The main defence against the development of hyponatraemia is the ability of the kidney to dilute the urine and excrete free water. The typical adult (assuming normal renal function) can excrete ap- proximately 15 litres of free water per day in the urine, hence ex- cess ingestion of water as the sole cause of hyponatraemia is rare outside of the setting of mental illness. There are numerous haemo- dynamic and nonhaemodynamic stimuli for ADH production which place virtually all acutely ill patients at risk for the develop- ment of hyponatraemia (Fig. 21.2.1.4). An underlying condition that impairs free-​water excretion is typically necessary in conjunc- tion with free-​water intake for the development of hyponatraemia. States of impaired water excretion are often states where ADH re- lease is a normal response to a physiological stimulus such as pain, nausea, volume depletion, postoperative state, or congestive heart failure. ADH release may also be pathophysiological such as occurs with thiazide diuretics or with other types of medications such as antiepileptic drugs, or in the syndrome of inappropriate diuresis. Brain defences against cerebral oedema Hyponatraemia leads to an osmotic gradient favouring water move- ment intracellularly, which—​if allowed to act unopposed—​could lead to cerebral oedema and severe neurological injury. The first-​ line defence against this is the blood–​brain barrier, which impedes the entry of water. This starts with tight junctions between vascular endothelial cells of the brain capillaries and their interface with the foot processes of astrocytes, the latter being a highly specialized subtype of glial cell that performs many supporting functions in maintenance of the fluid environment and electrolyte milieu of the extracellular space of the brain. The astrocytes are the main regulator of brain water content: they swell during hypotonic stress, whereas neurons do not, with this cap- acity largely due to the presence of a water channel specific to astro- cytes, aquaporin 4. Mice with targeted deletion of aquaporin 4 are protected from cytotoxic cerebral oedema caused by water intoxica- tion, brain ischaemia, or meningitis, but are particularly vulnerable to vasogenic cerebral oedema caused by, for example, cerebral abscess or tumour, or hydrocephalus. The response of the astrocyte is critical in determining the degree of cerebral oedema in response to hypo-​ osmolar stress, and modulation of aquaporin 4 production or function may prove useful in the management of a variety of cerebral disorders, including those associated with hyponatraemia, in the future. However, progressive and increasing swelling of astrocytes in the face of hyponatraemia would not protect the brain against ad- verse consequences, and there are several other protective mech- anisms. There is shunting of cerebrospinal fluid from within the brain: this is a rapid response, but its capacity to buffer significant volume change is limited. Ultimately, cell volume regulatory mech- anisms in the cerebral astrocytes must be active to decrease the brain size. This is accomplished by reduction in cellular osmolyte content (mainly electrolytes) using an ATP-​dependent mechanism that re- quires Na+,K+-​ATPase to extrude ions (electrolytes) from within, with water obligatorily following to reduce brain volume. In animal Nau + Ku < Nase + Kse Nau + Ku > Nase + Kse Measure Nau, Ku, Nase, Kse Retaining electrolyte- free water Excreting electrolyte- free water Fig. 21.2.1.3  Measurement of serum and urinary electrolytes can determine whether the patient is retaining or excreting electrolyte-​free water. Kse, serum potassium; Ku, urine potassium (spot); Nase, serum sodium; Nau, urine sodium (spot).

21.2.1  Disorders of water and sodium homeostasis 4733 models of acute hyponatraemia, brain water content is returned to near the baseline value 6 h after induction of acute hyponatraemia. As will be discussed later, several clinical factors have been shown to impair these glial cell adaptive responses, and these are the chief risk factors for poor patient outcome. Clinical manifestations Advanced symptoms of hyponatraemic encephalopathy include seizures, respiratory arrest, and noncardiogenic pulmonary oedema. The symptoms of hyponatraemia are attributable to osmotic swelling of the brain, with pressure on the brain parenchyma arising because of the rigid structures encasing the central ner- vous system. The manifestations can be varied and not necessarily related to the degree of decrease in serum sodium concentration, which is frequently less than 120 or 115 mmol/​litre in congestive heart failure and in cirrhosis with very few—​if any—​overt symp- toms (Fig. 21.2.1.5). Conversely, life-​threatening cerebral oedema can be the presentation of a patient with a serum sodium as high as 128 mmol/​litre. Hyponatraemic encephalopathy is defined as symptomatic cerebral oedema secondary to hyponatraemia:  the early signs are usually nonspecific—​nausea, vomiting, headache—​ and can often go unrecognized, with advanced symptoms being signs of brainstem herniation—​including seizures, respiratory ar- rest, noncardiogenic pulmonary oedema, dilated pupils, and decor- ticate posture—​which can lead to death if left untreated. Hyponatraemic encephalopathy Risk factors Not all patients are equal in terms of risk of morbidity and mortality following the development of hyponatraemia. Hyponatraemic en- cephalopathy is primarily encountered when there is an acute fall in serum sodium (<48 h), but can occur in chronic hyponatraemia in high-​risk patients (see Box 21.2.1.1 later in this chapter). Children are at particular risk for poor outcome following the development of hyponatraemia due to their high ratio of brain size to skull size, the skull not reaching its full size until age 16 years, whereas the brain reaches its adult size at approximately age 6 years. This means that children cannot accommodate as much increase in brain size as adults: there is less capacity for brain expansion before pressure is exerted on the brain parenchyma. For this reason, the long-​standing practice of administering hypotonic fluids to children is being chal- lenged: normal (0.9%) saline is the most appropriate fluid to use to prevent the development of iatrogenic hyponatraemic encephalop- athy in children. Hemodynamic stimuli Pain and stress Nausea and vomiting Hypoxemia and hypercapnia Hypoglycemia Medications Perioperative state Cancer Inflammation Pulmonary disease CNS disease Hypotension Volume depletion Cirrhosis Nephrotic syndrome Adrenal insufficiency Congestive heart failure Nonhemodynamic stimuli Fig. 21.2.1.4  Nonosmotic states of ADH excess. From Moritz ML, Ayus JC (2015). Maintenance Intravenous Fluids in Acutely Ill Patients. N Engl J Med, 373, 1350–​60. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission.

section 21  Disorders of the kidney and urinary tract 4734 Premenopausal women are another significant risk group in terms of neurological outcomes following hyponatraemia, being 25 times more likely to die following hyponatraemic encephalopathy than other groups of patients. This striking difference is not accounted for by differences in clinical presentation, and anatomical factors in terms of the brain size—​cranial vault size ratio (as is seen with children)—​cannot explain the disparity in outcomes. Differences in adaptive responses to hyponatraemia must exist. As previously de- scribed, it is known that ATP-​dependent mechanisms are important for the response to hypo-​osmolar stress in the brain. Oestrogens have a similar steroidal structure to ouabain and other cardiac glycosides (such as digoxin), which are known to inhibit the Na+,K+-​ATPase, and female sex hormones have been shown to inhibit the activity of this pump in diverse tissues such as mammalian heart, diaphragm, red blood cells, and liver. Sex steroids and gender also play a signifi- cant role in brain adaptation and in animal models of hyponatraemia. There is increased morbidity from hyponatraemia in female rats, and isolated synaptosomes from female hyponatraemic rats have an in- creased uptake of sodium compared with male hyponatraemic rats, suggesting impairment in sodium extrusion. Regulatory volume de- crease is also inhibited by the presence of oestrogen/​progesterone in rat astrocytes treated in vitro. These studies support the notion that the presence of female sex hormones can impair the critical energy-​ dependent astrocyte cell volume regulatory processes, with this im- pairment leading to more severe cerebral oedema. Finally, female rats have more intense vasoconstriction than male rats in response to ADH, which may lead to tissue hypoxia, which is another possible factor in producing poor outcomes. Role of hypoxia Animal studies have demonstrated that survival is severely im- paired and brain adaptation is significantly impaired following hyponatraemia and simultaneous brain hypoxia. Epidemiological studies have shown that patients with hypoxia at presentation of hyponatraemic encephalopathy have a poor outcome compared with those who are not hypoxic, even after adjustment for comorbid Box 21.2.1.1  Treatment of symptomatic hyponatraemia 1 A 2-​ml/​kg bolus of 3% NaCl, given IV over 10 min to maximum volume of 100 ml. 2 Repeat bolus one or two times as needed until symptoms improve, with goal being to produce a 5-​ to 6-​mmol/​litre increase in serum sodium in first 1 to 2 h. 3 Recheck serum sodium following second bolus or at 2 h. 4 Hyponatraemic encephalopathy is unlikely if there is no clinical improvement following an acute rise in serum sodium of 5 to 6 mmol/​litre 5 Stop further therapy with 3% NaCl boluses when patient is either:

—​ symptom free: awake, alert, responding to commands, resolution of headache and nausea

—​ there is an acute rise in sodium of 10 mmol/​litre in first 5 h 6 Correction in first 48 h should:

—​ not exceed 15–​20 mmol/​litre

—​ avoid normo-​ or hypernatraemia If 3% NaCl is not available, then an equivalent amount of 8.4% sodium bicarbonate (1 mEq/​ml) can be administered as a 1 ml/​kg bolus (max- imum 50 ml). Reproduced with permission from Moritz ML, Ayus JC (2010). New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephal- opathy in children. Pediatr Nephrol, 25(7), 1225–​38. Age <16 Female sex steroids Hypoxia Post-operative state Underlying CNS dis. Headache, nausea vomiting lethargy, confusion somnolence Blurred vision , dilated pupils Decorticate and decerebrate posturing Seizure Cerebral edema Intracranial hypertension Tentorial herniation Release of excitatory amino acids Exercise-associated hyponatremia Acute mountain sickness Ecstasy [3,4-MDMA] Post-operative state Neurogenic pulmonary edema Hypercapnic respiratory failure

21.2.1  Disorders of water and sodium homeostasis 4735 conditions. Since impairment of astrocyte adaptive mechanisms can explain poor outcome in premenopausal females, it has been pro- posed that hypoxia may similarly have an effect on astrocyte volume regulation. Impairment of energy utilization in the brain—​a common phenomenon following asphyxiation or cardiac arrest—​can lead to diffuse cerebral oedema, termed ‘cytotoxic’ cerebral oedema, related to the impairment of cell-​volume regulatory mechanisms. Hence, if hyponatraemia—​which will by itself induce cerebral oedema—​is compounded with impairment in volume regulatory mechanisms through hypoxia, then this is likely to lead to more severe cerebral oedema than if hypoxia were not present and a poor outcome. Hypoxia develops in patients with hyponatraemic encephalop- athy through two mechanisms: hypercapnic respiratory failure and neurogenic pulmonary oedema. Hypercapnic respiratory failure is secondary to central respiratory depression and is a first sign of impending brainstem herniation, with the hypoxaemia that then develops being due to the central respiratory depression further worsening astrocyte cell-​volume regulatory mechanisms and leading to worsening of brain oedema. Neurogenic pulmonary oedema, caused by increased vascular permeability and increased catechol- amine release that occurs secondary to elevated intracranial pressure, is a complication of cerebral oedema and can occur in the setting of hyponatraemic encephalopathy as well (Fig. 21.2.1.6). This form of noncardiogenic pulmonary oedema is known as the Ayus–​Arieff syndrome, and is secondary to increased intracranial pressure due to cerebral oedema. Hypoxaemia is therefore both a risk factor and a pathogenic mechanism in severe cerebral oedema, as once hyp- oxaemia is established, the underlying cerebral oedema will worsen because the hypoxia will initiate a vicious cycle that—​unless broken—​ results in worsening of the underlying cerebral oedema. Diagnostic approach to hyponatraemic patients With a patient with hyponatraemia, the first priority is to exclude a hyperosmolar state and verify that a hypotonic state exists by (when possible) measuring the serum osmolality. An osmotically active substance confined to the extracellular fluid—​most typically glucose, mannitol, or glycine—​leads to translocation of water from the intracellular space and to a decreased serum sodium concen- tration despite a net increase in serum osmolality. In assessing for a disturbance of sodium when hyperglycaemia is present, the serum sodium must be ‘corrected’ for the presence of hyperglycaemia by adding 1.4 mmol/​litre for every 5 mmol/​litre increase of the serum glucose above 5 mmol/​litre (or 1.6 mmol/​litre for every 100 mg/​dl above 100 mg/​dl). The possibility of pseudohyponatraemia should also be kept in mind. Hyperproteinaemia and hyperlipidaemia can lead to spuri- ously low serum sodium measurements despite a normal plasma osmolality by the displacement of plasma water. Serum sodium levels can be measured by direct or indirect-​reading ion-​selective electrode potentiometry. The direct method will not indicate pseudohyponatraemia because it measures the activity of sodium in the aqueous phase of plasma only. By contrast, the indirect method may indicate pseudohyponatraemia because the specimen is diluted with a reagent prior to measurement. Whole blood sodium concen- tration measurement using a blood gas or i-​Stat point-​of-​care ana- lyser is not subject to pseudohyponatraemia. The diagnostic approach is further based on the history, urinary electrolytes, and clinical assessment of the patient’s volume status (Fig. 21.2.1.7), which will be further demonstrated in the case dis- cussions to follow. Serum and urine biochemistries can be par- ticularly helpful in diagnosing the syndrome of inappropriate antidiuresis/​syndrome of inappropriate antidiuretic hormone se- cretion (SIADH), which occurs when hyponatraemia is due to nonhaemodynamic stimuli for ADH production. SIADH In SIADH, subclinical volume expansion triggers a haemodynamic regulatory mechanism that results in a natriuresis, with increased so- dium excretion in the urine in order to maintain plasma volume at the expense of serum sodium concentration. SIADH is a heteroge- neous condition with different patterns of ADH secretion, hence the urine osmolality and urinary sodium excretion are similarly variable. SIADH is essentially a diagnosis of exclusion: other conditions such as renal dysfunction, adrenal insufficiency, hypothyroidism, and disease states associated with haemodynamic stimuli for ADH production must be excluded. In addition to standard blood and urine chemical analysis, evaluation of plasma and urine uric acid can be helpful in confirming the diagnosis. SIADH is usually as- sociated with a combination of hypouricaemia (uric acid <240 μmol/​litre (4 mg/​dl)) and an elevated fractional excretion of urate (FEUrate >11%). This can be particularly helpful in distinguishing SIADH from other hyponatraemic states where the urinary sodium may be elevated, such as adrenal insufficiency or renal tubular dys- function, or if loop diuretics have been used. Urate excretion can also be helpful in distinguishing SIADH from a similar condition called cerebral salt wasting. Cerebral salt wasting Cerebral salt wasting is a rare condition that is primarily but not ex- clusively associated with central nervous system disease. It is best considered as a syndrome of inappropriate natriuresis that leads to volume depletion. The pathophysiology of SIADH and cerebral salt wasting are fundamentally different. In SIADH, the primary disorder   Hyponatraemia Cytotoxia cerebral oedema Increased intracranial pressure Centrally mediated increased vascular permeability Catecholamine release Pulmonary vasoconstriction Elevated capillary hydrostatic pressure Capillary wall injury Noncardiogenic pulmonary oedema Fig. 21.2.1.6  Mechanism of noncardiogenic pulmonary oedema in hyponatraemic encephalopathy.

section 21  Disorders of the kidney and urinary tract 4736 is the inappropriate (with regard to serum osmolality) release ADH. In cerebral salt wasting, there is inappropriate and excessive release of natriuretic peptides that leads to a primary natriuresis and volume depletion, with a secondary neurohormonal response of increased renin–​angiotensin system activation and ADH production. One might think that the two conditions could be easily distinguished on physical examination and by different serum and urinary biochemistries, but in fact they can be nearly indistinguishable at presentation. Signs of volume depletion are not always apparent, and there are no biochem- ical findings that reliably separate the two disorders at the time of pres- entation, although there is some data to suggest that urate excretion differs in SIADH and cerebral salt wasting following the correction of hyponatraemia. Urate excretion is said to normalize following the correction of hyponatraemia in SIADH, whereas hypouricaemia and an elevated FEUrate are said to persist in cerebral salt wasting, but additional data are needed to confirm these findings. Treatment of hyponatraemic encephalopathy A 100-​ml 3% NaCl bolus is the preferred treatment for symptomatic hyponatraemia. Hyponatraemic encephalopathy is a life-​threatening medical emergency that must be treated appropriately and in a timely manner to avoid death or severe neurological impairment. As previously de- scribed, early symptoms are headache, nausea, and vomiting, with seizures commonly seen if cerebral oedema worsens. The final stages, if not corrected, are coma, respiratory arrest, and death. The aims of treatment of hyponatraemic encephalopathy are to (1) remove patients with severe manifestations of cerebral oedema from immediate danger, (2)  correct serum sodium to a mildly hyponatraemic level, and (3) maintain this level of serum sodium to allow for the brain to adapt to the change in serum osmolality. Prompt treatment is essential in all patients with hyponatraemic encephalopathy, with the definitive therapy being administra- tion of hypertonic saline (3% NaCl, 513 mmol/​litre). Most of the morbidity associated with this condition results from insufficient therapy rather than overcorrection. Fluid restriction alone is inad- equate therapy for symptomatic hyponatraemia, and 0.9% NaCl, 1.8% NaCl, and V2 receptor antagonists are also inappropriate for the treatment of patients who are encephalopathic. Concentrations of 0.9% and 1.8% NaCl are not sufficiently hypertonic to consist- ently induce the rapid rise in plasma osmolality necessary for the reduction in cerebral oedema central to the management of this condition. The only consistent way of acutely increasing the plasma sodium and to most effectively treat hyponatraemic encephalopathy is to administer 3% NaCl, which has a sodium concentration that exceeds the kidney’s ability to generate free water. There are two pri- mary misconceptions related to the use of hypertonic saline in the treatment of hyponatremic encephalopathy which are barriers to its appropriate use; (1) the mistaken believe that the risks of developing cerebral demyelination associated with using hypertonic saline ex- ceeds the benefits and (2) that hypertonic saline must be adminis- tered through a central line in the intensive care unit. Studies have demonstrated that incidence of cerebral demyelination associated with correction of severe hyponatremia is very small and primarily in patients with multiple other risk factors. Short term infusions of hypertonic saline can also be given safely through a peripheral IV in a non-ICU setting and is not associated with phlebitis. We recommend that any patient with suspected hyponatraemic encephalopathy, with either mild or advanced symptoms, child or adult, should receive a 2 ml/​kg bolus of 3% NaCl to a maximum volume of 100 ml (Box 21.2.1.1). A single bolus results in at most a 2-​mEq/​litre acute rise in serum sodium, which would quickly re- duce brain oedema, and the bolus can be repeated one or two times if symptoms persist. The advantage of this approach over a continuous infusion of 3% NaCl is that there is a controlled and immediate rise in serum sodium and little or no risk of inadvertent overcorrection, as can occur if a 3% NaCl infusion runs for too long. At times the diagnosis of hyponatraemic encephalopathy can be difficult to establish, such as in patients with either (a) hepatic en- cephalopathy, (b)  central nervous system infections, tumours, or trauma, or c) postoperative nausea and vomiting with associated hyponatraemia. Bolus therapy with 3% NaCl can serve as a diag- nostic manoeuvre, as a patient who does not show some clinical im- provement after two to three boluses is most likely is not suffering from hyponatraemic encephalopathy. As long as it does not lead to a significant delay in pursuing other diagnostic possibilities, no harm could come from using this approach in a patient with suspected hyponatraemic encephalopathy, even if they subsequently prove not to have this condition, and a therapeutic trial of a bolus of 3% NaCl should precede radiological investigations because (a) neurological deterioration could occur if there is a delay in therapy, and (b) a CT scan cannot exclude the possibility of hyponatraemic encephalopathy. Serum Na < 135 mEq/L Plasma Osmolality

280 mOsm/kg H2O • Hyperglycemia • Mannitol • IV contrast • Pseudohyponatremia • Hyperlipidemia • Hyperproteinemia <200 mOsm/kg H2O, FE Urate < 11% • Psychogenic polydypsia • Water intoxication in infants • Reset Osmostat Urine Na < 30 mEq/L, FENa < 0.5% • Extrarenal losses • Edematous states Urine Na > 30 mEq/L, FENa > 0.5% • FE Urate <11% • Salt wasting nephropathy • Mineralocorticoid deficiency • Diuretics • Osmotic diuresis • FE Urate >11% • Cerebral/Renal salt wasting (CSW) Normonatremia • FE Urate < 11% ° SIAD • FE Urate > 11% ° CSW Urine Osmolality <280 mOsm/kg H2O 200 mOsm/kg H2O Effective Circulatory Volume Depletion No No Renal Insufficiency Hypothyroid Glucocorticoid deficiency Mineralocorticoid deficiency Diuretics Urine Na > 30 mEq/L, FENa > 0.5% • FE Urate > 11%

• SIAD

• CSW Yes Fig. 21.2.1.7  Diagnostic approach to hyponatraemia. DDAVP, deamino-​d-​arginine vasopressin; GI, gastrointestinal. Reproduced from Moritz ML. Syndrome of Inappropriate Antidiuresis. Pediatr Clin North Am 2019; 66(1): 209–​226 with permission from Elsevier.

21.2.1  Disorders of water and sodium homeostasis 4737 Recommended safe limits for the correction of hyponatraemia vary among experts depending on the setting of hyponatraemia, including 6–​8 mEq/​litre in 24 h or 20 mEq/​litre in 48 h, as do re- commendations for using hypertonic saline. Our recommenda- tion to use bolus therapy is an approach that would stay well within widely recommended limits of correction and can be used safely in any setting—​for children or adults, in chronic or acute symptom- atic hyponatraemia, and in the outpatient or inpatient setting. The approach is simple: it does not rely on formulas or complicated cal- culations, and it can be administered quickly in the emergency de- partment or at the bedside, prior to transfer to a monitored setting. A few precautionary points must be understood to prevent therapy-​induced brain injury: (1) the serum sodium should not be corrected to a normonatraemic or hypernatraemic level in a patient treated for hyponatraemic encephalopathy; (2)  following correc- tion, patients should be maintained at mildly hyponatraemic levels for a few days following hyponatraemic encephalopathy (this main- tenance period will allow the patient to adjust to the new serum tonicity); and (3) if the patient has decreased cardiac output and pulmonary oedema may develop with vigorous saline volume ex- pansion, then furosemide should be given in addition to hypertonic saline—​this should prevent volume overload and pulmonary oe- dema, but such a patient requires very close monitoring. Early recognition of hyponatraemic encephalopathy and institu- tion of prompt treatment are the factors most associated with good neurological outcomes. Appropriate treatment with hypertonic sa- line is safe and effective, but improper therapy can have severe con- sequences. Some authors describe formulas of varying complexity to guide treatment of hyponatraemia: these should not be used at all when determining the amount of hypertonic saline to give because they are fundamentally flawed. Ongoing water losses are unpredict- able, and formulas are not able to take these into account because they are based on a closed system assumption (i.e. no ongoing water losses). Significant overcorrection can occur if saline is prescribed according to formula when a patient undergoes a spontaneous water diuresis, which can easily occur when the stimulus for water reten- tion is removed and the body begins to respond appropriately to hypotonicity by suppressing ADH release and excreting dilute urine, hence the recommendations made in Box 21.2.1.1. Risk factors for the development of cerebral demyelination Cerebral demyelination is a potential complication of the over­ correction of chronic hyponatraemia. Cerebral demyelination is a serious complication that has been associated with the overcorrection of severe (serum sodium <115 mEq/​litre) chronic hyponatraemia (>48 h) and is rarely seen in acute hyponatraemia. The symptoms often become apparent days to weeks following correction of hyponatraemia, and can vary from being minimal or none to as severe as a pseudocoma with a ‘locked-​ in stare’. A key point is that the hourly rate of correction of serum sodium by itself is not predictive of cerebral demyelination, whereas the absolute change in serum sodium over 48 h is predictive. This is important because it is not appropriate to treat a patient with re- spiratory arrest due to hyponatraemic encephalopathy with a ‘slow’ infusion of hypertonic saline to increase the serum sodium by 0.5 to 1 mmol/​litre per hour. This type of patient—​with impending brain- stem herniation—​should be treated with a bolus of hypertonic sa- line to quickly reduce brain volume, after which the hourly rate of correction can be more modest as long as the total change in serum sodium does not exceed 15 to 20 mmol/​litre over 48 h and the pa- tient is not corrected to normonatraemic levels. There are numerous risk factors that increase the likelihood of cerebral demyelination independent of the degree of hyponatraemia or rate of its correction. These include hypokalaemia, thia- zide diuretic use, severe liver disease, alcoholism, malnutrition, hypophosphataemia, and hypoxia. These conditions can all con- tribute to intracellular solute depletion, which aggravates osmotic stress following correction. Most patients reported with demye- lination have had one of these risk factors, and some high-​risk patients—​particularly those with alcoholism or liver disease—​have had demyelination despite careful correction of hyponatraemia and, in some cases, in the absence of hyponatraemia. Preventing overcorrection of hyponatraemia Preventing an extreme rise in serum sodium (>25 mmol/​litre in 48 h) can be difficult, particularly in the severely hyponatraemic patient (serum sodium ≤115 mmol/​litre). The overall rate of cor- rection of hyponatraemia is primarily a determinant of the renal response to fluid therapy, more so than the composition of fluids administered. Hyponatraemia almost invariably develops due to a state of high ADH production. Once the stimulus for ADH produc- tion abates, there will be brisk urinary excretion of free water and hyponatraemia will correct rapidly. The main conditions in which correction by fluid therapy will induce a brisk free water diuresis are (1)  thiazide-​induced hyponatraemia, (2)  water intoxication, (3) gastroenteritis, (4) adrenal insufficiency following replacement therapy, and (5)  1-​deamino-​8-​d-​arginine vasopressin (DDAVP)-​ induced hyponatraemia following DDAVP withdrawal. Even in pa- tients who are not typically at high risk for overcorrection, such as those with SIADH and postoperative hyponatraemia, a free water diuresis will ensue when the stimuli for ADH production abates. In general, if the serum sodium is greater than 115 mmol/​litre, then even if there is a brisk free water diuresis, the absolute rise in serum sodium will not be likely to exceed 25 mmol/​litre, and the risk of brain injury is small. Box 21.2.1.2 outlines the measures that should be taken to prevent overcorrection of hyponatraemia. Under certain circumstances, the administration of DDAVP will be indicated to prevent an overcorrection, and this can also be used to therapeutic- ally relower the serum sodium following overcorrection of chronic hyponatraemia. In cases of DDAVP-​induced hyponatraemia, it may be safer to continue the DDAVP and administer 3% NaCl in order to achieve a controlled correction of hyponatraemia. This is particu- larly so if there is severe hyponatraemia (Na <115 mmol/​litre) or if there is a disorder in the thirst mechanism or restricted access to water as can occur in central diabetes insipidus. Asymptomatic hyponatraemia Asymptomatic hyponatraemia is an independent risk factor for falls and fractures in the elderly and for increased hospital mortality. It has become increasingly clear that any degree of hyponatraemia can have dangerous consequences and is associated with increased morbidity and mortality. Mild chronic hyponatraemia (sodium <130 mmol/​litre) can produce subtle neurological impairment af- fecting both gait and attention, similar to that of moderate alcohol intake. This may explain why hyponatraemia has been increasingly associated with falls and bone fractures in the elderly, in which regard

section 21  Disorders of the kidney and urinary tract 4738 there is additional evidence in both animals and humans that chronic hyponatraemia contributes to osteopenia. Hyponatraemia appears to induce bone loss by stimulating osteoclastogenesis and bone re- sorptive activity as a means of preserving sodium homeostasis (Fig. 21.2.1.8). It is now well established in adults that hospital-​ associated hyponatraemia is an independent risk factor for all-​cause mortality, with studies documenting an association in the ambula- tory setting and general medical wards, as well as in patients with community-​acquired pneumonia, congestive heart failure, and endstage liver disease. Hyponatraemia is also recognized as an inde- pendent predictor of increased medical costs in hospitalized patients. Treatment of asymptomatic chronic hyponatraemia Hyponatremia is a multifactorial condition that can result from numerous causes and management will vary depending on the underlying disease and etiology of hyponatremia. There are various therapies available, most of which have not been for- mally studied in great detail. Fluid restriction is the corner- stone in the management of hyponatremia, as hyponatremia is unlikely to occur in the absence fluid intake. Fluid restriction is primarily indicated as part of the management of euvolemic and hypervolemic hyponatremia, as is seen in SIADH and con- gestive heart failure. For fluid restriction to be successful, fluid intake from all sources will have to be less than the total daily urine output, and generally less then 600–1000 ml/day in an adult. It is generally a slow means of correcting hyponatremia and frequently ineffective. Isotonic saline is primarily indicated for the management of hypovolemic hyponatremia as can occur with gastrointestinal losses, diuretics or mineralocorticoid de- ficiency. Administering isotonic (0.9%) saline can also be useful in distinguishing hypovolemic hyponatremia from SIADH: it is generally ineffective in increasing the serum sodium in SIADH, whereas an appreciable rise in serum sodium is consistent with volume depletion. Saline should be avoided in patients with hypervolemic hyponatremia as it can worsen fluid overload. Studies are beginning to support the use of oral urea as practical therapy to correct asymptomatic chronic hyponatremia from SIADH. Urea primarily works as an osmotic diuretic by increasing the renal solute load. A commercially available lemon-flavored urea powder drink (Ure-Na by Nephcentric LLC) is now avail- able in the United States. In the US it is a medical food, Generally Regarded as Safe (GRAS) ingredient by the FDA, which can be purchased over the counter to be used under medical supervi- sion. It comes in 15 gm single serve packets to be mixed in 3–4 ounces of water or juice. It can be used in conjunction with other therapies such as sodium chloride tablets. It is generally well tol- erated and allows for a more liberal fluid restriction. Hypertonic saline is primarily indicated for the management of symptomatic hyponatremia, though in highly selected cases it may be used to correct asymptomatic hyponatremia unresponsive to conven- tional therapies in patients with SIADH, cerebral salt wasting and in conjunction with loop diuretics in congestive heart failure. A  new class of drugs which hold a promising but as yet un- defined role in the management of asymptomatic euvolaemic or hypervolaemic hyponatraemia are nonpeptide vasopressin V2 re- ceptor antagonists (vaptans) that selectively antagonize the anti- diuretic effect of ADH and result in a urinary free water diuresis (aquaresis) without increasing losses of electrolytes. There have been numerous placebo-​controlled trials that have demonstrated the safety and efficacy of these drugs for the treatment of hyponatraemia associ- ated with congestive heart failure, cirrhosis, and SIADH. The vaptans produce an aquaresis within 1 to 2 h of administration that abates within 12 to 24 h. When used to treat hyponatraemia they result in an approximately 5 to 7 mEq/​litre increase in serum sodium within the first 24 h of administration, but the effect is highly variable. The most common side effects are increased thirst, polyuria, and dry mouth. There are currently two vaptans that are FDA approved in the United Chronic hyponatremia (SNa < 135 mmol/L) CNS impairment • Unsteady gait • Decrease bone mineralization • Increase osteoclastic activity Fragile bones Fall Bone fracture • Confusion • Lethargy Osteoporosis Fig. 21.2.1.8  Mechanism of bone injury from chronic hyponatraemia in the elderly. SNa, serum sodium. Reprinted with permission from Ayus JC, Moritz ML. Bone disease as a new complication of hyponatremia: moving beyond brain injury. Clin J Am Soc Nephrol 2010; 5: 167–​8. Copyright 2010 American Society of Nephrology. Box 21.2.1.2  Preventing overcorrection of hyponatraemia 1 Overcorrection is defined as an increase in serum sodium (SNa) of greater than 25 mmol/​litre in 48 h 2 Identify patients at high risk for overcorrection

—​ Patients with SNa less than or equal to 115 mmol/​litre

—​ Patients at risk for a spontaneous free water diuresis: • Thiazide diuretics • Gastroenteritis • Water intoxication • DDAVP-​associated hyponatraemia • Adrenal insufficiency 3 Avoid excessive administration of 0.9% NaCl or 3% NaCl 4 Monitor for a spontaneous free water diuresis following the initial correction in SNa

—​ Check SNa every 4 h

—​ Monitor urine output carefully

—​ Check urine specific gravity or urine osmolality with each void 5 Evidence of a free water diuresis is as follows:

—​ Increase in SNa greater than 1 mmol/​litre per h

—​ Urine flow greater than 1–​2 ml/​kg per h

—​ Urine specific gravity less than 1.010

—​ Urine osmolality less than 250 mOsm/​kg 6 Treating patients with free water diuresis

—​ Restrict sodium containing fluids

—​ Encourage oral fluid intake

—​ Consider DDAVP

21.2.1  Disorders of water and sodium homeostasis 4739 States of America: tolvaptan, which is available in an oral formulation, and conivaptan, which is available in an intravenous preparation. While vaptans have proved to be effective in the management of hyponatraemia, there are no data to suggest that their use re- sults in decreased mortality, and safety concerns are beginning to arise. Tolvaptan was found to cause an elevation of serum alanine aminotransferase and hepatotoxicity with long-​term use in patients with autosomal dominant polycystic kidney disease. They can also result in overcorrection in hyponatraemia from excessive free water diuresis, and this effect is refractory to DDAVP until the vaptan wears off. Such overcorrection is of particular concern in the elderly, critic- ally ill, or moribund patient with restricted free access to water, and in patients with severe hyponatraemia (Na <120 mEq/​litre), and there are reports of demyelination associated with vaptan use. For these reasons, the most recent European guidelines have advised against their use in the management of hyponatraemia. If they are to be used, they should be initiated or reinitiated in the hospital. Furthermore, some patients have been reported to have a marked response to standard doses of tolvaptan, and it may need to be compounded in smaller doses. Vaptans are not appropriate for the treatment of symp- tomatic hyponatraemia as the onset of action and rate of correction are not sufficiently rapid, and nor is the response sufficiently predictable. Vaptans should not be used in hypovolaemic hyponatraemia, or in conjunction with saline-​containing intravenous fluids. These agents are inhibitors of cytochrome P450 and should not be used in conjunc- tion with other drugs known to be metabolized by this pathway. In summary, at the present time vaptans cannot be recommended as a first-​line agent in the management of hyponatraemia. They may be suitable as second-​line agents for short-​term use in pa- tients with mild to moderate chronic asymptomatic euvolaemic or hypervolaemic hyponatraemia, but it is not clear that their effect in raising serum sodium concentration leads to any substantial clinical benefit that can justify their considerable cost. Case discussions Case 1: postoperative hyponatraemia A 29-​year-​old woman without significant medical history undergoes an elective laparoscopic cholecystectomy. During the procedure, 5% dextrose in quarter-​strength normal saline (0.22% NaCl) is started and maintained at 125 ml/​h. There was some bleeding during the procedure, but blood transfusion was not required. The patient is kept in the hos- pital for observation because of the bleeding. She does not tolerate oral intake, and the intravenous fluids are continued at the current rate. At 4 a.m. the following day, the woman complains of headache and she is given paracetamol by the on-​call physician. At 10.30 a.m. the attending doctor is notified that the serum sodium is 128 mmol/​litre: no new or- ders are received. The woman is found to be lethargic by the nursing staff and an order is received to withhold pain medications. That after- noon the woman has a seizure and goes into respiratory failure. She is placed on mechanical ventilation and transferred to the intensive care unit. At the time of transfer, the serum sodium is 124 mmol/​litre. Discussion The patient has several nonosmotic stimuli for ADH secretion (postoperative, volume depletion, pain, nausea) and the admin- istration of a hypotonic fluid was not appropriate. Postoperative hyponatraemia can be prevented by the administration of 0.9% sa- line when parenteral fluids are indicated, with avoidance of the use of hypotonic fluids in a postsurgical patient. The induction of hyponatraemic encephalopathy is iatrogenic in this case and therapy needs to be instituted immediately, with a 100-​ml 3% NaCl bolus as described in Box 21.2.1.1 to try to prevent death or severe neuro- logical impairment. Case 2: exercise-​associated hyponatraemia A 24-​year-​old woman collapses 20 min after completing a mara- thon and is brought to the emergency department for evaluation. She has a decreased level of consciousness and is very short of breath. Cardiological examination is normal, but there are crackles in all lung fields. Neurological examination reveals a depressed mental status with no focal signs. The chest radiograph is consistent with pulmonary oedema. Serum electrolytes include sodium of 125 mmol/​litre and potassium of 3.3 mmol/​litre. Discussion Exercise-​associated hyponatraemia has been reported in mara- thon runners, with those at risk for this problem consuming large amounts of water throughout the course of the race. It is thought that significant amounts of this water remain unabsorbed, sequestered in the gut because blood flow is directed away from the splanchnic circulation while exercising vigorously. At the end of the race the sequestered water is absorbed and hyponatraemia develops rapidly, with water excretion being inhibited by high levels of ADH release secondary to extreme physical exertion. As with Case 1, treatment needs to be started immediately with a 100-​ml 3% NaCl bolus. This condition can be prevented by limiting fluid intake during endurance running: salt consumption or the use of hypotonic electrolyte sports drinks do not appear to be effective in prevention. Case 3: DDAVP withdrawal A 39-​year-​old man with a history of central diabetes insipidus following resection of a pituitary tumour is brought into the emergency department after a generalized seizure. He has previ- ously been taking DDAVP 10 µg intranasally twice a day for his condition. In the emergency department he is found to be leth- argic and unresponsive, with a pulse of 80 beats/​min and blood pressure of 135/​80 mmHg, and his serum sodium is 119 mmol/​ litre and serum potassium 4.0 mmol/​litre. It is not clear when the patient was last given a dose of DDAVP. Urine sodium is 125 mmol/​litre and urine potassium 20 mmol/​litre, with urine osmolality 585 mOsm/​kg. The man is given 2 litres of 0.9% saline in the emergency de- partment. Six hours after presentation, the serum sodium is 127 mmol/​litre and the man is admitted for management of hyponatraemia. The admitting physician continues to withhold the DDAVP and stops the intravenous fluids. The urine output increases significantly over the ensuing night, and the following morning the serum sodium is 158 mmol/​litre, urine sodium 17 mmol/​litre, urine potassium 10 mmol/​litre, and urine osmo- lality 70 mOsm/​kg. Discussion DDAVP by itself is not a cause of hyponatraemia. DDAVP will cause retention of free water and therefore dosing must be titrated in con- junction with the patient’s fluid intake. The patient must be closely

section 21  Disorders of the kidney and urinary tract 4740 monitored and the serum electrolytes closely followed. If DDAVP is withheld following DDAVP-​associated hyponatraemia, then a free water diuresis will ensue and dangerous overcorrection of the serum sodium hypernatraemia may occur, as observed here. This is espe- cially a concern in a patient such as this who has central diabetes insipidus and can rapidly excrete a large volume of dilute urine. An appropriate approach to this patient with diabetes insipidus and hyponatraemic encephalopathy due to DDAVP-​associated hyponatraemia would have been to continue DDAVP and restrict all enteral fluid intake. To correct the patient to the desired serum sodium level, 3% saline could have been used, and then discontinued. During this time, absolutely no hypotonic fluids would be given, and the patient would be monitored closely to restrict all enteral intake. A slow infu- sion of 0.9% saline could have been continued after the 3% saline was stopped if necessary to support volume status. This approach, coupled with frequent monitoring of the serum sodium, would have prevented overcorrection secondary to water diuresis as happened in this case. Case 4: hyponatraemia due to syndrome of inappropriate diuresis A 28-​year-​old man with HIV and a CD4 count of 75 is seen in follow-​up 3 days after being discharged from the hospital where he had been diag- nosed with pneumonia, suspected to be due to Pneumocystis jirovecii. His serum sodium had been decreased throughout the hospitalization, which was managed with fluid restriction. Current medications include a taper of prednisone and co-​trimoxazole. He is significantly improved since hospital discharge, with physical examination revealing that he is afebrile, with a pulse of 84 beats/​min, blood pressure of 104/​55 mmHg, and no abnormalities in the cardiac or respiratory systems—​the lungs are clear and there is no peripheral oedema. Laboratory values from the morning of the clinic visit reveal the following: • Serum—​sodium 113 mmol/​litre, potassium 3.9 mmol/​litre, blood urea nitrogen 19.6 mmol/​litre (7 mg/​dl), creatinine 64 µmol/​litre (0.7 mg/​dl), glucose 6.2 mmol/​litre (112 mg/​dl), uric acid 120 µmol/​litre (2.0 mg/​dl), and osmolality 248 mOsm/​kg • Urine—​sodium 105 mmol/​litre, potassium 18 mmol/​litre, and osmolality 590 mOsm/​kg Discussion This presentation is consistent with the syndrome of inappropriate diuresis, which is defined as hypotonic hyponatraemia, with a urine osmolality above 100 mOsm/​kg, in the absence of volume depletion, adrenal insufficiency, congestive heart failure, hypothyroidism, cir- rhosis, and/​or renal impairment. The laboratory values support the syndrome of inappropriate diuresis as the serum osmolality is de- creased, which rules out hyperosmolar hyponatraemia (also known as dilutional hyponatraemia) and pseudohyponatraemia, the urine osmolality is high, and there is hypouricaemia. If this patient was responding normally to the hypotonicity of the serum, the urine should be dilute. The fact that the urine is concen- trated is abnormal, but it is important to be sure that the patient does not have another cause of a water-​retentive state that is a physio- logical response. These are most commonly congestive heart failure, cirrhosis, and volume depletion. In these conditions, the low effective circulating blood volume initiates both sodium and water-​retentive mechanisms. Hence a similar set of laboratory values may be seen in these conditions, with the exception that the urine sodium should not be 105 mmol/​litre. When the kidney is conserving sodium, the urinary sodium is typically less than 20 mmol/​litre, but many patients with cirrhosis and congestive heart failure receive diuretics and inter- pretation of the urinary sodium must be done cautiously in this set- ting. The presence of severe congestive heart failure and cirrhosis is typically obvious based on history and physical examination. Volume depletion (not due to diuretic use) can be distinguished from the syn- drome of inappropriate diuresis based on the urine sodium, which should be less than 20 mmol/​litre. In addition, the low blood urea ni- trogen and hypouricaemia are more suggestive of a volume expanded state then a prerenal or volume-​depleted state. Other conditions leading to ADH release should also be con- sidered and ruled out before the syndrome of inappropriate diur- esis is diagnosed:  these include postoperative stress, medications, trauma, pain, and nausea. Pulmonary disease, especially pneumonia, is a common cause of the syndrome of inappropriate diuresis, as seen in this case: other causes are given in Table 21.2.1.1. The diagnosis of the syndrome of inappropriate diuresis is often made incorrectly: the syndrome is a diagnosis of exclusion and it is essential that the diagnostic approach is rigorously applied to pre- vent the wrong diagnosis and treatment. Despite the profound hyponatraemia, this man is clinically well and thus he does not require treatment with hypertonic saline. Fluid restriction should be advised, with regular monitoring of the serum sodium, which should increase as the syndrome of inappropriate diuresis resolves with recovery from pneumonia. If hyponatraemia is persistent and refractory to fluid restriction, then a V2 receptor blocker should be considered. Case 5: hyponatraemic encephalopathy in an elderly woman presenting with a fall A 77-​year-​old woman is brought to the emergency department after falling at home. Her past medical history is significant only with re- gard to osteoporosis, but the patient’s daughter states that 2 weeks ago she was started by her primary care physician on a blood pressure medication and that she has been slightly confused over the last few days. Physical examination reveals that she is afebrile, with a pulse of 70 beats/​min and blood pressure of 120/​60 mmHg. She is confused and not answering questions appropriately, but cardiac examination is normal, the lungs are clear, and she does not have any pedal oedema. Laboratory investigation reveals the following: • Serum—​sodium 110 mmol/​litre, potassium 2.7 mmol/​litre, cre- atinine 118 µmol/​litre (1.3 mg/​dl), urea 7.9 mmol/​litre (22 mg/​dl), glucose 6.2 mmol/​litre (108 mg/​dl), chloride 78 mmol/​litre, and bicarbonate 20 mmol/​litre Discussion Hydrochlorothiazide can lead to significant hyponatraemia and is one of the more common causes of hyponatraemia in an outpatient setting. Thiazide diuretics (but not loop diuretics) act at the level of the distal convoluted tubule and impair urinary concentrating cap- acity. ADH secretion is stimulated by a state of relative volume de- pletion, and the result is increased urinary concentration and water retention. Loop diuretics, by contrast, act in the ascending limb of the loop of Henle on the Na+/​K+/​2Cl− cotransporter and lead to im- pairment of both urinary concentrating and diluting capacity and are less likely to lead to hyponatraemia.

21.2.1  Disorders of water and sodium homeostasis 4741 Depending on the degree of this woman’s confusion, her immediate management could either be with the administration of 0.9% NaCl or with the administration of a 100 ml 3% NaCl bolus as described in Box 21.2.1.1. Her thiazide should be stopped. Intravenous fluids should not be continued following the administration of volume expansion, as this patient is at high risk for overcorrection of hyponatraemia from a spon- taneous free water diuresis and for the development of demyelination. She has many of the relevant risk factors, including chronic (>48 h) and severe hyponatraemia (115 mEq/​litre), thiazide diuretic use, hypokal- aemia, malnutrition, and the potential for overcorrection in the serum sodium by greater than 25 mEq/​litre in 48 h. Preventing overcorrection of severe hyponatraemia when a free water diuresis is occurring can be difficult (Box 21.2.1.2). In this situation, the safest and most effective approach is to administer desmopressin. Desmopressin is a synthetic replacement for human arginine vasopressin which increases renal water reabsorption. The administration of desmopressin will stop the free water diuresis, allowing the serum sodium to be corrected slowly with fluid restriction, with care taken to ensure that the serum sodium is not inadvertently lowered. Depending on definition, about 10% of patients develop hyponatraemia when given a thiazide, and older people are particu- larly susceptible. A proposed measure to detect those who might be retaining water and thereby becoming hyponatraemic is to have the patient weigh themselves before and 48 h after starting the medica- tion. If they fail to lose weight, or they actually gain weight, then the medication should be stopped and serum electrolytes checked. All patients given thiazide diuretics should have their electrolytes meas- ured after the onset of therapy or dose adjustments. Hypernatraemia Hypernatraemia, defined as a serum sodium concentration of greater than 145 mmol/​litre, is a commonly encountered problem. It occurs when water intake is inadequate to keep up with water losses, and, since the thirst mechanism is such a powerful stimulus, restricted ac- cess to water is nearly always necessary for its development. This oc- curs in a variety of settings, usually in the very young or very old, or in patients whose illness inhibits their access to water. Several other clinical factors typically seen in the hospital setting can contribute to hypernatraemia, including water losses due to solute diuresis (typically urea or glucose), loop diuretics, gastrointestinal fluid losses, and ex- cessive hypertonic sodium bicarbonate administration. Most patients who develop hypernatraemia have some combination of factors that lead to both impaired access to water and ongoing free-​water losses. Hypernatraemia is common in the hospital setting and is frequently iatrogenic during critical illness, typically involving the failure to rec- ognize significant water losses in the urine and to provide the appro- priate amount of replacement in either parenteral or enteral solutions. Pathogenesis When water intake falls below the level of ongoing water losses, the relative amount of exchangeable electrolytes in the body compared with water increases, and this leads to hypernatraemia. The thirst mechanism and the kidney’s ability to concentrate the urine are the defences against this. However, in patients with normal mental status it is rare for hypernatraemia to develop, irrespective of the degree of Table 21.2.1.1  Causes of the syndrome of inappropriate antidiuresis Neoplastic disease Carcinoma (bronchus, pancreas, bladder, prostate, duodenum) Thymoma Mesothelioma Lymphoma, leukaemia Ewing’s sarcoma Carcinoid Bronchial adenoma Neurological disorders Head injury, neurosurgery Brain abscess Brain tumour Meningitis, encephalitis Guillain–​Barré syndrome Cerebral haemorrhage Cavernous sinus thrombosis Hydrocephalus Cerebellar and cerebral atrophy Shy–​Drager syndrome Peripheral neuropathy Seizures Subdural haematoma Alcohol withdrawal Chest disorders Pneumonia Tuberculosis Emphysema Cystic fibrosis Pneumothorax Aspergillosis Drugs Chlorpropamide Opiates Vincristine, cis-​platinum Vinblastine Thiazides Dopamine antagonists Tricyclic antidepressants MAOIs SSRIs ‘Ecstasy’ (3,4-​MDMA) Anticonvulsants Miscellaneous Genetic—​loss of function of the osmoregulatory TRPV4 gene Idiopathic Psychosis Porphyria Abdominal surgery 3,4-​MDMA, 3,4-​methylenedioxymetamphetamnine; MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors.

section 21  Disorders of the kidney and urinary tract 4742 ongoing water losses, if access to water is not limited because the thirst mechanism will lead to increased water intake to match ongoing losses. The common causes of hypernatraemia are shown in Table 21.2.1.2. Hypernatraemia leads to osmolar forces that cause movement of water out of cells, which in particular subjects the brain to stress that can lead to significant damage. The brain attempts to counteract the osmolar stress during hypernatraemia through a series of adaptations, the principal among these being accumulation of osmotically active ions and de novo generation of osmotically active idiogenic osmoles. The earliest response involves accumulation of the osmotically active cations sodium and potassium. Idiogenic osmoles are a heterogeneous group of substances—​including glycerophosphocholine, choline, myoinositol, and sorbitol—​that are generated intracellularly to exert an osmotic effect and counteract osmotic forces favouring water re- moval from the cells. These responses are seen very quickly, and after 1 week of hypernatraemia no further changes in brain osmolality are observed. They serve to maintain brain volume during elevations in serum osmolality and prevent a significant decrease in brain size due to osmotic water losses. During correction of chronic hypernatraemia it must noted that idiogenic osmoles are not rapidly dissipated, and correction of chronic hypernatraemia over 24 h can lead to cerebral oedema. For this reason, chronic hypernatraemia should be treated cautiously to prevent the development of cerebral oedema. Clinical manifestations Clinical manifestations are mainly related to central nervous system dysfunction as cerebral dehydration and cell shrinkage occurs. Hypernatraemia, perhaps due to the underlying conditions that lead to its development, is associated with an overall mortality between 40 and 70%. Groups at particular risk for complications and poor outcomes from hypernatraemia are older people and patients with endstage liver disease. In the latter case, the use of lactulose in the treatment of hepatic encephalopathy frequently leads to an osmotic diarrhoea and significant water losses in the stool: if this is not ap- preciated and free water is not given (many encephalopathic patients are obtunded and unable to drink), then hypernatraemia can de- velop quickly and lead to severe morbidity. It is therefore mandatory to monitor the serum electrolytes closely in this setting, particularly given that patients with liver disease are at increased risk for cerebral demyelination during changes in the serum sodium. Diagnostic approach to hypernatraemic patients The first step in evaluating a patient with hypernatraemia is to take a detailed history focusing on fluid intake and losses. Various potential sources of water loss need to be assessed. This is generally straightfor- ward in the outpatient setting, where these are mainly in the urine, but in the patient in hospital, many sources of water losses may need to be considered: from the gastrointestinal tract (diarrhoea, nasogastric suction, and bowel fistulae), from the urine, and from insensible losses (fever, sepsis, massive diaphoresis, and burns). Whenever practical, these losses should be calculated or estimated. To assess urinary water losses it is necessary to measure the urinary cationic electrolytes (so- dium and potassium) and the urinary osmolality, these pieces of in- formation giving complementary but different information. However, a word of caution is necessary in the interpretation of urinary osmo- lality as errors are frequent in this area. The urinary osmolality alone cannot always determine the presence or absence of electrolyte-​free water losses in the urine, the reason for this being that water can be ex- creted with nonelectrolyte osmoles or with electrolyte osmoles. Both of these contribute to the osmolality of the urine, but their excretion will have different effects on water balance. Recall the relationship that the serum sodium is proportional to total body electrolytes relative to total body water (Equation 21.2.1.1). Therefore, when water is excreted with very few electrolytes, the loss of water is in excess of the loss of electro- lytes and hypernatraemia can develop if this water is not adequately replaced. This situation of a high urine osmolality, but very few elec- trolytes in the urine, most typically occurs when there is a significant amount of urea or glucose (e.g. with poorly controlled diabetes) in the urine. By contrast, when water is excreted with a significant amount of electrolyte osmoles, this will tend not to affect the serum sodium, as long as the concentration of electrolytes in the urine and serum are similar, because loss of water is proportional to the loss of electrolytes and therefore the value of the serum sodium does not change. When there is a high urea or glucose load, tremendous quantities of water can be lost in the urine despite maximal urinary concentra- tion. This is what occurs during a solute diuresis and such a patient is typically polyuric. However, if there is a failure to concentrate the urine during a time of hypernatraemia when the patient does not have a solute diuresis, then this should raise suspicion of a urinary concentrating defect. The most common causes of such urinary con- centrating defects are renal failure, loop diuretics, tubulointerstitial renal disease, and diabetes insipidus. Treatment of hypernatraemia Patients with hypernatraemia typically have significant intravascular volume depletion, hence the initial goal of treatment is to restore this, which is best accomplished with 0.9% saline or colloid. Focus then switches to correction of the serum sodium with free-​water replace- ment (Box 21.2.1.3). The rate of fluid administration required by the patient will depend significantly on the degree of ongoing water losses, so that the appropriate amount of replacement water can be given for these in addition to that required for correction of the hypernatraemic state. If there are extrarenal fluid losses, these will need to be estimated because accurate monitoring is typically not possible, and it is ne- cessary to assess any ongoing water losses in the urine to determine whether the kidneys are appropriately conserving water, or whether they are inappropriately continuing to excrete it. As described previ- ously, electrolyte-​free water losses in the urine can be calculated with the formula from Equation 21.2.1.2: [1 − ([Na+]u + [K+]u) /​ ([Na+]se + [K+]se)] × urinary   output   rate (ml) = rate   of   urinary   water   loss. Table 21.2.1.2  Common causes of hypernatraemia Lack of water intake • Decreased thirst (e.g. dementia, neurological impairment) • Bowel rest/​nasogastric suction • Dependent on others (e.g. mechanical ventilation, infants) Increased water losses • Solute diuresis (e.g. hyperglycaemia, urea loading from tube feeds, or hyperalimentation) • Loop diuretics • Gastrointestinal water losses • Diabetes insipidus

21.2.1  Disorders of water and sodium homeostasis 4743 Patients with hypernatraemia may be insulin resistant such that hyperglycaemia can result if dextrose-​containing solutions are given. For this reason, glucose-​containing solutions are potentially harmful and should be avoided if possible, but if they must be used (e.g. 5% dextrose in water), then plasma glucose should be moni- tored closely. When possible, the enteral route should be used before use of parenteral fluid administration. As with the treatment of patients with symptomatic hyponatraemia, patients with neurological impairment due to hypernatraemia re- quire serial measurement of electrolytes, every 2 h, until they are neurologically stable. In patients without evidence of encephalopathy, the serum sodium should not be corrected more quickly than 0.5 to 1 mmol/​litre per hour or 15 mmol/​litre over 24 h, and, in severe cases (serum sodium >170 mmol/​litre), sodium should not be corrected to below 150 mmol/​litre in the first 48 to 72 h. If the patient is at high risk for developing cerebral oedema, such as with head trauma or encephalitis, the rate of correction of hypernatraemia should be even slower. Case discussions The evaluation of a polyuric patient and differentiation of pri- mary polydipsia, central diabetes insipidus, nephrogenic diabetes insipidus (Table 21.2.1.3), and hypernatraemia due to a solute di- uresis can be complex and daunting to the general physician, but should be approached as described in the following case studies. Case 6: central diabetes insipidus A 45-​year-​old man weighing about 70 kg is involved in a motor vehicle accident and suffers a closed head injury, following which he is admitted to the intensive care unit. He is administered large amounts of 0.9% NaCl for fluid resuscitation and then prescribed continued 0.9% NaCl as maintenance fluid. He develops raised intra- cranial pressure with evidence of cerebral oedema, which is treated by placement of an extraventricular device and infusion of 3% NaCl. He then develops polyuria with urine output exceeding 500 ml/​h. His serum sodium increases to 184 mEq/​litre, with a spot urinary osmolality being 120 mOsm/​kg of H2O and the combined urinary sodium plus urinary potassium concentrations being 50 mEq/​litre. A continuous DDAVP infusion is started and the urine osmolality increases to 800 mOsm/​kg of H2O. Discussion This patient’s hypernatraemia is multifactorial. There is a brisk free water diuresis, and the patient is receiving both 0.9% saline and hypertonic saline, which in combination with urinary reten- tion of sodium has resulted in severe hypernatraemia. The initi- ation of DDAVP has stopped the free water diuresis and so the hypernatraemia should not worsen, indeed—​because the patient has a fixed inability to excrete free water while on DDAVP—​even 0.9% saline could in theory lead to a fall in serum sodium concen- tration, and this should be administered at a restricted rate of 50 ml/​ h to maintain water and sodium homeostasis. The optimum rate of correction of hypernatraemia is difficult to determine. A serum sodium of greater than 180 mmol/​litre could lead to brain injury, but a fall in the serum sodium could aggravate cerebral oedema. In this situation, the rate of sodium correction should probably not exceed 10 mmol/​litre per 24 h, and 5 mmol/​24 h should be initially attempted. If intracranial pressures increase with correction of hypernatraemia, a 100-​ml bolus of 3% NaCl should be administered to acutely raise the serum sodium and decrease the cerebral oedema. The free water required to correct the serum so- dium by 5 mEq is 1.25 litres (Box 21.2.1.3: [5/​140] × 35) or about 50 ml/​h over 24 h. An appropriate management strategy would there- fore be (in addition to giving the 0.9% saline described earlier) to administer 50 ml/​h of 5% dextrose in water, checking the serum so- dium every 2 h. If the serum sodium were to fall faster than antici- pated or the intracranial pressure to rise, the rate of the free water infusion would be adjusted accordingly. The rate of correction may end up being greater than predicted if a natriuresis were to ensue. Case 7: diarrhoeal dehydration A 77-​year-​old woman who is a nursing home resident develops vomiting and diarrhoea for 3  days, presenting to the emergency department with intravascular volume depletion and dehydration. Box 21.2.1.3  Treatment of hypernatraemia 1 Correct extracellular volume depletion with an isotonic fluid such as 0.9% saline until the patient is haemodynamically stable with good peripheral perfusion. 2 Estimate the free water deficit—​because of the many variables that can affect the serum sodium in clinical practice, making a very precise es- timate of the patient’s water deficit is not necessary. An approxima- tion of the free water deficit can be made by assuming that 4 ml/​ kg of free water will decrease the serum sodium by 1 mmol/​litre or that it is equal to [(serum sodium concentration −140)/​140] × total body water. For total body water, 0.5 × body weight is a close enough working approximation. Hence an 80-​kg man with serum sodium of 160 mmol/​litre has a water deficit of [(160 − 140)/​140] × 40 = 5.7 litres. 3 Replacement of ongoing water losses, estimated as described in the text, will be required in addition to that required to correct the deficit. 4 Aim of treatment—​to decrease serum sodium concentration by 0.5 mmol/​litre per hour and by no more than 15 mmol/​litre in the first 24 h. In severe hypernatraemia (>170 mmol/​litre), serum sodium should not be corrected to below 150 mmol/​litre in the first 48 to 72 h. 5 Give hypotonic fluid:

—​ Route and fluid: preferably water by mouth or nasogastric tube (or other feeding tube), but if parenteral treatment is required, the usual replacement fluid is 0.45% saline (77 mmol/​litre NaCl); a lower sodium concentration may be needed if there is a renal concentrating defect or sodium overload. Glucose-​containing so- lutions should be avoided.

—​ Volume: using the incorrect assumption of a closed system (see dis- cussion of treatment for hyponatraemia), and using the example described earlier in this box, to reduce the patient’s serum sodium by 10 mmol/​litre in the first 24 h would require administration of (10/​140) × 40 = 2.85 litres of water in addition to fluids required to accommodate ongoing loses. This could be administered as water by drinking or by feeding tube, or by intravenous infusion of twice the volume of 0.45% saline (given 77 mmol/​litre NaCl, half of the volume of a bag of 0.45% saline can be regarded as ‘free water’). In practice, if the patient cannot drink freely, does not have a feeding tube, and it is not possible or desirable to place one, then it is rea- sonable to give 0.45% saline at 250 ml/​h, adjusting the rate appro- priately in response to repeated monitoring. If 5% dextrose is used (125 ml/​h, all of which can be regarded as ‘free water’), then it is essential to monitor blood glucose regularly. 6 Monitoring—​serum electrolytes should be measured every 2 h until the patient is neurologically stable, and every 4 h while they remain on an intravenous infusion of hypotonic saline or 5% dextrose.

section 21  Disorders of the kidney and urinary tract 4744 On presentation her weight is 46 kg, down from 50 kg just 2 weeks earlier. Her blood pressure is 90/​40 mmHg with a pulse of 126/​min. Biochemical testing reveals a serum sodium concentration of 156 mEq/​litre, potassium 5.6 mEq/​litre, blood urea nitrogen 18 mmol/​ l (50 mg/​dl), and creatinine 130 μ mol/​l (1.4 mg/​dl). Urinary tests reveal a sodium concentration less than 5 mEq/​litre, potassium 20 mEq/​litre, and osmolality 800 mOsm/​kg of H2O. Discussion This woman has an estimated volume deficit of approximately 4 litres, based on her recent weight loss, which would have a composition of approximately 0.9% NaCl (154 mEq/​litre). To correct her serum so- dium by 10 mmol/​litre in 24 h, approximately 1.8 litres of free water would have to be administered (Box 21.2.1.3: [10/​140] × 25). She should initially be given 2 litres of 0.9% saline to acutely correct her intravascular volume depletion and restore circulatory perfusion. This would leave the remaining deficit of approximately 2 litres of isotonic fluid to be corrected over 24 h. Her typical maintenance fluid requirement would otherwise be about 2 litres for the next 24 h, which with the addition of 2 litres of deficit therapy would result in a total volume of 4 litres or 166 ml/​h. A total of 4 litres of 0.45% NaCl with 2.5% dextrose in water would provide the equivalent of 2 litres of free water and 2 litres of 0.9% saline and would be adequate therapy to correct both the remaining volume deficit and free-​water deficit and to provide for urinary losses. Polyuria and polydipsia The evaluation of a polyuric patient and differentiation of pri- mary polydipsia, central diabetes insipidus, nephrogenic diabetes insipidus (Table 21.2.1.3), and hypernatraemia due to a solute di- uresis can be complex and daunting to the general physician, but should be approached as described in the following case studies. Case 8: primary polydipsia A 27-​year-​old man with schizophrenia is being evaluated prior to admission to a psychiatric hospital. His only complaint is of frequent Table 21.2.1.3  Causes of polyuria–​polydipsia syndromes Cranial diabetes insipidus Familial Autosomal dominant inheritance—​mutation of the arginine vasopressin gene (AVP) Autosomal recessive inheritance—​DIDMOADa (Wolfram’s) syndrome type 1, caused by mutation in the gene wolframin (WFS1) that encodes a membrane glycoprotein of uncertain function which localizes primarily to the endoplasmic reticulum Acquired Idiopathic Inflammatory (lymphocytic infiltration, sarcoidosis, histiocytosis X autoimmunity, Guillain–​Barré syndrome) Trauma (neurosurgery, head injury) Neoplasms (craniopharyngioma, germinoma, pinealoma, hypothalamic metastasis, large pituitary tumour) Infection (meningitis, encephalitis) Vascular (sickle cell anaemia, aneurysms of anterior communicating artery, Sheehan’s syndrome) Pregnancy (associated with vasopressinase) Nephrogenic
diabetes insipidus Familial X-​linked inheritance—​mutation of the arginine vasopressin receptor-​2 gene (AVPR2) Autosomal inheritance—​mutation of the aquaporin-​2 gene (AQP2) can cause autosomal recessive or autosomal dominant disease Acquired Idiopathic Metabolic (hypercalcaemia, hypokalaemia) Vascular (sickle cell disease) Osmotic diuresis (glycosuria, postobstructive uropathy) Chronic renal disease (renal failure, amyloid, myeloma, sarcoidosis, pyelonephritis) Drugs (lithium, demeclocycline, amphotericin, glibenclamide, methoflurane) Primary polydipsia Unknown aetiology Psychogenic (compulsive water drinking) Psychotic (schizophrenia, mania) Idiopathic Secondary Granuloma (sarcoidosis) Vasculitis TB meningitis Multiple sclerosis Drugs (phenothiazines, tricyclic antidepressants) a DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, deafness (Wolfram syndrome).

21.2.1  Disorders of water and sodium homeostasis 4745 urination, approximately 15 times per day according to his family, and that he is always thirsty. He has had no recent seizures and his level of consciousness is normal. Routine physical examination is unremarkable. Laboratory values are as follows: • Serum—​sodium 131 mmol/​litre, potassium 4.0 mmol/​litre, chloride 96 mmol/​litre, bicarbonate 24 mmol/​litre, urea 5.7 mmol/​ litre (16 mg/​dl), creatinine 118 µmol/​litre (1.3 mg/​dl), and glucose 5.4 mmol/​litre (98 mg/​dl) • Urine—​sodium 10 mmol/​litre, potassium 8 mmol/​litre, and osmolality 65 mOsm/​kg Discussion This patient is very likely to be polyuric, given the history. Blood tests reveal mild hyponatraemia and near-​normal renal function (chronic kidney disease stage 3). Urinary parameters are consistent with a water diuresis. Calculation of the electrolyte-​free water clearance shows that he is losing significant amounts of water in the urine (Equation 21.2.1.2): ([Na+]u + [K+]u)/​([Na+]se + [K+]se) = (10 + 8)/​(131 + 4) = 0.13. This means that 87% of the patient’s urine output is electrolyte-​free water. The low urinary osmolality signifies that this is a water diuresis, rather than being driven by the presence of nonelectrolyte solute (e.g. glucose). The question now becomes whether the water diuresis is an appropriate response to excessive water intake or whether it is pathological, leading to excessive water losses that must then be re- placed. In this case, the most likely answer is excessive water intake because of the hyponatraemia and decreased serum osmolality. If a urine concentrating defect was the primary cause of the polyuria, then the patient should not be hyponatraemic unless they had both a urinary concentrating defect and excessive water intake. Case 9: primary polydipsia vs diabetes insipidus A 39-​year-​old mother is concerned because her 12-​year-​old daughter has noted frequent urination and says that she is always thirsty. The patient is a well-​adjusted adolescent with no past med- ical history and normal development up to this point. Her physical examination is normal. She also has had no recent seizures and her level of consciousness is normal. Serum electrolytes and the results of a 24-​h urinary collection are as follows: • Serum—​sodium 140 mmol/​litre, potassium 4.5 mmol/​litre, chloride 103 mmol/​litre, bicarbonate 25 mmol/​litre, urea 5.4 mmol/​litre (15 mg/​dl), creatinine 109 µmol/​litre (1.2 mg/​dl), and glucose 5.7 mmol/​litre (103 mg/​dl) • Uurine (24 h)—​total volume 9 litres, sodium 15 mmol/​litre, potas- sium 8 mmol/​litre, and osmolality 70 mOsm/​kg Discussion The 24-​h urinary collection volume clearly demonstrates that this girl is polyuric, and the urinary studies—​similar to Case 8—​are consistent with a water diuresis. However, the patient is normonatraemic and thus the serum electrolytes are not helpful in reaching a diagnosis: based on the information that we currently have, it is impossible to tell whether her polyuria is due to excessive water intake or to a urinary concen- trating defect, which is an important determination to make in this seemingly healthy adolescent. In order to distinguish between these two possibilities, a water deprivation test can be performed. This is usually done in a hospital setting because a patient with diabetes insipidus can rapidly develop hypernatraemia if water intake is restricted. The details of different protocols for water deprivation tests are beyond the scope of this chapter, but a typical test and its interpretation are shown in Box 21.2.1.4, the basic principle being that if a patient with diabetes insipidus is deprived of water and allowed to become mildly hypernatraemic, then such a patient will not have concentrated urine at that time. By contrast, a patient with primary polydipsia will begin to concentrate the urine if allowed to become mildly hypernatraemic. Case 10: nephrogenic diabetes insipidus A 41-​year-​old man presents for a routine physical examination. His past medical history is significant only for bipolar disorder, for which he has taken lithium carbonate for the last 15 years. This in- formation leads to further questioning, and he admits to frequent urination and excessive thirst, but denies any symptoms of hesitancy or dysuria. His physical examination is normal. Serum chemistry profile and urine studies are as follows: • Serum—​sodium 147 mmol/​litre, potassium 3.8 mmol/​litre, chloride 110 mmol/​litre, bicarbonate 26 mmol/​litre, urea 5.4 mmol/​litre (15 mg/​dl), creatinine 73 µmol/​litre (0.8 mg/​dl), and glucose 6.9 mmol/​litre (124 mg/​dl) • Urine—​sodium 25 mmol/​litre, potassium 22 mmol/​litre, and osmolality 160 mOsm/​kg Box 21.2.1.4  Procedure and interpretation of a water deprivation test Procedure 1 The patient is encouraged to drink normally in the evening/​night be- fore the test. 2 In the morning, at the beginning of the test, the patient is weighed and baseline measurements made of urinary volume, and urinary and serum osmolality. 3 All fluid intake is withheld for 8 h, with the patient weighed and urine and blood samples taken and analysed every 1–​2 h. The test is stopped if the patient loses more than 5% of their initial body weight, or if urinary osmolality above 750 mOsm/​kg is achieved. 4 DDAVP (2 µg) is given by intramuscular injection, and the patient is allowed to drink (sensibly) and eat. 5 Urinary samples are collected for the next 16 h. Interpretation Urine osmolality (mOsm/​kg) Diagnosis After dehydration After DDAVP

750 750 Normala <300 750 Cranial diabetes insipidus <300 <300 Nephrogenic diabetes insipidus 300–​750 <750 Partial cranial diabetes insipidus, partial nephrogenic diabetes insipidus, or primary polydipsiab, c a Assuming that serum osmolality remains in the normal reference range of
285–​295 mOsm/​kg. b The distinction of cranial or nephrogenic partial diabetes insipidus from each other and from primary polydipsia is difficult; measurement of plasma ADH may help in this circumstance. c Assuming significant urinary output, if the patient does not lose weight over 8 h and serum osmolality does not rise, then they must be drinking. The period of ‘water deprivation’ can be extended, but this is unlikely to be helpful if the patient has not abstained from drinking from the beginning of the test. In this situation, a hypertonic saline infusion test may be helpful. The diagnosis is likely to be primary polydipsia, but it may be difficult, if not impossible, to exclude mixed pathology.

section 21  Disorders of the kidney and urinary tract 4746 Discussion The laboratory data in this case are most consistent with diabetes insipidus. The history suggests polyuria, and, as nephrogenic diabetes insipidus is a complication of lithium therapy, it is appropriate to rule out this diagnosis in a patient such as this. In contrast with Case 9, we have a definite differentiation between primary polydipsia and dia- betes insipidus because the serum sodium is mildly elevated and the urinary osmolality is simultaneously low, which confirms the diag- nosis of diabetes insipidus. In a sense, by demonstrating the failure to concentrate the urine despite having hypernatraemia, we have the results of a water deprivation test. However, it is important to note that—​based solely on the information given here—​it is not known whether the patient has central or nephrogenic diabetes insipidus, although the latter would clearly be anticipated in a patient taking lithium. To make this distinction would require formalized testing to assess the response to exogenously administered DDAVP: if the patient fails to concentrate the urine following administration of DDAVP, then they have nephrogenic diabetes insipidus. Case 11: central diabetes insipidus A 28-​year-​old man is brought to the emergency department by am- bulance following a car accident during which he sustained severe head trauma. His past medical history is significant only for asthma as a child and a previous appendicectomy. He is taken immediately to surgery for evacuation of an acute epidural haematoma. During the course of surgery, his urinary output increases from 35 ml/​h to over 300 ml/​h. Blood tests taken immediately on admission to hospital reveal a serum sodium concentration of 141 mmol/​litre; the findings on serum chemistry profile and urine studies taken just after surgery when he arrives on the intensive care unit are as follows: • Serum—​sodium 148 mmol/​litre, potassium 4.5 mmol/​litre, chloride 112 mmol/​litre, bicarbonate 26 mmol/​litre, urea 6.8 mmol/​litre (19 mg/​dl), creatinine 127 µmol/​litre (1.4 mg/​dl), and glucose 6.4 mmol/​litre (115 mg/​dl) • Urine—​sodium 17 mmol/​litre, potassium 13 mmol/​litre, and osmolality 120 mOsm/​kg Discussion The history is highly suggestive of central diabetes insipidus due to head trauma as the cause of polyuria. The urinary studies, as in the three previous cases, show a water diuresis, and, as in Case 10, we have a definite diagnosis of diabetes insipidus because the patient is simultaneously hypernatraemic and undergoing a water diuresis. Again, based solely on the information given, it is not possible to say whether the patient has central or nephrogenic diabetes insipidus, but since the history is so suggestive of a central cause it is prudent to simply administer DDAVP and assess the response. If the patient fails to concentrate the urine following administration of DDAVP, then he has nephrogenic diabetes insipidus, whereas if the urine becomes concentrated—​as would be anticipated in this case—​then the diagnosis is central diabetes insipidus. When DDAVP is ad- ministered, water intake should be adjusted appropriately to avoid precipitation of significant hyponatraemia, and serum electrolytes should be monitored closely during dose titration. Central diabetes insipidus should always be suspected when the urine is not concentrated in the setting of hypernatraemia. Severe hypernatraemia can develop rapidly in an individual who has restricted access to fluids, such as a patient in an intensive care unit, and hence early recognition is vital. Case 12: solute diuresis from excess urea load A 58-​year-​old man with a long history of alcohol abuse and chronic liver disease is admitted with necrotizing pancreatitis. Among other manoeuvres, a urinary catheter is inserted, which demonstrates that his urinary output is 30 ml/​h. Admission laboratory test results are as follows: • Serum—​sodium 138 mmol/​litre, potassium 3.9 mmol/​litre, chloride 103 mmol/​litre, bicarbonate 21 mmol/​litre, urea 11.8 mmol/​litre (33 mg/​dl), and creatinine 136 µmol/​litre (1.5 mg/​dl) The patient is ordered to have no enteral intake overnight, and he re- ceives 5 litres of 0.9% (normal) saline volume expansion. His abdom- inal pain worsens 24 h after admission and he is continued without enteral intake. Repeat laboratory tests show that his serum sodium has risen to 146 mmol/​litre. Over the following 24 h his urinary output increases and infusion of 0.9% saline is continued at 100 ml/​h. Total parenteral nutrition is initiated with a daily regimen that com- prises a total volume of 1.5 litres, including 120 mmol of sodium and high amino acid content. Repeat laboratory tests are as follows: • Serum—​sodium 151 mmol/​litre, potassium 3.2 mmol/​litre, chloride 117 mmol/​litre, bicarbonate 26 mmol/​litre, urea 22.5 mmol/​litre (63 mg/​dl), creatinine 100 µmol/​litre (1.1 mg/​dl), and glucose 7.0 mmol/​litre (126 mg/​dl) • Urine—​volume 150 ml/​hour; sodium 50 mmol/​litre, potassium 13 mmol/​litre, and osmolality 650 mOsm/​kg Discussion What has occurred in this case is very typical of a solute diuresis leading to hypernatraemia in the critical care setting. The patient is significantly polyuric and has become progressively more and more hypernatraemic. It is important to recognize that, in contrast to pre- vious cases discussed, the urinary osmolality is high, meaning that ADH activity is present and it must be concluded that the patient is losing ‘free water’ (which has to be the situation because the serum so- dium is increasing in the absence of administration of any hypertonic sodium solution). The loss of free water occurring at the same time that the urine is highly concentrated may appear paradoxical, but the answer is evi- dent when the electrolyte-​free water is calculated. The ratio of the (sodium + potassium) in the urine to the (sodium + potassium) in the serum is 63/​159 = 0.39, hence at his current urinary output he is losing water at a rate of (0.61 × 150) or 91.5 ml/​h. Water replace- ment must be given at least equal to this rate to replace the ongoing urinary water losses. The low urinary sodium and potassium at a time when the urine osmolality is high signifies that there must be a nonelectrolyte osmole in the urine that is ‘obligating’ water loss. The patient is undergoing an osmotic diuresis secondary to a high urea load, this probably being secondary both to the hypercatabolic state of critical illness/​stress (protein breakdown is increased, leading to significant urea generation) and to the high amino acid content of the total parenteral nutrition. This scenario is commonly seen in critical illness and is easily preventable if the responsible clinician appreciates the possibility of free-​water loss in a patient who be- comes polyuric.

21.2.1  Disorders of water and sodium homeostasis 4747 FURTHER READING Achinger SG, Moritz ML, Ayus JC (2006). Dysnatremias: why are pa- tients still dying? South Med J, 99, 1–​12. Achinger SG, et al. (2014). Desmopressin acetate (DDAVP)-​associated hyponatremia and brain damage:  a case series. Nephrol Dial Transplant, 29, 2310–​15. Agre P, et al. (1993). Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol, 265, F463–​76. Arieff AI, Ayus JC (1993). Endometrial ablation complicated by fatal hyponatremic encephalopathy. JAMA, 270, 1230–​2. Arieff AI, Ayus JC, Fraser CL (1992). Hyponatraemia and death or per- manent brain damage in healthy children. BMJ, 304, 1218–​22. Ayus JC, Achinger SG, Arieff AI (2008). Brain cell volume regulation in hyponatremia: role of sex age, vasopressin, and hypoxia. Am J Renal Physiol, 295, F619–​24. Ayus JC, Arieff AI (1995). Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest, 107, 517–​21. Ayus JC, Arieff AI (1999). Chronic hyponatremic encephalopathy in postmenopausal women:  association of therapies with morbidity and mortality. JAMA, 281, 2299–​304. Ayus JC, Arieff AI, Moritz ML (2005). Hyponatremia in marathon runners. N Engl J Med, 353, 427–​8. Ayus JC, Krothapalli RK, Arieff AI (1987). Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med, 317, 1190–​5. Ayus JC, Moritz ML (2010). Bone disease as a new complication of hyponatremia: moving beyond brain injury. Clin J Am Soc Nephrol, 5, 167–​8. Ayus JC, Moritz ML (2019). Misconceptions and barriers to the use of hypertonic saline to treat hyponatremic encephalopathy. Front Med (Lausanne), 6, 47. Ayus JC, Wheeler JM, Arieff AI (1992). Postoperative hyponatremic encephalopathy in menstruant women. Ann Intern Med, 117, 891–​7. Ayus JC, et al. (2012). Is chronic hyponatremia a novel risk factor for hip fracture in the elderly? Nephrol Dial Transplant, 27, 3725–​31. Ayus JC, et al. (2015). Treatment of hyponatremic encephalopathy with a 3% sodium chloride protocol: a case series. Am J Kidney Dis, 65, 435–​42. Ayus JC, et al. (2016). Mild prolonged chronic hyponatremia and risk of hip fracture in the elderly. Nephrol Dial Transplant. 31(10), 1662–9. Danziger J, Zeidel ML (2015). Osmotic homeostasis. Clin J Am Soc Nephrol, 10, 852–​62. Fenske W, et al. (2008). Value of fractional uric acid excretion in dif- ferential diagnosis of hyponatremic patients on diuretics. J Clin Endocrino Metab, 93, 2991–​7. George JC, Zafar W, Bucaloiu ID, Chang AR (2018). Risk factors and outcomes of rapid correction of severe hyponatremia. Clin J Am Soc Nephrol, 13, 984–92. Greenberg A, et al. (2015). Current treatment practice and outcomes. Report of the hyponatremia registry. Kidney Int, 88, 167–​77. Heilig CW, et  al. (1989). Characterization of the major brain osmolytes that accumulate in salt-​loaded rats. Am J Physiol, 257, F1108–​16. Hew-​Butler T, et al. (2005). Consensus statement of the 1st International Exercise-​Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005. Clin J Sport Med, 15, 208–​13. Hoorn EJ, Zietse R (2013). Hyponatremia and mortality: moving be- yond associations. Am J Kidney Dis, 62, 139–​49. Knepper MA, Kwon TH, Nielsen S (2015). Molecular physiology of water balance. N Engl J Med, 372, 1349–​58. Maesaka JK, Imbriano LJ, Miyawaki N (2018). Determining ­fractional urate excretion rates in hyponatremic conditions and ­improved methods to distinguish cerebral/renal salt wasting from the syn- drome of inappropriate secretion of antidiuretic hormone. Front Med (Lausanne), 5, 319. McNab S, et al. (2015). 140 mmol/​L of sodium versus 77 mmol/​L of sodium in maintenance intravenous fluid therapy for children in hospital (PIMS): a randomised controlled double-​blind trial. Lancet, 385, 1190–​7. Moritz ML (2012). Syndrome of inappropriate antidiuresis and cere- bral salt wasting syndrome: are they different and does it matter? Pediatr Nephrol, 27, 689–​93. Moritz ML (2019). Syndrome of inappropriate antidiuresis. Pediatr Clin North Am, 66(1), 209–26. Moritz ML, Ayus JC (2003). Prevention of hospital-​acquired hyponatremia:  a case for using isotonic saline. Pediatrics, 111, 227–​30. Moritz ML, Ayus JC (2003). The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant, 18, 2486–​91. Moritz ML, Ayus JC (2004). Dysnatremias in the critical care setting. Contrib Nephrol, 144, 132–​57. Moritz ML, Ayus JC (2007). Hospital-​acquired hyponatremia—​why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol, 3, 374–​82. Moritz ML, Ayus JC (2008). Exercise-​associated hyponatremia: why are athletes still dying? Clin J Sport Med, 18, 379–​81. Moritz ML, Ayus JC (2009). New aspects in the pathogenesis, preven- tion, and treatment of hyponatremic encephalopathy in children. Pediatr Nephrol, 25, 1225–​38. Moritz ML, Ayus JC (2010). 100 cc 3% sodium chloride bolus: a novel treatment for hyponatremic encephalopathy. Metab Brain Dis, 25, 91–​6. Moritz ML, Ayus JC (2014). Management of hyponatremia in various clinical situations. Curr Treat Options Neurol, 16, 310. Moritz ML, Ayus JC (2015). Maintenance intravenous fluids in acutely ill patients. N Engl J Med, 373, 1350–​60. Nzerue CM, et al. (2003). Predictors of outcome in hospitalized pa- tients with severe hyponatremia. J Natl Med Assoc, 95, 335–​43. Papadopoulos MC, Verkman AS (2007). Aquaporin-​4 and brain edema. Pediatr Nephrol, 22, 778–​84. Robertson GL (2011). Vaptans for the treatment of hyponatremia. Nat Rev Endocrinol, 7, 151–​61. Rondon-Berrios H, et al. (2018). Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol, 13(11), 1627–32. Schrier RW, et  al. (2006). Tolvaptan, a selective oral vasopressin V2-​receptor antagonist, for hyponatremia. N Engl J Med, 355, 2099–​112. Simard M, Nedergaard M (2004). The neurobiology of glia in the con- text of water and ion homeostasis. Neuroscience, 129, 877–​96. Spasovski G, et al. (2014). Clinical practice guideline on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant, 29, ii1–​39. Verbalis JG, et  al. (2013). Diagnosis, evaluation, and treatment of hyponatremia:  expert panel recommendations. Am J Med, 126, S1–​42.

section 21  Disorders of the kidney and urinary tract 4748 21.2.2  Disorders of potassium homeostasis John D. Firth ESSENTIALS The normal range of potassium concentration in serum is 3.5 to 5.0 mmol/​litre and within cells it is 150 to 160 mmol/​litre, the ratio of intracellular to extracellular potassium concentration being a critical determinant of cellular resting membrane potential and thereby of the function of excitable tissues. Hypokalaemia Hypokalaemia is defined as a serum potassium concentration lower than 3.5 mmol/​litre and is the most common electrolyte ab- normality seen in clinical practice, found in about 20% of hospital inpatients. Clinical features and investigation—​mild hypokalaemia is asymp- tomatic, but nonspecific symptoms develop with more severe dis- turbance, and serious neuromuscular problems sometimes arise at serum potassium concentrations lower than 2.5 mmol/​litre. Extensive testing of patients with mild hypokalaemia is almost cer- tainly inappropriate and likely to be fruitless if pursued. Emergency management—​this is rarely required, but intravenous infusion of potassium should be given in the rare circumstances of life-​threatening cardiac arrhythmia or muscular paralysis. Aetiology—​there are a very large number of possible causes of hypokalaemia, but in most instances the diagnosis is immediately apparent, the most common causes being diuretics (particularly thiazides), vomiting, and diarrhoea. The differential diagnosis of patients with unexplained severe hypokalaemia usually comprises various abnormalities (usually genetic) of tubular potassium trans- port, concealed vomiting and/​or usage of purgatives, and concealed ingestion of diuretics. Renal tubular causes of hypokalaemia—​the most common genetic cause is Gitelman’s syndrome, an autosomal reces- sive condition caused by mutations in the Na–​Cl cotransporter
(NCCT) in the distal convoluted tubule that can cause nonspecific symptoms and is associated with hypotension, alkalosis, hypo- magnesaemia, hypocalciuria, and hypermagnesuria. Management is with potassium and magnesium supplements. Other causes of tubular wasting of potassium include Bartter’s syndrome (due to mutations in different tubular cotransporters, channels, or asso- ciated proteins—​NKCC2, ROMK, ClCN-​Ka, ClCN-​Kb, and barttin), and mineralocorticoid excess (real or apparent, each of various types). Altered internal balance causing hypokalaemia—​there are several rare conditions in which hypokalaemia is associated with episodes of extreme weakness/​paralysis, including thyrotoxic periodic paralysis and familial hypokalaemic periodic paralysis. Hyperkalaemia Hyperkalaemia, defined as a serum potassium concentration of greater than 5.0 mmol/​litre, is asymptomatic, and severe hyperkalaemia (>7 mmol/​litre) is the most serious of all electrolyte disorders because it can cause cardiac arrest. Clinical assessment—​the electrocardiogram (ECG) is the best guide to the significance of hyperkalaemia in any particular individual. As the serum potassium rises, the following changes are seen: (1) tenting of the T wave; (2) P-​wave flattening, prolongation of the P–​R interval, and widening of the QRS complex; and (3) a ‘sine wave’ pattern as a prelude to ventricular fibrillation and death. Emergency management—​patients with ECG manifestations more severe than tenting of the T waves should be given intravenous cal- cium gluconate (10 ml of 10%) followed by intravenous insulin and glucose, or nebulized salbutamol. Aetiology—​there are many causes of hyperkalaemia, but by far the most common are renal failure (acute kidney injury or chronic kidney disease) and/​or drugs, in particular, potassium supplements, potassium-​sparing diuretics, angiotensin-​converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers. Other causes of hyperkalaemia—​these include hyporeninaemic hypoaldosteronism, other drugs (nonsteroidal anti-​inflammatory agents, heparin, calcineurin inhibitors, and trimethoprim–​ sulfamethoxazole), and renal transport abnormalities (type IV
renal tubular acidosis and pseudohypoaldosteronism types 1 and 2 (Gordon’s syndrome)). Altered internal balance causing hyperkalaemia—​causes include exhaustive exercise, acidosis, drugs (e.g. digoxin and depolarizing muscle relaxants), and hyperkalaemic periodic paralysis (very rare). Potassium homeostasis Potassium is the most abundant cation in the body. Total body po- tassium ranges between 37 and 52 mmol/​kg of body weight, and of this 98% is found within cells, where its concentration is 150 to 160 mmol/​litre. By contrast, the normal range of potassium concen- tration in serum is 3.5 to 5.0 mmol/​litre. The ratio of intracellular to extracellular potassium concentration is a critical determinant of cellular resting membrane potential and thereby of the function of excitable tissues, particularly the nerves and muscles. Potassium tends to leak out of cells through a variety of ion-​selective potassium channels found in all cell membranes. The maintenance of the intra- cellular to extracellular gradient is largely dependent on the ubiqui- tous enzyme Na+,K+-​ATPase, which pumps two potassium ions into the cell for every three sodium ions extruded. The mechanisms of potassium homeostasis can be considered in terms of internal balance (the relationship between intracellular and extracellular potassium concentration) and external balance (which determines total body potassium). Internal balance A wide variety of factors modulate the distribution of potassium be- tween the intracellular and extracellular fluid compartments. These factors either alter the function of the Na+,K+-​ATPase or the rate of efflux of potassium from cells, which together dictate intracellular po- tassium concentration. In view of the importance of the ratio of in- ternal to external potassium concentration for critical neuromuscular functions, some of these mechanisms serve as essential acute defence

21.2.2  Disorders of potassium homeostasis 4749 mechanisms to counteract life-​threatening hyperkalaemia. Factors modulating internal potassium balance are shown in Box 21.2.2.1. External balance Dietary potassium intake in people in Western societies typically varies between 50 and 150 mmol/​day, but balance can be attained with an intake of up to 500 mmol/​day if homeostatic mechanisms are intact. In normal circumstances, potassium excretion in the stool is not regulated, but amounts to only 5 to 15 mmol/​day. When renal function is compromised, the absolute magnitude as well as the proportion of potassium in the faeces is increased, but variation in renal excretion of potassium is usually the only means by which the body achieves external potassium balance by ensuring that ex- cretion equals intake. With a normal intake of potassium, 10 to 20% of the potassium filtered at the glomerulus is excreted, but fractional excretion of po- tassium can vary from 1% when intake is restricted to over 100% when intake is excessive. Micropuncture studies have shown that the amount of potassium reaching the distal convoluted tubule does not vary in these circumstances, indicating that modulation of renal potassium excretion is normally a property of the distal nephron. Factors that modify potassium excretion by the distal nephron are shown in Box 21.2.2.2. These factors are clearly interrelated: it is rare that one is modified in isolation and the overall effect on potassium excretion is almost invariably the aggregate result of several comple- mentary or competing stimuli. Hypokalaemia A low serum potassium concentration (≤3.5 mmol/​litre) is the most common electrolyte abnormality seen in clinical practice, found in up to 20% of patients in hospital. Most have mild hypokalaemia, with serum potassium in the range 3.0 to 3.5 mmol/​litre, but 5% have a level lower than 3.0 mmol/​litre, and 0.03% (more in some series) have very severe hypokalaemia with serum potassium concentra- tion less than 2.5 mmol/​litre. Clinical features Patients with mild hypokalaemia often have no symptoms attrib- utable to their low serum potassium concentration. A  variety of nonspecific symptoms develop with more severe hypokalaemia, including lassitude, generalized weakness, and constipation. At a Box 21.2.2.1  Factors modulating internal potassium balance Acid–​base status Acidosis (excepting renal tubular acidosis) tends to diminish potas- sium uptake by cells and to cause hyperkalaemia; alkalosis has the op- posite effect. The relationship between pH and serum potassium is not simple, but in metabolic acidosis the serum potassium can rise by up to 0.7 mmol/​litre for each 0.1 unit fall in blood pH, and alkalosis reduces serum potassium by up to 0.3 mmol/​litre per 0.1 pH unit rise. Pancreatic hormones Insulin release is stimulated by hyperkalaemia and inhibited by hypokal- aemia. It induces cellular uptake of potassium by activating the Na +,K+-​ ATPase directly. Glucagon can increase serum potassium concentration. Catecholamines β2-​Adrenergic agonists promote cellular potassium uptake by activating the Na+,K+-​ATPase via a cAMP-​dependent mechanism. α-​Adrenergic agonists have the opposite effect. Exercise Exercise results in loss of potassium from muscle cells, which causes local vasodilatation and increases regional blood flow. Serum potassium can increase by as much as 50% after 10 to 15 min of vigorous exercise, falling precipitately in the recovery period. Aldosterone The most important actions of aldosterone are on external balance, but there is also evidence of effect on internal balance. Osmolality Hyperosmolality increases the serum potassium concentration. Total body potassium The distribution of potassium between intracellular and extracellular compartments is influenced by the total amount of potassium in the body. Changes in the extracellular compartment are always proportion- ately greater than those in the intracellular compartment. The mechan- isms are not known. Box 21.2.2.2  Factors that modify potassium excretion by the distal nephron Aldosterone Aldosterone is the dominant hormone regulating potassium homeo- stasis. An increase in serum potassium directly stimulates aldosterone secretion by the adrenal glands. In the principal cells of the collecting ducts, aldosterone binds to its intracellular mineralocorticoid receptor, is translocated to the nucleus, and induces production of basolateral Na+,K+-​ATPase and the apical sodium channel. The effect is to increase intracellular potassium concentration and the electrochemical potential favouring potassium secretion into the tubular fluid and hence its excre- tion from the body. Under normal conditions, changes in sodium intake lead to changes in plasma aldosterone (an increase leading to decreased secretion) such that potassium homeostasis is preserved despite alter- ation in sodium and fluid delivery to the distal nephron. Intravascular volume Reduction of intravascular volume leads to a ‘contraction alkalosis’, stimu- lated largely by aldosterone, and which is associated with hypokalaemia. Dietary potassium intake Chronic alterations in dietary potassium intake induce profound modifications in the renal capacity to excrete or conserve potassium. A low-​potassium diet leads to an enhanced renal capacity to conserve potassium and a high-​potassium diet enhances the ability to excrete a potassium load. The mechanisms involved in these adaptations are poorly understood, although aldosterone is involved. Serum potassium concentration The potassium concentration gradient across the basolateral membrane modulates potassium uptake by the cell and/​or passive back-​leakage, hence hyperkalaemia leads to enhanced potassium excretion. Acid–​base status Systemic pH modulates potassium uptake across the basolateral membrane and conductance of the luminal membrane, with acidosis inhibiting excretion. Chronic metabolic alkalosis is almost invariably as- sociated with potassium depletion. Urine flow rate Increased flow of tubular fluid lowers potassium concentration in that fluid and favours secretion across the luminal membrane. Sodium Reduced delivery of sodium (<30 mmol/​litre) to the distal nephron im- pairs potassium secretion by the cortical collecting duct. Other factors ADH, poorly reabsorbable anions (such as sulphates), glucocorticoids, and α-​adrenergic agonists stimulate potassium secretion.

section 21  Disorders of the kidney and urinary tract 4750 serum potassium level of less than 2.5 mmol/​litre, serious neuromus- cular problems sometimes arise. Muscle cramps, rhabdomyolysis, and myoglobinuria (see Chapter 21.5) can occur, and increases in serum creatine kinase activity indicative of muscle injury are fre- quently detectable in those with a serum potassium concentration below 3.0 mmol/​litre. Respiratory failure due to muscle weakness has been reported, and hypokalaemia can cause intestinal ileus, par- ticularly in the postoperative period when other factors also conspire to prevent normal gut motility. Paralysis of skeletal muscle has been reported, most dramatically in cases of hypokalaemic quadraparesis, which appears to be more common in India than elsewhere. A wide variety of cardiac arrhythmias can be seen. Paraesthesias and tetany have rarely been described. Hypokalaemia can cause impaired urinary concentrating ability with polyuria and polydipsia, as well as inducing increased produc- tion of ammonia by renal tubular cells and increased bicarbonate reabsorption by the renal tubule, leading to a metabolic alkalosis. Severe prolonged potassium depletion is associated with chronic interstitial nephritis, the presence of renal cysts (most prominent in the medulla), and the development of chronic renal failure. It is not always clear, however, whether hypokalaemia is the cause or effect of this condition. Hypokalaemia may be suspected from the clinical context (e.g. the patient taking diuretics or vomiting copiously), but there are no specific physical signs. Alterations induced in the ECG include flattening of the T wave, depression of the ST segment, and the de- velopment of prominent U waves, which can give the impression of a prolonged QT interval. These changes, typically observed with a serum potassium concentration lower than 3.0 mmol/​litre, provide a diagnostic clue to the presence of hypokalaemia, but do not have any serious clinical implications in a patient with a normal heart. However, hypokalaemia can cause problems in those whose heart is abnormal. There is a correlation between hypokalaemia and the de- velopment of ventricular tachycardia or fibrillation during the acute phase of myocardial infarction; hypokalaemia can provoke life-​ threatening arrhythmias in those receiving digoxin; patients whose serum potassium falls to less than 3 mmol/​litre on treatment with a thiazide diuretic are twice as likely to have ventricular arrhyth- mias on 24-​h cardiac monitoring as those whose potassium remains above this level, but whether this constitutes a risk factor for sudden cardiac death remains uncertain. Hypokalaemia may be associated with hypomagnesaemia, which can be caused by gastrointestinal losses (diarrhoea) or urinary losses (loop and thiazide diuretics, alcohol, some nephrotoxic drugs, proton pump inhibitors (PPIs), various renal magnesium wasting syndromes). Patients with this combination may not respond to potassium replacement alone, hence in refractory cases of hypokal- aemia the serum magnesium should be checked and magnesium given if hypomagnesaemia is present. Oral replacement is appro- priate for patients with no or minor symptoms; intravenous therapy (e.g. 50 mmol of magnesium over 8 h) should be reserved for those with pressing clinical indications (e.g. ventricular arrhythmias). Management In emergencies Emergency treatment of hypokalaemia is rarely required. In the rare circumstances of life-​threatening cardiac arrhythmia or muscular paralysis, intravenous infusion of potassium (usually potassium chloride) should be given immediately. This must be administered into a central vein (internal jugular, subclavian, femoral, or periph- erally inserted central catheter (PICC line)) since solutions con- taining the necessary high concentration of potassium cause pain and phlebitis if given peripherally, and can cause chemical burns if they extravasate. There is no good evidence on which to base a recommendation regarding dose and rate, but the maximum rate of infusion usually employed is 1 mmol/​min, which should be con- trolled with a volumetric pump. The main danger of giving potas- sium with such rapidity is the development of hyperkalaemia, hence the patient and their ECG should be observed continuously and the serum potassium checked frequently, and infusion should be slowed as soon as the life-​threatening problem has resolved (arrhythmia settled, muscular power improved). In one study, administration of 40 mmol of potassium over 1 h was found to increase serum potas- sium concentration by an average of 1.1 mmol/​litre in hypokalaemic patients with both normal and impaired renal function. In cases that are not emergencies In most circumstances, the management of a patient with hypokal- aemia requires a methodical approach to establishing the diagnosis, which is often readily apparent (but not always so), rectification (if possible) of the underlying cause, and administration of potassium at a less hurried rate than that described previously. In most cases of hypokalaemia, the fall in the serum potassium concentration rep- resents the tip of an iceberg, a reduction of 0.3 mmol/​litre typically reflecting a 100 mmol deficit in body stores. This relationship is vari- able, but it is important to remember that patients with even modest hypokalaemia may have a very considerable deficit of total body po- tassium that needs to be replaced. Potassium can be given orally or intravenously. Foods with high po- tassium content are listed later in this chapter, but it should be noted that the potassium which they contain is almost entirely coupled with phosphate. In the absence of adequate chloride intake they are therefore ineffective in replenishing body potassium in the many and common causes of hypokalaemia associated with chloride depletion, such as use of diuretics or vomiting (see later for further discussion). Potassium chloride can be given in either liquid or tablet form, typ- ically 2 to 4 g (c.25–​50 mmol) daily in divided doses. Both are well absorbed, but the liquid preparations are unpalatable to many pa- tients and slow-​release tablets have been associated with gastrointes- tinal ulceration, bleeding, and stricture, such that they must be taken with fluid while sitting or standing and not just before retiring to bed for the night. If intravenous administration of potassium is required, infusions containing a concentration of 20 mmol/​litre can usually be tolerated through a good peripheral line. If a higher concentration than this is required, central venous access will be necessary. Care must always be taken to monitor serum levels closely. Common causes There are a very large number of possible causes of hypokalaemia (Box 21.2.2.3), but in most instances the diagnosis is immedi- ately apparent. Whenever this is not so, it is wise to remember that common things are the most likely, and it is also important to rec- ognize that concealment of the cause is not infrequent, with diuretic abuse or covert vomiting more likely than the many more exotic and rare causes of hypokalaemia.

21.2.2  Disorders of potassium homeostasis 4751 Hypokalaemia is not a prominent feature of many of the dis- orders listed in Box 21.2.2.3: discussion in this chapter is limited to those conditions that are common, or where hypokalaemia is an important manifestation. A pragmatic approach is first to consider the most frequent causes of hypokalaemia—​diuretic ingestion and gastrointestinal fluid loss—​and then proceed to a systematic analysis if these are not evidently the cause of the problem. Diuretics The most common cause of hypokalaemia is diuretic therapy. All diuretics other than those acting directly on the collecting duct (amiloride, triamterene, spironolactone) block some form of chloride-​associated sodium transport. As a result, they increase the delivery of sodium to the collecting duct, where its reabsorp- tion creates a favourable electrochemical gradient for and obligates potassium secretion. Hypokalaemia frequently occurs together with metabolic alkalosis (serum bicarbonate concentration 28–​36 mmol/​ litre). In general, the hypokalaemia is mild, with serum potassium in the range 3 to 3.5 mmol/​litre, the average fall after initiation of the usual doses of loop diuretics (furosemide, bumetanide, torasemide) being about 0.3 mmol/​litre, somewhat more with the usual doses of thiazides (bendroflumethiazide, chlorothiazide, chlorthalidone) at about 0.6 mmol/​litre. In one analysis of publications on hypokal- aemia and diuretics, it was found that the fall in serum potassium was little influenced by the reason for prescription (hypertension or heart failure), or by the dose or duration of treatment. The question of whether or not patients receiving diuretics prone to induce hypokalaemia should be prescribed potassium supple- ments or potassium-​retaining diuretics has been much debated. There is no strong evidence on which to base recommendations. It seems common sense to monitor for and intervene to prevent hypo- kalaemia in those considered at particular risk of hypokalaemic complications, including those with a history of cardiac arrhythmia, those on digoxin, and those with liver disease in whom electrolyte imbalance might precipitate encephalopathy. Most patients do not fall into any of these categories, and here the balance is between an attempt to prevent a hypothetical but unproven hazard and the re- quirement for medication that is unpalatable to many and in rare in- stances can have significant side effects. As in many other aspects of medicine, the behaviour of the physician will say as much about them as about the condition that they are dealing with. Those that like all test results to be in the ‘normal range’ will prescribe, but short of stop- ping diuretic therapy, correcting diuretic-​induced hypokalaemia is not easy. In one study that monitored adverse drug reactions in 5047 consecutive inpatients, 2439 were taking potassium-​losing diuretics, in whom serum potassium was less than 3.5 mmol/​litre in 21%, and below 3.0 mmol/​litre in 3.8%. When the group taking potassium-​ losing diuretics was broken down into those taking them without any attempt to prevent hypokalaemia, those taking them in conjunction with potassium supplements, and those taking them together with a potassium-​sparing diuretic, then serum potassium below 3.5 mmol/​ litre was found in 24.9%, 19.7%, and 15.2%, respectively. Box 21.2.2.3  Causes of hypokalaemia Altered internal balance (redistribution of potassium from extracellular to intracellular compartment) • Alkalosis • Insulin (high doses) • β2-​Adrenergic stimulants • Vitamin B12 therapy of deficiency anaemia • Intoxications:

—​ Theophylline

—​ Toluene (paint/​glue sniffing)

—​ Barium • Periodic paralysis:

—​ Thyrotoxic periodic paralysis

—​ Sporadic periodic paralysis

—​ Familial hypokalaemic periodic paralysis • ?Aldosterone Altered external balance (low total body potassium) Renal losses (inappropriately high urinary potassium excretion, see text for further information) • Appropriate renal response to alkalosis:

—​ Vomitinga • Mineralocorticoid excess:

—​ Primary hyperaldosteronism (Conn’s syndrome)

—​ Fludrocortisone

—​ Congenital adrenal hyperplasia

—​ 11β-​Hydroxylase deficiency

—​ 17α-​Hydroxylase deficiency

—​ Renin-​secreting tumours

—​ Ectopic ACTH production

—​ Cushing’s syndrome

—​ Glucocorticoid-​responsive aldosteronism

—​ Renovascular hypertension

—​ Accelerated (malignant)-​phase hypertension

—​ Vasculitis • Apparent mineralocorticoid excess:

—​ Liddle’s syndrome

—​ Syndrome of apparent mineralocorticoid excess (hereditary 11β-​ hydroxysteroid dehydrogenase deficiency)

—​ Acquired 11β-​hydroxysteroid dehydrogenase deficiency:  liquorice, chewing tobacco, carbenoxolone • Impaired renal tubular ion transport:

—​ Diureticsa

—​ Bartter’s syndrome

—​ Gitelman’s syndrome

—​ Renal tubular acidosis (distal)

—​ High-​dose penicillins

—​ Magnesium depletion, including PPIs Extrarenal losses (appropriately low urinary potassium excretion, see text for further information) • Gastrointestinal losses:

—​ Biliary loss

—​ Lower gastrointestinal loss:  diarrhoea,a laxative abuse, villous adenoma

—​ Fistula

—​ Ureterosigmoidostomy • Skin losses a The most common causes are diuretics, vomiting, and diarrhoea—​these should be excluded before rare conditions are pursued.

section 21  Disorders of the kidney and urinary tract 4752 Loss of gastrointestinal fluid In one study of severe hypokalaemia (serum potassium <2.5 mmol/​ litre), gastrointestinal fluid loss was the main cause in 22% of cases. Vomiting The concentration of potassium in gastric and upper intestinal secre- tions is between 3 and 12 mmol/​litre. Reduced intake and direct loss of potassium in vomit are not, therefore, the cause of hypokalaemia, which is due to increased renal excretion of potassium. This arises as a result of the kidney’s response to metabolic alkalosis, which is the dominant metabolic problem. Aside from modest quantities of potassium, gastric juices contain sodium ions (30–​90 mmol/​litre), protons (90 mmol/​litre), and chloride (50–​125 mmol/​litre). Loss of gastric acid (HCl) pulls the buffer equation H2CO3 + Na+ + Cl− ⇔ Na+ + HCO3− + H+ + Cl− to the right, hence the main effect is meta- bolic alkalosis. Depletion of extracellular fluid volume also occurs, activating the renin–​angiotensin–​aldosterone system. As the bi- carbonate concentration in the blood rises, more is filtered at the glomerulus and some is excreted in the urine, partly in conjunction with potassium, whose distal excretion is stimulated by high levels of aldosterone. Considerations of acid–​base balance have taken pre- cedence over those of potassium homeostasis, and hypokalaemia results. An important point to note is that the combination of direct chloride loss in vomit and contraction of extracellular fluid volume lead to a situation where the kidney avidly retains chloride and the urinary concentration of chloride falls to a very low level (<10 mmol/​ litre, sometimes as low as 1–​2 mmol/​litre, when the normal range is 30–​120 mmol/​litre). This is of critical clinical significance be- cause reabsorption of filtered sodium and potassium ions by the renal tubule can only be achieved in combination with an anion, usually chloride, hence if urinary chloride concentration is already close to zero there is no way in which sodium and potassium can be reabsorbed efficiently, meaning that sodium and potassium that are administered can only be retained if provided in conjunction with chloride, and not if given as other salts. The renal response of chloride retention also means that measurement of urinary chloride concentration can be helpful in making the diagnosis of surrepti- tious vomiting (see later). Resuscitation of a patient with hypokalaemia due to vomiting re- quires the intravenous infusion of 0.9% sodium chloride, together with potassium supplementation as described previously. In severe cases, the total body deficit of fluid may be in excess of 5 litres, and of potassium of many hundreds of millimoles. Diarrhoea The concentration of potassium in stool is 80 to 90 mmol/​litre, hence—​given normal stool weight of 100 to 200 g/​day—​faecal loss of potassium is usually in the range 5 to 15 mmol/​day. The potassium concentration in the stool decreases as stool volume increases, but volume can increase massively, such that substantial potassium loss and profound hypokalaemia can complicate any severe diarrhoeal illness. Potassium loss in diarrhoeal states is usually associated with loss of bicarbonate, resulting in a coexisting metabolic acidosis, such that serum levels of potassium may not reflect the true body deficit. In this circumstance, the renal excretion of potassium is broadly appropriate, and potassium deficiency is not due to a renal leak. However, in some situations, potassium in stool is lost in conjunc- tion with chloride, resulting in a metabolic alkalosis and a picture similar to that seen with vomiting. A villous adenoma of the colon or rectum can rarely result in pro- found hypokalaemia. The mechanism seems to involve secretion of cAMP and prostaglandin E2 by the tumour, leading to disturb- ance of ion transport in the normal colonic mucosa. Treatment with nonsteroidal anti-​inflammatory drugs (NSAIDs) can significantly reduce stool volume and help to correct both volume depletion and hypokalaemia. Similar disturbances probably underlie the hypokal- aemia of patients with the watery diarrhoea, hypokalaemia, achlor- hydria syndrome, caused by excess vasoactive intestinal peptide secreted by certain tumours. In addition to treatment directed at the tumour itself, somatostatin or somatostatin analogues are effective in controlling symptoms. Hypomagnesaemia and proton pump inhibitors PPIs (e.g. omeprazole, esomeprazole, lansoprazole, and pantopra­ zole) are widely prescribed for the treatment of upper gastro- intestinal symptoms. In 2006, it was recognized that they could, by a generic effect, and particularly when taken in combination with diuretics, cause hypomagnesaemia associated with hypocal- caemia and relative hypoparathyroidism. The presumed mech- anism is by PPI-​induced inhibition of transient receptor potential melastatin-​6 (TRPM6) and TRPM7 channels in intestinal epi- thelial cells, which are responsible for absorption of magnesium from the gut. Hypokalaemia is thought to arise by the following mechanism: intracellular magnesium inhibits potassium secretion through luminal potassium channels (ROMK) in the connecting and cortical tubules, hence hypomagnesaemia and a reduction in intracellular magnesium concentration can induce kaliuresis and hypokalaemia by releasing this inhibitory effect. This provides an explanation for the clinical observation that treatment of hypo- kalaemia in the context of PPI use, or with other causes of hypo- magnesaemia, requires correction of magnesium depletion: it is refractory to potassium supplementation alone. Diagnosing the cause of hypokalaemia in difficult cases The diagnosis of the cause of hypokalaemia is usually straightfor- ward and explained by diuretic therapy or gastrointestinal fluid loss, as described earlier. In other patients, the abnormality is mild, with the occasional serum potassium concentration measured at just below the lower limit of the normal range, such that extensive inves- tigation is almost certainly inappropriate (and likely to be fruitless if pursued). However, some patients present with unexplained se- vere hypokalaemia, and these represent a considerable challenge for both diagnosis and management. The differential diagnosis in these cases usually lies between various abnormalities of tubular potas- sium transport, concealed vomiting and/​or usage of purgatives, and concealed ingestion of diuretics. It is important to ask directly for a history of vomiting or diar- rhoea, and about present or past use of any medications, particularly diuretics or purgatives. It is also worthwhile to ask about consump- tion of liquorice or chewing tobacco (see ‘Apparent mineralocor- ticoid excess’). Examination is likely to be unremarkable in cases of unexplained hypokalaemia, but pay particular attention to body

21.2.2  Disorders of potassium homeostasis 4753 weight, height, and body mass index, and to any other features that might support the diagnosis of an eating disorder such as anorexia nervosa or bulimia nervosa (see Chapter 26.5.10). A logical investigative approach to the patient with unexplained hypokalaemia begins with trying to establish whether or not the urinary potassium excretion is appropriate (Box 21.2.2.3). If potas- sium depletion is not due to urinary losses, then the normal renal response is to reduce urinary potassium concentration to less than 15 mmol/​litre or less than 30 mmol/​day. Values higher than these suggest that renal potassium loss is at least partly responsible for the hypokalaemia. However, the measurement of a ‘spot’ urinary potas- sium concentration may be misleading if the patient is polyuric, and 24-​h urinary collections are cumbersome at best, and cannot be reli- ably obtained from some patients. The effects of urinary dilution can be compensated for by esti- mation of the urinary potassium-​to-​creatinine ratio. In a study of 43 patients with severe hypokalaemia, estimation of the ratio of potassium excretion to creatinine excretion proved helpful in differentiating those with renal potassium wasting (ratio >2.5 mmol potassium/mmol creatinine, >22 mmol potassium/g creatinine)) from those with a nonrenal condition (ratio lower). A further re- finement is to calculate the transtubular potassium concentration gradient (TTKG), which estimates the potassium concentration at the end of the cortical collecting tubule (the site responsible for most potassium excretion) according to the formula: TTKG = urinary K plasma osmolality / plasma[K] urin ( [ ] ) ( × × ary osmolality) In a normal subject on a normal Western diet, the TTKG is 8 to 9. In a patient with hypokalaemia, a value below 3 suggests that the kidneys are trying to conserve potassium appropriately and a value above 3 that they are wasting potassium. A careful study reported the findings of extensive investigation of 27 adult patients (17 women) who presented with chronic hypo- kalaemia (serum potassium concentration <3.4 mmol/​litre) that was sustained for over 5 years and which had previously eluded diagnosis. The following diagnoses were established: diuretic abuse (in 5 patients), surreptitious vomiting (8), laxative abuse (1), renal tubular acidosis (1), and Gitelman’s syndrome (12). Medical work-​ up that had sought to make the diagnoses by measurement of plasma renin activity, plasma aldosterone concentration, and urinary potas- sium concentration failed to discriminate between these conditions. Investigations that were diagnostically helpful are given in Table 21.2.2.1, the most useful being the plasma pH and chloride concen- tration, urinary chloride concentration and screen for diuretics, and (in one case) stool weight. A report of 99 patients with chronic normotensive hypokalaemia (mean serum potassium 2.8 mmol/​L of 4 years’ duration) described similar diagnoses:  Gitelman’s syndrome (33 cases), Bartter’s syn- drome (10), distal renal tubular acidosis (12), anorexia/​bulimia nervosa (21), and surreptitious use of laxatives (11) or diuretics (12). An Indian study of 50 cases of hypokalaemic flaccid paralysis found underlying diagnoses of potassium loss due to excessive sweating, diarrhoea and vomiting, thyroid disorders (11 cases thyrotoxic, 3 cases hypothyroid), and renal tubular dysfunction (5 cases distal renal tubular acidosis, 4 cases Gitelman’s syndrome). The finding of a low plasma chloride concentration with the vir- tual absence of chloride from the urine supports the diagnosis of surreptitious vomiting. Screening the urine for diuretics is appro- priate if the urinary chloride concentration is above 20 mmol/​litre, and if no diuretics are found in samples with a chloride concen- tration of above 50 mmol/​litre then Gitelman’s syndrome is likely. Vomiting, diuretics, and Gitelman’s syndrome all cause alkalosis, whereas laxative abuse is associated with acidosis, as is renal tubular acidosis. The diagnosis of renal tubular acidosis can be established Table 21.2.2.1  Diagnostic clues in 27 cases of hypokalaemia that were hard to diagnose Investigation Normal range Diagnosis Diuretic consumption Vomiting Laxative consumption Renal tubular acidosis Gitelman’s syndrome Number of cases 5 8 1 1 12 Plasma/​serum Chloride 97–​108 mmol/​litre Low normal or low Low Low Normal Low normal or low Bicarbonate 22–​28 mmol/​litre High normal or high High Low Low High normal or high Magnesium 0.8–​1.1 mmol/​litre NR NR NR NR Low Urinary Sodium 40–​130 mmol/​litre Normal Normal Low Normal High normal or high Potassium 30–​110 mmol/​litre Normal Normal Normal Variable Normal Chloride 30–​120 mmol/​litre Normal Very low (<10 mmol/​litre) Low Normal High Calcium 2.5–​8.0 mmol per 24 h NR NR NR NR Low Magnesium 2.5–​7.5 mmol/​litre NR NR NR NR High Diuretic screen Positive Negative Negative Negative Negative Stool Weight 100–​200 g/​day Normal Normal High Normal Normal NR, not reported. Reproduced with permission from Gladziwa et al. (1995). Nephrology, Dialysis, Transplantation 10, 1607.

section 21  Disorders of the kidney and urinary tract 4754 by demonstrating an inability to produce acid urine in the presence of systemic acidosis (see Chapter 21.15 for further discussion). The management of cases of surreptitious vomiting, or diuretic or purgative abuse is difficult. Many patients will fulfil diagnostic criteria for anorexia nervosa or bulimia nervosa, and issues other than those simply and directly related to potassium homeostasis will clearly need to be considered. The physician may well need to seek expert psychiatric help. See Chapter 26.5.10 for further discussion. Rare causes of hypokalaemia due to altered external potassium balance Mineralocorticoid excess Hypokalaemia can be caused by a large number of causes of min- eralocorticoid excess, as shown in Box 21.2.2.3. Primary aldoster- onism is discussed in Chapters 13.5.1 and 16.17.3, congenital adrenal hyperplasia in Chapter 13.5.2, and glucocorticoid-​remediable aldos- teronism in Chapter 16.17.4. Hypokalaemia is rarely a prominent feature of the other conditions of mineralocorticoid excess listed, which are discussed elsewhere in this book. Apparent mineralocorticoid excess Activating mutations in the β-​ or γ-​subunits of the epithelial so- dium channel in the collecting duct causes Liddle’s syndrome. Disabling mutations in the type 2 11β-​hydroxysteroid dehydro- genase gene cause a deficiency of the enzyme, allowing cortisol access to the mineralocorticoid receptor and the syndrome of ap- parent mineralocorticoid excess. Acquired inhibition of the action of 11β-​hydroxysteroid dehydrogenase can be caused by liquorice, carbenoxolone, and chewing tobacco. Hypokalaemia with low plasma concentrations of renin and aldosterone are features of all of these conditions, which are discussed in Chapter 16.17.4. Renal tubular abnormalities of potassium transport Patients with ‘classic’ distal renal tubular acidosis are prone to hypo- kalaemia, as are most patients with proximal renal tubular acid- osis: these conditions are discussed in Chapter 21.15. In 1962, Bartter described ‘hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis:  a new syndrome’. Well over 100 papers were subsequently written to describe features of what was believed to be the same eponym- ously named condition. The picture became immensely confused, but since 1995 has been clarified by the recognition of distinct phenotypes within the group of patients previously thought to have ‘Bartter’s syndrome’ and the application of powerful molecular gen- etic methods to their study. These revealed that most adults previ- ously thought to have Bartter’s syndrome in fact have Gitelman’s syndrome. Gitelman’s syndrome Gitelman’s syndrome is the most common genetic cause of hypo- kalaemia. It is an autosomal recessive condition typically caused by biallelic inactivating mutations in the SLC12A3 gene that codes for the thiazide-​sensitive Na–​Cl cotransporter (NCCT; Fig. 21.2.2.1), which explains why the clinical phenotype is mimicked by con- sumption of such diuretics. However, some patients with a Gitelman phenotype will have an inactivating mutation in a single SLC12A3 allele combined with other abnormalities in the other allele, and mutations in CLCNKB (the cause of Bartter’s syndrome type III) are sometimes found. There are no dramatic clinical symptoms or signs, hence sus- picion of the diagnosis of Gitelman’s syndrome often arises only when hypokalaemia is found (or in screening of family members of a known case) (Table 21.2.2.1). However, when surveyed dir- ectly, most patients with Gitelman’s syndrome are found to be sig- nificantly symptomatic, reporting salt craving, musculoskeletal symptoms (cramps, muscle weakness, and aches), constitutional symptoms (fatigue, generalized weakness, and dizziness), nocturia, thirst and polydipsia, paraesthesia and numbness, and palpitations, with many patients considering their symptoms to be a moderate problem or worse. Whereas blood pressure is typically normal or low in young adults with the condition, hypertension can develop in later life for reasons that remain obscure. Arthralgia and/​or chondrocalcinosis are common, the latter possibly related to chronic hypomagnesaemia. The diagnosis of Gitelman’s syndrome can be confirmed by gen- etic testing and recent guidance (KDIGO Controversies Conference) suggested that this should be offered to all suspected of having the condition. However, this is not straightforward: the genes involved are large, with multiple mutations and lack of ‘hot spots’. Patients should be encouraged to indulge their tendency to consume salt (sodium chloride) ad libitum. Otherwise, lifelong oral magnesium and/​or potassium supplementation is required, with the intention of achieving a serum potassium concentration greater than 3.0 mmol/​ L and a serum magnesium concentration greater than 0.6 mmol/​L. It is noteworthy that magnesium deficiency aggravates hypokalaemia and renders this refractory to treatment with potassium. All types of magnesium salts are effective, but they are often poorly tolerated because of their propensity to cause diarrhoea. Organic salts (aspar- tate, citrate, lactate) have higher bioavailability than inorganic (oxide, Na 2Cl Distal convoluted tubule Medullary thick ascending limb Blood Cl ATP K ClC-Kb (Bartter’s III) Na Cl K Na K ATP Lumen K Na Blood Lumen NKCC2 (Bartter’s I) ROMK (Bartter’s II) NCCT (Gitelman’s) Fig. 21.2.2.1  Some genetic disorders of the renal tubule that cause hypokalaemia. ClC-​Kb, kidney-​specific chloride channel; NCCT, Na–​Cl cotransporter; NKCC2, Na–​K–​2Cl cotransporter; ROMK, ATP-​regulated potassium channel.

21.2.2  Disorders of potassium homeostasis 4755 hydroxide). Magnesium chloride will also compensate for urinary chloride loss, with a typical recommended starting dose being 300 mg/​day (magnesium component), best taken as slow-​release tablets in divided doses with meals. Potassium supplements should be given as chloride, initially 40 mmol/​day in divided doses, titrated up as needed. Intravenous potassium chloride and/​or magnesium chloride/​sulphate may be needed in extreme circumstances, for example, serious cardiac arrhythmia or muscular paralysis. Options to be considered in patients with persistent symptomatic hypokalaemia that is refractory to magnesium and/​or potassium supplements, or who cannot adhere to these, include potassium-​ sparing diuretics, renin–​angiotensin system blockers and (by sup- pressing an elevated level of renal prostaglandin E2 secretion) NSAIDs. Heterozygote carriers of Gitelman mutations have increased urinary sodium excretion (due to a self-​selected higher salt in- take), modestly lowered blood pressure and reduced chance of developing hypertension, a serum potassium concentration to- wards the lower limit of the normal range, and increased sus- ceptibility to hypokalaemia induced by diuretics. They also have increased bone density. See Chapter 21.16 for further discussion, in particular of genetic aspects and matters related to hypomagnesaemia. Bartter’s syndrome Bartter’s syndrome (types I–​IV) is caused by autosomal recessive mutations of ion transporters or ion channels in cells of the thick ascending limb of the nephron (Fig. 21.2.2.1). It generally presents in childhood with features including growth failure and mental re- tardation, polyuria, and polydipsia, associated with hypokalaemia and metabolic alkalosis. Type I and type II  Type I is caused by mutations in the SLC12A1 gene encoding the Na–​K–​2Cl cotransporter (NKCC2). Type II is caused by mutations in the KCNJ1 gene, which encodes the apical ATP-​sensitive potassium channel (ROMK) that recycles potassium back into the lumen and is critical for continued activity of the NKCC2 cotransporter. Both cause polyhydramnios in pregnancy and premature birth. Severe dehydration in the first few days of life or during intercurrent illness is associated with a high mortality rate before diagnosis. Other clinical manifestations in survivors include short stature, intellectual disability, generalized weakness, muscle cramps, and rickets. Aside from hypokalaemic alkalosis, biochemical and radiological features include severe hypercalciuria and nephrocalcinosis. Dehydration must be avoided, potassium supplementation is needed, and (by suppressing an elevated level of renal prostaglandin E2 secretion) NSAIDs may be helpful. Type III  Type III is caused by mutations in the CLCNKB gene encoding a kidney-​specific chloride channel (ClC-​Kb). This is the cause of the ‘classic’ form of Bartter’s syndrome. The clinical pic- ture is more varied than that for types I or II and ranges in severity from near-​fatal volume depletion with hypokalaemic alkalosis and respiratory arrest, to mild disease presenting in a teenager with polyuria and weakness, as can be seen in Gitelman’s syndrome (see ‘Gitelman’s syndrome’). Nephrocalcinosis is not a feature, but late manifestations can include proteinuria. Management is with potas- sium supplementation and care to avoid dehydration. Long-​term prognosis is uncertain. Type IV  This condition is caused by defects in function of two chloride channels, ClC-​Ka and ClC-​Kb. It may (type IV) be due to mutations in the BSND gene that encodes barttin, a protein which colocalizes with chloride channels in the kidney and inner ear, or (type IVb) to simultaneous mutations in CLCNKA and CLCNKB genes. Presentation is antenatal or in infancy, with congenial sen- sorineural deafness in addition to features as described for type I and type II Bartter’s syndrome. Type V  In this condition, a gain-​of-​function mutation in the cal- cium sensing receptor (CaSR) leads to inhibition of secretion of parathyroid hormone at a lower than normal level of serum calcium and hence to persistent hypocalcaemia. The CaSR receptor is also expressed in the medullary thick ascending limb, where its over- activity can affect ROMK and NKCC2 in such a way as to create a Bartter phenotype with hypokalaemia and metabolic alkalosis. Ureteric diversion into the colon Surgical diversion of the ureters into the colon (ureterosigmoido­ stomy) was previously performed as a method of urinary drainage, most commonly in children for the treatment of bladder exstrophy and in adults following total cystectomy. The operation is now rarely (if ever) performed because of the metabolic consequences, which have driven improvement in surgical techniques for ileal conduits and alternative urinary diversions. However, the consequence of ureterosigmoidostomy is that urine remains in contact with the co- lonic mucosa for a long time, in which case its response is to re- absorb urinary ammonium and secrete bicarbonate, leading to hyperchloraemic acidosis, and also for there to be stimulation of colonic potassium secretion, resulting in hypokalaemia. Profound and life-​threatening acidosis can occur with concurrent illness, and chronic renal failure can develop. Rare causes of hypokalaemia due to abnormal internal potassium balance Although there are many causes of hypokalaemia (Box 21.2.2.3), there are relatively few causes of hypokalaemia associated with ex- treme weakness, the most common explanation for this rare presen- tation being hypokalaemic periodic paralysis. In Western countries, most cases of hypokalaemic periodic paralysis are familial, termed familial periodic paralysis, whereas in Asian populations, the most common cause is thyrotoxic periodic paralysis. In all forms of hypo- kalaemic periodic paralysis the hypokalaemia and paralysis result from an acute shift of potassium into cells, the mechanism for which is unknown, although there is speculation that it is due to a transient hyperadrenergic state. Infection with dengue virus also needs to be considered in areas where this is endemic. One study reviewed the medical records of 97 patients who pre- sented over a 10-​year period to hospital in Taiwan with severe hypo- kalaemia (serum potassium <3.0 mmol/​litre, mean 2.2 mmol/​litre) and acute loss of muscle strength with inability to walk. The final diagnoses established are shown in Table 21.2.2.2. Treatment of acute attacks of hypokalaemic periodic paralysis traditionally involves the administration of intravenous potassium. Some patients recover with as little as 20 mmol, but others require over 200 mmol. In all types of this condition, a paradoxical fall in serum potassium concentration can occur at the start of treatment, and rebound hyperkalaemia is also seen.

section 21  Disorders of the kidney and urinary tract 4756 Thyrotoxic periodic paralysis The diagnosis of thyrotoxic periodic paralysis is established if hyper- thyroidism, usually but not always due to Graves’ disease, is present when hypokalaemic paralysis occurs. The condition is commonest in Asians, in whom about 2% of those with thyrotoxicosis are af- fected (compared to 0.1–​0.2% in non-​Asians), and over 95% of cases occur in men, with age of onset usually 20 to 40 years. Thyrotoxic periodic paralysis is associated in some cases with variants in genes encoding potassium channels: a study of Caucasian or Brazilian patients found that one-​third had a mutation in the KCNJ18 gene, which encodes Kir2.6, an inwardly rectifying potas- sium channel that is transcriptionally regulated by thyroid hormone; a case–​control study of Korean patients found the allelic frequency of a particular single nucleotide polymorphism adjacent to the KCNJ2 gene was significantly associated with the condition; muta- tions in various other genes have also been incriminated. This has led to the hypothesis that patients who are susceptible to thyrotoxic periodic paralysis may have an ion channel or other genetic defect that does not manifest clinically when they are euthyroid, but is prone to under the stress of hyperthyroidism. Typical presentation is with sudden attacks of generalized weak- ness, which most commonly begin at the same time as clinical mani- festation of hyperthyroidism, but can occur before or after. Weakness usually lasts for several hours. A variety of stimuli have been reported to provoke attacks, including large carbohydrate meals (perhaps via the mechanism of an exaggerated response to insulin), excessive physical activity, and stress. Aside from weakness (legs > arms, prox- imal > distal), physical findings during an attack include tachycardia (a useful diagnostic discriminator from sporadic periodic paralysis) and high blood pressure; signs of hyperthyroidism are absent in 20 to 40% of cases. Laboratory findings include hypokalaemia (mean serum potassium 2.1 mmol/​litre in one large series), elevated serum T4, and low serum TSH. Hypophosphataemia and hypomagnes- aemia are also found. Although treatment of thyrotoxic periodic paralysis has conven- tionally involved administration of potassium, there is considerable experience suggesting that patients with this condition respond rap- idly to the β-​blocker propranolol, which can be given intravenously (up to 3 mg total dose) or orally (3 mg/​kg) with the expectation that serum potassium concentration will return to normal and paralysis will resolve within 2 h. Effective treatment of hyperthyroidism prevents attacks, but about two-​thirds of patients will have recurrent paralytic attacks, most commonly in the first 3 months after diagnosis, while their hyper- thyroidism is brought under control. Propranolol, with or without potassium supplements, can also reduce the frequency of attacks. Familial hypokalaemic periodic paralysis Attacks typically begin in late childhood or adolescence and are vari- able in frequency (the typical interval between attacks is weeks to months) and duration (typically hours, but can range from minutes to days). They can sometimes be precipitated by administration of insulin or glucose and aborted by exercise, which induces an exag- gerated rise in serum potassium concentration. Rhabdomyolysis has been reported. A progressive proximal myopathy eventually de- velops in most patients. The diagnosis is established by finding a family history of attacks of flaccid weakness and hypokalaemia. Familial hypokalaemic peri- odic paralysis can be caused by mutations in several genes. The most common, accounting for about 70% of cases, is CACN1AS, which encodes a dihydropyridine receptor that functions as a voltage-​gated calcium channel and is also critical for excitation–​contraction coup- ling in a voltage-​sensitive and calcium-​independent manner. Other causes include mutation in (1) SCN4A, which encodes for a sodium channel and is also the site of mutations causing hyperkalaemic periodic paralysis; (2) KCNJ2, which encodes a potassium channel; and—​possibly but not certainly a cause of hypokalaemic periodic paralysis—​(3) KCNE3, which encodes a potassium channel β sub- unit. The conditions are autosomal dominant, with 100% pene- trance in males, but much less in females. Emergency treatment is with intravenous potassium: propranolol is ineffective. Dichlorphenamide (a carbonic anhydrase inhibitor) is effective at preventing attacks in most cases; acetazolamide (an- other carbonic anhydrase inhibitor), pinacidil (a potassium channel opener), potassium-​sparing diuretics, and verapamil have also been used. Nonfamilial (sporadic) periodic paralysis The cause of this condition is not known:  patients do not have a family history of hypokalaemic periodic paralysis and do not have hyperthyroidism. A genome-​wide association study in a Han Chinese population found a novel disease-​associated gene (CTD-​ 2378E21.1) for both thyrotoxic periodic paralysis and sporadic peri- odic paralysis that may negatively regulate KCNJ2 expression. There Table 21.2.2.2  Final diagnoses established in 97 patients initially diagnosed as having hypokalaemic periodic paralysis Final diagnosis Number Mean age (years) Male:female ratio Patients with hypokalaemic periodic paralysis Thyrotoxic periodic paralysis 39 28 39:0 Sporadic periodic paralysis 29 26 23:6 Hypernatraemic hypokalaemic periodic paralysisa 3 18 3:0 Familial periodic paralysis 2 16 2:0 Patients who did not have hypokalaemic periodic paralysis Metabolic alkalosis Primary aldosteronism 6 39 2:4 Bartter’s or Gitelman’s syndromes 6 21 4:2 Diuretics 3 40 0:3 Hyperchloraemic acidosis Distal renal tubular acidosis 6 47 3:3 Toluene abuse 3 28 1:2 a Mean serum sodium concentration was 167 mmol/​litre. Two patients had brain tumours and one patient had hypothalamic involvement with tuberculosis. It is possible that diabetes insipidus was the explanation for their presentation and there is insufficient evidence in the paper to justify the naming of a new syndrome. Patients with hypokalaemic periodic paralysis do not have an acid–​base disorder: arterial pH, Pco2, and bicarbonate are all within the normal range. A key finding is that the urinary potassium concentration is low (mean 8 mmol/​litre). There is also a low transtubular potassium concentration gradient (TTKG = (urine K/​serum K)/​(urine osmolality/​serum osmolality)) of <3: the normal renal response to hypokalaemia of nonrenal origin being a TTKG <2, whereas a renal cause of hypokalaemia is usually associated with TTKG >5). Reproduced with permission from Lin et al. (2001). Quarterly Journal of Medicine 94, 133–​9.

21.2.2  Disorders of potassium homeostasis 4757 are no obvious precipitating factors for acute attacks. Heart rate at presentation is lower than for those with thyrotoxic periodic par- alysis (mean 76 compared with 105 beats/​min). Treatment is as for familial hypokalaemic periodic paralysis. Sudden unexplained death during sleep Sudden unexplained death during sleep (SUDS), known in Japan as ‘Pokkuri Death Syndrome’, in Thai as lai-​tai, and as the Filipino folk term bangungut (meaning ‘to rise and moan during sleep’), is not uncommon in Asians and is a leading cause of death in young men in rural north-​eastern Thailand. A  survey in the Philippines reported an annual incidence of 22 per 100 000 in the 20-​ to 39-​year age group (mostly in men) and 43 per 100  000 overall. It has been recorded over the years as the cause of death of many hundreds of apparently healthy male Thai migrant workers in Singapore. Women are rarely, if ever, affected. Death occurs at rest and is nocturnal in most (84%) cases. In cases that are observed, witnesses often report that death is preceded by a few minutes of groaning, choking, coughing, and muscular spasticity or paralysis. There has been much speculation over the cause of SUDS, with a popular hypothesis being that it could be caused by potassium deficiency. Survivors of SUDS-​like attacks and relatives of victims of SUDS have been reported to have significantly lower activity of erythrocyte Na+,K+-​ATPase and lower serum potassium con- centration than controls. However, a recent forensic autopsy of 42 Thai SUDS victims has given important new insight. This re- vealed possible causes of death (e.g. coronary artery disease) in 17 cases. Whole-​exome sequencing was undertaken in the remaining 25 and enabled potential identification of the cause of death in 18 (72%). The commonest (8/​18) was a mutation in the TTN gene, which encodes for titin, a protein expressed in cardiac and skeletal muscle and implicated in some forms of cardiomyopathy. One case had a mutation in the cardiac sodium channel gene SCN5A that causes Brugada syndrome. Whether or not hypokalaemia plays any significant role in SUDS remains uncertain. Dengue virus Case reports describe patients presenting after a short-​lasting febrile illness with acute onset, rapidly worsening pure motor paralysis as- sociated with hypokalaemia. In one series of 12 patients, baseline serum potassium was 2.7 mmol/​litre and weakness improved in all over 24 to 72 h with correction of serum potassium. Hyperkalaemia Clinical features Hyperkalaemia is the most serious of all electrolyte disorders, des- pite being relatively infrequent, because it can cause cardiac ar- rest. Some patients report muscular symptoms such as weakness, stiffness, or simply a ‘funny feeling’, but the significance of these is rarely appreciated. A high serum potassium concentration leads to membrane depolarization in excitable tissues, making the initi- ation of an action potential more likely, and to increased membrane potassium conductance, which impairs recovery after an action potential. The effect is to cause electrical instability with the risk of life-​threatening arrhythmia. The likelihood of such an event increases as the serum potassium concentration rises, but some patients are more resistant to the cardiac effects of hyperkalaemia than others: for instance, those with endstage renal failure on long-​ term dialysis may be habitually hyperkalaemic (although this is not to be encouraged) and tolerate a serum potassium concentra- tion that would kill a normal person if imposed acutely. Management In emergencies The best guide to the significance of hyperkalaemia in any particular individual is the impact that it is having on the ECG, and an ECG should be obtained immediately in any patient in whom the question of hyperkalaemia arises. The earliest change is tenting of the T wave, progressing as the serum potassium concentration rises to P-​wave flattening, prolongation of the PR interval, widening of the QRS com- plex, and eventually a ‘sine wave’ pattern as a prelude to ventricular fib- rillation and death. All involved in the care of acutely ill patients must be able to recognize this pattern of ECG changes and give effective emer- gency treatment for severe hyperkalaemia, as described in Chapter 21.5. In cases that are not emergencies The management of patients with hyperkalaemia but without sig- nificant ECG changes is also discussed in Chapter 21.5. Key elem- ents are advice to avoid high potassium foods and drinks (Table 21.2.2.3) and stop drugs that increase serum potassium. Use of cal- cium resonium, patiromer or other similar agents that exchange cal- cium for potassium in the gastrointestinal tract is rarely the most appropriate method of clinical management. Causes of hyperkalaemia There are many causes of a high serum potassium concentra- tion (Box 21.2.2.4), but a survey of over 400 cases found that renal failure was present in 43% and potassium supplements or potassium-​sparing diuretics had been taken by 37%. Life-​ threatening hyperkalaemia is almost exclusively seen in those with renal failure, often in conjunction with another exacerbating cause. Common scenarios would be a patient with acute kidney injury who is hypercatabolic or who has extensive tissue destruction, as in rhabdomyolysis, or a patient with endstage renal failure who has missed a dialysis treatment, not adhered to a low-​potassium diet (Table 21.2.2.3), or suffered an upper gastrointestinal haem- orrhage, thereby inadvertently consuming a high-​potassium meal. Hyperkalaemia is not a prominent feature of many of the con- ditions listed in Box 21.2.2.4: further discussion in this chapter is limited to disorders other than renal failure that are not discussed elsewhere in this textbook and in which hyperkalaemia is a common or important manifestation. Pseudohyperkalaemia Haemolysed samples show hyperkalaemia, which also occurs when there is considerable delay between venepuncture and separation of red cells and plasma or serum in the laboratory, allowing potas- sium to leak out of red cells after venesection. However, aside from these common and banal explanations, there are other reasons for pseudohyperkalaemia. Potassium is released from white blood cells and platelets as blood coagulates, causing the serum potassium concentration to exceed, by a few tenths of a millimole per litre, that of plasma estimated in a parallel sample. This process is greatly exaggerated when gross

section 21  Disorders of the kidney and urinary tract 4758 leucocytosis or thrombocytosis is present, such that the serum po- tassium concentration can be over 2 mmol/​litre higher than that in plasma. The plasma and not the serum potassium concentration should obviously be measured in this circumstance. There is also the rare syndrome of familial pseudohyperkalaemia, where mutation of the ABCB6 gene, which encodes a red blood cell membrane ABC transporter protein, leads to a cold-​induced leak of red cell potassium ions into plasma. This can be of clinical import- ance if a person with the condition donates blood, when after storage for 5 or 6 days the plasma potassium concentration is much higher than expected. Surveys of European blood donors suggest that the prevalence of familial pseudohyperkalaemia is about 1:500, leading to the suggestion that donors should be screened for the condition. Abnormal external potassium balance Mineralocorticoid deficiency Hyporeninaemic hypoaldosteronism It is not uncommon to find patients with chronic kidney disease who have hyperkalaemia despite a glomerular filtration rate (GFR) that should be sufficient to maintain normokalaemia. Two-​thirds of these will have the syndrome of hyporeninaemic hypoaldosteronism, which should be suspected in any patient with hyperkalaemia without other obvious explanation. The condition typically occurs at age 50 to 70 years, in women more than men, with diabetes mellitus and/​or chronic tubulointerstitial nephritis being the commonest forms of renal disease. The hyperkalaemia is usually asymptomatic, but presentation with cardiac arrhythmia and/​or muscle weakness has been described. Characteristics of the syndrome include low levels of plasma renin activity, which are unresponsive to sodium restriction or fur- osemide, low plasma and urinary aldosterone, hyperkalaemia, and hyperchloraemic metabolic acidosis. Fractional potassium excretion is low for the GFR, and the response to kaliuretic stimuli is blunted. Glucocorticoid metabolism is normal. The cause of both hyporeninism and hypoaldosteronism is not known, but reduced renin secretion in patients with diabetes mellitus may arise from injury to the juxtaglomerular apparatus, de- ficient conversion of prorenin to renin, autonomic dysfunction, or volume expansion due to a primary increase in renal salt retention. Hypoaldosteronism is probably related to the low level of plasma renin activity, but the situation is probably more complicated than this since most patients secrete subnormal amounts of aldosterone in response to infusion of both angiotensin II and ACTH, suggesting a defect in the function of the adrenal gland. Criteria for establishing the diagnosis of hyporeninaemic hypoaldosteronism are not well defined, but supportive evidence would be finding levels of renin and aldosterone below their reference Box 21.2.2.4  Causes of hyperkalaemia Pseudohyperkalaemia (test-​tube phenomena where measured serum potassium concentration does not reflect that in the patient’s plasma in vivo) • Tight tourniquet with or without limb exercise • Test-​tube haemolysis • Leukaemia with very high white cell count • Thrombocytosis Altered internal balance (redistribution of potassium from extracellular to intracellular compartment) • Exercise • Metabolic acidosis (inorganic) • Massive tissue destruction:a

—​ Crush injuries

—​ Rhabdomyolysis

—​ Burns

—​ Tumour lysis • Insulin deficiency, hyperglycaemia, hyperosmolality • Drugs/​toxins:

—​ Digoxin poisoning

—​ Succinylcholine

—​ Arginine

—​ Fluoride intoxication

—​ β-​blockade • Malignant hyperthermia • Hyperkalaemic periodic paralysis Altered external balance (high total body potassium) Excessive ingestionb • Consumption of high-​potassium foods (Table 21.2.2.3) • Potassium supplements • Low-​salt diet (high in potassium) • ‘Salt substitutes’ (contain potassium) • Upper gastrointestinal haemorrhage (‘blood meal’) Impaired excretion General impairment of renal function • Acute kidney injury • Chronic kidney disease Defects that specifically impair renal potassium excretion • Mineralocorticoid deficiency:

—​ Renin deficiency—​hyporeninaemic hypoaldosteronism, which can be either idiopathic or drug induced (NSAIDs or calcineurin inhibi- tors such as tacrolimus and ciclosporin)

—​ ACE inhibition—​drug induced (lisinopril, ramipril, enalapril, etc.)

—​ Angiotensin II receptor blockade—​drug induced (losartan, candesartan, etc.)

—​ Defective aldosterone production—​generalized adrenal failure (Addison’s disease) • Deficiency of aldosterone synthesis:

—​ Drug induced (heparin)

—​ Enzyme deficiencies

—​ Idiopathic Impaired tubular ion transport • Drugs:

—​ Potassium-​sparing diureticsc

—​ Trimethoprim

—​ Calcineurin inhibitors (ciclosporin, tacrolimus) • Pseudohypoaldosteronism:

—​ Type 1

—​ Type 2 (Gordon’s syndrome) a Often associated with acute kidney injury. b Note that it is very rare for hyperkalaemia to be caused by excessive ingestion if renal excretory mechanisms for potassium are working normally. c These drugs should generally be avoided in patients with significant renal impairment.

21.2.2  Disorders of potassium homeostasis 4759 Table 21.2.2.3  Potassium content of various foodstuffs High-​potassium foods (to be avoided in those with hyperkalaemia) Suitable low-​potassium alternatives Dairy products Single cream Reasonable daily allowance of milk Condensed/​evaporated milk Various commercial coffee whiteners Food drinks Meats Ready cooked meals in sauce All kinds of meat Fish Ready cooked fish pies, fish in sauce, etc. All kinds of fish Fruit All dried fruit Apples Apricots Grapefruit Avocado pears Kiwi fruit Bananas Passion fruit Cherries Pears Grapes Satsumas Melons Tangerines Oranges Peaches Pineapples Plums Raspberries Rhubarb Strawberries Tinned fruit of all types—​but after draining off the juice or syrup, which contains a lot of potassium Vegetables Artichokes Aubergines Bamboo shoots Beans—​French, runner Beans—​baked, butter, haricot Cabbage Beetroot Carrots Cabbage—​red Cauliflower Corn on the cob Celery Mushrooms Courgettes Peas—​chick, split Cucumber Potatoes—​ jacket, chips, crisps, sweet Lettuce Spinach Marrow Tomato Onions Watercress Peas Potato—​boiled in plenty of water Radish Spring greens Sprouts Swedes Turnips Cakes Any containing dried fruit or nuts Dough Chocolate Fruit pies—​if fruit not high potassium Coffee Jam tarts Flapjacks Meringue Gingerbread Scones—​plain (continued)

section 21  Disorders of the kidney and urinary tract 4760 ranges after a manoeuvre to stimulate the renin–​angiotensin–​ aldosterone system (by upright posture or furosemide). However, it is uncommon for patients to be investigated intensively in routine clinical practice since treatment is usually straightforward. Therapy for hyporeninaemic hypoaldosteronism includes dietary potassium restriction and avoidance of drugs that can cause hyper­ kalaemia. Measures to increase urinary excretion of potassium, such as the use of thiazide or loop diuretics, can be useful. Although min- eralocorticoid replacement (fludrocortisone, 0.2 mg/​day) effectively treats the hyperkalaemia, sodium retention and worsening hyper- tension are often unacceptable side effects. Cation exchange resins can be used to increase elimination of potassium from the gut, but compliance with long-​term use of these medications can be difficult to achieve, although newer preparations (e.g. patiromer) may be better tolerated. Effects of drugs on the renin–​angiotensin–​aldosterone system NSAIDs  Prostaglandin synthetase inhibitors produce hypo­ reninaemic hypoaldosteronism by interfering with prostacyclin-​ mediated renin secretion, with reduction in GFR and distal sodium delivery as potential contributory factors. These effects, as might be expected, become more important in the context of renal im- pairment: in one study, approximately one-​quarter of patients with chronic renal failure developed hyperkalaemia after treatment with indometacin. ACE inhibitors and angiotensin II receptor blockers  These pro- duce hyperkalaemia by impairing angiotensin II-​mediated secretion of aldosterone. In one study, hyperkalaemia was found in 46 of 119 (39%) patients taking ACE inhibitors who were attending a renal clinic. The higher the serum creatinine concentration, the greater the chance of hyperkalaemia. Those with diabetes were also at par- ticular risk. The treatment had to be stopped in 15 patients (13%). ACE inhibitors and spironolactone have been found to improve prognosis in heart failure, but care is needed when prescribing for those who might be prone to hyperkalaemia. One study reported life-​threatening hyperkalaemia (mean serum potassium 7.7 mmol/​ litre) in 25 patients who had received this combination of medica- tions. Combined treatment with both an ACE inhibitor and an angio- tensin II receptor blocker is more likely to induce hyperkalaemia than either agent given alone, but this combination of drugs is no longer recommended for any indication. Heparin  Hyperkalaemia occurs in about 7% of patients given heparin, which is a potent inhibitor of aldosterone production. It can arise with doses as low as 10 000 units/​day, but—​as with most other hyperkalaemic stimuli—​clinically important elevations in the High-​potassium foods (to be avoided in those with hyperkalaemia) Suitable low-​potassium alternatives Mince pies Victoria sandwich—​plain Parkin Sweets and biscuits Any containing dried fruit or nuts Chocolate Barley sugar Biscuits—​plain Fruit gums Honey Fudge Humbugs Liquorice Jam Marzipan Marmalade Toffee Mints Beverages Cocoa Coca-​Cola Coffee—​instant Coffee—​percolated Drinking chocolate Fruit juices—​if pure and containing any high-​potassium fruit Fruit squashes—​unless with high juice content Lemonade and other fizzy drinks Tea—​instant Soda water Tea—​infusion Tonic water Cereals Muesli and other cereals containing dried fruit or nuts Bread Breakfast cereals—​most types Pasta Rice Other Salt substitutes This list is not exhaustive. If a patient with hyperkalaemia seems to be consuming an unusual diet, then obtain dietetic advice. Table 21.2.2.3  Continued

21.2.2  Disorders of potassium homeostasis 4761 serum potassium concentration are found only when more than one homeostatic mechanism for potassium is deranged. Patients with endstage renal failure who receive unfractionated heparin to pro- vide anticoagulation during haemodialysis treatments have a higher predialysis serum potassium than those given low molecular weight heparin. The most important mechanism of aldosterone inhibition appears to involve reduction in both numbers and affinity of angio- tensin II receptors in the zona glomerulosa, which is reduced in width by prolonged use of heparin. Direct inhibition of the enzyme 18-​hydroxylase has also been postulated. Production of other cor- ticosteroids is not affected. Calcineurin inhibitors  Hyperkalaemia is a well-​documented complication of the immunosuppressive drugs ciclosporin and tacrolimus. Two mechanisms are possible, both of which may be exacerbated by reduction in GFR caused by nephrotoxicity: (1) drug-​induced hyporeninaemic hypoaldosteronism, which is well documented with tacrolimus; and (2)  in association with a distal tubular acidification defect that is caused (mechanism un- known) by both ciclosporin and tacrolimus. Renal transport abnormalities Tubulointerstitial renal disease A few hyperkalaemic patients with chronic renal failure but a GFR that should be adequate for potassium homeostasis have normal levels of aldosterone and plasma renin activity and seem to have a primary defect in the ability of the distal nephron to excrete po- tassium. They also typically have tubulointerstitial types of renal diseases, the abnormality being documented in patients with obstructive uropathy, renal transplants, sickle cell disease, sys- temic lupus erythematosus, amyloidosis, and medullary sponge kidney—​all of which can also be associated with hyporeninaemic hypoaldosteronism. In contrast to patients with hyporeninaemic hypoaldosteronism, their hyperkalaemia is unresponsive to min- eralocorticoid replacement therapy. Type IV renal tubular acidosis Hyperkalaemia due to impaired renal excretion of potassium may be a feature of type IV or voltage-​dependent renal tubular acidosis. The lumen-​negative potential difference along the distal nephron normally facilitates the excretion of potassium and hydrogen ions, and hyperkalaemia and metabolic acidosis occur when this is re- duced. This condition is discussed in Chapter 21.15. Potassium-​sparing diuretics Spironolactone is increasingly used in the management of resistant hypertension. This, and other potassium-​sparing diuretics, are obvi- ously likely to cause hyperkalaemia in patients with any predispos- ition to this condition, and they should only be used with great care in those with renal failure. The serum potassium concentration must be monitored closely in patients taking these agents who become acutely unwell. Trimethoprim–​sulfamethoxazole and pentamidine A review of 80 patients treated with standard-​dose trimethoprim (up to 320 mg/​day) and sulfamethoxazole (up to 1600 mg/​day) showed that this increased the serum potassium concentration by an average of 1.2 mmol/​litre, whereas there was no change in a control group receiving other antibiotics. Some studies have shown a lesser effect than this, but even larger increases in serum potas- sium concentration have been reported in patients receiving high-​ dose trimethoprim–​sulfamethoxazole to treat pneumocystis, and hyperkalaemia is also reported with use of pentamidine. Both tri- methoprim and pentamidine block the apical sodium channel in the distal nephron in a manner similar to amiloride. Pseudohypoaldosteronism type 1 There are autosomal recessive and autosomal dominant forms of this rare condition (see Chapter 16.17.4 for further discussion of the gen- etic abnormalities). The recessive form typically presents in infancy with vomiting and feeding difficulty. There are signs of volume de- pletion and laboratory findings of hyponatraemia, hyperkalaemia, and acidaemia. The plasma renin concentration is usually increased and plasma aldosterone concentration is markedly elevated. The sodium concentration in urine, sweat, saliva, and stool is high. Treatment is with salt supplements that must usually be continued into adulthood. By contrast, the autosomal dominant form has a milder phenotype, with symptoms that remit with age. Pseudohypoaldosteronism type 2 (Gordon’s syndrome) This is a rare autosomal dominant condition (see Chapter 16.17.4 for further discussion of the genetic abnormalities) in which hyper- tension is accompanied by hyperkalaemia despite normal GFR. The condition is usually asymptomatic and detected fortuitously if serum potassium concentration is measured for any reason, or in the course of family studies, but it can rarely present in late child- hood or adulthood with hyperkalaemic periodic paralysis. There is a hyperchloraemic acidosis, a low level of plasma renin activity, and normal or slightly low plasma aldosterone concentration. Giving exogenous aldosterone does not increase urinary potassium excre- tion or reduce hyperkalaemia. Because a kaliuresis can be provoked by infusion of sodium sulphate or sodium bicarbonate, but not so- dium chloride, it has been suggested that enhanced reabsorption of chloride at a distal nephron site may underlie the abnormality in potassium secretion. Physiological abnormalities can be corrected with thiazide diuretics, which may provide effective treatment. Abnormal internal potassium balance Exercise Exercise-​related rises in the serum potassium concentration are a normal phenomenon and usually modest, but increases to 7 mmol/​ litre occur during acute, maximal, physical performance and levels as high as 10 mmol/​litre have been reported with prolonged exhaustive exercise such as in marathons. Exercise-​induced hyperkalaemia is accentuated by β-​adrenergic blockade or α-​adrenergic agonists, and in patients with chronic kidney disease. Acidosis Acidosis diminishes potassium uptake by cells (Box 21.2.2.1) and causes hyperkalaemia. The increase in the serum potassium con- centration is greater with metabolic than respiratory acidosis, and occurs more markedly with hyperchloraemic than with organic acid-​induced forms of metabolic acidosis. Stimulation of insulin re- lease by organic acids appears to account for this divergent response, explaining the pathophysiology of disturbed potassium homeostasis

section 21  Disorders of the kidney and urinary tract 4762 in diabetic ketoacidosis. At presentation, when insulin is deficient, potassium is redistributed in a fashion comparable with mineral acid-​induced metabolic acidosis and patients are hyperkalaemic. However, the preceding kaliuresis (caused by polyuria) has ren- dered the body enormously deficient in potassium, and the serum potassium concentration falls rapidly as soon as insulin is provided, allowing potassium to return to the cells. Indeed, dangerous hypo- kalaemia can develop if adequate potassium is not given during treatment. Drugs Several drugs can produce hyperkalaemia by altering the transcellular distribution of potassium. Digoxin and similar preparations diminish cellular potassium uptake by inhibiting the Na+,K+-​ATPase pump, and substantial hyperkalaemia can accompany digoxin intoxication. Succinylcholine and other depolarizing muscle relaxants increase the potassium permeability of muscle: the serum potassium concentra- tion typically increases by 0.5 to 1.0 mmol/​litre, but hyperkalaemia can be more severe in patients with burns or neuromuscular diseases. Infusion of 30 g of the cationic amino acid arginine HCl increases serum potassium concentration by 0.5 to 1.0 mmol/​litre and can pro- duce life-​threatening hyperkalaemia in individuals with deranged potassium metabolism. Fluoride intoxication appears to increase the serum potassium concentration by provoking leakage from the intra- cellular compartment, and associated hypocalcaemia enhances the cardiac risks of fluoride-​induced hyperkalaemia. Although β2-​adrenergic stimulants cause hypokalaemia and can be used to treat hyperkalaemia (see Chapter  21.5), the adminis- tration of β-​blockers typically increases the serum potassium con- centration only modestly (by 0.1 to 0.2 mmol/​litre). However, the hyperkalaemic effect can be much more prominent when other potassium homeostatic mechanisms are deranged, for example, in patients receiving intermittent haemodialysis, the predialysis serum potassium concentration is increased on average by 1.0 mmol/​litre. Hyperkalaemic periodic paralysis Hyperkalaemic periodic paralysis is a rare (prevalence of five per million population) autosomal dominant condition caused by mu- tations in the sodium channel gene SCN4A, mutations in which can also cause hypokalaemic periodic paralysis. Clinical presentation is with episodic attacks of focal weakness (rather than paralysis), often of the thigh/​calf muscles or arms/​hands, that typically last 1 to 2 h. The bulbar and respiratory muscles are sometimes involved. Attacks usually begin in the first decade of life, with frequency that plateaus in early adulthood and later declines. They may come out of the blue, but the most commonly reported triggers are cold envir- onments, rest after exercise, stress or fatigue, alcohol, and hunger. The serum potassium concentration is usually, but not always, raised during an acute attack, and it may be low in rare instances. Many pa- tients report myotonia and paramyotonia, and one-​third develop a progressive myopathy. Thyroid dysfunction affects about 20%. Attack frequency may be reduced by consuming regular small/​ medium-​sized meals and taking carbohydrate rich snacks in be- tween, and by avoidance of alcohol, cold foods and drinks, and high potassium foods. Hydrochlorothiazide (reduces the serum potas- sium level), mexiletine (for myotonia) and flecainide were the drugs most commonly taken by patients who regarded their condition as ‘mostly controlled’ in one careful study. Patients very variably report that an acute attack can be amelior- ated by manoeuvres such as doing gentle exercise, keeping warm, eating sweet foods, and drinking water. Treatment with an inhaled β2-​agonist is helpful, and intravenous glucose and insulin is war- ranted in severe cases. FURTHER READING Blanchard A, et al. (2017). Gitelman syndrome: consensus and guid- ance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 91, 24–​33. Charles G, et al. (2013). Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals. J Neurol, 260, 2606–​13. Ernst ME, Moser M (2009). Use of diuretics in patients with hyperten- sion. N Engl J Med, 361, 2153–​64. Fergeson SB, Linas S (2010). Mechanisms of type I  and type II pseudohypoaldosteronism. J Am Soc Nephrol, 21, 1842–​5. Gennari FJ (1998). Hypokalemia. New Engl J Med, 339, 451–​8. Gladziwa U, et al. (1995). Chronic hypokalaemia of adults: Gitelman’s syndrome is frequent but classical Bartter’s syndrome is rare. Nephrol Dial Transplant, 10, 1607–​13. Grier JF (1995). WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. Southern Med J, 88, 22–​4. Halevy J, et al. (1988). Life-​threatening hypokalemia in hospitalized patients. Miner Electrolyte Metab, 14, 163–​6. Hamill RJ, et  al. (1991). Efficacy and safety of potassium infu- sion therapy in hypokalemic critically ill patients. Crit Care Med, 19, 694–​9. Hooen EJ, et al. (2010). A case series of proton pump inhibitor-​induced hypomagnesemia. Am J Kidney Dis, 56, 112–​16. Hsieh MJ, et  al. (2008). Hypokalemic thyrotoxic periodic par- alysis: clinical characteristics and predictors of recurrent paralytic attacks. Eur J Neurol, 15, 559–​64. Kruse JA, et al. (1994). Concentrated potassium chloride infusions in critically ill patients with hypokalemia. J Clin Pharmacol, 34, 1077–​82. Kung AW (2006). Clinical review:  thyrotoxic periodic paralysis:  a diagnostic challenge. J Clin Endocrinol Metab, 91, 2490–​5. Lin SH, Lin YF (2001). Propranolol rapidly reverses paralysis, hypo- kalemia, and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis, 37, 620–​3. Lin SH, et al. (2001). Hypokalaemia and paralysis. QJM, 94, 133–​9. Lin SH, et al. (2004). Laboratory tests to determine the cause of hypo- kalemia and paralysis. Arch Int Med, 164, 1561–​6. Mohapatra BN, et  al. (2016). Clinical and aetiological spectrum of hypokalemic flaccid paralysis in western Odisha. J Assoc Physicians India, 64, 52–​8. Morgan DB, Davidson C (1980). Hypokalaemia and diuretics: an ana- lysis of publications. Br Med J, 280, 905–​8. Older J, et al. (1999). Secretory villous adenomas that cause depletion syndrome. Arch Intern Med, 159, 879–​80. Oster JR, et al. (1995). Heparin-​induced aldosterone suppression and hyperkalemia. Am J Med, 98, 575–​86. Palmer BF, Clegg DJ (2019). Physiology and pathophysiology of po- tassium homeostasis: core curriculum 2019. Am J Kidney Dis, pii: S0272-6386(19)30715-2. doi: 10.1053/j.ajkd.2019.03.427. Preston RA, et al. (1998). University of Miami Division of Clinical Pharmacology therapeutic rounds:  drug-​induced hyperkalemia. Am J Ther, 5, 125–​32.

21.2.2  Disorders of potassium homeostasis 4763 Ryan DP, et al. (2010). Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell, 140, 88–​98. Sansone V, et al. (2008). Treatment for periodic paralyses. Cochrane Database Syst Rev, 23, CD005045. Saperstein DS (2008). Muscle channelopathies. Semin Neurol, 28, 260–​9. Schepkens H, et  al. (2001). Life-​threatening hyperkalemia during combined therapy with angiotensin-​converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med, 110, 438–​41. Simon DB, Lifton RP (1998). Ion transporter mutations in Gitelman’s and Bartter’s syndromes. Curr Opin Nephrol Hypertens, 7, 43–​7. Souza AGP, et al. (2016). Hyporeninemic hypoaldosteronism and dia- betes mellitus: pathophysiology assumptions, clinical aspects and implications for management. World J Diabetes, 7, 101–​11. Widmer P, et  al. (1995). Diuretic-​related hypokalaemia:  the role of diuretics, potassium supplements, glucocorticoids and
β2-​adrenoceptor agonists. Results from the comprehensive hos- pital drug monitoring programme, Berne (CHDM). Eur J Clin Pharmacol, 49, 31–​6. Wu KL, et al. (2017). Identification of the causes for chronic hypo- kalemia:  importance of urinary sodium and chloride excretion.
Am J Med, 130, 846–​55.

21.3 Clinical presentation of renal disease 4764 R

21.3 Clinical presentation of renal disease 4764 Richard E. Fielding and Ken Farrington

ESSENTIALS Renal disease may present in many ways, including (1) the screening of asymptomatic individuals; (2)  with symptoms and signs re- sulting from renal dysfunction; and (3) with symptoms and signs of an underlying disease, often systemic, which has resulted in renal dysfunction. History and clinical signs—​in many cases these are nonspecific or not apparent, and detection of renal disease relies on a combination of clinical suspicion and simple investigations, including urinalysis (by dipstick for proteinuria and haematuria, with quantification of proteinuria most conveniently performed by estimation of the albumin:creatinine ratio, ACR, or protein:creatinine ratio, PCR) and estimation of renal function (by measurement of serum creatinine, expressed as estimated glomerular filtration rate, eGFR). Asymptomatic renal disease—​this is common and most often de- tected as chronic depression of eGFR (known as chronic kidney dis- ease, CKD), proteinuria, or haematuria, either as isolated features or in combination. Symptomatic renal disease—​may present in many ways, including (1)  with features of severe chronic depression of GFR—​‘uraemia’, manifesting with some or all of anorexia, nausea, vomiting, fatigue, weakness, pruritus, breathlessness, bleeding tendency, apathy and loss of mental concentration, and muscle twitching and cramps; (2) acute kidney injury (AKI); (3) with urinary symptoms—​frequency, polyuria, nocturia, oliguria, anuria, and visible (macroscopic) haema- turia; and (4) loin pain. Specific renal syndromes—​these include (1) nephrotic syndrome—​ comprising oedema, proteinuria, and hypoalbuminaemia—​caused by primary or secondary glomerular disease; and (2) rapidly progres- sive glomerulonephritis with AKI. Other conditions—​renal disease may be associated with and present in the context of many underlying conditions, including (1)  diabetes mellitus; (2)  renovascular disease; (3)  myeloma and other malignancies; (4) infectious diseases, either as a nonspecific manifestation of the sepsis syndrome or as a specific complica- tion of the particular infection (e.g. haemolytic uraemic syndrome, poststreptococcal glomerulonephritis, hantavirus infection, lepto- spirosis, and HIV nephropathy); (5) systemic inflammatory diseases (e.g. systemic vasculitides, rheumatological disorders, sarcoidosis, and amyloidosis); (6) drug-​induced renal disease; and (7) pregnancy. Introduction Renal disease may present in a multitude of ways. In practice, it is usually detected as a result of: • screening of asymptomatic individuals • symptoms and signs resulting from renal dysfunction • symptoms and signs of an underlying disease, often systemic, which has resulted in renal dysfunction Symptoms and signs of renal pathology are often absent or subtle, even in the presence of significant disease, hence the detection of renal problems requires careful evaluation of the history and clin- ical findings to assess the potential risk of underlying renal disease. This evaluation should focus on features of systemic and inflamma- tory disease as well as those relating directly to the renal tract, and similarly a drug and obstetric history may help elucidate the cause of renal disease. However, in many cases the history and clinical signs are nonspecific or not apparent, with detection of renal disease relying on a combination of clinical suspicion and simple investiga- tions, including urinalysis and estimation of renal function. Presentation of asymptomatic renal disease Asymptomatic renal disease is common and may often remain stable and undetected. However, some patients with asymptomatic disease are at increased risk of developing renal failure with the passage of time or in the event of intercurrent illnesses. Active screening for subclinical disease is thus carried out in certain subpopulations with the result that patients may be identified with abnormal renal func- tion or with abnormalities on urinalysis that may indicate significant renal pathology. Examples of such screening include: • screening patients in primary care—​general population screening via eGFR reporting (see ‘Asymptomatic renal dysfunction and 21.3 Clinical presentation of renal disease Richard E. Fielding and Ken Farrington

21.3  Clinical presentation of renal disease 4765 screening for chronic kidney disease’); monitoring of patients at ‘high risk’ of developing renal disease (e.g. hypertension, diabetes, or multisystem disease); and occupational and insurance medicals • screening patients admitted to hospital with acute illnesses—​as an incidental finding, and as part of renal and electrolyte surveillance in patients at risk (e.g. in the presence of sepsis, hypovolaemia, and usage of nephrotoxic drugs) • incidental finding on abdominal imaging—​stones, cysts and tu- mours, or reduced renal size • screening of the family members of patients with inherited renal disease Asymptomatic renal dysfunction and screening for chronic kidney disease Traditionally, the main means of assessing renal function has been estimation of serum creatinine, and this can be used—​with or without estimation of urinary creatinine excretion—​to estimate the GFR, as described in Chapter 21.4. The Cockcroft–​Gault equa- tion, which estimates creatinine clearance from serum creatinine, weight, age, and sex, has largely given way as a screening tool to the Modification of Diet in Renal Disease (MDRD) formula, which in its simplest form generates an eGFR normalized to body surface area from serum creatinine, age, sex, and race. Using this method, popu- lation studies have estimated the global prevalence CKD as around 15%, with that of moderate to severe kidney failure (eGFR <60 ml/​ min per 1.73 m2 body surface area—​stage 3 to 5 CKD) as around 8% (Fig. 21.3.1). Over 90% of these subjects have CKD stage 3 (eGFR 30–​59 ml/​min/​1.73m2), most of whom are elderly, and it is notable that very few progress to require treatment for endstage kidney dis- ease (ESKD). Over a five-​year period, only around 1 to 3% of people with CKD stage 3 progress, compared with about 20% of those with CKD stage 4, but it is increasingly recognized that CKD is an im- portant risk factor for cardiovascular mortality. People with CKD are around 10 times more likely to die than to progress to ESKD, with cardiovascular disease being the commonest cause of death. Population and ‘risk group’ screening for renal dysfunction Population data suggest that most renal disease identified by screening is not progressive, but there are subpopulations in which progressive renal disease is more likely and in whom early inter- vention and optimal management may delay or prevent the need for dialysis. Hence in the United States of America and the United Kingdom, guidelines have been drafted in which ‘risk groups’ are screened for renal dysfunction/​CKD (Box 21.3.1). It is not yet known whether screening for renal dysfunction has any effect on outcome, but in the United Kingdom, data on the prevalence of CKD and associated information such as blood pressure measurement, its control, and the use of angiotensin-​converting enzyme (ACE) in- hibitors in the CKD population, were incorporated into the Primary Care Quality and Outcomes Framework, which linked funding to the achievement of targets. As a consequence, there has been a sub- stantial rise in the number of patients identified with asymptom- atic renal dysfunction, and an increased rate of referral to secondary care, especially of elderly patients. There is still considerable doubt about the validity and value of labelling many very elderly people as having moderate to severe renal failure, especially since in many pa- tients an eGFR in this range seems to confer a very much higher risk of cardiovascular demise than of ESKD. Stage 3 (7.6%) Stage 2 (3.9%) Stage 1 (3.5%) Stage 4 (0.4%) Stage 5 (0.1%) Fig. 21.3.1  Global prevalence of chronic kidney disease (CKD stages 1–​5) in the general population. Overall global prevalence of CKD (stages 1–​5) has been reported as over 15%. Box 21.3.1  Summary of United Kingdom guidelines for serum creatinine measurement and estimation of GFR Serum creatinine concentration should be measured at initial assess- ment and then at least annually in all adult patients with the following conditions: • Previously diagnosed CKD:

—​ Persistent proteinuria

—​ Unexplained haematuria

—​ Identified renal pathology • Conditions associated with a high risk of developing obstructive kidney disease:

—​ Bladder voiding dysfunction (outflow obstruction, neurogenic bladder)

—​ Urinary diversion surgery

—​ Urinary stones • Conditions associated with a high risk of silent development of paren- chymal kidney disease:

—​ Diabetes

—​ Hypertension

—​ Cardiovascular disease—​ischaemic heart disease, chronic heart failure, peripheral vascular disease, and cerebrovascular disease • Conditions requiring long-​term treatment with potentially nephro- toxic drugs:

—​ ACE inhibitors, angiotensin receptor blockers, NSAIDs, lithium, mesalazine, ciclosporin, and tacrolimus • Multisystem diseases that may involve the kidney:

—​ Systemic lupus erythematosus

—​ Systemic vasculitides

—​ Myeloma

—​ Rheumatoid arthritis

—​ Individuals with a family history of stage 5 CKD or hereditary renal disease

section 21  Disorders of the kidney and urinary tract 4766 Employment or insurance health screening As well as targeted screening of ‘at-​risk’ populations, asymptom- atic renal disease may also be identified as a result of employment or insurance health screening. Common abnormalities identified are hypertension or abnormal urinalysis, such as proteinuria and nonvisible (microscopic) haematuria. Patients identified in this way will often be referred for subsequent investigation. Screening for renal dysfunction in secondary care In the secondary care setting, patients in specialist clinics who are at risk of renal disease, such as patients with diabetes, are periodic- ally screened for the development of hypertension, proteinuria, and renal dysfunction. Renal disease also often presents in acute med- ical and surgical patients, with up to 15% of patients admitted as emergencies to hospital suffering some acute deterioration of kidney function, mostly due to hypotension, sepsis, or the use of nephro- toxic drugs (see Chapter 21.5). Monitoring renal function in such patients may help in the acute management of their illness and may also identify those with underlying chronic renal impairment who require long-​term management. Screening for drug-​induced renal disease Renal disease resulting from the use of nephrotoxic drugs is often asymptomatic, and CKD may develop as a result of long-​term use of agents such as nonsteroidal anti-​inflammatory drugs (NSAIDs), lithium, and calcineurin inhibitors. Often the only evidence for this is a progressive rise in serum creatinine and fall in eGFR, which may be progressive and—​if not detected by routine screening—​may pre- sent with advanced renal failure. Other drugs such as ACE inhibitors may cause an acute deterioration in renal function, screening for which is required, especially in high-​risk groups. Other incidental findings of renal disease Subclinical renal disease may also present as an incidental finding on biochemical testing, for example, abnormalities of potassium and acid–​base homeostasis identified on a ‘routine’ sample may in- dicate a renal tubular acidosis and prompt further investigation for an underlying cause. Renal disease identified incidentally with imaging Advances in imaging technology combined with their widespread use have increased the number of incidental renal abnormalities identified. Many of these are anatomical abnormalities which are of little consequence, such as duplex ureters and isolated renal cysts, but significant pathology is sometimes found incidentally, such as polycystic kidneys, renal tumours, and asymmetrical kidneys. Family screening for renal disease Patients with a family history of inherited renal disease may also be identified with early, asymptomatic renal disease as a result of screening. The most common example is autosomal dominant poly- cystic kidney disease, which may be reliably identified by ultrason- ography from the third decade onwards. The identification of disease genes for inherited renal diseases such as autosomal dominant poly- cystic kidney disease, tuberous sclerosis, von Hippel–​Lindau dis- ease, Alport’s syndrome, and congenital nephrotic syndrome raises the possibility of future antenatal screening and early detection of these diseases long before they become clinically manifest. Proteinuria Detection of proteinuria The availability of reliable and cheap urine dipstick reagent strips has led to their widespread use to screen for and monitor renal disease in primary and secondary health care (Fig. 21.3.2). Most multireagent strips are sensitive to 100 to 200 mg/​litre of pro- tein, giving either a ‘trace’ or ‘+’, although some designed to screen for microalbuminuria are more sensitive. Within the general popu- lation, up to 5% of apparently healthy adults and 16% of those aged over 80 years have either a ‘trace’ or ‘+’ of protein, but most of these do not have significant treatable disease, making routine population screening uneconomic and unnecessary. Reagent strips do not de- tect low molecular weight proteins such as immunoglobulin light chains, and thus assay of light chains using urine immunoelectro- phoresis is essential as part of the investigations for myeloma, pri- mary amyloidosis, and light-​chain glomerulopathy. The kidney normally excretes less than 150 mg of protein in 24 h, mainly due to failed tubular reabsorption of albumin. Urinary pro- tein excretion also reduces overnight while recumbent, but increases during the day owing to posture and exercise. Urinary protein con- centration also depends on urine flow rate. To overcome the di- urnal variation, proteinuria has been traditionally evaluated from a 24-​h urine collection, but these have been largely superseded by measuring the ratio of albumin or protein to creatinine in the urine (albumin:creatinine ratio, ACR; protein:creatinine ratio, PCR). This method has been validated against 24-​h urinary collections and—​as a rule of thumb—​a urinary ACR of 70 mg/​mmol or PCR of 100 mg/​ mmol equates approximately to a 24-​h protein excretion of 1 g/​24 h. Screening for proteinuria Guidelines aimed at identifying subclinical renal disease recom- mend screening for proteinuria only for patients with renal disease or at increased risk of renal disease. The guidelines recommend use of the urinary ACR rather than standard reagent sticks in this popu- lation. Current United Kingdom guideline recommendations (2014) for screening in this population are summarized in Box 21.3.2. Approach to patient with proteinuria Proteinuria may be an early presentation of renal disease, but tran- sient proteinuria is not associated with significant renal disease. A finding of proteinuria should lead the physician to take a his- tory focusing on risk factors for renal disease (e.g. diabetes, drugs, Fig. 21.3.2  Multireagent test strips used to screen patients for proteinuria and nonvisible haematuria.

21.3  Clinical presentation of renal disease 4767 multisystem disease, and family history), to measure the blood pres- sure, and examine for oedema (Box 21.3.3). In the absence of risk factors or signs of renal disease, transient proteinuria is not likely to indicate underlying renal disorder, hence an initial finding of proteinuria on dipstick testing should be re- peated a week or so later, and any positive result confirmed and quantitated by estimation of ACR (or PCR). If postural or ortho- static proteinuria is suspected, an early-​morning urine specimen should be sent for ACR (or PCR). The diagnosis is substantiated by the finding of normal urinary protein excretion in this specimen. Management of asymptomatic proteinuria Persistent proteinuria (ACR >70 mg/​mmol, PCR >100 mg/​mmol) on two or more occasions requires further investigation with: • renal function (eGFR) • serum albumin, for diagnosis of nephrotic syndrome • serum paraprotein electrophoresis and urinary Bence Jones pro- tein for myeloma • immunological screen (antinuclear antibodies, complement, antineutrophil cytoplasmic antibodies (ANCAs)) • renal ultrasonography • consideration of renal biopsy The presence of nonvisible haematuria in addition to proteinuria im- plies a high likelihood of intrinsic renal disease. It may be the first sign of a severe glomerulonephritis, perhaps in relation to multisystem disease. Apparently asymptomatic patients with persistent protein- uria and haematuria may describe subtle symptoms on close ques- tioning (e.g. myalgia, arthralgia, ‘sinusitis’, rash, or fever) which may be clues to an underlying multisystem disorder. Nephrology referral for further investigation, including serum ANCAs, antiglomerular basement membrane (anti-​GBM) antibodies, antinuclear and anti-​ double-​stranded DNA antibodies, complement levels, and renal bi- opsy, is indicated. Those with abnormal renal function, haematuria, and proteinuria require urgent referral. Asymptomatic nonvisible haematuria Nonvisible haematuria may potentially arise from anywhere in the urinary tract. As with renal dysfunction and proteinuria, isolated nonvisible haematuria, that is in the absence of other features of renal disease—​hypertension, renal impairment, proteinuria, sys- temic disease, or a family history of renal disease—​is common. Population studies indicate a prevalence between 0.2 and 16%, with a higher prevalence of up to 18% in men aged over 50 years. Studies of male army recruits screened and followed up for 12 years showed that 39% had nonvisible haematuria on one occasion, and 16% had nonvisible haematuria on two or more occasions. Although isolated nonvisible haematuria may be associated with benign glomerular disease, in practice, the main concern is the possibility of urinary tract malignancy. Urothelial and bladder carcinomas account for approximately 5% of nonvisible haematuria. This risk increases with age, particularly in men over the age of 65 years. In contrast, underlying malignancy in those younger than 40 years is very rare, particularly in the absence of risk factors such as smoking and exposure to azo dyes. Causes of nonvisible haematuria The causes of nonvisible haematuria are summarized in Box 21.3.4. The true prevalence of intrinsic renal disease is unknown because renal biopsies are not routinely performed in the absence of protein- uria or abnormal renal function. However, small biopsy studies of patients with no other cause for haematuria identified a glomerular cause in 16 to 30%. Within this group, IgA nephropathy and thin basement membrane disease are most common. Management strategy for nonvisible haematuria The key to managing patients with asymptomatic nonvisible haema- turia is identifying risk factors for malignancy. In routine practice, patients older than 50 years, smokers, or those with an occupational history of dye exposure should be investigated for malignancy and referred to a urologist for cystoscopy. Numerous different approaches to the management of patients with nonvisible haematuria have been published, reflecting a lack of consensus and an insufficient evidence base. There are no in- dications for screening for nonvisible haematuria as the positive Box 21.3.2  United Kingdom guidelines for screening for albuminuria in patients at risk of CKD ACR estimation should be carried out in people with: • diabetes • hypertension • cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease, or cerebral vascular disease) • structural renal tract disease identified on imaging • recurrent renal calculi or prostatic hypertrophy • multisystem diseases with potential kidney involvement—​for example, systemic lupus erythematosus, vasculitis, and myeloma • family history of ESKD (glomerular filtration rate <15 mL/​min per 1.73 m2) or hereditary kidney disease • opportunistically detected haematuria • following an episode of AKI if the GFR remains below 90 mL/​min per 1.73m2 Box 21.3.3  Approach to the patient with dipstick-​positive proteinuria Key features to establish • Is there any evidence of urinary tract infection? • Is there any evidence of diabetes? • Are there any risk factors for, or signs of, renal disease? • Is proteinuria transient or persistent? Transient proteinuria Causes include: • urinary tract infection • fever • exercise • orthostatic proteinuria Persistent proteinuria • Send urine for spot ACR (or PCR) • Evaluate risk factors for renal disease:

—​ Diabetes, hypertension, systemic inflammatory disease, myeloma, and family history of renal disease

—​ Are there any features of nephrotic syndrome (heavy proteinuria with oedema and low serum albumin)?

section 21  Disorders of the kidney and urinary tract 4768 predictive value for malignancy is as low as 5% in an elderly popu- lation, and there is little evidence that early detection of disease im- proves prognosis. Following the detection, on urine dipstick, of nonvisible haema- turia without proteinuria, a history of recent menstruation, exercise, or sexual activity should be elicited and the urine sent for micros- copy and culture. Urinalysis should be repeated after 7 days. If still positive for blood, in the absence of urinary tract infection, further evaluation is required including measurement of blood pressure, urinary ACR or PCR, and serum creatinine/​eGFR. Patients should be referred to urological services to exclude urinary tract malignancy and disease if they are over 40 years of age with: 1. persistent asymptomatic haematuria (defined as two out of three positive dipsticks), or 2. symptomatic nonvisible haematuria, or 3. visible haematuria Patients should be referred to a nephrologist if a urological cause has been excluded, or the criteria for urological assessment are not met, and the patient has: 1. declining GFR, or 2. CKD stage 4 or 5, or 3. proteinuria with urinary PCR greater than 50 mg/​mmol or ACR greater than 30 mg/​mmol, or 4. age less than 40 years and hypertension Patients not meeting criteria for referral to urological or renal services, or who have had negative urological or nephrological in- vestigations, need long-​term monitoring in primary care due to the uncertainty of the underlying diagnosis, with appropriate referral should they develop: 1. voiding lower urinary tract symptoms, or 2. visible haematuria, or 3. significant or increasing proteinuria, or 4. progressive renal impairment (falling eGFR), or 5. hypertension Symptomatic renal disease Many patients with renal disease remain asymptomatic, but others develop symptoms that may be nonspecific (e.g. due to the gradual onset of uraemia in patients with progressive CKD), renal spe- cific (e.g. loin pain or polyuria), or unrelated to the kidney and manifesting as isolated ‘nonrenal’ symptoms or as a constellation of symptoms suggestive of a particular systemic condition. Key features to establish are the duration of symptoms, the presence of nonspecific symptoms possibly related to uraemia, the presence of specific renal symptoms, and the presence of symptoms possibly in- dicative of systemic disease. Chronic kidney disease The symptoms of CKD are attributed to the gradual onset of ur- aemia, anaemia, and salt and water retention. Patients often develop these slowly and may not report them until renal function is severely impaired, perhaps even an eGFR as low as 10 ml/​min per 1.73 m2 or less. The number of symptoms and their severity tend to increase as renal function declines, forming a spectrum from asymptomatic to overtly symptomatic uraemia. Symptoms and the level of eGFR may not correlate well: some patients with an eGFR of 15 to 20 ml/​ min per 1.73 m2 may be symptomatic, whereas a few with an eGFR around 5 ml/​min per 1.73 m2 may be remarkably symptom free. Most patients have some symptoms by the time that they start dialysis. Indeed, the presence of uraemic symptoms in the context of CKD stage 5 (eGFR <15 ml/​min per 1.73 m2) (Box 21.3.5) is now considered the indication to start dialysis. These include anor- exia, nausea, and vomiting (in 76% of patients), fatigue and weak- ness (72%), pruritus (40%), breathlessness and orthopnoea (26%), bleeding tendency (14%), apathy and loss of mental concentration (12%), and muscle twitching and cramps (11%). Factors contributing to the development of ‘uraemia’ and other symptoms include retention of small-​molecular nitrogenous sub- stances and other end products of protein metabolism, metabolic acidosis, salt and water retention, disturbances of mineral metab- olism (e.g. phosphate retention), malnutrition, and anaemia. Some of these symptoms may be improved by treatment with agents such as erythropoietin, diuretics, and oral sodium bicar- bonate, and dietary advice to improve malnutrition and phosphate control. Others respond to the initiation of dialysis. Some symptoms may persist in spite of all these measures. It is unfortunately not uncommon for patients to present for the first time very late in the course of progressive CKD, with profound and symptomatic uraemia. This is the initial mode of presentation in Box 21.3.4  Causes of nonvisible haematuria without proteinuria Glomerular disease • IgA nephropathy • Thin basement membrane disease • Hereditary nephritis (Alport’s syndrome) • Other glomerulonephritides (mesangiocapillary glomerulonephritis, vasculitis, lupus, etc.) Nonglomerular renal disorders • Nephrolithiasis • Pyelonephritis • Renal cell carcinoma • Cystic kidney disease (polycystic and medullary sponge) • Trauma • Papillary necrosis • Ureteric strictures • Hydronephrosis • Sickle cell disease • Renal infarcts and arteriovenous malformations • Renal tuberculosis Lower urinary tract disorders • Cystitis, prostatitis • Bladder carcinoma • Benign bladder and ureteral tumours and polyps • Urethral strictures Miscellaneous • Exercise • Over-​anticoagulation • Factitious

21.3  Clinical presentation of renal disease 4769 around 20% of patients entering dialysis programmes in the United Kingdom, who tend to be older, more dependent, and with greater comorbidities than those presenting earlier. Late presentation pre- sents major problems: it is not possible to plan dialysis initiation, and patient choice of modality is limited, with haemodialysis being the default mode. Furthermore, it is often not possible to create defini- tive vascular access, hence patients often need to begin dialysis with temporary or semi-​permanent central venous lines. These and other features increase morbidity and mortality after late presentation. It can be difficult and sometimes impossible to distinguish patients presenting late with advanced CKD (‘crash-​landers’) from those with severe AKI with potentially reversible causes. Failure to be- come dialysis independent by 90 days after dialysis initiation is often taken as proof that the acute presentation was with ESKD rather than AKI. Patients who ‘crash-​land’ are often extremely unwell and may be obtunded with uraemic encephalopathy. Fluid overload is common, with pulmonary and peripheral oedema. Metabolic acid- osis is often present and if severe may cause Kussmaul’s respiration as well as cerebral and cardiac depression. Patients may also show signs of muscle twitching, which may be a sign of hyperkalaemia or hypocalcaemia. A pericardial friction rub indicates uraemic pericar- ditis, which if unrecognized may lead to pericardial tamponade and occasionally to fatal pericardial haemorrhage. See Chapter 21.6 for further discussion of CKD. Acute kidney injury Acute kidney injury is discussed in detail in Chapter 21.5, but, in brief, causes can be classified as being prerenal, renal (due to intrinsic renal disease), or postrenal (obstruction). In the general hospital set- ting, most cases are prerenal and occur as the result of reduced renal perfusion due to volume depletion (30%), cardiac failure (12%), and sepsis (12%). Drug-​induced kidney injury accounts for 30%, urinary tract obstruction 10%, and acute glomerular disease and acute inter- stitial nephritis cause 5 to 10%. Key features to establish sequentially when managing a patient with AKI are as follows: 1. How ill are they? The condition of patients with similar bio- chemical abnormalities can range from the asymptomatic to the moribund: those with cardiorespiratory compromise need crit- ical care support. 2. Does the patient need emergency haemodialysis or haemo­ filtration? The major indications are severe hyperkalaemia, pulmonary oedema, profound acidosis, and severe uraemia—​the latter being defined more on clinical than biochemical grounds. 3. Is there a prerenal element that may respond to volume reple- tion or inotropic support? Clinical examination, perhaps supple- mented by central venous pressure measurement, facilitates this decision. 4. Is the patient obstructed? Clinical features can be helpful, and ultrasonography of the urinary tract is usually diagnostic. 5. Is this AKI or chronic renal failure? Sometimes this is difficult or impossible to determine on clinical grounds, but small kidneys on ultrasonography signify chronic disease. 6. Is this intrinsic renal disease? Clinical features of systemic dis- ease and relevant immunological tests (including ANCAs and anti-​GBM antibody) must be pursued, and renal biopsy will usu- ally be required to establish the diagnosis. As with CKD, many of the symptoms and signs attributed to loss of renal function are nonspecific and occur with advanced AKI (GFR <15 ml/​min per 1.73 m2). However, in contrast to CKD, the acute metabolic changes are often less well tolerated. The greatest danger is hyperkalaemia, which may develop quickly and is almost always asymptomatic until the onset of cardiac arrhythmias and potentially cardiac arrest. Other potentially life-​threatening features include pulmonary oedema, metabolic acidosis, and uraemic pericarditis. The clinical context and history are of overriding importance in establishing the likely aetiology of AKI. A patient developing AKI after surgery is likely to have prerenal and acute tubular injury due to a combination of hypovolaemia, sepsis, and analgesia with an NSAID. A patient presenting acutely after a prolonged period of un- consciousness following a drug overdose is likely to have rhabdo- myolysis. A patient with a past history of lupus presenting with a recent fever, myalgia, and rash is likely to have rapidly progressive lupus nephritis. A patient with a history of lower urinary tract symp- toms or of urinary stones is likely to have obstruction. It is always important to consider the possibility of urinary tract obstruction as it may be readily reversible. Complete anuria is highly suggestive of total obstruction, although it may also occur in pa- tients with rapidly progressive glomerulonephritis (RPGN) and those with acute obstruction of the renal arterial supply. However, urinary output is generally a poor guide to the presence of urinary tract obstruction, and a normal or even increased output does not exclude the diagnosis. All patients with unexplained AKI should undergo ultrasound imaging of the kidneys and urinary tract. This permits the diagnosis or exclusion of obstruction in most cases, and also allows renal size to be assessed: small kidneys indicate chronic renal failure. It is important to emphasize that, after stabilization, patients in whom the clinical features and initial investigations do not give suf- ficient clues to allow a diagnosis to be established will require a renal biopsy to avoid missing potentially reversible intrinsic renal disease. Details of important and common presentations of acute renal dis- ease are discussed later in this chapter and in Chapter 21.5. Urinary symptoms Micturition Most symptoms related to micturition relate to problems arising in the lower urinary tract. Bladder outflow obstruction is commonly Box 21.3.5  Features of uraemia and an eGFR less than 15 ml/​min per 1.73 m2 body surface area • Anorexia and malnutrition • Nausea and vomiting • Tiredness • Fluid overload with oedema, breathlessness, and orthopnoea • Anaemia • Pruritus • Mental apathy and depression • Muscle twitching, restless legs, and cramps • Bleeding tendency—​haematemesis, epistaxis • Sexual dysfunction—​loss of libido and impotence • Cardiac—​pericarditis

section 21  Disorders of the kidney and urinary tract 4770 associated with symptoms such as urgency, hesitancy, poor urinary stream, nocturia, dysuria, and dribbling. Recognition of these symp- toms is important as outflow obstruction may result in complete ob- struction with AKI or chronic obstructive uropathy with CKD. Patients may also describe discomfort or pain on micturition. This symptom of dysuria may also be associated with burning within the urethra or suprapubic pain during or after micturition. When as- sociated with urinary frequency or fevers in young women, dysuria is likely to be caused by a urinary tract infection. However, dysuria occurring in isolation in men of any age suggests structural lesions within the prostate or bladder and warrants further investigation. Perineal or rectal pain associated with micturition suggests prostatic inflammation, such as prostatitis or malignancy. Frequency Patients may present with symptoms of increased frequency of mic- turition. In this situation, it is important to distinguish between frequent voiding of small volumes of urine and an overall increase in urinary volume with more frequent emptying of a full bladder. Charting urinary frequency and voided volumes over a number of days can allow these to be distinguished. The frequent passage of small volumes of urine suggests bladder irritation (from inflam- mation, stone, or tumour) or reduced volume from extrinsic com- pression or contraction (e.g. following radiotherapy). Increased frequency of emptying a full bladder is suggestive of polyuria. Polyuria Polyuria (defined as a urinary output >3 litres/​24 h) may result from solute diuresis, water diuresis, or a combination of both. Solute di- uresis occurs in conditions such as hyperglycaemia and salt-​losing states (e.g. overuse of diuretics and salt-​losing nephropathies). Water diuresis may result from primary polydipsia, failure to synthesize or secrete ADH normally (congenital and acquired cranial diabetes insipidus), or failure of cortical and medullary collecting ducts to respond to ADH (congenital and acquired nephrogenic diabetes insipidus). There are numerous causes of acquired nephrogenic diabetes insipidus, including CKD (especially associated with ureteric ob- struction, postobstructive states, and chronic interstitial nephritis), electrolyte abnormalities (hypercalcaemia and hypokalaemia), nephrotoxic drugs (such as lithium and amphotericin), and many other miscellaneous conditions including sickle cell disease, Sjögren’s syndrome, and sarcoidosis. Most patients with polyuria have asso- ciated thirst, polydipsia, and nocturia. Polyuria needs confirmation by 24-​h urinary collection as most patients are unclear as to their true daily urine output. Once it is established that the patient is poly- uric, common causes such as hyperglycaemia and excessive diuretic use need to be excluded, after which investigations should focus on excluding primary polydipsia and distinguishing between cranial and nephrogenic diabetes insipidus, as discussed in Chapter 21.2.1. Nocturia Nocturia is defined as the need to get up once or more times for noc- turnal voids. It may have a considerable negative impact on quality of life and in older people predisposes to falls. Three types of nocturia have been identified: low voided volume, nocturnal polyuria, and mixed origin. Nocturia due to low voided volumes occurs in pa- tients with bladder outflow obstruction and those with hyperactive bladders from any cause. Nocturnal polyuria occurs when there is a reversal of the normal circadian pattern of voiding such that there is an increased urine output overnight. These types of nocturia are dis- tinguishable by the use of voiding diaries. Elderly patients who void in excess of 33% of their total 24-​h output between 11 p.m. and 7 a.m. are said to have nocturnal polyuria, the corresponding fraction in young adults being 20%. Factors predisposing to nocturnal poly- uria include renal impairment, diabetes mellitus, congestive cardiac failure, sleep apnoea, and the mobilization of peripheral oedema due to any cause. In patients without predisposing causes, usually eld- erly, low nocturnal levels of ADH have been described. Oliguria and anuria Oliguria is arbitrarily defined as a urinary output of less than 400 ml/​ 24 h or 0.5 ml/​kg of body weight per hour. Oliguria is the normal renal physiological response to reduced renal perfusion from any cause and is common in hospital inpatients, particularly those with acute illnesses associated with hypotension and reduced effective circulating volume. Monitoring of fluid balance and urinary output in such patients allows its early detection and treatment, which may help prevent progression to established AKI. The recognition of oli- guria should prompt an evaluation of the patient with attention to volume status, blood pressure, and the detection/​exclusion of sepsis, followed by appropriate management to optimize blood pressure and circulating volume. Oliguria may also be a feature of intrinsic renal failure due to nephrotoxic drugs, acute glomerulonephritis, or interstitial neph- ritis, but it is a poor marker of intrinsic renal disease as urinary output often remains normal despite significantly impaired renal function. The development of anuria, meaning the total absence of urine, is strongly suggestive of urinary tract obstruction, which may occur at any level in the urinary tract. A careful history, examination for an enlarged bladder, and digital rectal examination for a prostatic or pelvic mass, should be followed by urgent ultrasonography of the kidneys and bladder. Very occasionally, anuria may be a manifest- ation of severe intrinsic renal disease, such as a RPGN, cortical ne- crosis, or renal infarction. Urine appearance and visible haematuria Visible haematuria is the most common abnormality of the urine noted by patients. As little as 5 ml of blood in a litre of urine will lead to a visible change in urinary colour. Haematuria may arise from anywhere within the urinary tract, but bright red haematuria (with or without clots) is suggestive of lower urinary tract bleeding, whereas dark, smoky brown–​black urine is more suggestive of renal pathology. Haematuria at the beginning of micturition, which then clears, suggests urethral pathology, whereas end-​stream haematuria is consistent with bladder pathology. Although the causes of haema- turia are numerous (Box 21.3.6), infection, stones, and malignancy are the most common. Visible haematuria warrants investigation in all patients. Frank haematuria is uncommon in glomerular disease, with the notable exception of IgA nephropathy in which visible haematuria classically occurs immediately following mucosal inflammation, typically an upper respiratory tract infection. In patients with poly- cystic disease, cysts may haemorrhage to cause loin pain and haema- turia. This may be associated with infection of the cysts and usually

21.3  Clinical presentation of renal disease 4771 resolves with conservative management, with antibiotics if there are signs of infection. Red–​brown–​black urine is occasionally caused by haemoglobin- uria due to haemolysis or myoglobinuria precipitated by rhabdo- myolysis. Beetroot and food colouring may turn the urine pink, whereas drugs such as rifampicin may discolour the urine orange–​ red. Rarely, urine is found to darken following exposure to light, sug- gesting a diagnosis of porphyria or alkaptonuria. Turbid white urine suggests chyluria. Loin pain The presence of pain in the renal angle (loin pain) is consistent with inflammation, obstruction, or stretching of the renal capsule by a mass lesion. Pain arising from acute obstruction is common and typ- ically colicky in nature, with radiation into the groin and scrotum. The pain may be exacerbated by oral fluids, which increase urinary volume and pressure within the renal pelvis. Acute pyelonephritis typically causes renal angle pain on the affected side and is often as- sociated with pyrexia and leucocytes in the urine. Similarly, a renal abscess extending into the renal capsule may present with loin pain or with isolated symptoms of diaphragmatic irritation or involve- ment of the psoas muscle, with pain on leg extension. Patients with polycystic kidneys may also develop loin pain as a result of infection or haemorrhage of single or multiple cysts. Renal pain is an uncommon feature of glomerulonephritis and other intrinsic renal diseases: IgA nephropathy is very occasion- ally associated with renal pain, but active necrotizing glomerulo- nephritis and acute interstitial nephritis are almost invariably pain free. Loin pain–​haematuria syndrome Rarely, patients may present with recurrent intermittent loin pain, haematuria (nonvisible or visible), and normal renal function, with no relevant structural abnormality of the renal tract. The cause of this condition, termed the loin pain–​haematuria syndrome, is un- known: it is a diagnosis of exclusion which is most often seen in young women. The pain—​often described as ‘deep’, ‘burning’, or ‘throbbing’—​is usually felt in the loin, but can radiate in a typical renal pattern to the groin, genital area, and medial thigh. Some will describe a psy- chologically traumatic event before the onset of pain. The pain can sometimes be induced or exacerbated by exercise and affected by posture (e.g. sitting for a prolonged length of time can be uncom- fortable), and in some cases there is associated nausea and vomiting. Some patients report continuous pain that never goes away, whereas others describe episodic pain that lasts more or less continuously for days or (more typically) weeks, interspersed with periods of re- mission. The pain is usually unilateral at presentation, but many pa- tients eventually develop pain bilaterally. Many patients are taking large quantities of opioids and other analgesics (e.g. amitriptyline or gabapentin) by the time they are referred to specialist services. Urological investigation is unremarkable, or shows incidental abnormalities only. If renal biopsy is performed, the appearances may be normal, but thinning or thickening of the GBM has been reported in about 60% of cases in some series, appearances of IgA nephropathy are sometimes seen, and deposition of complement component C3 in the renal arterioles has been described, but the relationship—​if any—​between these findings and symptomatology remains obscure. Aside from loin pain, many patients will have other medically unexplained somatic symptoms, raising the possibility that this symptom is also a somatoform disorder. Patients may request neph- rectomy and/​or renal autotransplantation, which the wise physician will not accede to, preferring to help the patient by sympathetic dis- cussion and referral to pain management services. Specific renal syndromes Nephrotic syndrome Definition Nephrotic syndrome is the triad of oedema, proteinuria, and hypoalbuminaemia (see Box 21.3.7 for a case study). Proteinuria is usually greater than 3.5 g in 24 h, which equates approximately to an ACR of 250 mg/​mmol or PCR of 350 mg/​mmol. When patients have clinically apparent oedema, serum albumin is usually less than 25 g/​litre (Fig. 21.3.3). However, in practice, the definition is some- what arbitrary, and the correlation between the degree of protein- uria, serum albumin, and presence of oedema is poor. Some patients (particularly older people) may develop oedema with proteinuria less than 3.5 g, whereas others remain free of oedema despite having a serum albumin considerably less than 25 g/​litre. Other patients may have heavy proteinuria but maintain a normal serum albumin and remain free of oedema. Nephrotic syndrome indicates the presence of glomerular dis- ease. Causes can usefully be divided into primary glomerular dis- eases and those arising secondary to systemic disease (Box 21.3.8), Box 21.3.6  Causes of visible haematuria • Infections:

—​ Cystitis and pyelonephritis

—​ Prostatitis

—​ Urethritis

—​ Schistosomiasis • Urinary stones • Tumours:

—​ Renal cell

—​ Transitional cell

—​ Prostatic

—​ Urethral • Glomerular diseases:

—​ IgA nephropathy

—​ Alport’s syndrome

—​ Crescentic glomerulonephritis • Interstitial and medullary renal diseases:

—​ Polycystic kidneys

—​ Interstitial nephritis

—​ Papillary necrosis

—​ Tuberculosis • Miscellaneous causes:

—​ Release of urinary obstruction

—​ Trauma

—​ Loin pain–​haematuria syndrome

—​ Arteriovenous malformations

—​ Anticoagulation

—​ Factitious

section 21  Disorders of the kidney and urinary tract 4772 with the geographical context important in determining the most likely cause in any particular case. The most common cause of neph- rotic syndrome in Western countries is diabetes mellitus, whereas in developing countries it is most commonly associated with infection. Nephrotic syndrome due to malaria and hepatitis are particularly common in sub-​Saharan Africa, and poststreptococcal glomerulo- nephritis is also an important cause. Pathophysiology The traditional explanation for oedema formation—​known as the ‘underfill hypothesis’—​is that, via alterations in Starling forces, hypoalbuminaemia leads to intravascular volume depletion, stimulation of the renin–​angiotensin–​aldosterone system, and thereby to sodium retention. This is likely to be correct in chil- dren with minimal change nephrotic syndrome, but the evidence is much less convincing in adults, in whom nephrotic syndrome is more likely caused by an intrinsic renal inability to excrete salt (‘overfill hypothesis’). The cause for this inability is uncertain, but it may be due to the activation of the epithelial sodium channel in the distal nephron by serine proteases in the glomerular filtrate of nephrotic patients. Clinical features One of the earliest symptoms patients may report is that of frothy urine. This often occurs before the onset of oedema and may be a useful indicator of the onset of heavy proteinuria. As proteinuria de- velops and serum albumin falls, patients gradually develop oedema. This may be noticed first as periorbital swelling and ‘puffiness’ in the morning, or as ankle swelling in the evening due to the effects of gravity. Worsening leg oedema develops as salt and water retention Box 21.3.7  Case illustration—​proteinuria and oedema A 54-​year-​old woman presents with worsening peripheral oedema. She had been diagnosed with type 2 diabetes 6 months earlier, but remained well until 4 weeks ago, when she suddenly noted frothy urine and mild peripheral oedema. Over the following weeks the oedema had worsened and she noted some abdominal distension. Her only regular medication is gliclazide. Examination • Pitting oedema to her lumbar spine, with bilateral small pleural effusions • Jugular venous pressure not elevated and heart sounds normal • Mild erythema over right ankle and lower leg Investigations • Urine dipstick test: protein 4+, no haematuria • ACR: 452 mg/​mmol • A 24-​h urinary collection: 6.8 g proteinuria • Serum albumin: 13 g/​litre • Serum creatinine: 82 µmol/​litre • Autoimmune and hepatitis serology: negative • Renal ultrasonography and venous Doppler: normal • Doppler ultrasonography of right leg: normal • Renal biopsy: membranous nephropathy with subepithelial spikes on silver stain Diagnosis • Membranous nephropathy with nephrotic syndrome Comment Frothy urine, oedema, and hypoalbuminaemia indicate the onset of heavy proteinuria and nephrotic syndrome. The rapid onset of symp- toms suggests a primary glomerular lesion rather than long-​standing diabetic nephropathy. The presence of leg erythema may be due to in- fection or deep venous thrombosis, hence a Doppler ultrasound scan was requested. To make the diagnosis, a renal biopsy was performed, which showed membranous nephropathy. The patient was initially man- aged conservatively with diuretics and low molecular weight heparin as thromboembolic prophylaxis. Fig. 21.3.3  Severe peripheral oedema of the lower legs with pitting below the right knee (arrow). Box 21.3.8  Causes of nephrotic syndrome • Primary glomerular diseases:

—​ Minimal change

—​ Focal segmental glomerulosclerosis (FSGS)

—​ Membranous

—​ Mesangiocapillary glomerulonephritis (MCGN) • Secondary glomerular diseases:

—​ Diabetes

—​ Amyloid • Drugs:

—​ Gold, penicillamine, NSAIDs, captopril, heroin • Systemic disease:

—​ Lupus • Infectious diseases:

—​ Poststreptococcal glomerulonephritis

—​ Hepatitis B and C

—​ HIV

—​ Malaria

—​ Schistosomiasis

—​ Filaria • Malignancy:

—​ Minimal change

—​ Membranous • Pre-​eclampsia • Hereditary:

—​ Alport’s syndrome

—​ Nail–​patella syndrome

21.3  Clinical presentation of renal disease 4773 increases, followed by abdominal distension from ascites. In men, scrotal oedema may be marked and very uncomfortable. Further fluid retention leads to pleural effusions, which are often bilateral but may be unilateral. Patients often feel lethargic, with a loss of ap- petite and nausea due to associated gut oedema. Clinical examination of the patient’s volume status may reveal a normal or low jugular venous pressure despite marked oedema. Although rare in untreated adult patients, it is important to identify intravascular volume depletion because the use of high-​dose diur- etic therapy in this setting may provoke circulatory collapse from hypovolaemia, or less dramatically may further reduce renal perfu- sion and exacerbate renal dysfunction. Conversely, a raised jugular venous pressure with a low blood pressure may suggest a significant pericardial effusion or underlying amyloid with cardiac involvement. Patients may also present with complications associated with nephrotic syndrome. Thromboembolism may be difficult to de- tect clinically. Patients with marked peripheral oedema often have swollen legs of unequal size and associated erythema due to an in- creased susceptibility to cellulitis. These may mask the signs of deep venous thrombosis. Similarly, subtle symptoms of breathlessness, perhaps suggesting pulmonary embolism, or headache, perhaps suggesting cerebral venous sinus thrombosis, may be overlooked. In practice, a low threshold is required for investigation and treatment of suspected thromboembolism. The combination of severe peripheral oedema and susceptibility to infection following skin breakdown often leads to cellulitis. Long-​ standing hypoalbuminaemia may lead to leuconychia. Severe hyper- lipidaemia, which is a feature of nephrotic syndrome, may lead to cutaneous xanthomas. Establishing a clinical diagnosis of nephrotic syndrome is often straightforward. The clinical history and examination may also pro- vide clues to an underlying cause, which may be clear, such as in a patient with long-​standing diabetes and progressive diabetic neph- ropathy. Alternatively, the immediate cause may only become ap- parent after a detailed history revealing long-​standing use of drugs that may precipitate the condition (e.g. ACE inhibitors, NSAIDs, gold, or penicillamine). A history of chronic infections (such as hepatitis) may suggest an underlying membranous or mesangiocapillary glom- erulonephritis, whereas a rash and arthralgia may lead to a diagnosis of an autoimmune condition such as systemic lupus erythematosus or cryoglobulinaemia. The presence of other long-​standing inflam- matory conditions, such as rheumatoid arthritis, raises the possibility of systemic amyloidosis. In older patients, an associated malignancy remains a possibility and should be sought in the history and exam- ination, but does not warrant further investigation apart from a chest radiograph in the absence of clinical clues (e.g. disturbance of bowel habit which would merit imaging of the colon). Very occasionally, a family history may reveal an inherited nephrotic syndrome such as familial focal segmental glomerulosclerosis. Rapidly progressive glomerulonephritis with acute kidney injury Around 5% of cases of AKI are caused by a RPGN. Recognizing this relatively small group of patients is important because many respond well to treatment, provided the diagnosis is made early and appro- priate management started promptly. The key to making a diagnosis is having a high index of clinical suspicion such that important fea- tures of the syndrome are identified (see Box 21.3.9 for a case study). The hallmarks of a RPGN are rapidly declining renal function, haematuria and proteinuria on urine dipstick testing, dysmorphic red cells or red cell casts on urine microscopy, and crescentic and focal necrotizing glomerulonephritis on renal biopsy. Clinical presentation A RPGN may present either de novo in a previously well patient or as a complication in a patient known to have a systemic disease (Box 21.3.10). The clinical features may be diverse. Occasionally, Box 21.3.9  Case illustration—​ANCA-​associated vasculitis An 80-​year-​old woman presents with a 2-​week history of increasing mal- aise and lethargy. On close questioning she also reported arthralgia in the small joints of her hands, and numbness in her hands and feet in the last few months. Examination • Subtle purpuric rash on both legs • Bibasal crepitations • Reduced pinprick sensation in a glove and stocking distribution Investigations • Creatinine: 854 µmol/​litre (56 µmol/​litre 10 months before) • Urea: 45 mmol/​litre • Haemoglobin: 8.3 g/​dl • Urine dipstick test: blood 3+, protein 2+ • Urine microscopy: red cell casts • Serological testing: perinuclear ANCA positive, with myeloperoxidase titre 78% • Renal biopsy: focal necrotizing glomerulonephritis Diagnosis • AKI due to microscopic polyangiitis (an ANCA-​associated vasculitis) with associated peripheral neuropathy Comment The history is nonspecific, except that the onset of symptoms is recent and suggestive of a systemic disorder. The presence of a purpuric rash makes the diagnosis of vasculitis a possibility. Dipstick testing of the urine and checking the renal function are critical in making the diagnosis of AKI due to an inflammatory condition. Confirmation of a systemic vasculitis is made with a positive perinuclear ANCA and renal biopsy. Box 21.3.10  Causes of a rapidly progressive glomerulonephritis • ANCA-​associated vasculitis:

—​ Granulomatosis with polyangiitis

—​ Microscopic polyangiitis

—​ Eosinophilic granulomatosis with polyangiitis • Other primary systemic vasculitides (ANCA negative) • Other systemic disorders:

—​ Systemic lupus erythematosus

—​ Cryoglobulinaemia

—​ Henoch–​Schönlein purpura • Infection-​related glomerulonephritis:

—​ Postinfectious glomerulonephritis

—​ Infective endocarditis • Anti-​GBM disease (Goodpasture’s syndrome) • Crescentic phase of a primary glomerulonephritis:

—​ IgA nephropathy

—​ Mesangiocapillary glomerulonephritis

section 21  Disorders of the kidney and urinary tract 4774 patients may present with very few symptoms and signs, except for proteinuria and haematuria with a recent decline in renal function, and at the other end of the spectrum, patients may present with se- vere AKI associated with features of uraemia. Importantly, patients may also present with clinical features of systemic inflammation that indicate an underlying cause for glomerulonephritis. These range from the subtle, such as arthralgia or myalgia, to the florid, such as a purpuric rash (Fig. 21.3.4), haemoptysis, and peripheral neuropathy. Clinical features of specific inflammatory diseases asso- ciated with a RPGN are detailed in Table 21.3.1. In practice, specific features to elicit in patients presenting with an acute decline in renal function include arthralgia and arthritis, myalgia and muscle tenderness, rashes, eye symptoms (pain and redness), ear, nose, and throat symptoms (epistaxis, nasal crusting, and new deafness), haemoptysis (important, as it may indicate a life-​threatening pulmonary haemorrhage), and neuropathic symp- toms and signs. Conversely, the clinician should have a high index of suspicion for a RPGN in patients presenting with any of these fea- tures, and in this context suspicions are heightened by the presence of dysmorphic red cells and red cell casts on urinary microscopy (Fig. 21.3.5). If a RPGN is suspected, investigations should include ANCAs, anti-​GBM antibodies, antinuclear and anti-​double-​stranded DNA antibodies, serum complement, antistreptolysin-​O titre, and im- munoglobulins and serum electrophoresis (including tests for cryo- globulins). It is almost certain that a patient with a RPGN will require a renal biopsy to confirm the diagnosis and to guide management. All patients with suspected RPGN should be referred urgently to a nephrologist. Presentation of renal disease associated with  other underlying diseases Renal disease can present in many complex and diverse ways, and many renal problems arise as either direct or indirect complications of other diseases. Examples include AKI caused by sepsis, and pro- gressive CKD due to diabetes (Box 21.3.11). This section illustrates some common and important presentations of renal disease. Diabetic nephropathy In the Western world, diabetes is the most common cause of renal disease, accounting for around 45% of new cases of ESKD in the United States of America and around 25% in the United Kingdom (Box 21.3.12). Diabetic nephropathy develops over the course of years and is preceded by a clinically silent phase of microalbuminuria, which is often detected as a result of diabetic screening programmes, enabling a targeted approach to manage- ment in which tight glycaemic control and blood pressure control with the use of agents to block the renin–​angiotensin system aim to reduce the rate of progression of the nephropathy. As with other causes of progressive CKD, patients with diabetic nephropathy often only develop symptoms of kidney disease late in the course of their disease, but there is a tendency for those with this condition to become symptomatic, particularly in relation to anaemia and fluid retention, with lesser degrees of impairment of renal function than their nondiabetic counterparts. This leads to an earlier requirement for initiation of dialysis in patients with diabetic nephropathy. Screening patients with diabetes for microalbuminuria and hypertension enables early diagnosis of complications and intensive management of glucose and blood pressure. As eGFR falls below 30 ml/​min per 1.73 m2, patients should be referred to a nephrologist to plan for renal replacement therapy. Patients with diabetes are also subject to develop other micro- vascular and macrovascular complications, which may lead to superimposed renal atheroembolic disease and renal artery sten- osis. These may present as an abrupt decline in renal function following the introduction of an ACE inhibitor or angiotensin re- ceptor antagonist. Patients with diabetic nephropathy are also at in- creased risk of AKI or chronic renal failure, with common causes Fig. 21.3.4  Purpuric rash affecting the lower legs, consistent with a systemic vasculitis. Table 21.3.1  Key features of specific systemic inflammatory diseases causing a rapidly progressive glomerulonephritis Feature Type Disease Skin rashes Purpuric Lupoid Any vasculitis Lupus Ear, nose, and throat symptoms Nasal crusting Deafness Oral ulceration Granulomatosis with polyangiitis Granulomatosis with polyangiitis Any vasculitis or lupus Eye symptoms Scleritis and episcleritis Any vasculitis, lupus, rarely Behçet’s disease Myalgia, arthralgia, and arthritis Any vasculitis, Henoch–​Schönlein purpura, cryoglobulinaemia, lupus, rheumatoid arthritis, systemic sclerosis Haemoptysis Goodpasture’s disease, any vasculitis, lupus Neuropathy Any vasculitis, lupus, cryoglobulinaemia

21.3  Clinical presentation of renal disease 4775 for this including use of radiocontrast media for investigations such as coronary or peripheral angiography, surgery (especially cardiac surgery), and in the context of diabetic emergencies, particularly diabetic ketoacidosis. See Chapter  21.10.1 for further discussion of diabetic renal disease. Renovascular disease Many patients with diffuse atherosclerosis have evidence of reno­ vascular disease. A  history of cerebrovascular, coronary, or per- ipheral vascular disease makes a diagnosis of renovascular disease likely. Up to 24% of patients presenting with peripheral vascular (b) (a) Fig. 21.3.5  Phase contrast micrographs showing dysmorphic erythrocytes (a) and a red cell cast (b) within the urine. Box 21.3.11  Important and common presentations of renal disease • Diabetic nephropathy with progressive CKD • Vascular disease:

—​ Renal atheroemboli

—​ Renal artery stenosis • Underlying malignancy:

—​ Urinary tract obstruction

—​ Membranous glomerulonephritis

—​ Myeloma

—​ Hypercalcaemia • Infection:

—​ Acute presentation with renal failure:  (1) general syndromes—​ sepsis, rhabdomyolysis, HUS, postinfectious glomerulonephritis, tubulointerstitial nephritis; (2)  specific syndromes—​hantavirus, leptospirosis, malaria

—​ Chronic infections associated with renal disease: hepatitis B, hepa- titis C, filaria, schistosomiasis, HIV • Systemic inflammatory disease:

—​ Systemic vasculitides

—​ Systemic lupus erythematosus

—​ Sarcoidosis • Drug-​induced renal disease • Pregnancy Box 21.3.12  Case illustration—​progressive CKD due to diabetic nephropathy A 66-​year-​old Asian man presents with nausea, anorexia, ankle swelling, and breathlessness. He has a 25-​year history of type 2 diabetes mellitus, a 14-​year history of hypertension, and had coronary artery bypass grafts 3 years ago. Insulin, furosemide, and ramipril are his only regular medications. Examination • Cardiovascular—​blood pressure 167/​88 mmHg, jugular venous pres- sure +3 cm, cardiomegaly, bibasal crepitations, and peripheral oedema to sacrum • Fundi—​treated diabetic retinopathy • Neurological—​reduced pinprick sensation in stocking distribution to knees, with absent ankle reflexes, proprioception, and vibration sensation Investigations • Urine dipstick test: protein 4+, no haematuria • Urine ACR: 1720 mg/​mmol • Serum creatinine:  568 µmol/​litre (eGFR 9 ml/​min per 1.73 m2 body surface area) • Serum bicarbonate: 15 mmol/​litre • Full blood count: haemoglobin (Hb) 9.8 g/​dl • HbA1C: 10.2% Further history Five years previously, his blood pressure was 189/​92 mmHg with cre- atinine of 154 µmol/​litre and protein+ on urine dipstick. At the time of his coronary surgery, blood pressure was 165/​86 mmHg with creatinine 210 µmol/​litre. Over the last year he had felt well until the last 2 months, since when he had developed increasing lethargy, anorexia, and breath- lessness on exertion, and noted increasing ankle swelling. Comment This man with long-​standing diabetes presents with nonspecific symp- toms and oedema. He also has evidence of end-​organ damage, with cardiovascular disease, retinopathy, and neuropathy. Five years ago he had evidence of nephropathy with proteinuria and an eGFR of 43 ml/​ min (CKD stage 3). Since then his blood pressure and glycaemic control have been poor, which contributed to the progression of nephropathy to eGFR of 30 ml/​min (CKD stage 3/​4) 3 years ago, and now to CKD stage 5 with symptoms of uraemia.

section 21  Disorders of the kidney and urinary tract 4776 disease have stenoses in both renal arteries, and up to 50% have more than 50% stenosis in at least one renal artery. The absence of peripheral pulses and the presence of a femoral bruit make the diagnosis of renovascular disease likely, although most of these pa- tients remain asymptomatic from the renal point of view. Common presentations of renovascular disease are outlined in Box 21.3.13. See Chapter  21.10.10 for further discussion of renovascular disease. Myeloma and other malignancies Myeloma can cause AKI in a number of ways. Features suggestive of underlying myeloma in a patient presenting with unexplained renal failure are older age, bone pain (often nonspecific), hypercalcaemia (sometimes mild, and sometimes ‘relative’ considering the degree of renal impairment), anaemia (often inappropriately severe for the de- gree of renal impairment), an abrupt decline in renal function after a relatively minor prerenal ‘insult’, and unremarkable urine dipstick findings. Up to 50% of patients presenting with myeloma have impaired renal function at the time of diagnosis. This may be reversible and due to hypercalcaemia, dehydration, hyperuricaemia, or infection. Cast nephropathy accounts for 10% of all renal dysfunction in pa- tients with myeloma and is characterized by the formation of tubular casts of excreted light chains and Tamm–​Horsfall protein: these are thought to cause renal failure by obstructing the tubule and by direct tubular toxicity. The key to the diagnosis is to maintain a high index of suspicion, particularly in elderly patients presenting with renal failure and hypercalcaemia. Serum electrophoresis and urinary Bence Jones proteins and serum free light chains are the required investigations, leading on to bone marrow examination. Other malignancies may present with renal involvement through a number of mechanisms, including AKI due to urinary tract ob- struction by pelvic or retroperitoneal tumour. Other possible causes are outlined in Box 21.3.14. See Chapters 21.10.5 and 21.10.9 for further discussion. Renal presentation of infectious diseases A wide range of systemic infections can affect the kidney and result in either AKI or CKD. The presentation of infection-​related kidney disease varies worldwide, and in the developing world—​in contrast to the developed world—​infectious diseases are the leading cause of both AKI and CKD. AKI may occur as part of a general systemic syndrome induced by infection, such as sepsis and septic shock, haemolytic uraemic syn- drome (HUS), rhabdomyolysis, postinfectious glomerulonephritis, and acute tubulointerstitial nephritis. Alternatively, an infectious agent may cause specific nephrotoxicity, for example, hantavirus, leptospirosis, or malaria. General systemic syndromes caused by infection In Western countries, the most common infectious cause for renal disease is sepsis, which accounts for 10% of all hospital-​acquired renal failure and, if severe, may lead to AKI in the context of multiorgan failure. Other general syndromes that may be induced by infection in- clude HUS and rhabdomyolysis. For example, the verotoxin of Escherichia coli O157:H7 causes (D+) HUS, which is a thrombotic microangiopathy characterized by diarrhoea, AKI, and thrombo- cytopenia. Patients with influenza, legionella, or streptococcal in- fection may present with fever, severe myalgia, and dark urine in the context of AKI due to rhabdomyolysis. Poststreptococcal glomerulonephritis is still one of the most common causes of AKI in the developing world, although now seen rarely in the United Kingdom and developed countries. Typical presentation is 10 days to a few weeks following a streptococcal in- fection of the throat or skin with a ‘nephritic’ syndrome character- ized by hypertension, oedema, haematuria, proteinuria, and AKI. Specific nephrotoxicity caused by infection Hantavirus and leptospirosis Hantaviruses are endemic in specific rodent reservoirs and are trans- mitted to humans by inhalation of infectious aerosols or rodent ex- creta. In Europe, the main pattern of disease is haemorrhagic fever with renal syndrome. The disease presents in four stages: (1) an abrupt febrile stage characterized by fever, loin or abdominal pain, nausea, vomiting, and periorbital oedema, lasting for 3 to 7 days; (2) a hypo- tensive phase associated with haemorrhages and ecchymoses, lasting hours to 2 days; (3) an oliguric phase for 3 to 14 days, with worsening AKI due to a tubulointerstitial nephritis and haemorrhage; and (4) a polyuric phase as renal function returns to normal. Leptospirosis may present with similar features to hantavirus. However, leptospirosis is endemic worldwide and is typically asso- ciated with jaundice and hepatomegaly. AKI occurs in 20 to 85% of patients due to acute tubulointerstitial nephritis. Malaria Severe infection with Plasmodium falciparum occurs in nonimmune adults. AKI may occur either in the acute phase of the disease or Box 21.3.13  Common presentations of renovascular disease • As part of the investigation for acute, severe, or refractory hypertension • An acute rise (>20%) in creatinine following introduction of an ACE inhibitor or angiotensin receptor antagonist • Incidental finding of asymmetric kidney size on renal ultrasonography • As part of the investigation for progressive CKD. • Symptomatically as acute (‘flash’) pulmonary oedema in the absence of cardiac failure or fluid overload • Postoperative AKI, especially following coronary artery bypass or aortic aneurysm surgery Box 21.3.14  Renal presentations associated with malignancy • AKI:

—​ Urinary tract obstruction

—​ Hypercalcaemia

—​ Tumour lysis with urate nephropathy

—​ Chemotherapy (e.g. cisplatin, ifosfamide)

—​ Leukaemic infiltration

—​ Microangiopathy • Paraneoplastic glomerular disease:

—​ Membranous

—​ Amyloid

—​ Mesangiocapillary glomerulonephritis

21.3  Clinical presentation of renal disease 4777 in the recovery phase. Sequestration of parasitized erythrocytes in the renal vasculature and proinflammatory cytokine release cause tubular cell ischaemia and injury. Rarely, patients with falciparum malaria present with ‘blackwater fever’ due to massive intravascular haemolysis, which often occurs following quinine administration in association with glucose-​6-​phosphate dehydrogenase deficiency. Infections and CKD In the developing world, CKD is commonly secondary to infectious disease, with the underlying infection often remaining subclin- ical until the presentation with renal manifestations. Examples of CKD secondary to infective agents include hepatitis B, hepatitis C, P. malariae, filaria, schistosomiasis, and HIV. Hepatitis B is classically associated with nephrotic syndrome due to membranous nephropathy, but occasionally it may result in a mesangiocapillary glomerulonephritis. Hepatitis B virus infection is also associated with the development of polyarteritis nodosa, al- though the reported frequency of this appears to be falling. Patients who develop such complications usually have chronic hepatitis, having contracted the virus in childhood. Hepatitis C is increasingly recognized as a common cause for cryoglobulinaemia. This remains asymptomatic in most patients, with only a few developing clinical evidence of vasculitis. The associ- ated mesangiocapillary glomerulonephritis can present as nephrotic syndrome or CKD. Many infectious agents endemic in sub-​Saharan Africa may also cause a mesangiocapillary glomerulonephritis presenting as neph- rotic syndrome. Most common is P. malariae, but filaria and schisto- somiasis remain in the differential diagnosis. HIV-​associated nephropathy (HIVAN) is an increasingly rec- ognized complication of HIV infection, and it now accounts for around 1% of the dialysis population in the United States of America. Patients usually present with heavy proteinuria and nephrotic syn- drome due a collapsing form of focal segmental glomerulosclerosis. HIVAN predominates in young African American men. See Chapters 21.5, 21.10.8, and 21.11 for further discussion. Systemic inflammatory diseases Patients with systemic inflammatory disease are at risk of developing renal disease. Sometimes this may be the presenting feature of the condition, such as systemic vasculitis or systemic lupus, and on other occasions renal disease may develop as a complication later in the course of disease. Examples of systemic inflammatory diseases associated with renal involvement are detailed in Box 21.3.15. The presentation of an acute glomerulonephritis and progressive renal failure due to systemic inflammatory diseases such as the vasculit- ides and systemic lupus erythematosus has been discussed earlier in the chapter, and further details can be found in Chapters 21.10.2 and 21.10.3. Other inflammatory diseases may present in different ways. Sarcoidosis Renal disease is common in sarcoidosis and characterized histologically by granulomatous tubulointerstitial nephritis. The mean prevalence from biopsy studies is 35%, but this is likely to be an overestimate. Most renal disease is subclinical, but may be iden- tified by the presence of proteinuria or tubular dysfunction with a renal tubular acidosis. However, sarcoidosis may present with AKI, which may be caused by an acute tubulointerstitial nephritis associated with an eosinophilia and eosinophiluria, or be precipi- tated by hypercalcaemia, which may be more common in summer months due to ultraviolet light exposure. The presence of extrarenal features of sarcoidosis (including bilateral hilar lymphadenopathy and erythema nodosum) helps to establish the diagnosis, but some- times the diagnosis may only become apparent on finding a high level of serum ACE or following a renal biopsy for unexplained renal impairment. See Chapters 21.10.4 and 18.12 for further discussion of sarcoidosis. Systemic sclerosis Systemic sclerosis may present with an acute crisis characterized by an abrupt rise in blood pressure (>160/​90 mmHg) with hypertensive encephalopathy, AKI, and a microangiopathic haemolytic anaemia. This may occur before the onset of the cutaneous features of the dis- ease. Patients are typically tachycardic, with evidence of heart failure and a high systemic vascular resistance. This diagnosis should be suspected in any patient presenting with malignant-​phase hyperten- sion and AKI. See Chapter 19.11.3 for further discussion of systemic sclerosis. Systemic amyloidosis Systemic amyloidosis is characterized by extracellular deposition of insoluble fibrillar proteins that lead to organ dysfunction. In AL amyloidosis this arises from light chains produced by a ma- lignant plasma cell clone. AA amyloidosis occurs in the setting of long-​standing inflammation, the amyloidogenic protein being an N-​terminal fragment of serum amyloid A (SAA), an acute phase reactant. Patients may present with heavy proteinuria or neph- rotic syndrome. Renal involvement can be demonstrated by serum amyloid P scanning or by renal biopsy. See Chapter 12.12.3 for fur- ther discussion of the amyloidoses. Drug-​induced renal disease Numerous drugs have the potential for causing both AKI and CKD (Box 21.3.16). As well as prescribed and over-​the-​counter medica- tion, renal disease may also arise from herbal and traditional Chinese medicines or illicit drugs. Mechanisms by which drugs cause renal disease include salt and water depletion, effects on renal perfusion, direct nephrotoxicity, and intrarenal obstruction. Box 21.3.15  Systemic inflammatory diseases associated with renal involvement • Typically associated with renal involvement:

—​ Systemic vasculitides

—​ Systemic lupus erythematosus

—​ Sarcoidosis

—​ Systemic sclerosis

—​ Henoch–​Schönlein purpura

—​ Cryoglobulinaemia • Unusually associated with renal involvement:

—​ Relapsing polychondritis

—​ Ankylosing spondylitis

—​ Behçet’s disease

—​ Rheumatoid arthritis • Renal complications of multisystem conditions:

—​ Amyloidosis (of AA type)

section 21  Disorders of the kidney and urinary tract 4778 Salt and water depletion AKI may follow hypotension and reduced renal perfusion due to so- dium and water depletion. This may be caused by excess diuretic use or diarrhoea and vomiting as a drug side effect. Effect on renal perfusion and the regulation of intrarenal haemodynamics Overdose of any hypotensive agent may compromise renal per- fusion and interfere with renal function. Agents which block the renin–​angiotensin system, the ACE inhibitors, and angiotensin receptor blockers, require special consideration. These agents ab- rogate the effect of angiotensin II on efferent arteriole constriction, which is the normal adaptive response to any reduction in renal perfusion. A small and acceptable deterioration in renal function (up to a 20% increase in serum creatinine) often occurs following the introduction of an ACE inhibitor. A greater increase in serum creatinine may indicate underlying renal artery stenosis, for which further investigation may need to be carefully considered. These agents are implicated in a significant proportion of cases of AKI in patients with sepsis and dehydration. This is because renal perfusion is frequently compromised in these settings and the kidney is unable to autoregulate its blood flow in the presence of renin–​angiotensin system blockade. NSAIDs have numerous renal effects, including disturbances of autoregulation of intrinsic renal haemodynamics. These effects are mediated by inhibition of prostaglandin synthesis from arachi- donic acid by nonspecific blocking of the enzyme cyclooxygenase. This may lead to vasoconstriction and reversible renal impairment in volume-​contracted states. Long-​term use of NSAIDs may cause chronic renal impairment, with selective COX-​2 inhibitors seeming to confer no renal advantage. Direct nephrotoxicity The mechanisms of drug toxicity on the kidney include direct tubulotoxicity, drug-​induced tubulointerstitial nephritis, tubular dysfunction, and glomerular disease. Common nephrotoxic drugs and mechanism are outlined in Box 21.3.16. Tubulointerstitial nephritis is classically caused by penicillins, NSAIDs, and proton pump inhibitors but most drugs have the potential to cause the condition. Drug-​induced tubulointerstitial nephritis usually occurs days to weeks after starting the drug. Symptoms may be nonspecific, with malaise, fatigue, and anorexia. A low-​grade fever, fleeting rash, and arthralgia may also be reported. Investigations show a variable degree of renal dysfunction along with proteinuria and nonvisible haematuria. Urine microscopy may show white and red cell casts, and there may be a blood eosinophilia. However, in practice, the key is to suspect the diagnosis, stop the po- tentially offending drug (or drugs), and proceed with a renal biopsy if renal function is severe or does not improve. Obstruction Specific drugs, such as aciclovir and the protease inhibitor indinavir, may precipitate as crystals within the tubule, causing obstruction and sometimes renal failure. This is more likely to occur if the pa- tient is dehydrated, hence adequate fluid input to achieve a high urinary volume is advised before these drugs are taken. See Chapter 21.19 for further discussion of drugs and the kidney. Pregnancy Pregnancy provides a unique set of circumstances in which renal disease may present. Pre-​existing renal disease may be detected as part of screening for proteinuria and hypertension during the first trimester. Alternatively, de novo renal disease may be precipitated by pregnancy and present with specific syndromes, such as nephrotic syndrome or AKI due to pre-​eclampsia. A summary of the presenta- tion of renal disease in pregnancy is detailed in Box 21.3.17. Box 21.3.16  Adverse effects of drugs on the kidney AKI • Acute tubular cell injury (acute tubular necrosis, ATN)

—​ Aminoglycosides

—​ Amphotericin

—​ Cisplatin

—​ NSAIDs

—​ Radiocontrast media

—​ Paracetamol poisoning

—​ Statins (by inducing rhabdomyolysis) • Interstitial nephritis:

—​ Proton pump inhibitors

—​ β-​Lactam antibiotics (penicillins, cephalosporins)

—​ NSAIDs

—​ Diuretics, particularly thiazides

—​ Allopurinol

—​ Sulphonamides

—​ Other antibiotics (e.g. ciprofloxacin, rifampicin)

—​ Indinavir

—​ Aristolochic acid (‘Chinese herb nephropathy’) Nephrotic syndrome • Membranous glomerulonephritis:

—​ High-​dose captopril

—​ Gold

—​ Penicillamine

—​ Phenytoin • Minimal change:

—​ NSAIDs • Focal segmental glomerulosclerosis:

—​ Pamidronate

—​ Heroin Tubular dysfunction • Renal tubular acidosis:

—​ Acetazolamide

—​ Amphotericin

—​ Lithium • Nephrogenic diabetes insipidus:

—​ Lithium

—​ Demeclocycline Others • Renal papillary necrosis:

—​ Aspirin with phenacetin

—​ NSAIDs • Crystalluria with tubular obstruction

—​ Aciclovir

—​ Indinavir

—​ Methotrexate

—​ Sulphonamides

21.3  Clinical presentation of renal disease 4779 The clinical presentation of renal disease during pregnancy is often varied and nonspecific, but certain features may guide the diagnosis. Key points to note are as follows: • Is there evidence of pre-​existing renal disease? • Were previous pregnancies complicated by hypertension or pre-​eclampsia? • What was the time of onset of renal disease during pregnancy? Onset in late pregnancy implies that the renal disease is likely to be pregnancy induced. • Hypertension with proteinuria and oedema suggest pre-​eclampsia or underlying renal disease (e.g. systemic lupus erythematosus). • Hypotension and hypovolaemia suggest sepsis or haemorrhage. See Chapter 14.5 for further discussion of renal disease in pregnancy. Pre-​eclampsia and HELLP Pre-​eclampsia classically presents with hypertension, oedema, and proteinuria. Other recognized features include elevation of serum urate, liver transaminases, and haematocrit, along with thrombo- cytopenia. However, patients may not be hypertensive or demon- strate other features, hence distinguishing pre-​eclampsia from pre-​existing renal disease may be difficult, and the condition may oc- casionally present with heavy proteinuria and nephrotic syndrome. The HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets) is a severe variant of pre-​eclampsia that is commonly asso- ciated with renal failure, severe haemolysis, and coagulopathy, and may progress to multiorgan failure. See Chapters 14.4 and 14.9 for further discussion. Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura HUS and thrombotic thrombocytopenic purpura are related dis- orders that are occasionally associated with pregnancy. Both can cause AKI. HUS usually occurs 2 days to 10 weeks postpartum and may cause severe renal failure. By contrast, thrombotic thrombocytopenic purpura usually presents in the first or second trimester with predominant neurological features and only mild proteinuria and haematuria. See Chapters 21.10.6, 22.7.3, and 22.7.5 for further discussion. FURTHER READING Bauer SR, Carroll PR, Grady D (2019). Hematuria practice guidelines that explicitly consider harms and costs. JAMA Intern Med, doi: 10.1001/jamainternmed.2019.2269. Cohen RA, Brown RS (2003). Clinical practice. Microscopic hema- turia. N Engl J Med, 348, 2330–​8. Doshi SM, Friedman AN (2017). Diagnosis and management of type 2 diabetic kidney disease. Clin J Am Soc Nephrol, 12, 1366–​73. Hill NR, et al. (2016). Global prevalence of chronic kidney disease—​a systematic review and meta-​analysis. PLoS One, 11, e0158765. Joint Specialty Committee on Renal Medicine of the Royal College of Physicians of London and the Renal Association (2006). Chronic kidney disease in adults: UK guidelines for identification, management and referral. Royal College of Physicians of London, London. Keith DS, et al. (2004). Longitudinal follow-​up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med, 164, 659–​63. Kodner C (2016). Diagnosis and management of nephrotic syndrome in adults. Am Fam Physician, 93, 479–​85. Krogsbøll LT (2014). Guidelines for screening with urinary dipsticks differ substantially—​a systematic review. Dan Med J, 61, A4781. Lamb EJ, Stevens PE (2014). Estimating and measuring glomerular fil- tration rate: methods of measurement and markers for estimation. Curr Opin Nephrol Hypertens, 23, 258–​66. Leung N, Nasr SH (2014). Myeloma-​related kidney disease. Adv Chronic Kidney Dis, 21, 36–​47. Lopez-​Vargas PA, et al. (2013). Prevention, detection and management of early chronic kidney disease: a systematic review of clinical prac- tice guidelines. Nephrology (Carlton), 18, 592–​604 Moroni G, Ponticelli C (2014). Rapidly progressive crescentic glomerulonephritis: early treatment is a must. Autoimmun Rev, 13, 723–​9. National Institute for Health and Care Excellence (2014). Chronic kidney disease in adults:  assessment and management. Clinical Guideline 182. http:/​www.nice.org.uk/​guidance/​cg182 Niemi MA, Cohen RA (2015). Evaluation of microscopic hematuria: a critical review and proposed algorithm. Adv Chronic Kidney Dis, 22, 289–​96. Papadopoulou-​Marketou N, Chrousos GP, Kanaka-​Gantenbein C (2017). Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev, 33, e2841. Radhakrishnan J, Perazella MA (2015). Drug-​induced glomerular dis- ease: attention required! Clin J Am Soc Nephrol, 10, 1287–​90. Raghavan R, Eknoyan G (2014). Acute interstitial nephritis—​a re- appraisal and update. Clin Nephrol, 82, 149–​62. Box 21.3.17  Renal disease in pregnancy AKI in pregnancy • Hypovolaemia:

—​ Hyperemesis

—​ Haemorrhage

—​ Sepsis

—​ Abruption • Infection:

—​ Pyelonephritis

—​ Septic abortion

—​ Puerperal sepsis • Obstruction:

—​ Gravid uterus • Endothelial dysfunction:

—​ Pre-​eclampsia

—​ Acute fatty liver of pregnancy

—​ HELLP syndrome

—​ HUS Exacerbation of pre-​existing renal disease • CKD of any cause with deterioration of function, proteinuria, and pre-​eclampsia • Flare of systemic and renal disease (systemic lupus erythematosus and systemic sclerosis) New-​onset nephrotic syndrome • Pre-​eclampsia • Systemic lupus erythematosus • Minimal change disease

section 21  Disorders of the kidney and urinary tract 4780 Siew ED, Davenport A (2015). The growth of acute kidney injury: a rising tide or just closer attention to detail? Kidney Int, 87, 46–​61. Tesar V, Hruskova Z (2013). ANCA-​associated renal vasculitis—​an update. Contrib Nephrol, 181, 216–​28. Torres PA, et al. (2015). Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J, 15, 58–​69. van der Velde M, et al. (2009). Screening for albuminuria identifies individuals at increased renal risk. J Am Soc Nephrol, 20, 852–​62. Webster AC, et  al. (2017). Chronic kidney disease. Lancet, 389, 1238–​52. Webster P, et  al. (2017). Pregnancy in chronic kidney disease and kidney transplantation. Kidney Int, 91, 1047–​56. Wingo CS, Clapp WL (2000). Proteinuria: potential causes and ap- proach to evaluation. Am J Med Sci, 320, 188–​94. Zubair AS, et al. (2016). Loin pain hematuria syndrome. Clin Kidney J, 9, 128–​34.

21.4 Clinical investigation of renal disease 4781

21.4 Clinical investigation of renal disease 4781 Andrew Davenport

ESSENTIALS An accurate history and careful examination will determine the sequence and spectrum of clinical investigations required to make a diagnosis or decide on prognosis or treatment. Examination of the urine Midstream urine (MSU) sample—​this standard investigation requires consideration of (1)  macroscopic appearance—​this may be sug- gestive of a diagnosis (e.g. frothy urine suggests heavy proteinuria); (2)  stick testing—​including for pH (<5.3 in an early-​morning spe- cimen makes a renal acidification defect unlikely), glycosuria, spe- cific gravity (should be >1.024 in an early-​morning or concentrated sample), nitrite (>90% of common urinary pathogens produce nitrite), and leucocyte esterase; and (3) microscopy—​for cellular elements (in particular red cells, with the presence of dysmorphic red cells de- tected by experienced observers indicative of glomerular bleeding), casts (cellular casts indicate renal inflammation), and crystals. Quantification of proteinuria—​this is important because the risk for progression of underlying kidney disease to endstage renal failure is related to the amount of protein in the urine. Quantification by 24-​h urinary collection is cumbersome and unreliable in many patients, and has been replaced by estimation of the urinary albumin:creatinine ratio (ACR; normal is <2.5 mg/​mmol for men and <3.5 mg/​mmol for women) or protein:creatinine ratio (PCR; normal is <13 mg/​mmol) on a spot sample. An ACR of 100 mg/​mmol ap- proximately corresponds to proteinuria of 1.5 g/​day, and 350 mg/​ mmol to nephrotic-​range proteinuria. Low molecular weight proteinuria—​is caused by proximal tubular injury and can be detected with markers including α-​glutathione-​S-​ transferase, α1-​macroglobulin, and retinol-​binding protein. Estimation of glomerular filtration rate Knowledge of the glomerular filtration rate (GFR) is of crucial import- ance in the management of patients, not only for detecting the pres- ence of renal impairment, but also in the monitoring of all patients with or at risk of renal impairment, and in determining appropriate dosing of those drugs cleared by the kidney. Measurement of plasma creatinine remains the standard biochemical test used to assess renal function. Estimating the glomerular filtration rate (eGFR)—​from a measure- ment of plasma creatinine concentration, the standard method uses the simplified Modification of Diet in Renal Disease (sMDRD) formula, which was based on a predominantly Caucasoid North American cohort with chronic kidney disease, and requires know- ledge of the patient’s sex, age, and ethnicity (but not their weight or height). On the basis of the eGFR, stages of chronic kidney disease (CKD) are classified as follows: Limitations of the eGFR—​this has not been validated in people below 18 years of age, hospitalized patients, or those with acute kidney injury, pregnancy, oedematous states, muscle-​wasting dis- orders, amputations, or malnourishment. Similarly, it has not been validated for extremes of age or body weight, or for ethnic groups other than whites of northern European origin and African Americans. Because of the inaccuracy of the MDRD equation, par- ticularly for those with eGFRs greater than 60 ml/​min, a revised ver- sion (CKD-​EPI) has been introduced. Other methods of measuring GFR—​isotopic methods can provide the most accurate determination of GFR, but are not often required in routine clinical practice. Estimation of creatinine clearance with a 24-​h urinary collection remains a useful test, particularly when there is reason to doubt the validity of the eGFR. Investigation of tubular function Proximal tubule—​analysis of excretion of the following substances can assist in the diagnosis of proximal tubular disorders: (1) glucose—​the maximum reabsorption rate for glucose (TmG) in the proximal tubule can
21.4 Clinical investigation of renal disease Andrew Davenport CKD stagea eGFR (ml/​min per 1.73 m2 body surface area) 1

90, with other evidence of renal disease 2 60–​89, with other evidence of renal disease 3A 45–​59 3B 30–​44 4 15–​29 5 <15, or receiving renal replacement therapy a The suffix (p) can be used to denote the presence of proteinuria as defined by a spot urinary ACR of ≥30 mg/​mmol, which is approximately equivalent to a PCR of ≥50 mg/​mmol (≥0.5 g/​24 h).

section 21  Disorders of the kidney and urinary tract 4782 be determined following infusion of 20% dextrose and is normally about 15 mmol/​litre (TmG/​GFR); (2)  phosphate—​the theoretical maximum tubular threshold of phosphate (TMP/​GFR) can be estimated by formula from the plasma and urinary phosphate and creatinine concentra- tions, or can be measured directly following infusion of phosphate; and (3) amino acids—​five types of renal aminoaciduria are distinguished: di- basic amino acids, neutral amino acids (monoaminomonocarboxylic acids), glycine and imino acids, dicarboxylic amino acids, and general- ized amino aciduria (Fanconi’s syndrome). Distal tubule—​a water-​deprivation test can help to distinguish pa- tients with primary or secondary nephrogenic or cranial diabetes insipidus from those with primary polydipsia, who may all present with polyuria. Renal-​induced electrolyte and acid–​base imbalances—​(1) estimation of urinary free-​water clearance is useful in the analysis of patients with hyponatraemia (see Chapter 21.2.1); (2) estimation of transtubular po- tassium gradient is advocated by some as useful in analysis of disorders of potassium homeostasis (see Chapter  21.2.2); (3)  tests of urinary acidification are discussed in Chapter 21.15. Renal imaging Ultrasonography—​this noninvasive, safe, versatile, and (relatively) in- expensive technique is the first-​line method for imaging the kidney and urinary tract in many clinical circumstances. Ultrafast multislice CT scanning—​this allows resolution of 2 to 3 mm or less and has become the mainstay of renal imaging. CT urography can be performed with a combination of unenhanced, nephrogenic-​ phase, and excretory-​phase imaging: the unenhanced images are ideal for detecting urinary calculi; renal masses can be detected and characterized with the combination of unenhanced, nephrogenic-​ phase, and excretory-​phase imaging; the excretory phase provides imaging of the urothelium. CT angiography is the first-​line investiga- tion in the evaluation of acute renal trauma, assessment of tumour blood supply in cases of nephron-​sparing surgery, and for the diag- nosis of renal artery stenosis and/​or aneurysms. MRI—​this is an alternative to CT scanning in patients who are al- lergic to conventional iodine-​based radiocontrast media and has particular value in the staging of renal carcinoma and assessment of complex renal cysts. Magnetic resonance angiography tends to over- emphasize the significance of stenoses. Gadolinium contrast scanning should be carefully considered in patients with eGFR below 30 ml/​ min because of the risk of nephrogenic systemic fibrosis, which limits the utility of magnetic resonance techniques for many renal patients. Renal nuclear medicine scanning—​(1) dimercaptosuccinic acid (DMSA), used in estimation of differential renal function and detection of scarring (usually associated with reflux); (2) mercaptoacetyltriglycine (MAG3), used in detection of functionally significant obstruction, esti- mation of differential renal function, screening for renal artery stenosis, and monitoring of renal transplants. Fluorodeoxyglucose positron emission tomography (FDG-​PET) scanning combines the functional aspects of a nuclear medicine scan with the anatomical definition of CT scanning and is used to investi- gate renal tumours and to diagnose and monitor large vessel vasculitis. Invasive techniques—​these can allow therapeutic intervention as well as diagnosis, including antegrade or retrograde ureteropyelography (insertion of stents to relieve urinary obstruction) and angiography (angioplasty or stenting of the renal artery). Renal biopsy A renal biopsy should be considered in any patient with disease af- fecting the kidney when the clinical information and other laboratory investigations have failed to establish a definitive diagnosis or prog- nosis, or when there is doubt as to the optimal therapy. However, renal biopsy has the potential to cause morbidity and (on rare oc- casions) mortality, hence its risk must be outweighed by the poten- tial advantages of the result to the individual patient. Biopsies which would be ‘of interest’ but ‘not in the patient’s interest’ should not be performed. Introduction The key to making any correct diagnosis depends on a careful his- tory and thorough examination. In patients with kidney disease, the history and examination should attempt to differentiate acute from chronic kidney disease, single-​organ system involvement from multisystem disease, and obstruction from intrinsic or prerenal dis- ease. Kidney disease may be associated with preceding infections and the ingestion of drugs or herbal remedies. An accurate history and careful examination will determine the sequence and spectrum of clinical investigations required to make a diagnosis or decide on prognosis or treatment. Examination of the urine Urine collection To minimize contamination, standard investigation is of a mid- stream urine (MSU) sample. Voiding from a full bladder containing at least 200 ml of urine should remove urethral organisms before the MSU is collected. Even so, in women, vaginal leucocytes and bacteria may contaminate the urine, and men should retract the foreskin to minimize contamination. Suprapubic aspiration is the technique of choice in babies and infants, and occasionally in adults who cannot cooperate to provide an MSU. The second urine of the morning is the best for microscopy as it is still acidic and concen- trated, but without the overnight stay in the bladder that results in the degeneration of casts and cells. Cell lysis can occur in both hypo- tonic and alkaline urine. Only the first 10 ml of the stream should be collected in cases of suspected urethritis. Macroscopic appearance Fresh urine usually has a yellow colour due to the presence of urochromes, but occasionally it will have a milky appearance due to pus, spermatozoa, insoluble phosphates in alkaline urine (sometimes seen following heavy meals), or occasionally in cases of chyluria, or urate crystals in acid urine. Foamy or frothy urine is typical of heavy proteinuria. Certain agents and conditions can discolour urine. Pink to red coloration Haematuria may result in a range of colours from smoky pink through to port-​wine red in cases of frank macroscopic haematuria. Other causes of a pink or red urine include eating sweets containing aniline dyes, beetroot, blackberries and rhubarb, or other foodstuffs

21.4  Clinical investigation of renal disease 4783 containing anthocyanins; haemoglobin; myoglobin; some drugs including rifampicin, phenazopyridine, phenindione, phenol- phthalein, and senna-​containing laxatives; chronic poisoning with lead or mercury; and (if the urine is left to stand) porphyrins in cases of acute intermittent porphyria. Blue or green coloration Blue or green coloration can be caused by pseudomonas urinary sepsis, methylene blue, biliverdin, triamterene, amitriptyline, chlorophyll-​containing breath mints (Clorets), excessive use of mouthwash and deodorants, magnesium salicylate (Doan’s pills), phenyl salicylate, guaiacol (in cough remedies), thymol (in volatile oils and horesemint), iodochlorhydroxyquin, tolonium, Evans blue, methocarbamol, Diagnex blue, indigo blue, resorcinol, azuresin, bromoform, and occasionally propofol and indomethacin. Phenol and lysol can result in a green or black discolouration. Orange coloration Orange coloration can be caused by dehydration, and drugs including anthraquinone-​containing laxatives, rifampicin, phenazopyridine, sulfasalazine, and some chemotherapeutic agents, and excess urobilinogen particularly in patients with obstructive jaundice. Yellow urine Yellow urine may be found in patients prescribed mepacrine or phenacetin, those taking excessive amounts of riboflavin, and icteric patients with conjugated hyperbilirubinaemia. Black or brown urine Alkaptonuria results in black or brown urine, whereas myoglobin and melanin only lead to black urine on standing. Other causes of brown urine include high dietary ingestion of fava beans, rhubarb and aloe, bilirubin, chloroquine, l-​dopa, niridazole, furazolidone, laxatives containing senna or cascara, methocarbamol, metronida- zole, notrofurantoin, phenazopyridine, and primaquine—​after standing—​haemoglobin and myoglobin. As mentioned earlier, phenol and lysol can result in a black or green discolouration. Purple urine Patients with indwelling urinary catheters may present with the purple urine bag syndrome, when their urine becomes infected, typically with Gram negative Providencia stuartii and rettgeri, Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli, Morganella morganii, and Pseudomonas aeruginosa, as these bac- teria may contain the enzyme indoxyl phosphatase which converts indoxyl sulphate to the red indirubin and blue indigo compounds. Stick testing The upper limit of normal for protein excretion in the urine is 128 mg/​24 h. Although albumin is the largest single component, more than half of the protein content comprises low molecular weight proteins and protein fragments. Commercial sticks such as Albustix are very sensitive, detecting protein in urine starting at con- centrations around 100 mg/​litre. Since these sticks detect protein on a concentration basis using bromocresol green as an indicator dye, the results they give are affected by urine flow rate and urine dilu- tion or concentration. The sticks are treated with a buffer to keep their pH constant: an elevated urinary protein concentration can erroneously be recorded if the buffer is washed off by leaving the stick in the urine for too long, and with very alkaline urine. Some antiseptics used to clean the skin, including cetrimide and chlor- hexidine, may also react and cause a false-​positive result. More re- cently, antibody-​based dipsticks have been developed for detecting microalbuminuria. pH Normal urine is slightly acidic, but can vary between pH 4.5 and 8.0. If an early-​morning urine specimen is under pH 5.3, then there is unlikely to be a significant defect in urinary acidification. Alkaline pH is often found in urine infected with urea-​splitting bacteria. In some cases of urinary stone disease, particularly in cystinuria and urate nephropathy, crystal solubility is greater in alkaline urine, and patients should regularly check their urine pH. Haemoglobin and myoglobin are also more soluble in alkaline urine, hence maintaining a forced alkaline diuresis is important in the manage- ment of patients following tumour lysis and those with rhabdo- myolysis or haemoglobinuria. Glycosuria The stick reaction is based on glucose oxidase, which releases hydrogen peroxide from glucose, so producing a graded colour change by oxidizing an indicator. This reaction is specific for glu- cose and does not detect other sugars. The reaction can be blocked by large doses of ascorbic acid. A positive stick test for glucose must be interpreted in light of the plasma glucose level as glycosuria may reflect a defect in renal tubular glucose absorption. Specific gravity Specific gravity is a measure of the number of particles dissolved in a litre, whereas osmolality is the number of particles per kilo- gram. Protein and glucose increase the specific gravity more than the osmolality as they are dense particles. In normal patients, the early-​morning, or concentrated, urine sample should have a specific gravity of 1.024 or more. Nitrite stick test Nitrite sticks contain an aromatic amine that reacts with nitrites, which are produced by bacterial reduction of nitrate, to form a pink-​coloured diazonium complex. More than 90% of the common urinary pathogens are nitrite-​forming bacteria. However, pseudo- monas, Staphylococcus albus, S.  saprophyticus, and Enterococcus faecalis may have minimal or no nitrite-​producing capacity. Other false-​negative results may be obtained in alkaline urine, in patients taking large doses of vitamin C, and with frequent voiding of dilute urine when the urinary nitrite concentration is too low. Leucocyte esterase stick test This stick test is based on the presence of a leucocyte esterase and is very specific for the presence of urinary leucocytes, both intact and lysed. This test may be more accurate than microscopy when the urine is alkaline or hypotonic. However, the test can be inhibited by high concentrations of glucose (20 g/​litre or more), ketones, and antibiotics including cefalexin, cefalotin, nitrofurantoin, tetracyc- line, and tobramycin. The sensitivity of this test is also reduced when the specific gravity of the urine is high, for instance in the presence of a heavy proteinuria.

section 21  Disorders of the kidney and urinary tract 4784 Urine microscopy To obtain reproducible results, urine should be processed in a standard manner and examined under the microscope as soon as possible. In the author’s institution, a few drops of acetic acid (10% v/​v) are added to ensure a pH of 6.0 or less; then 10 ml of urine is centrifuged for 5 min at 1500 rev/​min (750 g), following which 9.5 ml of supernatant is removed and the deposit resuspended. One drop (50 µl) is placed on a microscope slide and covered with a standard coverslip (24 × 32 mm). Although phase-​contrast micros- copy is an advantage in identifying red cells and casts, a standard microscope will suffice. A semiquantitative assessment of casts is made at low power (160×) and other elements at high power (400×), expressing the counts as numbers per field. Normal urine contains 1 or 2 leucocytes per high-​power field (HPF), 1 erythrocyte per 2 or 3 HPF, 1 tubular cell per 10 HPF, and both hyaline casts (1 per low-​ power field, LPF) and granular casts (1 per LPF). Physical exercise can result in haematuria and cylindruria for several hours. Stains such as modified Sternheimer’s stain (Sedi-​stain) can be used to help differentiate renal tubular cells from leucocytes. To improve the de- tection of casts, urine can be filtered through a 5-​µm Millipore filter, and the retained casts stained with Papanicolaou’s stain. Cellular elements The morphology of the erythrocytes in the urine can give valuable information as to the source of bleeding. Those which have passed through the glomerulus and then along the renal tubule can become distorted or dysmorphic, whereas those originating from other sources within the urinary tract, such as the bladder, typically show much less evidence of damage so that they more closely resemble erythrocytes in the peripheral blood and are termed isomorphic. To establish a diagnosis of glomerular haematuria there should be a min- imum of three different forms of dysmorphic erythrocytes present. One particular type of dysmorphic erythrocyte, the acanthocyte, is reported to have 52% specificity and 98% sensitivity for glomerular haematuria when the acanthocyte count is 5% or more. However, not all workers have found erythrocyte morphology to be useful in discriminating glomerular from nonglomerular bleeding, and the physician who only occasionally examines urine under the micro- scope is unlikely to obtain clear, reproducible, and useful discrimin- ation between dysmorphic and isomorphic cells. Some centres use automated haematological cell counters (Coulter counter) to assess red cell morphology in both urine and peripheral blood. The distribution pattern for red cell size for lower urinary tract haematuria is similar to that of the peripheral blood, with a relatively narrow size range and a high frequency distribution curve, whereas the typical pattern for dysmorphic haematuria is one of a broader range of red cell sizes, with a lower frequency distribution. To have any reliability, urine samples must be processed rapidly by those who do it regularly. Microscopy may also reveal renal tubular epithelial cells. These cells are shed into the urine in acute tubular necrosis, in response to certain drugs (both nephrotoxic and ischaemic), and also in acute renal allograft rejection. In patients with nephrotic syndrome, these cells are seen as oval fat bodies, laden with lipid droplets. Squamous epithelial cells from the urethra and vagina and transitional cells from the ureter and bladder may also be present in normal urine. Urine cytology may reveal malignant transitional epithelial and/​or metaplastic squamous cells from the bladder. During infection, the urine may contain large numbers of leuco- cytes and bacteria. When large numbers of leucocytes are present in the absence of bacteria (so-​called sterile pyuria), then a variety of conditions should be considered: urinary stone disease, analgesic nephropathy, interstitial nephropathy, proliferative glomerulo- nephritis (rarely), renal tuberculosis, schistosomiasis, and partially treated bacterial urinary tract infection. Phase-​contrast microscopy can distinguish lymphocytes from neutrophils, but eosinophils can only be identified with specific stains (Hansel’s stain). Urinary eo- sinophilia classically occurs in cases of acute interstitial nephritis, typically due to drugs, and also in cholesterol atheroembolic disease. Urinary casts Casts form from the transformation of Tamm–​Horsfall glycopro- tein, secreted by the distal tubular cells, into a gel matrix. They typically assume a tubular structure. Hyaline casts only contain Tamm–​Horsfall glycoprotein and are found in a variable amount in the urine of normal subjects (Fig. 21.4.1). Fever, cardiac failure, strenuous exercise, and some drugs, such as furosemide and ethacrynic acid, increase hyaline cast excretion. During pas- sage through the distal tubule and collecting duct, a variety of proteins, pigments, and cells can adhere to the Tamm–​Horsfall protein, producing a wide variety of casts. Granular casts have deposits of either fine or coarse protein granules (Fig. 21.4.2). Although they may occur in normal subjects, or after exercise, they are typically found in cases of parenchymal renal disease. In patients with proteinuria, the protein deposited comes from the glomerulus, whereas in acute tubular necrosis, the protein comes from degenerate tubular cells. Broad waxy casts are much larger Fig. 21.4.1  Papanicolaou-​stained urine showing a hyaline cast with both normal transitional and squamous cells and renal tubular cells. Courtesy of Dr Deery. Fig. 21.4.2  Unstained urine specimen showing a granular cast.

21.4  Clinical investigation of renal disease 4785 than normal casts and have clear-​cut edges: they are formed in dilated hypertrophied tubules, as found in patients with chronic renal failure. Casts containing erythrocytes (red cell casts) indi- cate renal bleeding and are typically found when there is acute glomerular inflammation caused by glomerulonephritis or vascu- litis (Fig. 21.4.3). White cell casts (containing leucocytes) can be found in proliferative glomerulonephritis, acute interstitial neph- ritis, and acute pyelonephritis. Crystals Urine may contain several types of crystals, depending on the pH. The presence of a few crystals of uric acid, calcium oxalate, or cal- cium phosphate is usually not clinically relevant, although thin hexagonal crystals of cystine are a marker of cystinuria. In a few cases, crystalluria may be associated with intratubular obstruc- tion and acute kidney injury. Such cases would include acute uric acid nephropathy, ethylene glycol poisoning, and drugs including aciclovir, amoxicillin, indinavir, naftidrofuryl oxalate, sulfadiazine, and vitamin C. Urine cytology The importance of urine cytology in detecting urological malig- nancy is well established. However, exfoliated cells, particularly single cells, deteriorate rapidly and degenerative changes may be present with an hour. Collecting MSU samples in 5 ml of absolute alcohol helps slow down bacterial growth, and it is preferable to prepare the sample first and then stain the cells, rather than fix the cells and then prepare the sample. Standard preparation would in- clude centrifugation at 1500 rpm for 5 min, followed by a further cytocentrifugation at 1200 rpm for 5 min to prepare a cytospin preparation, which can then be spray fixed using a mixture of 80 ml polyethylene glycol, 690 ml isopropanol, 170 ml acetone, and 60 ml distilled water. Following a minimum of 5 min drying time, cytospin preparations can be stained using Papanicolaou’s tech- nique with a Shandon Linistain GLX. In addition to examining the urine for dysplastic or malignant cells in cases of bladder, pros- tate, and kidney cancers, urine cytology may also be helpful in establishing viral infections following renal transplantation (cyto- megalovirus and BK virus inclusions in renal epithelial cells.), and in acute kidney injury necrotic tubular cells may be present following ischaemic renal injury, but may also be present fol- lowing administration of antibiotics (aminoglycosides and ceph- alosporins) and chemotherapeutic agents. Urine cytology may also act as an adjunct to urine microscopy in assessing cellular components of urine (red and white blood cells, eosinophils, casts, etc.) and bacteriuria. Measurement of proteinuria Quantification of proteinuria is important as the risk for progres- sion of underlying kidney disease to endstage renal failure is related to the amount of protein in the urine. Traditionally, proteinuria has been measured using 24-​h urine collections and expressed as grams per day. This has the advantage that it averages out protein excre- tion and is not therefore affected by its normal diurnal variation (less overnight and first thing in the morning) or urine concentration. Several different methods are used to measure the protein content of 24-​h urine collections, ranging from the biuret method, which uses a copper-​based method to precipitate proteins, to dye-​binding methods using Coomassie Brilliant Blue as the indicator. These are more accurate than the turbidimetric methods, which use trichloro- acetic or sulphosalicylic acid and measure turbidity with a densi- tometer. Radiocontrast media and some drugs (including penicillin, sulphonamides, and tolbutamide) may give false-​positive results for proteinuria with the sulphosalicylic acid method. The biuret method measures total proteins, whereas the turbidimetric method provides different readings for albumin and globulins, as may do the dye-​ binding methods. However, because of the inherent problems of accuracy and reliability with 24-​h urine collections, the assessment of protein in spot urine samples has become the standard method of as- sessing proteinuria in routine clinical practice. Urinary albumin concentration is measured by a variety of methods based on an antibody technique for detecting serum albumin, including radio- immunoassay, nephelometry, immunoturbidity, and enzyme-​ linked immunosorbent assay (ELISA). Under resting conditions, urinary creatinine excretion is relatively constant throughout the day, hence to overcome the problems of timing of urinary collections, proteinuria in spot urine samples is expressed as an albumin:creatinine ratio (ACR; normal is <2.5 mg/​mmol for men and <3.5 mg/​mmol for women in a daytime urine or 24-​h col- lection, and <1.5 mg/​mmol for an overnight or early-​morning sample). An ACR of 100 mg/​mmol approximately corresponds to 1.5 g/​day, and 350 mg/​mmol to nephrotic-​range proteinuria. To improve the reliability of trends in serial samples over time, then as urinary protein has a diurnal variation, it is advisable to com- pare similar timed samples (morning or afternoon etc.) because of the diurnal variation of urinary protein excretion. However, albumin is not the only protein in urine and the rela- tionship between albumin and total urinary protein is not linear, with a ratio of 50% albumin with a urinary protein of 300 mg/​litre increasing to 70% at 1000 mg/​litre. As the measurement of protein in spot urine samples is cheaper than albumin, it has been suggested that, for patients with more than 1+ proteinuria on dipstick testing, the protein:creatinine ratio (PCR) should be used in routine clinical practice. The normal PCR is less than 13 mg/​mmol, with a dipstick value of 1+ roughly equiva- lent to a PCR of 45 to 149 mg/​mmol and ACR above 30 mg/​mmol, a dipstick of 2+ to a PCR of 150 to 449 mg/​mmol, and 3+ to 450 mg/​ mmol or more. Aside from their use to replace 24-​h urine collections, spot urine collections are particularly useful in the diagnosis of orthostatic Fig. 21.4.3  Papanicolaou-​stained urine deposit showing a red cell cast.

section 21  Disorders of the kidney and urinary tract 4786 proteinuria, in other words where the patient has a normal urinary protein excretion when recumbent, or overnight, but has marginally increased proteinuria in the ambulant or daytime sample. The ACR should not be measured during acute illness, menstru- ation, or intercurrent illness as these will temporarily increase the degree of proteinuria. Microalbuminuria Various antibody-​based assays for albumin can detect an increased urinary albumin excretion in patients with normal levels of protein- uria. High-​performance liquid chromatography detects more urinary albumin than the radioimmunoassay and other serum antibody-​ based tests. Normoalbuminuria is defined as an excretion rate of 20 µg/​min or less. Proteinuria is usually detectable on dipstick testing at rates of over 200 µg/​min, hence microalbuminuria is defined as an excretion rate between 20 and 200 µg/​min. The albumin excretion rate is some 25% higher during the day than the night. The classification of abnormal urinary albumin excretion is shown in Table 21.4.1. There is a good correlation between the morning albumin excretion rate and the ACR in the first urine sample of the morning. A further advantage of spot urines is that patients can provide a sample when they attend the clinic: provided these are taken at the same time and the patient’s dietary intake is relatively constant, they are very useful in assessing patients over time. A further advantage of measuring the ACR instead of albumin excretion rate is that the former, but not the latter, eliminates the need for timing of urinary samples. Microalbuminuria is not only an adverse factor for the progres- sion of diabetic renal disease, but is also predictive of cardiovas- cular events in both the diabetic and nondiabetic population. To grade this increased risk, then the United Kingdom (UK) National Institute for Clinical Excellence (NICE) guidelines proposed a grading system for ACR from grade A normal to mildly increased risk (< 3 mg/mmol), B moderately increased risk (3-30 mg/min) and C severe risk (>30 mg/min). In addition to those with diabetes, microalbuminuria may be found in patients with hypertension, car- diac failure, treatment with chemotherapeutic agents, and following a pyrexial or viral illness. Similarly, microalbuminuria may be pre- sent in healthy subjects after exercise and during normal pregnancy. Selectivity of proteinuria Patients with glomerular disease typically have a nonselective pro- teinuria, with a similar clearance of both high and low molecular weight plasma proteins. However, those with minimal change dis- ease may have selective proteinuria, with clearance of predominantly low molecular weight proteins, the demonstration of which is useful in paediatric practice where patients are often treated with steroids without a renal biopsy. Most laboratories compare the clearance of IgG as the large mo- lecular weight protein (150 kDa) to that of albumin (or transferrin, 88 kDa) as the low molecular weight protein. Both plasma and spot urine samples are required. Protein concentrations are measured ei- ther by laser nephelometry or radial immunodiffusion. Nonselective proteinuria is taken as an ([IgG]urine/​[IgG]plasma) × ([transferrin]plasma/​ [transferrin]urine) ratio of 0.2 or more, whereas selective proteinuria is taken as a ratio of 0.1 or less. Spill-​over proteinuria Patients with myeloma, some types of amyloidosis, and those with reticuloendothelial disorders may have a spill-​over proteinuria due to glomerular filtration of complete and incomplete κ and λ chains and immunoglobulin light chains. These low molecular weight pro- teins are not detected by simple urine stick testing, or by standard biochemical methods to determine urine protein concentration. Thus, when clinically appropriate, urine should specifically be sent for immunoelectrophoresis to exclude myeloma. However, light chains in particular may still not be detected, hence further inves- tigation with specific antisera may be required if their presence is suspected. Renal tubular proteinuria Interstitial renal disease can result in proteinuria, usually of less than 2 g/​day. Proximal tubular injury leads to increased low molecular weight proteinuria, characterized by an excess of intestinal alkaline phosphatase, N-​acetylglucosaminidase, retinol-​binding protein, tissue-​specific alkaline phosphatase, α-​glutathione-​S-​transferase (α-​GST), α1-​macroglobulin, and β2-​microglobulin. By contrast, Tamm–​Horsfall glycoprotein and α-​GST are increased in distal tubular injury. β2-​Microglobulin is freely filtered at the glomerulus and then re- absorbed in the proximal tubule, such that less than 1% of the filtered load is excreted in the urine of normal subjects (normal is <370 µg/​ 24 h). Thus urinary β2-​microglobulin excretion has been used as a marker of proximal tubular damage. However, β2-​microglobulin is unstable in urine, and its excretion can be affected both by an in- creased production rate (found in cases of myeloproliferative dis- ease, chronic inflammatory states, and acute liver disease) and by saturation of β2-​microglobulin tubular uptake due to an excess of dibasic amino acids. Table 21.4.1  Classification of abnormal urinary albumin excretion 24-​h urine albumin
(mg/​24 h) Overnight albumin
(µg/​min) Spot albumin
(mg/​litre) Spot urine ACR (mg/​mmol) PCR (mg/​mmol) Normal <15 <10 <10 M <1.25 F <1.75 <13 Microalbuminuria 30 to <300 20 to <200 20 to <200 M 2.5 to <25 F 3.5 to <35 16 to <160 Macroalbuminuria

300 200 200 M >25 F >35 160 ACR, albumin:creatinine ratio; F, female; M, male; PCR, protein:creatinine ratio. The normal ACR ratio is lower in men than women due to higher urinary creatinine excretion.

21.4  Clinical investigation of renal disease 4787 More reliable markers of tubular proteinuria are now available. These include α-​GST, α1-​macroglobulin, and retinol-​binding pro- tein. Turbidimetric or enzyme assays are now available. Results are expressed as either excretion rates (e.g. normal α-​GST is <12.5 ng/​min or <11.5 µg/​litre) or as a ratio to urinary creatinine (e.g. normal reference range for retinol-​binding protein:creatinine is <0.019 mg/​mmol). Typically in cases of renal tubular protein- uria the ratio of retinol-​binding protein:creatinine is equal to or greater than that of albumin:creatinine, whereas normally the ratio of urinary albumin:creatinine is twice that of retinol-​binding protein:creatinine. These tests of renal tubular proteinuria are helpful in investigating patients with suspected Chinese herbal nephropathy, Asian subcon- tinent nephropathy, and Balkan nephropathy, and they may also be useful in monitoring progression of these diseases and other tubulointerstital diseases such as adult polycystic kidney disease. Industrial workers exposed to heavy metals and organic chemicals, such as those used in the dry-​cleaning industry, may develop inter- stitial renal disease characterized by increased urinary low mo- lecular weight proteinuria. Urinary biomarkers in acute renal injury Advances in urinary proteomics have led to the search for bio- markers of acute kidney injury and acute renal transplant rejection. Urinary biomarkers fall into three main categories:  (1) markers of kidney function, similar to creatinine, typified by cystatin C; (2) markers of the severity of the inflammatory response made by the individual to the insult, including neutrophil gelatinase-​associated lipocalin (NGAL), liver type fatty acid binding protein, and urinary IL-​18; (3) markers of kidney damage, such as kidney injury molecule (KIM-​1), urinary enzymes (α1-​microglobulin, α1-​acid glycopro- tein, N-​acetyl-​β-​d-​glucosaminidase, γ-​glutamyltranspeptidase, and alkaline phosphatase) and albumin; and (4) inducers of cell cycle G1 arrest, including urinary insulin-​like growth factor-​binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-​2 (TIMP-​2). Whereas these biomarkers are associated with acute kidney injury, others such as urinary hepcidin-​25 have been reported to be asso- ciated with a reduced risk of kidney injury, and urinary hepatocyte growth factor with an earlier renal recovery. Preliminary single-​centre studies in children with pre-​existing normal renal function have shown that urinary biomarkers are more effective in predicting both acute renal injury and severity than changes in serum creatinine, as creatine generation and conversion to creatinine typically falls during acute kidney injury. However, these encouraging findings have not always been replicated in multicentre studies that included patients with established chronic kidney disease, hence urinary biomarkers currently remain a research tool in acute kidney injury. However, whereas many of these biomarkers were ori- ginally only available as research assays, or required specialized tech- niques such as time of flight mass spectroscopy, commercial ELISA assays are now becoming available. Currently NGAL and KIM-​1 ap- pear the most promising as markers of the severity of acute kidney injury, and the inducers of cell cycle G1 arrest (IGFB7 and TIMP-​2) as early biomarkers of acute renal injury, whereas urinary hepcidin-​25 appears to have a negative predictive effect. Similarly, further studies are required to determine the role of urinary biomarkers such as granzyme in distinguishing renal trans- plant rejection from ischaemic renal injury. Studies evaluating the role of urinary biomarkers in assessing progression of chronic kidney disease are currently under way. Estimation of glomerular filtration rate Biochemical tests Knowledge of the glomerular filtration rate (GFR) is of crucial im- portance in the management of patients, not only for detecting the presence of renal impairment but also in the monitoring of all pa- tients with or at risk of renal impairment, and in determining ap- propriate dosing of those drugs cleared by the kidney. Measurement of plasma creatinine remains the standard biochemical test used to assess renal function. Unfortunately, the plasma creatinine concen- tration is not linearly related to the GFR, hence some 30% of patients with significantly impaired renal function still have a plasma cre- atinine value within the normal range (<120 µmol/​litre). Creatinine Creatine, which is endogenously synthesized in the liver or exogen- ously supplied by meat in the diet, is transported to muscle and con- verted to creatinine by nonenzymatic dehydration. Muscle mass represents some 98% of the total body creatine pool. Thus gender, ra- cial, and age-​related differences in body composition, physical training and exercise, muscle-​wasting diseases, paralysis, and intercurrent illnesses will all affect the production rate of creatinine and therefore both the plasma creatinine concentration and urinary creatinine ex- cretion (Table 21.4.2). Hence in young children there is a steady in- crease in the plasma creatinine level as their muscle mass increases. Dietary influences will affect plasma creatinine levels, with a reduction Table 21.4.2  Factors affecting creatinine generation Factor Effect on serum creatinine Ageing Decreased Female sex Decreased Race or ethnic group (compared with white) Black Increased Hispanic Decreased Oriental Decreased South Asian Decreased Body habitus Muscular Increased Amputation Decreased Obesity Decreased Chronic illness Cirrhosis, malnutrition, chronic inflammation, cancer, severe cardiovascular or respiratory disease, hospitalized patients Decreased Neuromuscular diseases Decreased Hypothyroidism Increased Diet Vegetarian diet Decreased Ingestion of cooked meat Increased

section 21  Disorders of the kidney and urinary tract 4788 in strict vegans and increased values in those with a high meat intake (particularly stewed meat: cooking leads to the conversion of creatine to creatinine) or those taking creatine supplements. For any individual, the plasma creatinine level is relatively constant throughout the day, although there is a tendency for it to increase slightly in the afternoon. Creatinine is not only freely filtered by the glomerulus but is also secreted into the renal tubule. Creatinine reabsorption may occur at low urinary flow rates, such as in congestive cardiac failure, and cir- rhosis. The relative proportion of renal tubular creatinine secretion to that filtered increases as renal function declines. In addition, in oedematous states such as nephrotic syndrome, calculated creatinine clearance exceeds inulin clearance, suggesting increased tubular cre- atinine secretion. Several drugs are known to block the tubular secre- tion of creatinine and thus cause an increase in the serum creatinine level:  these include the diuretics amiloride, spironolactone, and triamterene; also cimetidine, aspirin, probenecid, and trimethoprim. The most accurate method of measuring plasma creatinine is by isotope dilution mass spectrometry (IDMS), followed by enzym- atic methods, but these are costly compared with the standard Jaffé assay. Most laboratories therefore measure plasma creatinine using standard automated analysers that assess the chromogenic product of creatinine and alkaline picrate (Jaffé reaction). Table 21.4.3 lists some substances which in high concentration can act directly or indirectly as chromogens, or affect the background control blanks, and so result in a spurious increase in the plasma creatinine level. In clinical practice, these may lead to an overestimation of creatinine in people with poorly controlled diabetes, and an underestimation in deeply jaundiced patients, such as those with primary biliary cir- rhosis. Blank and more recently compensated Jaffe rate reactions have been introduced in an attempt to overcome some of these tech- nical problems, but other enzymatic methods may provide greater accuracy, although at potentially greater cost. Reciprocal creatinine or logarithm of creatinine values As the plasma creatinine level roughly doubles for every 50% re- duction in GFR, expressing (transforming) the results as the recip- rocal or logarithm is useful in assessing serial plasma values, which changes the graph from an exponential to a straight-​line plot. The advantage of using a straight-​line plot of plasma creatinine is that it allows the rate of renal decline to be calculated, which can then be used to predict the onset of endstage renal failure and the require- ment for dialysis treatment in many patients. The reciprocal cre- atinine plot assumes a constant rate of loss, whereas the logarithm a constant fractional loss of renal function. Patients with diabetic nephropathy tend to have a faster rate of de- cline in renal function than those with glomerular disease, who tend to have a faster rate than those with tubulointerstitial renal disease. In addition, it is easier to assess the effect of treatment interventions on the progression of renal disease by analysing transformed data, and also to recognize when there has been a sudden and unexpected deterioration in function that requires urgent investigation. Prediction of creatinine clearance from the plasma creatinine level and estimation of GFR (eGFR) Despite the potential inaccuracies in the determination of plasma creatinine, variations in endogenous creatinine production rates, and the relative increase in renal tubular and intestinal creatinine secretion with deteriorating renal function, formulas based on the plasma creatinine level are used in clinical practice to estimate cre- atinine clearance. The first commonly used equation, validated in adults, was the formula of Cockcroft and Gault, later modified by Gault: Creatinine clearance (140 age) weight(kg) 72 plasma creatini

− × × ne concentration(mg/dl) Or Creatinine clearance (ml/min) 1.2 weight(kg) 72 plasma creat

× × inine concentration( mol/litre) µ In the original formula there was a different equation for women, with a factor of 0.85 (instead of 1.2) to allow for the lower rate of cre- atinine production in women due to differences in their body com- position. As creatinine turnover is affected by muscle mass and body size, Salazar and Corcoran modified the Cockcroft–​Gault equation to correct for size by using an estimate of fat free weight: Male: 137 age yr 0.285 wt kg 12.1 ht m /51 seru ( ( )) ([ ( )] [ ( )]) 2 − × × + × × m creatinine mg/dl ( ) Female: 148 age yr 0.257 wt kg 9.74 ht m /60 seru ( ( )) ([ ( )] [ ]) 2 − × × + × × m creatinine mg/dl ( ) (To convert creatinine µmol/​litre to mg/​dl, divide by 88.4.) Similar equations were developed for children: Schwartzequation: GFR ml/min/1.73 m 0.55 ht m /serum cre ( ) [ ( )] 2 = × atinine mg/dl ( ) Counahan Barratt equation: GFR ml/min/1.73 m 0.43 ht m ( ) [ ( )] 2 −

× /serum creatinine mg/dl ( ) Although these formulas may be helpful in clinical practice to provide an estimation of renal function (eGFR), they are not al- ways accurate, particularly in people with diabetes and in African Americans (due to differences in body composition). Another equation was developed in 1999 following the Modification of Diet in Renal Disease (MDRD) trial, based on 1628 adult, predominantly Caucasoid patients in the United States of Table 21.4.3  Compounds that can affect the measurement of plasma or urinary creatinine concentration Endogenous compounds Exogenous compounds Protein Acetohexamide Ketones Cephalosporins Ketoacids 5-​Fluorocytosine Glucose Methanol metabolites Fatty acids Phenylacetylurea Urate Dopamine Urea Bilirubin

21.4  Clinical investigation of renal disease 4789 America with chronic kidney disease, and this was further revised in 2005 as the simplified MDRD equation (sMDRD): eGFR ml per m serumcreatinine mg dl ( ) [ ( )] ( /min . / . 1 73 175 2 1 154

× × − age inyears if female if black ) ( ) ( ) . . . − × × 0 203 0 742 1 212 eGFR ml per m serumcreatinine mol litre ( ) ([ ( )/ . /min . / 1 73 175 1 2 = × µ 004 0 011312 1 154 1 212 ] . ) ( ) ( ) . . × × − − age inyears if black The sMDRD equation has the advantage over the Cockcroft–​Gault and many other formulas in being easier to calculate as it does not require knowledge of the patient’s weight, and their sex and age are routine demographics collected for sample identification. Use of the sMDRD equation has now been introduced into standard clinical practice in the United States of America, the United Kingdom, and Australia to define stages of chronic kidney disease, the intention being to encourage recognition of renal impairment at an early stage in the population at large, and therefore allow management of risk factors to reduce both renal progression and cardiovascular risk (Table 21.4.4). The Kidney Disease Improving Global Outcomes (KDIGO) group suggested combining both CKD grade and urinary proteinuria to risk assess patients for adverse events. Because of the inaccuracy of the MDRD equation for patients with an eGFR of 60 ml/​min per 1.73 m2 or greater, a further modi- fication has been published, termed CKD-​EPI (Chronic Kidney Disease Epidemiology Collaboration): For men with serum creatinine <0.9 mg/​dl:
GFR ml/​min per 1.73 m2 = 141 × (serum creatinine/​0.9)−0.411

= 0.993age = 1.159 (if black) For men with serum creatinine >0.9 mg/​dl:
GFR ml/​min per 1.73 m2 = 141 × (serum creatinine/​0.9)−1.209

= 0.993age = 1.159 (if black) For women with serum creatinine <0.7 mg/​dl:
GFR ml/​min per 1.73 m2 = 144 × (serum creatinine/​0.7)−0.329

= 0.993age = 1.159 (if black) For women with serum creatinine >0.7 mg/​dl:
GFR ml/​min per 1.73 m2 = 144 × (serum creatinine/​0.7)−1.209

= 0.993age = 1.159 (if black) (Divide by 88.4 to convert serum creatinine µmol/​litre to mg/​dl.) However, these equations have not been validated for elderly pa- tients or those from ethnic minorities. Furthermore, they were de- rived based on iothalamate urinary clearances, which themselves have inherent inaccuracies, both because of the requirement for urinary collections, and also the relative importance of nonrenal ex- cretion at low levels of GFR. Further refinements to the predictive equations will probably be developed. The first problem in rolling out such a programme of population screening was to standardize the measurement of plasma creatinine. For example, in the United Kingdom alone there were 31 different modifications of the standard Jaffé reaction used in routine clinical practice. Rather than each laboratory changing its method/​ana- lyser, each individual laboratory had to develop correction factors from the IDMS-​traceable version of the MDRD equation. Thus in the United Kingdom the following equation is employed using an IDMS-​based national external quality assessment service: eGFR (ml/​min per 1.73 m2) = 175 × (([creatinine (μmol/​litre)
− intercept]/​slope) × 0.011312)−1.154 × (age in years)−0.203
× 0.742 (if female) × 1.212 (if black) where intercept and slope are the individual laboratory correction factors for the IDMS method. The eGFR has not been formally validated in people younger than 18 years, hospitalized patients, or those with acute kidney in- jury, pregnancy, oedematous states, muscle-​wasting disorders, am- putations, or malnourishment. Similarly, it has not been validated for ­extremes of age or body weight, or for ethnic groups other than whites of northern European origin and African Americans. In the United Kingdom, the value of the eGFR falls within 30% of the true GFR in 90% of patients. Typically, the eGFR under- estimates true renal function in patients with hyperfiltration, with its accuracy improving as renal function deteriorates. In the United States of America, Australia, and Scotland, laboratories were initially instructed to report all eGFR values higher than 60 ml/​min per 1.73 m2 simply as ‘greater than 60’ because of in- creased inaccuracy at higher eGFR, whereas in the United Kingdom the advice to laboratories is to report values up to 90 ml/​min per 1.73 m2, and then ‘greater than 90’. Although the eGFR, however estimated, has inherent inaccuracies, it is now universally employed, may prove useful in assessing stability or progression of renal function over time in the general population, and can allow a rational basis for referral to specialist renal physicians. Creatinine clearance In clinical practice, creatinine clearance is now being replaced by the eGFR, as the accuracy of the creatinine clearance method depends on patient compliance to provide an accurate 24-​h urine collection. Even when patients are in a steady state, urinary creatinine excre- tion varies from day to day, and reliability can be increased by per- forming consecutive daily clearances. Creatinine clearance is calculated as follows: Creatinine clearance (ml/min) urinevolume(ml/24h) urinecrea

× tinine concentration( mol/litre) plasmacreatinineconcentrat µ ion( mol/litre) 24 60 µ × × Table 21.4.4  The stages of chronic kidney disease (CKD) CKD stagea eGFR (ml/​min per 1.73 m2 body surface area) 1

90, with other evidence of renal disease 2 60–​89, with other evidence of renal disease 3A 45–​59 3B 30–​44 4 15–​29 5 <15, or receiving renal replacement therapy a The suffix (p) can be used to denote the presence of proteinuria as defined by a spot urinary ACR of ≥30 mg/​mmol, which is approximately equivalent to a PCR of ≥50 mg/​mmol (≥0.5 g/​24 h). Patients with CKD stages 3A, 3B, 4, and 5 may or may not have any other evidence of renal disease.

section 21  Disorders of the kidney and urinary tract 4790 With regard to the use of the creatinine clearance measurement as an estimate of GFR, two errors tend to balance each other out. The chromogenic assay tends to overestimate the plasma, but not urinary, creatinine concentration, leading to an underestimation of GFR. By contrast, creatinine is not only excreted by glom- erular filtration: some is secreted by the renal tubules, leading to an overestimation of the GFR. However, in patients with im- paired renal function these contrasting effects are not balanced, and the relative increase in tubular creatinine secretion results in creatinine clearance exceeding GFR. This problem can be over- come by the administration of 400 mg of cimetidine to block renal tubular creatinine secretion, but this manoeuvre is rarely (if ever) performed in clinical practice solely for this purpose. By convention, creatinine clearance values are commonly corrected for body surface area to adjust for differences in muscle mass, assuming a fixed mathematical relationship between body sur- face area and the relative proportions of fat to muscle. However, body composition is not only age and gender dependent, but also varies from race to race, and other inaccuracies occur in oedema- tous and obese states. Cystatin C Cystatin C is a low molecular weight basic protein (13.26 kDa) from the cystatin superfamily of cysteine proteinase inhibitors that is produced by all nucleated cells. It is freely filtered by the glomerulus and initially was thought not reabsorbed, secreted or catabolized by the renal tubules during its passage into the urine. The generation of cystatin C appears to be less variable from person to person than creatinine and is not affected by dietary protein intake, hence it has been advocated as a better marker for GFR than creatinine. However, it is now realized that cystatin C generation varies more than creatinine and is increased in inflammatory states, including cardiac failure, but appears to be reduced in acute kidney injury. Rapid and fully automated immunonephelometric assays are now avail- able, but there is assay variation between different manufac- turers, also with different assay platforms, and as such there has been a recent move to standardize commercially available assays. Currently cystatin C assays are more costly than those of creatinine. As with creatinine, several equations have been proposed to allow estimation of GFR (ml/​min per 1.73 m2) based on serum cystatin C measurements (mg/​litre): • Larsson equation: GFR = 77.329 × cystatin C−1.2623 • Hoek equation: GFR = −4.32 + 80.34 × 1/​cystatin C • Le Bricon equation: GFR = 78 × (1/​cystatin C) + 4 • Rule equation: GFR = 76.6 × cystatin C−1.16 • Filler–​Lepage equation: GFR = 1.962 + [1.123 × log (1/​cystatin C)] • Grubb equation: GFR = 84.69 × cystatin C−1.68 • Grubb equation (children): GFR = 84.69 × cystatin C−1.68 × 1.34 (if <14 years old) • Stevens equation (children): GFR = 76.7 × cystatin C−1.19 CKD-​ EPI GFR= 133 × min(cystatin C/​0.8, or 1)−0.499 × max(cystatin C/​0.8, or 1)−1.328 × 0.999age × 0.932(if female) In addition there are combined serum creatinine and cystatin C equations: • Berlin Initiative Study: GFR = 767 × cystatin C−0.4 × creatinine−0.4 × age−0.57 × 0.87 (if female) • CKD-​EPI: GFR = 135 × min(creatinine/​k, 1)a × max(creatinine/​ k, 1)–​0.601 × min(cystatin/​0.8, 1)–​0.375 × max(cystatin/​0.8, 1)–​0.711 × 0.995age × 0.969 (if female) × 1.08 (if black) in which k is 0.7 for women and 0.9 for men, a is –​0.248 for women and –​0.207 for men, min indicates the minimum of serum creatinine/​k or 1, and max indicates the maximum of serum creatinine/​k or 1 In most studies, the accuracy of cystatin C assessment of GFR is superior to that of creatinine-​based eGFR (using the sMDRD for- mula) in those patients in the crucial chronic kidney disease stage 3 and 4 groups, both in children and adults. However, evidence is accumulating that the serum concentration of cystatin C is in- fluenced by many factors, including corticosteroid use, sex, age, weight, height, smoking status, proteinuric states, chronic liver dis- ease, heart failure, malignancy, and the level of C-​reactive protein, even after adjustment for creatinine clearance. Cystatin C has also been reported to be reduced in renal transplant recipients, with some drugs (including valsartan), in bone marrow transplant pa- tients, following myeloablative chemotherapy, and in hypothyroid states, and to be increased in thyrotoxicosis. These factors coupled with the variation between different assays accounts for the number of different equations proposed to equate cystatin C concentrations with GFR. For these reasons, amongst others, cystatin C has failed to replace creatinine as a biomarker of renal function in routine clinical practice. Combined serum creatinine and cystatin C equa- tions have been developed and may have an advantage for elderly patients, and those with early chronic kidney disease stages without proteinuria. In addition, these equations may be applicable to dif- ferent racial groups. Carbamylation Urea accumulates with deteriorating renal function and in plasma can spontaneously dissociate to form a reactive cyanate species that can react with the terminal valine of haemoglobin α and β chains (and also similar valine molecules in other proteins). This reaction is termed ‘carbamylation’ and the product ‘carbamylated haemoglobin’ (or other protein). Whereas glycosylated haemo- globin has proved useful in clinical practice for assessing time-​averaged diabetic control, carbamylated haemoglobin or carbamyl-​lysine adducts have not been shown to be superior to simple serum creatinine measurements in determining stable renal function. However, they are useful in helping to differen- tiate acute from chronic renal failure, because of the time course of the carbamylation reaction, and also in the assessment of time-​ averaged urea levels in the dialysis patient with endstage renal failure. However, until the relevant assays are commercially avail- able, their use will remain experimental. Other methods Isotopic methods The GFR can be determined by the clearance of a compound which is freely filtered by the glomerulus and then passes through the nephron without tubular reabsorption or secretion. Traditionally, inulin—​a naturally occurring polyfructose—​was given as a con- stant infusion to achieve a constant plasma concentration, and

21.4  Clinical investigation of renal disease 4791 then clearance determined from timed urinary collections. This was a laborious technique. Furthermore, the biochemical esti- mation of inulin was initially tedious and difficult, with signifi- cant interassay variation, and accurate timed urine collections are unreliable in patients with urinary tract anomalies. To overcome these and other difficulties, compounds other than inulin are gen- erally used to estimate GFR, and methods other than constant infusion. Following a single bolus injection, depending on the compound used, the fall in plasma concentration follows either a single-​ or two-​compartment model related to renal clearance. Chromium-​ labelled ethylenediaminetetraacetic acid ([51Cr]EDTA) is the most commonly used isotope. After the single injection, three timed plasma samples are taken to calculate the plasma decay rate and the GFR is then calculated by taking the linear decay slope back to the abscissa and estimating the area under the curve. More recently it has been showed that only a single blood sample at 4 h is required for a GFR over 30 ml/​min. At GFRs above 30 ml/​min there is a very good correlation between inulin and [51Cr]EDTA clearance, but below 30 ml/​min the accuracy of the isotope tech- nique is reduced, there being some renal tubular reabsorption. Accuracy can be improved in this situation by taking a delayed (24-​h) plasma sample, especially in patients with peripheral oe- dema and ascites. Other isotopes that have been used to estimate GFR include [125I] iothalamate, which when given as a subcutaneous injection results in a constant plasma concentration equivalent to the infusion tech- nique, and 99Tcm-​diethylenetriaminepentaacetic acid (DTPA), which is less accurate because of its short half-​life (6 h) and dissoci- ation of DTPA from the radionuclide. With all the isotopic methods, it is conventional for the GFR to be corrected for the size of the patient. This correction as- sumes a fixed relationship between the weight and height of an individual: hence serial estimations to detect a change in renal function are more likely to be accurate than single estimations. However, the normal relationship between body surface area and muscle mass may well be lost in patients with chronic kidney disease who may have protein energy wasting, or volume over- loaded, and similarly patients at the extremes of body habitus, and those with cancer cachexia, so introducing an error in GFR when scaling to body surface area. Other errors arise as single bolus iso- topic determinations are determined by the area under the curve, and as such will overestimate the GFR in patients who are fluid overloaded, and also by affecting the decay slope in those with ascites, such as patients with cirrhosis, due to initial redistribu- tion of the tracer into the ascitic fluid followed by return into the plasma. This redistribution and return error can be overcome by using a continuous infusion technique to establish equilibrium, which may require significant time (8–​10 h), or by taking delayed samples at 24 h. Radiological methods Iohexol is a nonionic, low-​osmolality radiocontrast dye. It can be used to estimate GFR following a single bolus injection of between 2 and 5 ml. In patients with a clearance of over 30 ml/​min, a single plasma sample taken 3 h after injection provides an accurate esti- mation, whereas additional later samples are required to improve the accuracy in those with severely impaired renal function. Iohexol should not be used in patients with known iodine sensitivity, and has the same errors as single bolus isotopic methods. Summary Because of the difficulty in interpreting plasma creatinine concen- trations below 150 µmol/​litre as an assessment of renal function, the eGFR was initially introduced into clinical practice in the United States of America, Australia, and the United Kingdom to detect pa- tients with early stages of chronic kidney disease, and is now be- coming widespread. It is an appropriate and adequate technique for most clinical purposes. When more precise estimation of GFR is required, an isotopic assessment is the most accurate method of determination, otherwise two 24-​h urine collections with corres- ponding plasma samples should be used to calculate the GFR by cre- atinine clearance. Cystatin C has failed to replace serum creatinine in clinical practice as yet and predominantly remains a research tool. To examine changes in renal function, where eGFR measurements are not available, plasma creatinine concentrations should be trans- formed to either the reciprocal or the logarithm to assess trends in serial results. Estimation of renal blood flow Renal blood flow can be estimated noninvasively using Doppler flow probes, provided there is a single renal artery and adequate imaging is possible. This is technically easier for a transplanted kidney than a native kidney. The recent development of contrast agents for ultrasonography may increase the reliability of these estimations. Alternatively, renal blood flow can be estimated from the measure- ment of the renal plasma flow and the haematocrit. However, the haematocrit of peripheral venous blood may not be the same as that entering the renal artery. More recently, the development of positron emission tomography (PET) coupled with CT has allowed assess- ment of renal blood flow using 15O-​labelled water, 82Rb, and other tracers. Renal plasma flow Ideally, any compound used to assess renal plasma flow should have 100% uptake by the kidney, with any fraction not filtered by the glom- erulus being extracted by the tubules and secreted. p-​Aminohippurate is the most commonly used compound, but is only 85% extracted during a single passage through the kidney, and thus at best only provides an estimate of renal plasma flow. Continuous infusion of p-​aminohippurate provides a more accurate estimation of renal plasma flow than single-​injection techniques. Renal blood flow varies in normal subjects with pain, stress, physical exercise, and normal pregnancy, and following a high-​protein meal. In patients with impaired renal function, the decline in renal plasma flow generally corresponds to the decrease in GFR. However, in some con- ditions where there may be renal tubular hypoxia or toxicity, such as in patients with severe heart disease or those with ciclosporin nephro- toxicity, the reduction in estimated renal plasma flow is greater than that expected for the change in GFR, due to a reduction in the renal tubular uptake of p-​aminohippurate. Similarly, p-​aminohippurate up- take is reduced in small children. [125I]o-​Iodohippurate has also been used to estimate renal plasma flow, but this has a lower extraction than p-​aminohippurate (75%), and is less reliable.

section 21  Disorders of the kidney and urinary tract 4792 Investigation of tubular function In a normal subject, some 180 litres of glomerular filtrate is produced each day and less than 3% of this is excreted, due to reabsorption by the tubules. The proximal and distal tubules have different functions, and traditionally each is considered separately. Proximal tubular function Defects in proximal tubular function may be isolated or generalized, as in Fanconi’s syndrome. Glucose, phosphate, amino acids, and organic ions are reabsorbed by the apical border of proximal renal tubular cells by sodium-​dependent cotransporters, and are then transported across the basolateral membrane by different, sodium-​ independent, cotransporters. Glucose There is a maximum reabsorption rate for glucose (TmG) in the prox- imal tubule of 15.1 ± 2.5 mmol/​litre (TmG/​GFR), above which glyco- suria will be present. To determine TmG/​GFR, a 20% dextrose infusion is administered at increasing rates to produce a slow rise in the plasma glucose up to a maximum of 30 mmol/​litre, which is maintained for a minimum of 1 h. Plasma and urine samples are collected every 30 min. Renal function is determined by [51Cr]EDTA-​GFR. The glucose ab- sorption rate is calculated as the difference between the filtered load in urine (urine volume × [glucose]urine) and the filtered load in plasma (GFR × [glucose]plasma). Patients with type A renal glycosuria typically have a reduced threshold of around 5 mmol/​litre. Phosphate Phosphate is normally filtered at the glomerulus and reabsorbed in the proximal tubule, with only 10 to 20% of the filtered load being excreted. The normal tubular reabsorption of phosphate (TRP) is above 85% and can be calculated from: %TRP (1 [ ]) 100 phosphate clearance/eGFR

− × If renal function is normal, then this can be simplified by col- lecting an early-​morning specimen of urine, and: %TRP 1 [phosphate] [creatinine] [creatinine] urine plasma urin

− × e plasma [phosphate] 100 × ×     Alternatively, the theoretical maximum tubular threshold of phosphate (TmP) can be estimated from: Tm plasma urine plasm P GFR phosphate phosphate creatinine

× [ ] [ ] [ ] a urine creatinine [ ] or measured directly as for TmG, following an infusion of phosphate (1.0 litre of 0.1 mol/​litre sodium phosphate at pH 7.4) with a corres- ponding [51Cr]EDTA-​GFR. Renal tubular epithelial cell phosphate transport is regulated by phosphatonins, and several genetic conditions (X-​linked hypophosphataemic rickets, autosomal dominant and autosomal recessive hypophosphataemic rickets) and other diseases have now been described with excessive phosphate losses due to phosphatonins, including tumour-​associated osteomalacia. Excessive urinary phos- phate losses occur in proximal tubular disorders such as Fanconi’s syndrome, primary and secondary hyperparathyroidism, and mito- chondrial disorders, both primary and secondary, including those due to antiretroviral therapy, particularly the nucleotide analogue reverse transcriptase inhibitors, such as tenofovir. In the various forms of hypophosphataemic rickets, phosphaturia occurs with a characteristically reduced TmP/​GFR of less than 0.56 mmol/​litre. Amino acids Apart from the reabsorption of histidine (90–​95%), that of other amino acids is almost complete (97–​99%). Although amidoaciduria can occur as a result of overflow when the plasma concentra- tion exceeds the tubular transport maximum, this is very rarely the cause of aminoaciduria in adults. In general, five types of renal aminoaciduria are distinguished: dibasic amino acids, neutral amino acids (monoaminomonocarboxylic acids), glycine and imino acids, dicarboxylic amino acids, and generalized aminoaciduria in the case of Fanconi’s syndrome. Generalized and specific aminoacidurias can be detected and quantified by thin-​layer chromatography. In Fanconi’s syndrome, amino acids from all four groups are present, whereas in glycinuria there is only excess glycine. Classic cases of cystinuria have increased urinary arginine, ornithine, lysine, and cystine; and patients with Hartnup’s disease have an excess of neutral amino acids. For more detailed discussion of other aspects of proximal tubular function and their diseases, see Chapter 21.16. Distal tubular function Patients with primary or secondary nephrogenic or cranial diabetes insipidus and those with primary polydipsia may present with poly- uria. A water-​deprivation test can help to differentiate between these conditions, and can be performed as follows. The patient should be ad- mitted to a metabolic ward on the evening prior to the test, be weighed, and have samples taken for baseline plasma osmolality, chemistries, and arginine vasopressin (AVP) measurement. An osmolality above 295 mOsm/​kg and a sodium concentration above 143 mmol/​litre ex- clude a diagnosis of primary polydipsia. After midnight, no oral fluids are allowed until completion of the test. The early-​morning urine osmolality is measured, and if it is above 800 mOsm/​kg (normal re- sponse) the test is abandoned. Thereafter, the patient’s weight, plasma and urine osmolality, and plasma AVP concentration should be re- corded regularly. If weight loss exceeds 5%, then the test should be abandoned to prevent dangerous dehydration. Once urine osmolality reaches a plateau (an hourly increase of less than 30 mOsm/​kg for 3 consecutive hours), then five units of aqueous vasopressin is adminis- tered subcutaneously and urine and plasma osmolality measured after a further 30 min, and then at hourly intervals. Comparison of the last urine osmolality reading prior to the admin- istration of vasopressin with the maximum osmolality following vaso- pressin is used to categorize patients. Those with nephrogenic diabetes insipidus will produce a urine osmolality under 300 mOsm/​kg, with no response to exogenous vasopressin, and they will have high AVP levels. Those with severe cranial diabetes insipidus will have dilute urine, again less than 300 mOsm/​kg, but they will respond to exogenous vaso- pressin by increasing urine osmolality by 50% or more, accompanied by low endogenous AVP levels. Both cranial and nephrogenic diabetes insipidus can occur as partial forms, which show some response to dehydration, but they can be discriminated by analysing the relative changes in endogenous AVP and the urinary and plasma osmolalities. Patients with primary polydipsia do not show pituitary suppression, and have little or no response to exogenous vasopressin.

21.4  Clinical investigation of renal disease 4793 Renally induced electrolyte imbalances Sodium and water There are many causes of hyponatraemia, as discussed in Chapter 21.2.1. Patients with cardiac failure, chronic liver disease, nephrotic syn- drome, and prerenal acute renal failure will have a fractional excretion of sodium (FENa) of less than 1% (normal is 1–​2%), where: %FE sodium creatinine sodium crea Na urine plasma plasma

× × [ ] [ ] [ ] [ tinine urine ] ×100 A reduced effective circulating volume stimulates antidiuretic hormone release, increasing distal sodium and water reabsorp- tion. Hence a reduced fractional excretion of urea (<35%) is more sensitive and specific than reduction in FENa in differentiating be- tween prerenal and renal causes of acute kidney injury, especially when diuretics have been given, and also in hepatorenal syndrome. However, values of both FENa and FEUrea are not always reliable in making a clear distinction between different forms of acute kidney injury, and most nephrologists do not use them routinely. Patients with the syndrome of inappropriate diuresis preferen- tially retain water and have a normal FENa, indeed the diagnosis cannot be made if FENa is low, but when interpreting measurements of FENa it must be remembered that this is increased by diuretic ad- ministration and in chronic renal failure. Both those with reduced effective circulating plasma volume and those with the syndrome of inappropriate diuresis have impaired free-​water excretion, which can be tested by giving the patient 20 ml/​kg body weight of water to drink after voiding. More than 75% of the water load should be excreted within 3 h, and the urine osmolality should fall to under 100 mOsm/​kg (specific gravity <1.003), although this test can be affected by gastrointestinal dis- ease, smoking, and emotional factors. The free-​water clearance (Ch2o) can be quantitated from: CH O urine volume in ml min osmolality osmolality ur urine plasma 2

− × inevolume in ml min / A positive free-​water clearance occurs when the urine is more di- lute than plasma, and a negative free-​water clearance when the urine is more concentrated. For further discussion of these issues, and the clinical approach to disorders of sodium and water homeo- stasis, see Chapter 21.2.1. A water loading test may also be useful in investigating patients with cyclical or idiopathic oedema. Diuretics should be avoided for at least 10 days, and then—​after an overnight fast—​20 ml/​kg of water is consumed in 30 min, the bladder emp- tied, and all urine collected over the following 4 h. In normal indi- viduals, more than 70% of the ingested water should be recovered when the test is performed with the patient in the supine position, and also when they are ambulant, whereas in cases of idiopathic cyclical oedema, the urinary volume and sodium excretion are re- duced in the ambulant test, typically with a urinary sodium con- centration of less than 33% in the ambulant compared to the supine position. Renal salt wasting It has been recognized for many years that patients with acute sub- arachnoid haemorrhage and after pituitary surgery can develop an acute renal sodium wasting condition, previously termed cerebral salt wasting. It is now realized that this condition may also occur with other illnesses, including pneumonia. In severe cases, patients can lose more than 600  mmol sodium/​day and suffer depletion of intravascular volume and dehydration. However, in less severe forms clinical dehydration may not be obvious and there can be some biochemical similarities to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Table 21.4.5). Renal salt wasting is associated with a proximal tubular defect, leading to increased distal delivery of sodium that blunts the otherwise an- ticipated rise in plasma renin, and also with increased fractional excretion of urate and sometimes phosphate. Although fractional excretion of urate is also initially raised in SIADH, this typically corrects once the serum sodium rises, whereas that in renal salt wasting persists. Potassium To determine whether there is a renal tubular cause for potassium disturbances, the transtubular potassium gradient (TTKG) can be calculated. This attempts to estimate the potassium concentration in the cortical collecting duct as follows: TTKG potassium potassium osmolality osm urine plasma plasma

× [ ] [ ] olality urine In a patient with hypokalaemia, a TTKG of less than 2 suggests a nonrenal cause, whereas a high TTKG (>10) is associated with mineralocorticoid excess, Liddle’s syndrome, or drugs such as acetazolamide, fludrocortisone, and amphotericin. In a patient with hyperkalaemia, a TTKG above 10 implies a nonrenal cause and a low TTKG (<2) would be found in cases of potassium-​sparing diuretics, hypoaldosteronism, and pseudohypoaldosteronism. However, while having some theoretical attraction, it is doubtful whether such analysis helps greatly in the diagnosis or management of patients with hypokal- aemia or hyperkalaemia. Bartter’s and Gitelman’s syndromes are the classic renal tubular de- fects presenting with hypokalaemia, hypomagnesaemia, metabolic alkalosis, hyperreninaemic hyperaldosteronism, and normotension. Each syndrome contains a number of different channelopathies, thus in Bartter’s syndrome most children have hypercalciuria, in- creased urinary prostaglandins, and hypomagnesaemic, but not all. Table 21.4.5  Biochemical differences and similarities between renal salt wasting and the syndrome of inappropriate antidiuretic hormone (SIADH) Renal salt wasting SIADH Serum sodium (mmol/​litre) <135 <135 Serum osmolality (mOsmol/​kg) <285 <285 Urine osmolality (mOsmol/​kg)

200 200 Urine sodium (mmol/​litre) 25 25 Serum renin ±↑ ±↓ Serum aldosterone ↑ ±↓ Serum urate ↓↓ Normal or ↓ Fractional excretion urate ↑↑ Normal or ↑ Fractional excretion phosphate ±↑ Normal

section 21  Disorders of the kidney and urinary tract 4794 Similarly in Gitelman’s syndrome, children or adults have the classic phenotype of hypokalaemia, hypomagnesaemia, and hypocalciuria, with normal urinary prostaglandins. For further discussion of these issues, and the clinical approach to disorders of potassium homeostasis, see Chapter 21.2.2. Renal tubular acidosis Renal tubular acidosis should be considered in cases of metabolic acidosis with a normal anion gap (serum sodium + potassium –​ chloride –​ bicarbonate = 12–​16 mmol/​litre, corrected for albumin to exclude dehydration), and no evidence of intestinal bicarbonate losses. Arterial blood gases are required to confirm metabolic acid- osis with a reduced bicarbonate, as serum bicarbonate may appear to be reduced due to sample analysis delay, and failure to fill sample tube correctly. Serum potassium is typically reduced in classic distal tubular acidosis (DTA) and may also be reduced in proximal tubular acidosis (PTA), whereas it is increased in hyperkalaemic DTA and in hyporeninaemic states or hypoaldosteronism. Spot urine pH testing of the first urine of the morning is persistently greater than 5.5 in DTA. If the urinary pH is alkaline, then urinary ammonia determination can help diagnose mixed forms of DTA from classic DTA, which has reduced urinary ammonia (normal 100 mmol/​litre). If laboratories cannot directly measure urinary ammonia, then the ammonia can be calculated by measuring the urine osmolar gap and subtracting the calculated urine osmolality, provided renal and hepatic function are normal: Urinary ammo- nium mmol/​litre = 0.5 × (measured UOsmo –​ UOsmo calculated as (2 UNa + 2 UK) + UGlucose +UUrea). Milder forms of renal tubular acidosis may have low normal serum bicarbonate and further testing may be required, including the furosemide and fludrocortisone test, which is now the screening test for DTA. On arrival in the morning, the patient produces a fresh urine sample as a baseline for testing with a pH electrode meter, after which 40 mg furosemide and 1 mg of Fludrocortisone are administered orally, with hourly urine sam- ples tested thereafter for 6 h. The test is negative if the urine pH falls below 5.5, although it should continue to the full 6 h to fully characterize urinary acidification. If this test is inconclusive, then a formal ammonium chloride test is required. Following a base- line venous bicarbonate estimation, the patient is requested to drink ammonium chloride (100 mg/​kg body weight) with water over a period of up to 1 h. In the author’s hospital, the ammo- nium chloride tablets are specially prepared by in-​house phar- macy to disguise the taste. Urine samples are collected every hour (or when passed), checking volume and pH, and stored at 4°C, whilst the patient drinks regularly to maintain an adequate urine flow. Further venous bicarbonate measurements are made after 3 h and then at the end of the test at 6 h to ensure an adequate fall in serum bicarbonate of 4 to 5 mmol/​litre. Urine samples are stored at −20°C and then checked for pH, ammonia, and chloride. If urine pH falls below 5.5 with an adequate fall in serum bicar- bonate, then the test is negative. Urinary citrate is reduced in DTA, whereas in cases of PTA pa- tients may have increased urinary phosphate losses, glycosuria, renal tubular and microalbuminuria, and hypouricaemia. For more detailed discussion of other aspects of distal tubular function and their diseases, including tests of urinary acidification, see Chapter 21.15. Biochemical screening investigations for patients with renal calculi Renal stones are common in patients from developed countries, with an estimated prevalence of 5% in North Americans. Most stones contain calcium, and stones that are passed should be sent for chemical analysis whenever possible. Routine screening would include serum calcium, magnesium, uric acid, bicarbonate, chloride, parathyroid hormone and 1,25 vitamin D.  Spot urine samples should be tested for pH (calcium salts are less soluble at pH >6.5, whereas urate and cystine are more insoluble at lower pH), specific gravity, microbacteriology, and dibasic amino acids. Twenty-​four-​hour urine collections are helpful in assessing volume of urine passed, and also biochemical analysis, with urine col- lected in plain containers to exclude increased excretion of calcium (normal upper limit for males 7.5 mmol/​day and females 6.0 mmol/​ day, but risk is increased if >6.25 and 4.25 mmol/​day, respectively), magnesium (0.6–​4.8 mmol/​day), sodium (normal 50–​125 mmol/​ litre or 100–​250 mmol/​day), creatinine (normal 7–​18 mmol/​day), urate (normal excretion 500–​800 mg/​day or 3.0–​4.8  mmol/​day, with increased risk of uric acid stones >750 mg uric acid/​day for men and >800 mg/​day for women), and cystine (normal 30 g/​day or 0.13 mmol/​day, with increased risk with >75 g cystine/​litre). In addition, acid-​washed urine containers are required for collection of oxalate (normal 0.1–​0.46 mmol/​day, with values found in cases of primary hyperoxaluria typically being 9–​30 mmol/​day) and cit- rate to exclude hypocitraturia (<350 mg/​day for males, and <500 mg/​day for females). Imaging of patients with renal disease There are a number of techniques that can be used to image the kidney: a simple comparison of some of these is given in Table 21.4.6. Plain radiography Plain abdominal radiographs may demonstrate opaque urinary stones, nephrocalcinosis, and the renal outlines. Ultrafast, noncontrast CT scanning with three-​dimensional reconstruction has generally replaced nephrotomograms for detecting low-​opacity renal stones. Chest radiography may be helpful in the diagnosis of pulmonary oedema, and also in demonstrating the cardiac silhouette and lung pathology sometimes associated with renal disease, such as pul- monary haemorrhage and cavitation. Multiple rib fractures may suggest multiple myeloma. Intravenous urography Intravenous urography (IVU) is no longer the standard investiga- tion in nephrology, but still has an important place in the investi- gation of patients with suspected obstruction, particularly of the upper urinary tract. As with all radiographic procedures, potential fetal irradiation should be avoided. Bowel preparation is no longer standard, due to the risks of dehydration in older people and of gas- eous distension of the bowel obscuring the urinary tract. Even the newer nonionic lower-​oncotic contrast media can cause nephrotox- icity in some patients, and care should be taken to ensure that those at risk (older people, and those with diabetes, myeloma, or pre-​ existing renal impairment) are adequately hydrated. Normal renal

21.4  Clinical investigation of renal disease 4795 length is between three and four lumbar vertebrae, with a width ap- proximately half that of the length. The calyces and papillae are well demonstrated by IVU, which may be diagnostic in cases of medullary sponge kidney, papillary necrosis, and sloughed papillae. Similarly, intraluminal radio- lucent foreign bodies may be demonstrated surrounded by contrast, typified by radiolucent stones, blood clots, fungal ball, tumour, or sloughed papillae. Abnormalities of the ureteric wall such as localized thickening are found in cases of transitional cell carcinoma, oedema, tuberculosis, and parasitic granuloma. The IVU may also demonstrate external compression: this can be due to aberrant blood vessels in the upper tract, retroperitoneal fibrosis affecting the middle ureter, or prostatic pathology in the lower tract. The IVU may provide valuable information about renal size and possible intrarenal masses. It retains a role for investigation of upper tract pathology to detect intraluminal tumours and blood clot, but has been replaced by other techniques, such as ultrasonography and ultrafast CT scanning, to investigate renal colic. Other conventional uroradiological techniques Further information about the site and nature of any obstruction can be obtained by ureteropyelography. An antegrade study in- volves percutaneous puncture of the renal pelvis, with immediate relief of the obstruction by nephrostomy, and allows demonstration of the site of obstruction following an injection of contrast media (antegrade ureteropyelography) (Fig. 21.4.4). A retrograde study re- quires cystoscopy, allowing direct visualization of the distal ureter and the possibility of removing an obstructing stone, with injection of contrast media from below demonstrating the site of obstruction (retrograde ureteropyelography). Passage of a double JJ stent from above (antegrade) or below (retrograde) can relieve obstruction by allowing internal drainage into the bladder (Fig. 21.4.5). By definition, vesicoureteric reflux is diagnosed by a micturating cystourtherogram (MCUG), staged according to the severity of calyceal dilatation and hydronephrosis (stages I–​V), and subdiv- ided into active, with reflux demonstrated during micturition, and passive, with no reflux on micturition. As a MCUG has a high radi- ation dose, it is usually restricted to infants less than 6 months, and ultrasonography is the screening test of choice. Antegrade techniques are usually more successful in relieving obstruction, particularly in those with pelvic malignancy or ob- struction of a renal transplant. In cases when renal obstruction is considered, but investigation inconclusive, a pragmatic trial of antegrade stent insertion should be undertaken. Improvement of renal function confirms obstruction. Retrograde urethrocystography is performed in women to detect lower urinary tract abnormalities, such as fistulas or urethral diver- ticula. Sequential films taken during micturition may detect active reflux. In men, urethrocystography can be complicated by trauma Table 21.4.6  Comparison of standard methods for radiological imaging of the kidney Imaging method Advantages Disadvantages General Imaging General Imaging Ultrasonography Noninvasive Safe Versatile Cost (cheap) First-​line imaging for excluding obstruction Can be used to guide intervention Operator/​machine dependent Dependent on patient having suitable body habitus Intravenous urography (IVU) Cost (cheap) Good for definition of upper tract anatomy Contrast exposure Good images not obtainable with eGFR <20 ml/​min Multislice three-​ dimensional CT Widely available High resolution, allowing best anatomical definition Radiation dose CT KUB (kidneys, ureter, and bladder) No contrast exposure First-​line imaging for urinary stones Can detect nonrenal pathology Limited study Not good at detecting small blood clots CT urography First-​line imaging for upper tract Contrast exposure Good images not obtainable with eGFR <15 ml/​min Limited for imaging of bladder pathology CT angiography First-​line imaging of renal arteries Contrast exposure MRI without contrast Noninvasive Avoidance of radiation dose allows repeated studies Good anatomical definition Can visualize the whole of the urinary tract Good for staging of renal carcinoma Good for assessment of complex renal cysts Patient needs to be able to hold their breath Cost (expensive) Not possible in all patients, e.g. prevented by cardiac pacemaker, cochlear implant, intracranial clips MRI with contrast (gadolinium)—​ urography and angiography Used to confirm normal vascular anatomy, e.g. in assessment of potential kidney donors Careful consideration if eGFR <30 ml/​min (nephrogenic systemic fibrosis) Tends to overestimate the significance of stenoses Likely to miss small accessory renal arteries Renal angiography The gold standard investigation for renal artery stenosis and brisk renal bleeding Can be therapeutic as well as diagnostic, e.g. stent/​angioplasty, embolization by coiling/​gel foam Invasive Contrast exposure Requires considerable technical expertise Risk of plaque rupture, vessel dissection, haemorrhage Contrast nephrotoxicity with iodinated-​based contrast agents is increased when eGFR <60 ml/​min per 1.73 m2.

section 21  Disorders of the kidney and urinary tract 4796 and infection to the lower urinary tract, hence suprapubic bladder puncture is recommended. Retrograde studies may be helpful in imaging ileal or colonic loop bladders to exclude outflow and ureteric inflow stenoses. Renal ultrasonography The normal kidney and chronic kidney disease The normal adult kidney is between 10 and 12 cm long, with a thin, bright capsule surrounded by highly reflective perinephric fat. The healthy cortex returns mid-​level grey echoes, the pyramids are darker, and the renal sinus, containing fat and the major vascular pedicle, is bright with high reflectivity. Colour (flow) Doppler ultra- sonography can be used to visualize the flow of urine from the native ureters into the bladder. In most causes of chronic kidney disease, the kidneys become smaller, with reduced cortical thickness and increased cortical re- flectivity when qualitatively compared with the liver. Diastolic blood flow is reduced on the Doppler scan in chronic kidney dis- ease, but can also be reduced in acute kidney injury due to increased intrarenal interstitial pressure, but this is nonspecific and can also be found in cases of pyelonephritis and obstruction. The renal ultra- sound appearances are characteristic in some conditions, including focal segmental glomerular sclerosis secondary to HIV infection, in which the kidney is reported to be large and the cortex uniformly of a high reflectivity, greater than that of the renal sinus. Scars, either vascular or infective, may often be too small to be detected by ultra- sound examination, especially in the neonate. Renal masses Ultrasonography is useful in the assessment of renal masses. Benign cysts have a smooth outline with well-​demarcated borders and an echo-​free centre, whereas renal tumours are usually irregular with (b) (a) Fig. 21.4.4  Antegrade puncture of the collecting system of the left kidney: (a) the nephrostomy needle (arrowed) has punctured an upper pole calyx, confirmed by injection of contrast medium that can be seen outlining the dilated pelvicalyceal collecting system, with some flow into the upper ureter; and (b) the nephrostomy needle has been replaced by an antegrade nephrostomy tube (arrowed), with injection of contrast medium demonstrating a block to flow (due to retroperitoneal fibrosis in this case) in the mid ureter. Fig. 21.4.5  Abdominal radiograph showing a double JJ stent placed in the left ureter. This was placed antegradely (from the kidney); some contrast medium from the preceding antegrade ureteropyelogram remains in the renal pelvis.

21.4  Clinical investigation of renal disease 4797 heterogeneous echo reflectivity. Typical standard, real-​time, two-​ dimensional B mode ultrasonography may be able to detect renal masses and/​or cysts as small as 2 to 3 mm in size, depending on the experience of the operator and the specification of the scanner, but this ability is reduced by several patient factors including high-​ density fat and muscle, and position, particularly when the kidneys are covered by the ribcage. Most tumours are vascular, with high flow during both systole and diastole on colour Doppler scanning, and adenocarcinomas in particular may be seen to extend into the renal vein. Renal transitional cell carcinomas are not readily detected unless large because ultrasonography does not visualize individual calyces well. Angiolipomas may have a characteristic appearance due to their fat content which has high reflectivity, but confirmatory CT scanning is required. In adult polycystic kidney disease, the kidneys are typically en- larged with multiple bilateral cysts. Middle-​aged women (particu- larly but not exclusively) may also have hepatic cysts. It is important to remember that, if patients are scanned in their teenage years or before, then cysts may not have developed to a size detectable by ultrasonography. Haemorrhage, infection, or malignant change all result in complex echoes within cysts, which cannot be differenti- ated by ultrasound scanning. Autosomal recessive polycystic kidney disease can be detected in utero with antenatal scanning. There is an increased incidence of cystic change in the kidneys of patients with endstage renal failure, and occasionally these cysts may become malignant. It has been suggested that dialysis patients should be screened by ultrasonography every 3 years, and then an- nually if cystic changes develop. Urinary obstruction In most centres, ultrasonography of the urinary tract is the first in- vestigation performed when urinary obstruction is suspected. When urinary obstruction has been present for some time, the high reflect- ivity of the central renal sinus becomes replaced by echo-​free urine, with distension of the calyces (Fig. 21.4.6). However, it is important to recognize that in acute obstruction, and in cases where the kidney and ureter are encased (usually the result of tumour), the standard ultrasound examination may appear normal. In these circumstances, a colour Doppler scan may show reduced diastolic blood flow due to increased intrarenal pressure, and a difference in resistivity index (RI)—​which equals (peak systolic velocity − end diastolic velocity)/​ peak systolic velocity)—​of more than 0.1 between the two kidneys is thought to be a reliable parameter for diagnosing acute unilateral ureteric obstruction. Similarly, absence of the normal pulsatile jets of urine from the ureter into the bladder may be demonstrated on the side with acute obstruction. Urethral valves and vesicoureteric reflux may be detected on ante- natal ultrasonography, with hydronephrosis. Ultrasonography is not usually diagnostic of the cause of obstruc- tion, but it may detect para-​aortic nodes, a bladder mass, prostatic en- largement, or a ureterocoele. Further investigation with transvaginal, transrectal, or transurethral ultrasonography may confirm the cause of obstruction, with transrectal ultrasonography being particularly useful in the detection of local invasion from prostatic carcinoma. Urinary tract stones Renal stones appear on ultrasonography as a bright echogenic focus with a distal acoustic shadow. Ultrasonography can be used to follow up patients with renal calculus disease by assessing the number and size of stones. Nephrocalcinosis may result in an increase in medul- lary echoreflectivity due to calcium deposition, which usually affects the whole medulla, whereas calcification from papillary necrosis has an appearance more like that of a renal stone. Renovascular disease Colour Doppler can be used to investigate renal arterial and venous disease. Thrombosis of major vessels produces absent flow or changes to the intrarenal blood flow pattern. More recently, colour Doppler scanning has been used as a screening test for renovascular disease, as the higher the stenotic gradient in the renal artery, the slower and smoother the systolic upstream with identical diastolic velocity. This so-​called parvus–​tardus flow results in a decrease in RI, which can be compared with the contralateral kidney, and an RI difference of more than 0.05 (based on three to six measurements) between the kidneys has been reported to be a reliable parameter to detect significant uni- lateral renal artery stenosis. Furthermore, one study suggested that assessment of the RI in patients with atherosclerotic renovascular disease had prognostic value: those patients with an RI above 0.8 did not improve following renal artery angioplasty. Atherosclerotic renal artery stenosis occurs bilaterally in 20 to 30% of cases, and often affects the ostium, hence blood flow velocity at the ostium and along the renal artery should both be assessed. Thresholds ranging from 1.8 to 2.0 m/​s (flow rate is accelerated in a narrowed stenotic artery) have been reported to have sensitivity and specificity of 70 to 90%, respectively, for renal artery stenosis, but the procedure is difficult and time-​consuming, and even with an experi- enced operator it will be impossible to visualize the renal arteries ad- equately in some 20% of patients. Colour Doppler ultrasonography is thus not a routine technique for screening for or investigating cases of renal artery stenosis, except in centres that have particular interest and expertise in the technique. Renal transplantation Ultrasound examination is an important investigation in the man- agement of renal transplant recipients. Compared with the native kidney, the calyces and ureter are frequently visible in otherwise normal allografts, so experience is required in the interpretation of mild or even moderate calyceal dilatation. Early graft dysfunction mandates investigation to exclude a technical problem with either the renal artery or vein, or a urinary leak. Fig. 21.4.6  Ultrasound scan of an obstructed kidney showing a massively dilated pelvicalyceal system.

section 21  Disorders of the kidney and urinary tract 4798 Colour Doppler scanning provides valuable information about the vascular supply of the graft (Fig. 21.4.7), and as with renovascular disease can be used to assess iliac artery and anastomotic stenoses. Estimation of the RI has been advocated to monitor early graft func- tion, but acute tubular necrosis, acute rejection, acute renal vein thrombosis, graft pyelonephritis and acute calcineurin toxicity all cause increased intrarenal pressure with reduced diastolic flow and increased RI. Similarly, by affecting the end-​diastolic velocity, the RI can be reduced by tachycardia, and increased by bradycardia, com- pression of the transplant with the transducer, or Valsalva’s man- oeuvre through breath-​holding. In addition, the RI is affected by vascular compliance, and older transplant recipients with stiffness of the prerenal vessels (aorta and iliac) will have an increased RI in- dependently of graft function. Thus, the RI cannot be used solely to monitor graft function, but serial measurements can guide the timing of graft biopsy. Fluid collections (commonly lymphoceles) appear as echo-​free or echo-​poor areas, and such perinephric collections can be drained under ultrasound guidance for diagnostic purposes or to relieve ob- struction. As with the native kidney, percutaneous nephrostomy is the emergency treatment of choice for obstruction of a renal transplant. Colour Doppler scanning can detect the presence of arteriovenous fistulas, which are not uncommon following transplant biopsy. Contrast agents for ultrasonography Colour Doppler ultrasonography can detect bubbles present in in- jected contrast medium. Application of this technique can change the use of ultrasonography from simple anatomical visualization of the kidneys to dynamic testing by assessment of the perfusion quotient. However, this remains an experimental investigation and not in routine clinical use, although it potentially has the capacity of allowing ultrasonography to determine relative renal function, and improve investigation for obstruction, renovascular disease, and vascular rejection in renal transplants. CT scanning Ultrafast multislice CT scanning, with workstation reconstruction down to a resolution of 2 to 3 mm or less, has become the mainstay of renal imaging (Fig. 21.4.8). CT urography can be performed with a combination of unenhanced, nephrogenic-​phase and excretory-​ phase imaging. The unenhanced images are ideal for detecting urinary calculi. Renal masses can be detected and characterized with the combination of unenhanced, nephrogenic-​ and excretory-​phase imaging. The excretory phase provides imaging of the urothelium. As with the standard IVU, iodine-​based contrast media may cause renal impairment, but only a single dose is required and contrast exposure is usually much less than that required for coronary angiography. Unenhanced CT scanning For patients with suspected renal colic due to stones, low-​dose, unenhanced helical CT has become the gold standard investiga- tion, particularly for patients with ureteric obstruction and kidney failure. CT allows both the cause and the level of the obstruction to be determined. Practically all stones (apart from indinavir) can be detected, hydronephrosis with perinephric stranding can usu- ally be readily identified, and there may be hydroureter down to the level of the obstruction. In cases where a stone has passed, oe- dema may be noted at the vesicoureteric junction, with residual stranding around the ureter. Other pathology may be identi- fied in patients presenting with loin pain, such as renal enlarge- ment with perinephric fat stranding, or oedema in cases of acute pyelonephritis, renal vein thrombosis, or acute arterial occlusion. Fig. 21.4.7  Doppler ultrasound scan of a renal transplant showing normal systolic and diastolic waveform (resistivity index <0.65). (a) (b) Fig. 21.4.8  CT imaging: (a) showing dilatation of both renal pelvices (arrowed) in a case of urinary obstruction; and (b) after relief of obstruction by placement of double JJ stents in both ureters (arrowed).

21.4  Clinical investigation of renal disease 4799 Small blood clots can be difficult to identify. Other nonrenal path- ology may be identified, including leaking abdominal aorta, diver- ticular disease, or appendicitis. CT angiography Contrast administration allows a CT angiogram phase to be ac- quired (Fig. 21.4.9). Compared with magnetic resonance angiog- raphy (MRA), CT angiography is more sensitive in detecting small accessory renal arteries and it does not overestimate the length and severity of stenoses, which appear greater during MRA due to the combination of slower speed of data acquisition and blood flow. The main indications for CT angiography include the evaluation of acute renal trauma, tumour blood supply in cases of nephron-​ sparing surgery, the diagnosis of renal artery stenosis and/​or aneur- ysms, defining the arterial supply in potential living renal donors, and prior to pyeloplasty for ureteropelvic junction obstruction, as endoluminal pyelomyotomy is not as successful as laparoscopic or open pyelomyotomy if there are posterior and/​or anterior vessels. Three-​dimensional reconstruction can help detect aberrant vessels, and partial obstruction to flow as found in the nutcracker syndrome. Some centres have used CO2 as a contrast agent to reduce the risk of contrast nephropathy and volume loading, but the images are not as good as with conventional CT angiography and tend to overestimate strictures. CT imaging of the renal parenchyma Due to the speed of data acquisition, there is a cortical phase fol- lowed by an excretory phase, which allows imaging of both the cortex and then the medulla. Thus CT scanning is useful in the in- vestigation of congenital and anatomical abnormalities of the renal tract (such as renal agenesis), nephrocalcinosis (before calcification can be detected on plain films), and papillary sloughing. Apart from the investigation of cystic renal disease, CT scanning is used to investigate renal masses. Renal cell carcinomas vary in appearance: some show calcification both within and surrounding the tumour on nonenhanced scans, some are solid, and others are cystic or have necrotic centres. Most tumours are vascular and readily enhance with contrast, but those with heavy calcifica- tion may not. CT scanning is important in tumour staging and in determining the extent of perirenal spread, renal vein involvement, and enlargement of local lymph nodes. Occasionally, secondary deposits due to metastatic spread and secondary involvement in lymphomas and leukaemia can be found on contrast-​enhanced renal scans. These are usually small, multiple intrarenal masses, often bilateral, typically homogeneous, and solid in lymphomas. Although ultrasonography is used to screen and assess Wilms’ tumours in children, CT scanning is important in excluding pul- monary metastases. Angiolipomas can be recognized with ultrasonography but should be confirmed on CT scanning as some renal cell carcinomas may contain small amounts of fat. In tuberous sclerosis, angiolipomas may be associated with renal cysts. Although angiolipomas are benign mesenchymal tumours, they can rarely rupture, especially those with intrarenal haematomas and aneurysms. Early detection by CT scanning allows prophylactic embolization of these vascular lesions. Renal oncocytomas, another benign renal tumour, may have a central lucent area due to fibrosis on CT scanning. However, a pro- portion of oncocytomas may become malignant, hence any small renal lesion which is not a simple cyst or angiolipoma must be re- garded as potentially malignant and surveillance with repeat CT scanning (or ultrasonography) should be recommended. Renal tract imaging in patients with acute pyelonephritis is usu- ally requested to exclude the presence of obstruction, or when there has been an inadequate response to treatment. CT scanning defines the extent of disease better than ultrasonography, detects abscesses, and can also exclude obstruction. Whereas focal acute bacterial pyelonephritis should respond to antibiotics, renal abscesses may require drainage. CT scanning may also detect gas bubbles within the renal parenchyma or perirenal space, which is characteristic of the emphysematous pyelonephritis that is typically found in people with diabetes Similarly, CT scanning may establish a diagnosis of xanthogranulomatous pyelonephritis, with an enlarged kidney con- taining areas of scarring, focal loss of renal parenchyma, and mul- tiple low-​density masses, often following recurrent infections in patients with staghorn calculi. CT urography Scanning during the excretory phase provides a CT urogram of high definition, which may detect filling defects within the collecting system, such as transitional cell carcinoma, blood clot, or stone, and also external compression due to vasculature. Review of three-​ dimensional formatted images allows surgical planning. The use of CT urography is currently limited to assessing local extravesicle extension or metastatic disease in the staging of bladder tumours. With further developments in computer software, it will be possible to perform virtual cystoscopy to detect intravesicle lesions of at least 5 mm or in size after distending the bladder with CO2 or saline. Functional CT An estimate of GFR can be made using nonionic contrast media, which may be helpful when deciding on nephron-​sparing surgery for renal tumours, and assessing patients with renovascular disease before and after interventional stenting. MRI CT scanning and ultrasonography are good reliable techniques for detecting and evaluating renal masses. MRI is an alternative in Fig. 21.4.9  Contrast-​enhanced CT scan showing thrombosed aorta and renal arteries.

section 21  Disorders of the kidney and urinary tract 4800 patients who are allergic to conventional iodine-​based radiocontrast media, but the current generation of MRI scanners does not have the resolution of the ultrafast three-​dimensional CT scanners. Gadolinium contrast used in MRI is taken up by the proximal tu- bule in a similar manner to aluminium. The dose of gadolinium-​ based contrast agent required is much less than those of standard iodinated contrast agents. Their biological half-​life is increased in severe renal impairment, and they can result in spurious hypocal- caemia for up to 24 h after administration due to chelation with the commonly used automated assays for measuring serum calcium. Although gadolinium-​based contrast agents generally have a good safety profile, there are a few reports of acute kidney in- jury following their administration, in particular with high doses and intra-​arterial administration, and they have also been found to cause nephrogenic systemic fibrosis/​nephrogenic sclerosing dermopathy. Nephrogenic systemic fibrosis Nephrogenic systemic fibrosis is caused by exposure of patients with renal impairment to gadolinium-​based contrast agents. The first cases were identified in 1997 and the condition first clearly de- scribed in 2000. Within weeks, months or (less commonly) years of exposure, patients develop a scleroderma-​like disease, usually rec- ognized with the development of areas of thickened and hardened skin that can progress rapidly to produce flexion contractures and joint immobility. The lungs, myocardium, and skeletal muscle can be involved. Gadolinium can be detected in skin biopsy specimens. Mortality is up to 30% in some series. There is no known effective treatment, and dialysis immediately after exposure does not prevent the condition. It is difficult to determine the incidence of nephrogenic systemic fibrosis because mild cases undoubtedly go undetected. Release of free gadolinium ions (Gd3+) appears to be crucial in pathogenesis, hence not all gadolinium-​based contrast agents are equally culp- able. Those with a cyclical structure are less likely to do so (and are therefore considered safer) than those with a linear nonionic struc- ture, which in turn are better than those with a linear ionic struc- ture. Most cases have been related to gadodiamide, with perhaps 2 to 4% of patients with significant renal impairment who received this agent developing the condition, although much higher rates (up to 25%) have been reported in some series. Recognition of nephrogenic systemic fibrosis has led to the rec- ommendation that cyclical gadolinium-​based contrast agents should be cautiously used in patients with an eGFR of less than 30 ml/​min (chronic kidney disease stage 4 and stage 5), and in patients with an eGFR of between 30 and 60 ml/​min (chronic kidney disease stage 3) the clinician should consider whether the necessary imaging in- formation could better be obtained by another imaging technique. Although some authorities recommend haemodialysis immediately after gadolinium-​enhanced MRI scanning, this has not been shown to prevent the development of nephrogenic systemic fibrosis. If MRI is the best imaging technique, then to reduce the risk of nephrogenic systemic fibrosis the cumulative exposure to gadolinium should be considered, a cycle chelate preferred, with use of the minimum dose required. Spurious hypocalcaemia may occur post MRI scanning as free gadolinium may interact with colourimetric methods used to determine serum calcium by modern day automated biochemical analysers. Plain and conventional gadolinium-​enhanced MRI MRI is expensive, but does have some advantages over conventional CT. Tissues surrounded by fat, such as enlarged lymph nodes, or tu- mour extension into the renal vein, and angiomyolipomas are better demonstrated on MRI than CT. Thus MRI is useful in staging renal cell carcinoma, and by being able to distinguish blood from tissue can help to differentiate simple cysts complicated by haemorrhage from those that are malignant. The fact that MRI does not expose the patient to radiation also offers an obvious advantage over CT in those requiring repeated imaging. The whole of the urinary tract can be visualized, in a manner similar to an IVU, by using a heavily weighted T2 fast spin-​echo sequence. This rapid acquisition and relaxation enhancement scan can be used to as- sess potential live donors for renal transplantation, by demonstrating the renal vasculature, renal anatomy, and urinary drainage with one investigation. The quality of image provided by MRI can be very high (Figs. 21.4.10 and 21.4.11), and in general MRI can distinguish an Fig. 21.4.10  Gadolinium-​enhanced MRI showing left-​sided pyelonephritic scarring, with a reduction in cortical thickness and scarring. Fig. 21.4.11  Gadolinium-​enhanced MRI showing a hydronephrotic left kidney and dilated upper two-​thirds of the ureter following gynaecological surgery.

21.4  Clinical investigation of renal disease 4801 acute process, such as pyelonephritis, from scarring from previous in- fections, but current MRI resolution is not as good as the new gener- ation of ultrafast three-​dimensional CT scanners. In some cases, abnormal signal intensity on MRI is sufficiently characteristic to allow a specific radiological diagnosis. For ex- ample, low-​signal magnetic resonance images are seen in three main categories:  haemolysis (e.g. paroxysmal nocturnal haemoglobin- uria, cortical haemosiderin deposition from mechanical haemolysis, sickle cell disease, haemorrhagic fever with renal syndrome), vas- cular disease (renal arterial infarction, acute renal vein thrombosis, renal cortical necrosis, acute renal transplant rejection), and acute nonmyoglobinuric renal failure. MRI has become the standard in- vestigation for prostate cancer and targeting suspicious areas for bi- opsy, termed fusion-guided prostate biopsies. As with the developments in CT, three-​dimensional MRI scanners coupled with greater data acquisition are being developed to increase image resolution. New contrast agents such as gadolinium DTPA (see ‘Dynamic imaging—​radiolabelled DTPA and MAG3’) are being trialled with some success in a technique known as dynamic con- trast magnetic resonance renography (MRR), which has the potential to provide complete anatomical and physiological kidney-​specific evaluation. Similarly, functional MRI techniques, including perfu- sion, diffusion-​weighted imaging, and blood oxygen level-​dependent (BOLD) MRI, have been developed to investigate renal blood flow and oxygen uptake in the kidney in disease states and in response to drugs. However, these currently remain research investigations re- quiring further technical and clinical validation, and demonstration of cost-effectiveness before they enter routine clinical practice. Magnetic resonance angiography This technique (Fig. 21.4.12) overemphasizes any stenotic area or other vascular abnormality and may miss minor accessory renal arteries. MRA is useful in confirming normality, and is commonly used in the preoperative assessment of living related kidney donors. A normal study of the renal arteries excludes renal artery stenosis and significant intrarenal vascular disease. MRA has become the screening technique of choice for excluding renal transplant artery stenosis in renal transplant patients with otherwise unexplained raised serum creatinine or difficult-​to-​control hypertension. Newer techniques are being developed to improve image acqui- sition and reduce respiratory artefacts to improve image resolution, including high-​resolution three-​dimensional unenhanced ECG-​gated respiratory-​navigated MRA of the renal arteries, and balanced steady-​ state free precession, which do not require gadolinium contrast. Magnetic resonance venography As with MRA, magnetic resonance venography using gadolinium contrast can be used to assess renal venous patency. Patients with nephrotic syndrome and those with renal adenocarcinoma may de- velop renal venous thrombosis, which can be difficult to positively diagnose with other imaging techniques. Angiography and digital subtraction angiography Although formal renal angiography remains the gold standard tech- nique for assessing renovascular disease (Fig. 21.4.13), it has largely been replaced by ultrafast CT angiography and MRA in clinical practice. However, given that (as stated previously) current MRA techniques overestimate stenosis, angiography is then often used to confirm the severity of a stenosis, allowing both the anatomy and direct pressure measurements to be assessed before proceeding to angioplasty/​stenting. Renal angiography is not without hazard: it involves an arterial punc- ture and the use of potentially nephrotoxic contrast agents, and carries the risk of dislodging aortic and renal artery plaques, which can result in intrarenal, intra-​abdominal, and peripheral cholesterol embolization. Aside from the investigation of suspected chronic renovascular disease, renal and coeliac arteriography can establish a diagnosis of classical macroscopic polyarteritis nodosa. Occasionally, renal angiography is helpful in assessing renal tumour vascularity, and in determining whether partial nephrectomy can be performed. In some cases of persistent nonglomerular haematuria, formal renal angiography reveals a vascular abnormality as the underlying cause. Digital subtraction angiography (DSA) uses a venous injection of contrast and computer-​derived images to view the major renal ar- teries and intrarenal vessels. High doses of contrast media may be Fig. 21.4.12  Magnetic resonance angiogram showing a tight proximal stenosis in the single left renal artery (arrow) with post-​stenotic dilatation. There is a single right renal artery, without significant stenosis. Fig. 21.4.13  Renal arteriogram showing fibromuscular hyperplasia of the renal artery.

section 21  Disorders of the kidney and urinary tract 4802 required, but even so insufficient anatomical definition is obtained in between 5 and 20% of cases. Interventional renal arteriography Interventional renal arteriography should only be undertaken by experienced interventional radiologists with the support of vas- cular surgeons because it may be complicated by renal artery dis- section or rupture. Embolization with gel foam or metal coils can be used to selectively control renal haemorrhage, which is par- ticularly useful when this follows renal biopsy, and also in cases of arteriovenous malformation or tumour. Occasionally, a whole kidney is embolized. Some atheromatous renovascular stenotic le- sions can be usefully treated by transluminal angioplasty and/​or stenting. Renal venography Selective renal venous catheterization for blood sampling is still useful in patients with severe renovascular disease. The relative renal vein renin concentrations may aid the decision-​making process in deciding whether to perform a surgical or medical nephrectomy in a patient with a small, poorly functioning kidney due to severe renal artery stenosis. Renal venography is the gold standard test to diag- nose the rare nutcracker syndrome, a clinically manifest variant of the renal vein entrapment syndrome, or mesoaortic compression of the left renal vein. Nuclear medicine The main uses of renal nuclear medicine scans are given in Box 21.4.1. Static imaging—​radiolabelled DMSA Technetium-​labelled dimercaptosuccinic acid (DMSA) binds to renal proximal tubular cells, and after an intravenous injection some 70% of the dose is taken up by viable tubules within 3 to 4 h. This can be detected by a gamma camera. DMSA scans provide information about the relative function of each kidney, and show areas of scarring due to renal stone disease, infection, and vascular disease. In children with urinary tract sepsis suspected of having re- flux nephropathy, serial DMSA scans are used to assess progressive cortical scarring. During acute pyelonephritis, the DMSA scan may appear to show scars. These photopenic areas are due to inflamma- tion and increased intrarenal pressure and can return to normal following resolution of infection. DMSA scans are also used to con- firm the congenital absence of a kidney, to detect ectopic kidneys and other congenital malformations such as horseshoe kidney, du- plex systems, and cross/​fused ectopia, and to confirm absence of renal function. More recently, the introduction of single-​photon emission CT (SPECT) DMSA scans has improved resolution, although this starts to fade at GFRs below 30 ml/​min. These scans have shown that renal scars occur more frequently than previously thought, both in pa- tients with acute pyelonephritis and also following lower urinary tract infection in renal transplant recipients (Fig. 21.4.14). Dynamic imaging—​radiolabelled DTPA and MAG3 Technetium-​labelled DTPA and MAG3 are both filtered by the glomerulus and then rapidly excreted by the kidney. MAG3 is now largely replacing DTPA as it has a better extraction efficiency and therefore offers improved image definition, particularly in patients with chronic kidney disease, with a lower absorbed radiation dose. The renograms produced have three phases: vascular, accumulation within the kidney, and excretion. Renal artery stenosis and acute tubular necrosis can reduce uptake, flattening the second and third phases of the renogram. Similarly, intrinsic renal disease flattens the second phase, and makes interpretation difficult when renal func- tion is impaired. Urinary obstruction Radiolabelled DTPA and MAG3 scans are used to assess urological obstruction (Fig. 21.4.15), and can be useful in the management of patients with urinary calculi in assessing the functional signifi- cance of any obstruction, monitoring progress and the timing of intervention, ureterocoele, cases of differential obstruction such as a duplex kidney where obstruction is more likely to affect the upper pole, and possible obstruction following urinary diversion. Occasionally, patients with polycystic kidney disease present with severe pain due to the obstruction of a cyst, and DTPA/​MAG3 scanning provides a dynamic test to confirm this. In cases of ob- struction, the scan shows retention of tracer in the pelvicalyceal Box 21.4.1  Main uses of renal nuclear medicine scans • DMSA (dimercaptosuccinic acid):

—​ Estimation of differential renal function

—​ Imaging of scarring (reflux) • MAG3 (mercaptoacetyltriglycine):

—​ Detection of obstruction

—​ Estimation of differential renal function

—​ Screening for renal artery stenosis

—​ Renal transplant monitoring Fig. 21.4.14  A SPECT DMSA scan showing a large wedge-​shaped defect within the upper pole of the renal transplant. There is another smaller peripheral defect suggestive of renal scarring.

21.4  Clinical investigation of renal disease 4803 system, and the first change noted in the curve is a flattening of the third phase. When obstruction is established, the second phase is prolonged and the third phase continues to rise, and at worst all three phases are affected due to ensuing poor renal function. In cases of vesicoureteric reflux, MAG3 renograms with late films, de- layed until the child voids, can be used as an indirect micturating cystogram. In patients with dilated collecting systems, it is important to dif- ferentiate congenital megaureter from obstruction. Excretion may be slow due to pooling in a dilated system, but obstruction is un- likely if there is a brisk washout following the administration of intravenous furosemide, although patients with impaired renal function may have a reduced response to furosemide, making inter- pretation of the renogram less reliable. Thus, in cases with impaired renal function, direct pressure measurement within the renal pelvis following percutaneous puncture may be required to exclude partial obstruction (Stamey test). DTPA/​MAG3 scans are also used to detect and monitor reflux in children, as reflux may be demonstrated during the ‘emptying’ phase of the renogram. If not, then an indirect micturating cystogram can be performed using the radioactivity which has passed into the child’s bladder. Hypertension The main role of nuclear medicine in hypertension is the screening and diagnosis of renal artery stenosis (Fig. 21.4.16). Patients with renal artery stenosis may have a delay in uptake time (the time taken from injection to peak activity) and an increased intensity and dur- ation of MAG3 accumulation (due to increased tubular salt and water reabsorption, not seen in the case depicted in Fig. 21.4.16). If there is significant stenosis of a major branch artery, perfusion to one pole may be delayed. Two scans are performed to improve the sensitivity and specifi- city of the MAG3 renogram in the detection of renal artery sten- osis, one with and one without prior administration of captopril. The captopril–​MAG3 renogram can also be used as a screening test to determine whether the use of angiotensin converting enzyme in- hibitors or angiotensin II receptor blockers might be detrimental to renal function in patients with an increased risk of atheromatous renovascular disease, including those with severe cardiac failure or diabetes and elderly hypertensive patients, but it is rarely used for this purpose—​the usual practice is to measure the serum creatinine before and 1 to 2 weeks after starting these drugs, and then stopping them (and considering imaging of the renal arteries) if this has risen by more than 20 to 30%. As MAG3 can provide an assessment of divided renal function (although not as accurately as DMSA, particularly in infants), serial scanning may be helpful in monitoring patients over time to de- termine whether intervention with angioplasty or stenting is war- ranted, and similarly postintervention. Bilateral disease is more difficult to diagnose, but usually one kidney is more affected than the other. Following kidney transplantation, serial MAG3 isotope scans can be used to monitor graft function. In cases of major arterial or venous thrombosis, and hyperacute rejection, the graft appears to have no perfusion. Acute tubular necrosis, rejection, and calcineurin toxicity may all have similar appearances. MAG3 scans may also re- veal perirenal haematoma, lymphocele, and urinary leaks before they are clinically manifest. Later isotope scans may detect obstruc- tion due to ureteric stenosis. MAG3 can be used in anuric patients with acute renal failure to show vascular supply, such as those developing acute kidney injury after aortic surgery. Other isotopes Methyldiphosphonate (MDP) is filtered by the glomerulus, pro- viding an immediate dynamic renogram. It is later taken up by inflamed muscles (found in patients with myositis and rhabdo- myolysis) and the skeleton (detecting single or multiple bone me- tastases, and also metabolic bone disease in patients with endstage renal failure). Right Left 1750 1500 1250 1000 750 500 250 00 4 8 12 16 20 Counts per minute Minutes Fig. 21.4.15  DTPA renogram showing increasing uptake by the right kidney in a case of right-​sided ureteric obstruction. Right Left 150 125 100 75 50 25 0 0 4 8 12 16 20 Counts per minute 153 Minutes Fig. 21.4.16  MAG3 renogram demonstrating reduced uptake by the left kidney in a case of left-​sided renal artery stenosis.

section 21  Disorders of the kidney and urinary tract 4804 Combination techniques PET scanning, using fluoride-​labelled deoxyglucose (FDG), in combination with CT scanning was introduced to improve ana- tomical localization of tumours. Combining PET with standard CT improves lesion localization and characterization, and tumour staging (Fig. 21.4.17). The role of PET/​CT in primary staging of renal and prostate cancer has yet to be established, but it does have a role in detecting testicular tumours and in managing patients with advanced/​metastatic renal and bladder cancer. However, PET/​CT scanning also localizes areas of infection and inflam- mation and hence can be used to image and monitor response to treatment in a variety of circumstances, for example, infected cysts in patients with adult polycystic kidney disease, large-​vessel vasculitis in cases of Takayasu’s arteritis (Fig. 21.4.18), and retro- peritoneal fibrosis. Renal biopsy Indications A renal biopsy should be considered in any patient with disease af- fecting the kidney when the clinical information and other labora- tory investigations have failed to establish a definitive diagnosis or prognosis, or when there is doubt as to the optimal therapy. However, renal biopsy has the potential to cause morbidity and (on rare occasions) mortality, hence its risk must be outweighed by the potential advantages of the result to the individual patient. Biopsies which would be ‘of interest’ but ‘not in the patient’s interest’ should not be performed. Indications for renal biopsy must be considered on an individual basis, with the clinical presentations that warrant native renal biopsy given in Box 21.4.2. Diabetic patients with proteinuria would not normally be bi- opsied unless they had other conditions, such as haematuria or sudden-​onset nephrotic-​range proteinuria, suggesting there might be an alternative or additional diagnosis to diabetic nephropathy. Fig. 21.4.17  FDG-​PET scan highlighting a renal cell cancer (arrow) that developed in a patient with adult polycystic kidney disease. Fig. 21.4.18  FDG-​PET scan from a patient with aortitis showing increased uptake in the aortic arch (arrows point to the ascending and descending aorta). Box 21.4.2  Possible indications for native kidney biopsy • Asymptomatic proteinuria less than or equal to 1.5 g/​day:

—​ With controlled hypertension

—​ With dysmorphic haematuria

—​ With reduced GFR

—​ With any combination of the above • Asymptomatic proteinuria greater than 1.5 g/​day • Nephrotic syndrome • Nonvisible or dysmorphic haematuria:

—​ Hereditary condition

—​ Insurance company requirement

—​ Patient request

—​ With proteinuria

—​ With hypertension

—​ With reduced GFR • Acute kidney injury—​exclude ischaemic ATN:

—​ With abnormal urinary sediment

—​ With proteinuria

—​ Positive ANCA/​ANA/​anti-​GBM

—​ Severe hypertension

—​ No obvious cause

—​ Prolonged history • Acute kidney injury—​presumed ischaemic ATN:

—​ Delayed recovery • Chronic kidney disease (reasonable, equal-​sized kidneys):

—​ With proteinuria

—​ With dysmorphic haematuria • Known renal diagnosis (reasonable equal-​sized kidneys):

—​ Sudden unexplained reduction in GFR

—​ Unexplained increase in proteinuria Indications may be clear-​cut (e.g. acute kidney injury of unknown cause with abnormal urinary sediment; adult with nephrotic syndrome) but they are not always so, and not all nephrologists would recommend biopsy in all of the circumstances listed (e.g. many would elect not to biopsy, but to arrange continued monitoring, for patients with asymp- tomatic proteinuria and stable renal function). ANA, antinuclear factor; ANCA, antineutrophil cytoplasmic antibody; ATN, acute tubular necrosis; GBM, glomerular basement membrane.

21.4  Clinical investigation of renal disease 4805 Most paediatricians would treat small children presenting with nephrotic syndrome with steroids and only consider renal biopsy if they did not respond to treatment. Some conditions, in particular lupus nephritis and membranous glomerulonephritis, may change histological grading, so requiring repeat biopsy. Renal biopsy is an important investigation in the management of patients with a renal transplant. Postoperative oliguria and/​ or deterioration in renal function requires urgent investigation to differentiate acute ischaemic tubular necrosis from calcineurin (ciclosporin or tacrolimus) or other drug toxicity, acute rejection (vascular and/​or cellular), urinary obstruction and/​or leakage, and even frank infarction. Serial biopsies may be required to monitor the response to antirejection therapy, and at a later stage to examine for recurrence of the original renal disease, or de novo glomeruloneph- ritis in the graft. Contraindications Percutaneous renal biopsy should not be undertaken in patients with polycystic kidney disease. Similarly, patients with renal masses, such as tumours or cysts, should only be biopsied under direct vision, either by real-​time ultrasonography or CT scanning, or by formal open surgical biopsy. Patients with a solitary (or solitary func- tioning) native kidney are normally considered only for open sur- gical biopsy, although the transjugular approach may be an option. Haemorrhage is more likely to occur in patients with uncontrolled hypertension or hereditary or acquired coagulation disorders, and in those taking anticoagulants or antiplatelet agents, and both an- aemia and uraemia impair platelet aggregation. Blood pressure should be controlled and coagulation abnormalities treated before biopsy. Patients with renal amyloid also have an increased risk of haemorrhage, as may those with classic polyarteritis nodosa. Patients with chronic renal failure and bilaterally small kid- neys should not undergo biopsy. This would be technically diffi- cult (the kidneys are small and hard) and the biopsy appearances of endstage renal failure are exceedingly unlikely to provide any information that might alter the clinical course or management. Percutaneous renal biopsy should not be performed in patients with untreated acute pyelonephritis due to the risk of developing a perinephric abscess. Technique ‘Blind’ biopsy of the native kidney, meaning biopsy without imaging for localization, should not be performed unless there are truly ex- ceptional circumstances. It is possible to visualize the kidney and biopsy under fluoroscopic control after injection of radiocontrast medium as for an IVU, but the most commonly used method for directing biopsy is ultrasound guidance. This can either be used to record the depth of the lower pole from the skin and mark the sur- face position vertically above it on inspiration, or to provide real-​ time guidance. Occasionally, CT guidance is required. Percutaneous renal biopsy should be carried out using sedation and local anaesthesia. Children may require general anaesthesia. For ultrasound-​guided biopsy of the native kidney, the patient should be placed prone on top of pillows or folded sheets to compress the upper abdomen and lower ribs and fix (to some degree) the position of the kidneys. Under real-​time ultrasonography, the kidneys are visualized, the patient asked to take and hold a deep breath in inspir- ation, and the kidney which is thought to be technically the easiest to biopsy is targeted. To avoid major vessels, the aim should be for the lateral border of the lower pole. Either 14-​ or 18-​gauge Tru-​Cut-​type needles are commonly used, with most centres now using an auto- mated spring-​loaded biopsy gun. Under direct vision, the needle tip is advanced to the renal capsule, and with the kidney fixed in inspir- ation, biopsy is performed. The advent of colour Doppler means that the operator can deliberately avoid the major intrarenal vessels. Transjugular biopsy can be performed in patients who have an increased likelihood of bleeding complications. Technical develop- ments have now allowed biopsy needles to be passed reliably from the renal vein into the renal cortex, such that in the author’s own institution, all such biopsies in the last 8 years have been diagnostic. Occasionally, open surgical biopsy is required, with the biopsy taken under direct vision and local bleeding controlled. Renal transplants, usually placed in one or other iliac fossa, are biopsied in the supine position. Pillows can be placed under the side with the transplant to help move bowel and fat pad away from the transplant. Biopsies are taken from the lateral border of the upper pole, avoiding the major vessels and ureter. The obvious risk of renal biopsy is haemorrhage. All patients should be placed on strict bed rest for at least 6 h after the procedure, and pulse and blood pressure should be checked frequently during this period. Hypotension, tachycardia, abdominal/​back pain, and macroscopic haematuria are indications for urgent medical review. Complications Routine imaging after renal biopsy has shown that most patients de- velop a perirenal haematoma (Fig. 21.4.19), which is usually asymp- tomatic. Arteriovenous fistulas may also develop acutely following biopsy, most of which disappear spontaneously with time, with only the occasional one requiring treatment by the interventional radiologist. Macroscopic haematuria occurs in fewer than 10% of patients, and bleeding sufficient to warrant blood transfusion in around 1%. Rarely, severe haemorrhage may necessitate treatment with the insertion of coils or gel foam embolization. Exceptionally, death may occur, usually due to failure to detect haemorrhage and provide appropriate resuscitation. Complication rates are increased in patients with both acute and chronic renal failure. Uraemia prolongs the bleeding time, even when Fig. 21.4.19  CT scan showing haemorrhage (arrow) around the right kidney following a biopsy.

section 21  Disorders of the kidney and urinary tract 4806 the conventional coagulation screening is normal (prothrombin time, activated partial thromboplastin time, and peripheral platelet count). The risk of uraemic haemorrhage can be at least partially reversed prior to biopsy by good dialysis to improve platelet function, correc- tion of the haematocrit and any underlying coagulation defect, and by giving an infusion of deamino-​d-​arginine vasopressin (DDAVP) immediately prior to the procedure (0.3 µg/​kg body weight, over 30 min), but vasopressin may cause cardiac ischaemia and should be avoided in patients with critical coronary or vascular artery disease. FURTHER READING Urine microscopy Birch DF, et al. (1994). A color atlas of urine microscopy. Chapman and Hall, London. Chawla LS, et al. (2008). Urinary sediment cast scoring index for acute kidney injury: a pilot study. Nephron Clin Pract, 110, c145–​50. Fogazzi GB, et al. (2015). The urinary sediment. An integrated view, 3rd edition. Masson, Milan. Renal function Alpern RJ, Moe OW, Caplan M (2013). The kidney: physiology and pathology, 5th edition. Academic Press, London. Schrier RW (2017). Renal and electrolyte disorders, 8th edition. Lippincott Williams & Wilkins, Philadelphia. Skorecki K, et al. (2015). Brenner & Rector’s the kidney, 10th edition. Elsevier, Philadelphia. Turner N, et al. (2015). Oxford textbook of clinical nephrology, 4th edi- tion. Oxford University Press, Oxford. White SL, et al. (2009). Diagnostic accuracy of urine dipsticks for de- tection of albuminuria in the general community. Am J Kidney Dis, 58, 19–​28. Witte EC, et al. (2011). First morning voids are more reliable than spot urine samples to assess microalbuminuria. J Am Soc Nephrol, 20, 436–​43. Creatinine/​eGFR/​cystatin C Cockcroft DW, Gault MH (1976). Prediction of creatinine clearance from serum creatinine. Nephron, 16, 31–​41. Gansevoort RT, de Jong P (2010). Challenges for the present CKD clas- sification system. Curr Opin Nephrol Hypertens, 19, 308–​14. Grubb A, et al. (2005). Simple cystatin C based prediction equations for glomerular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the Schwartz and the Counahan–​Barrat prediction equations for children. Clin Chem, 51, 1420–​31. Inker LA, et  al. (2012). Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med, 367, 20–​9. Lamb EJ, Stevens PE (2014). Estimating and measuring glomerular fil- tration rate: methods of measurement and markers for estimation. Curr Opin Nephrol Hypertens, 23, 258–​66. Levey AS, Stevens L (2010). Estimating GFR using the CKD Epidemiology Collaboration (CKD-​EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions. Am J Kidney Dis, 55, 622–​7. Levey AS, et al. (2000). A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol, 11, A0828. Levey AS, et  al. (2009). CKD-​EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glom- erular filtration rate. Ann Intern Med, 150, 604–​12. Myers GL, et al. (2006). Recommendations for improving serum cre- atinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program. Clin Chem, 52, 5–​18. National Kidney Foundation, K/​DOQI (2018). Estimated glomerular filtration rate (eGFR). https://​www.kidney.org/​atoz/​content/​gfr Randers E, et al. (1998). Serum cystatin C as a marker of the renal func- tion. Scand J Clin Lab Invest, 58, 585–​92. Shlipak MG, Praught ML, Sarnak MJ (2006). Update on cystatin C: new insights into the importance of mild kidney dysfunction. Curr Opin Nephrol Hypertens, 15, 270–​5. Stevens LA, et al. (2006). Assessing kidney function –​ measured and estimated glomerular filtration rate. N Engl J Med, 354, 473–​83. Stevens LA, et al. (2011). Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities. Kidney Int, 79, 555–​62. Renal imaging Agrawal K, et al. (2011). Polycystic kidney disease: renal cyst infection detected on F-​18 FDG PET/​CT. Clin Nucl Med, 36, 1122–​3. Allan PL, Dubbins P, Pozniak MA (1997). Clinical Doppler ultrasound. Churchill Livingstone, Edinburgh. Gerst S, et al. (2011). Evaluation of renal masses with contrast-​enhanced ultrasound: initial experience. Am J Roentgenol, 197, 897–​906. Ghantous VE, et al. (1999). Evaluating patients with renal failure for renal artery stenosis with gadolinium enhanced magnetic resonance angiography. Am J Kidney Dis, 33, 36–​42. Hain SF (2006). Renal imaging. Clin Med (Lond), 6, 244–​8. Helenon O, et al. (1997). Renovascular disease: Doppler ultrasound. Semin Ultrasound, 18, 136–​42. O’Neill WC, et al. (2011). Imaging for renovascular disease. Semin Nephrol, 31, 272–​82. Tamburrini O, Balducci A (2012). Gadolinium and nephrogenic systemic fibrosis: have the alarm bells been silenced? Radiol Med, 117, 1–​5. Testa HJ, Prescott MC (1996). Nephrourology, British Nuclear Medicine Society. BPC Wheatons, Exeter. Ultrasound scanning Krumme B (2006). Renal Doppler sonography—​update in clinical nephrology. Nephron Clin Pract, 103, c24–​8. CT scanning Read S, Allen C, Hare C (2006). Applications of computed tomog- raphy in renal imaging. Nephron Clin Pract, 103, c 29–​36. MRI Cowper SE (2008). Nephrogenic systemic fibrosis: an overview. J Am Coll Radiol, 5, 23–​8. Do C, Barnes JL, Tan C, Wagner B (2014). Type of MRI contrast, tissue gadolinium, and fibrosis. Am J Physiol Renal Physiol, 307, F844–​55. Ebrahimi B, Textor SC, Lerman LO (2014). Renal relevant radi- ology: renal functional magnetic resonance imaging. Clin J Am Soc Nephrol, 9, 395–​405. Laissy JP, et al. (2006). Magnetic resonance imaging in acute and chronic kidney diseases: present status. Nephron Clin Pract, 103, c50–​7. Nuclear medicine Hain SF (2006). Renal imaging. Clin Med (Lond), 6, 244–​8.

21.5 Acute kidney injury 4807 John D. Firth

21.5 Acute kidney injury 4807 John D. Firth

ESSENTIALS Definition—​for practical clinical purposes, acute kidney injury (AKI) is defined as a significant decline in renal excretory function occurring over hours or days, detected by either a fall in urinary output or a rise in the serum concentration of creatinine. Oliguria—​defined (ar- bitrarily) as a urinary volume of less than 400 ml/​day—​is usually pre- sent, but not always. Three stages of AKI are recognized, depending on the degree of the reduction in urinary output and/​or the mag- nitude of the rise in serum creatinine, the latter now being widely used to trigger automated alerts from biochemistry laboratories to clinical staff. Epidemiology—​the annual incidence of AKI in the United Kingdom population is about 0.6%, and AKI complicates 10 to 20% of medical and surgical admissions. Severe AKI (serum creatinine >500 µmol/​ litre) affects 200 to 750 per million adult population per year in the United Kingdom. Clinical approach Diagnosis—​all patients admitted to hospital with acute illness, but particularly older people and those with pre-​existing chronic kidney disease, should be considered at risk of developing AKI. The most common precipitant is volume depletion, ​early detection of which requires careful monitoring of fluid input and output, lying and standing (or sitting) pulse and blood pressure, and daily weighing. Serum creatinine and electrolytes should be measured on admission in all acutely ill patients, and repeated daily or on alternate days in those who remain so. Assessment—​after treatment of life-​threatening complications, the initial assessment of a patient who appears to have AKI must an- swer three questions: (1) is the kidney injury really acute?—​has serum creatinine been measured previously?; (2) is urinary obstruction a possibility?—​renal ultrasonography is required urgently when the diagnosis of AKI is not clear cut (but remember that 5% of cases of obstruction will have a misleading initial ultrasound report); and (3) is there a renal inflammatory cause?—​stick testing of the urine is man- datory in any patient with AKI, with urinary microscopy for cellular casts if this reveals significant proteinuria or haematuria. Red cell casts are found in acute glomerulonephritis, renal vasculitis, accelerated-​ phase hypertension, and (sometimes) in interstitial nephritis—​their presence indicates the need for urgent specialist renal referral. General aspects of management The immediate management of a patient with renal impairment is directed towards three goals:  (1) recognition and treatment of any life-​threatening complications of AKI, (2)  prompt diagnosis and treatment of hypovolaemia, and (3) specific treatment of the underlying condition—​if this persists untreated then renal function will not improve. Life-​threatening complications—​the greatest danger is hyper­ kalaemia, which can cause cardiac arrest without any preceding symptoms whatsoever. All doctors who work with acutely ill pa- tients should be able to recognize the characteristic ECG ap- pearances, which are a better indicator of cardiac toxicity in the individual patient than the serum potassium level. As serum potas- sium rises, the following changes occur progressively: (1) ‘tenting’ of the T wave; (2) reduction in size of P waves, increase in the PR interval, widening of the QRS complex; (3) disappearance of the P wave, further widening of the QRS complex; (4) irregular ‘sinus- oidal’ ECG; and (5) asystole. Severe hyperkalaemic changes require immediate treatment with intravenous calcium (usually given as calcium gluconate, 10 ml of 10% solution, intravenously over 60 s), after which intravenous insulin/​glucose or nebulized salbutamol can be used to reduce the serum potassium for a few hours to allow time for renal excretion (in cases of renal failure that are rap- idly treatable, e.g. bladder outflow obstruction) or initiation of renal replacement therapy. Fluid management—​a key part of the immediate assessment and management of any patient who is very ill, which will include many of those with AKI, is to make a correct assessment of their intravascular volume status and to resuscitate rapidly and effect- ively, as discussed in Chapter 17.1. Once this has been achieved, in the patient who remains oliguric, fluid intake should be limited to the volume of the previous day’s urine output and gastrointestinal losses, plus 500 ml, but this allocation may need to be substantially increased in the presence of fever or in hot environments, when insensible losses may be much increased. To keep the patient in the optimal state of fluid balance, there is no substitute for careful, twice-​daily clinical examination for signs of intravascular volume depletion or excess, supplemented by accurate daily weighing, to gauge the overall net fluid balance, and an intelligent flexible re- sponse to the findings. 21.5 Acute kidney injury John D. Firth

section 21  Disorders of the kidney and urinary tract 4808 Renal replacement therapy—​mandatory indications for immediate instigation are (1)  refractory hyperkalaemia; (2)  intractable fluid overload; (3) metabolic acidosis producing circulatory compromise; and (4) overt uraemia manifesting as encephalopathy, pericarditis, or uraemic bleeding. Modern practice is (whenever possible) to begin renal replacement therapy when the serum creatinine reaches 500 to 700 µmol/​litre, unless there is clear evidence that spontan- eous recovery is occurring or there are other reasons to maintain a conservative approach. Renal biopsy—​should be considered when (1) the history, examin- ation, or laboratory tests suggest a systemic disorder that could cause AKI and could be diagnosed by renal biopsy; (2) the urinary sediment contains red cell casts; (3) the case history is atypical; and (4) renal failure is unusually prolonged (say, beyond 6 weeks). Specific causes of acute kidney injury There are many possible causes of AKI, but in any given clinical con- text few of these are likely to require consideration. By far the most frequent are prerenal failure and acute tubular necrosis, which to- gether account for 80 to 90% of cases of AKI seen by physicians. Prerenal failure and acute tubular necrosis—​these can best be re- garded as a continuum of renal response to ischaemic injury, in much the same way that stable angina, non-​ST-​elevation myocar- dial infarction, and ST-​elevation myocardial infarction are a con- tinuum of cardiac response to ischaemia. Prerenal failure describes renal dysfunction that is entirely attributable to hypoperfusion, and where restoration of renal perfusion leads to rapid recovery. Acute tubular necrosis describes a clinical entity comprising AKI with three main characteristics: (1) it is seen in specific clinical contexts, fre- quently involving circulatory compromise and/​or nephrotoxins; (2) urinary abnormalities usually suggest tubular dysfunction; and (3) recovery of renal function is expected within days or weeks, in most cases, if the patient survives the precipitating insult. There is no specific treatment for acute tubular necrosis, and it is a marker of severe illness with mortality around 15% in all cases, and 40 to 60% in series from intensive care units of patients receiving renal replacement therapy in the context of mechanical ventilation for respiratory failure. Introduction Definition For practical clinical purposes, acute kidney injury (AKI) has trad- itionally been defined as a significant decline in renal excretory function occurring over hours or days, detected by either a fall in urinary output or a rise in the serum concentration of creatinine. Oliguria—​defined (arbitrarily) as a urinary volume of less than 400 ml/​day—​is usually present, but not always. The international guideline group, Kidney Disease:  Improving Global Outcomes (KDIGO), has defined AKI more precisely as being any one of the following: • Increase in serum creatinine by greater than 0.3 mg/​dl (>26 µmol/​ litre) within 48 h • Increase in serum creatinine to greater than 1.5 times baseline level within 7 days (known or presumed) • Urinary output less than 0.5 ml/​kg body weight per hour for 6 to 12 h AKI is then staged for severity according to criteria shown in Table 21.5.1, and the automated application of standard algorithms to measurements of serum creatinine performed in biochem- ical laboratories has led to the widespread practice of automated AKI alerts being sent to clinical staff (as now mandated by NHS England) in addition to the creatinine reading. Widespread agree- ment on the staging system for AKI has also been useful in sup- porting high-​quality epidemiological studies, which have been important in showing that AKI is common, and also emphasizing that acute deterioration in renal function that leads to a small rise in serum creatinine is associated with poorer patient outcome: a little bit of kidney failure does matter. Epidemiology The application of automated alert systems has provided high-​ quality data on the epidemiology of AKI in patients in developed countries. In a large United Kingdom teaching hospital, from 2011 to 2013 the overall incidence of AKI in inpatients was 10.7%, with the highest stage being stage 1 in 7.2%, stage 2 in 2.2%, and stage 3 in 1.3% (with mortality 12.5%, 28.4%, and 35.7% respectively; overall 18.5%). Similar methodology applied prospectively to a population of three million in Wales (United Kingdom) in 2015 showed an incidence of AKI (of any stage) of 577 per 100  000 population, with community-​acquired AKI accounting for 49% of episodes, and 42% occurring in the context of pre-​existing chronic kidney disease. Ninety-​day mortality was 25.6%. A 2011 United Kingdom population-​based study reported the incidence of AKI requiring renal replacement therapy to be 184 per million popula- tion per year, which is very similar to the figure of 133 per million population per year reported in 2010 from Japan. Similar data are not available from resource-​poor countries, but here the incidence of AKI is likely to be higher. Table 21.5.1  Stages of AKI AKI stage Urine output Serum creatinine 1 <0.5 ml/​kg body weight per hour for 6-​12 h Increase to 1.5–​1.9 times baseline level within 7 days (known or presumed), or Increase by >0.3 mg/​dl (>26 µmol/​litre) within 48 h 2 <0.5 ml/​kg body weight per hour for >12 h Increase to 2.0–​2.9 times baseline level within 7 days (known or presumed) 3 <0.3 ml/​kg body weight per hour for 24 h, or anuria for >12 h Increase to >3 times baseline level within 7 days (known or presumed), or Increase to >4 mg/​dl (354 µmol/​litre), or Initiation of renal replacement therapy Urinary obstruction must be excluded as a cause of low urine output. The most abnormal parameter—​urine output, serum creatinine, or GFR—​is used for classification.

21.5  Acute kidney injury 4809 A United Kingdom National Confidential Enquiry into Patient Outcome and Death (NCEPOD) of patients dying with a hospital-​ recorded diagnosis of AKI, published in 2009, examined the case notes and/​or completed clinician questionnaires of 700 patients. This found an even split between men and women (48% vs 52%), and that most patients dying with AKI are elderly, with mean age 83 years (Fig. 21.5.1). Of the cases who had renal disease on admis- sion to hospital, 46% had a new diagnosis of AKI, 38% had acute on chronic renal failure, and 16% had chronic kidney disease (and developed additional AKI after admission). AKI developed before admission in 79% of patients and after admission in 21%. Causes AKI may arise as an isolated problem, but much more commonly occurs in the setting of circulatory disturbance associated with se- vere illness, trauma, or surgery, and in patients with many risk factors for AKI, most notably old age, medical comorbidities, medi- cations, previous chronic kidney disease, and hypovolaemia. There are many possible causes of AKI (Box 21.5.1), but in any given clinical context few of these are likely to require consideration. Table 21.5.2 shows the diagnoses made in 129 cases of acute renal impairment in 2216 consecutive medical and surgical admissions, and Table 21.5.3 shows the diagnoses established in 748 cases of AKI admitted to hospital in a prospective, multicentre, community-​ based study. Although these data are somewhat dated, they still re- flect current practice. The frequency of particular causes of AKI will vary considerably depending on the population studied. An observational cohort study of 618 patients in five American intensive care units found that over 70% of cases were due to or associated with ischaemic and/​or nephrotoxic (radiocontrast media, rhabdomyolysis) acute tubular necrosis, prerenal failure, cardiac failure, or liver disease, and that the patients had extensive comorbidities (chronic kidney disease 30%, coronary artery disease 37%, diabetes mellitus 29%, and chronic liver disease 21%). Reports based on data from bio- chemical laboratories (including cases both admitted to hos- pital and managed in primary care) find that urinary obstruction (mainly prostatic) typically accounts for 25% or more of cases of acute impairment of renal function. Obstetric causes account for around 1% of cases of AKI in developed countries, but in some parts of the world up to 30%, and for obvious reasons snake bite is a common cause of AKI in some places, but exceptionally rare in others (see Chapter 21.11 for further discussion of renal disease in the tropics). 140 Number of patients 120 100 80 60 40 20 0 36 – 40 41 – 45 46 – 50 51– 55 56– 60 61– 65 66– 70 71– 75 76 – 80 Age (years) 81 – 85 86 – 90 91 – 95 96 – 100

100 Fig. 21.5.1  Age distribution of 631 patients who died in hospitals in the United Kingdom with a diagnosis of AKI. Reproduced with permission from Stewart J, et al. (2009). Adding Insult to Injury. A review of the care of patients who died in hospital with a primary diagnosis of acute kidney injury (acute renal failure). National Confidential Enquiry into Patient Outcome and Death. http://​www.ncepod.org.uk/​2009aki.html Box 21.5.1  Some causes of acute kidney injury • Prerenal uraemia • ‘Acute tubular necrosis’—​following haemodynamic compromise, com- monly with sepsis or following exposure to nephrotoxins, including drugs, chemicals, rhabdomyolysis, or snake bite (Table 21.5.7 and Box 21.5.3) • Vascular causes:

—​ Renal cortical necrosis

—​ Large-​vessel occlusion

—​ Small-​vessel occlusion—​accelerated-​phase hypertension and systemic sclerosis • Glomerulonephritis and vasculitis • Acute interstitial nephritis • ‘Haematological’ causes:

—​ Haemolytic uraemic syndrome/​thrombotic thrombocytopenic purpura

—​ Myeloma • Hepatorenal syndrome • Urinary obstruction:

—​ Intrarenal crystalluria

—​ Postrenal—​renal stones, papillary necrosis, retroperitoneal fibrosis, bladder/​prostate/​cervical lesions, massive lymphadenopathy (lymphoproliferative disorders, secondary carcinoma)

section 21  Disorders of the kidney and urinary tract 4810 Clinical approach to patients with or at risk of acute kidney injury Diagnosis of the presence of acute kidney injury Symptoms and signs attributable to the accumulation of fluid, electro- lytes, acid, or uraemic wastes within the body are not apparent until AKI is far advanced, and the symptoms and signs that may arise are not specific: unsuspected hyperkalaemia is the greatest danger, since this may produce no symptoms whatsoever before causing cardiac arrest. All patients admitted to hospital with acute illness must therefore be considered at risk of developing AKI, and those who have pre-​existing chronic kidney disease are particularly susceptible to acute exacerba- tions. This group includes all elderly patients, in whom a combination of low muscle mass and low dietary meat consumption may conspire to maintain an apparently ‘normal’ serum creatinine level, despite a reduction in glomerular filtration rate (GFR) to considerably less than 50% of that expected in a healthy young adult. For early recognition of AKI, the basic care of all acutely ill pa- tients should include careful monitoring of fluid input and output, lying and standing (or sitting) blood pressure, daily weighing, and regular estimation of serum creatinine and electrolytes. These blood tests should be performed on admission in all acutely ill patients, and repeated daily or on alternate days in those who remain so. If acted upon, these measurements will ensure that advanced AKI does not seem to have occurred ‘suddenly’ in patients already in hospital. Measurement of serum creatinine It is important to emphasize that a single measurement of serum cre- atinine cannot in isolation be used to determine the severity of acute renal impairment: if a patient with serum creatinine of 100 µmol/​litre were to have both kidneys removed today, then the creatinine to- morrow would be only 150 to 200 µmol/​litre. Clinical judgement, un- supported by measurement of serum creatinine, is a poor predictor of whether or not a patient has AKI, and patients who develop AKI after hospital admission not infrequently receive poor care. In the NCEPOD enquiry, the study’s advisors considered that 20% (22/​107) of cases of AKI that developed after admission and which led to the patient’s death had been both predictable and avoidable. It is this, to- gether with other similar data, that has driven the introduction of the automated alert systems discussed previously, with the intention that these should support and stimulate clinicians to provide better care. Measurement of fluid input and output, and daily weighing Although it might seem to the inexperienced physician to be a simple matter to monitor fluid input and output, this is often not so in prac- tice, excepting in patients who are restricted to parenteral fluids and who have a urethral catheter. Drinks may be spilt, extra drinks may be acquired from a variety of sources, urine may be spilt, and vomit and diarrhoea are often found in places where they are difficult to quantitate. These considerations mean that the most likely explan- ation for fluid balance charts being difficult to interpret is the erro- neous recording of input or output. Daily weighing on accurate scales provides a much more reliable picture of net overall fluid balance. Patients who are acutely ill in- variably lose flesh weight, commonly at a rate of up to a few hundred grams per day. If weight appears to fall at a rate faster than this, then negative fluid balance is the reason, with the occurrence of greatly increased ‘insensible’ losses through the skin and lungs during fever being a common explanation. Physical signs Aside from weight loss, the most reliable physical signs of significant intravascular volume depletion are the development of postural diz- ziness, a postural rise in pulse rate (>30 beats/​min), and the finding Table 21.5.2  Causes of development of acute impairment of renal function in 2216 consecutive medical and surgical admissions Cause Number of patients Acute tubular necrosis:   Hypovolaemia 22   Congestive cardiac failure 10   Sepsis 10   Nephrotoxins 25   Postsurgical 23   Other 12 Hepatorenal syndromea   5 Obstruction   3 Vasculitis   2 Other/​multifactorial/​unknown 17 Total 129 (5.8% of admissions) Acute impairment of renal function was diagnosed when the serum creatinine concentration rose by a predetermined amount (approximately one-​third of the baseline) during the period of hospital admission. During the period of study, 46 patients were excluded from analysis because they were either admitted specifically for treatment of acute renal failure or were recipients of long-​term haemodialysis. Dialysis was required in 10 cases. a The frequency of hepatorenal syndrome was higher in this study than in routine clinical practice in most centres, presumably as a reflection of referral bias. Modified from The American Journal of Medicine 74;2;6, Hospital-​acquired renal insufficiency: A prospective study, Hou, Bushinsky, Wish, Cohen & Harrington © 1983, with permission from Elsevier. Table 21.5.3  Causes of acute kidney injury established in all cases (748) admitted to 13 tertiary-​care hospitals in Madrid, Spain, over a 9-​month period Cause Proportion of patients (%) Acute tubular necrosis 45 Prerenal 21 Acute-​on-​chronic kidney disease 13 Urinary tract obstruction 10 Glomerulonephritis or vasculitis   4 Acute interstitial nephritis   2 Atheroemboli   1 AKI was diagnosed when a sudden rise in serum creatinine to >177 µmol/​litre was found in patients with previously normal renal function, or when there was a sudden rise of

50% in those known to have mild to moderate chronic renal failure. Most cases of acute-​on-​chronic kidney disease were due to prerenal cause or acute tubular necrosis, and most cases of obstruction were due to prostatic disease in elderly men. Dialysis was required in 36% of cases. Modified from Liano F, Pascual J. (1996). Epidemiology of acute renal failure: a prospective, multicenter, community-​based study. Madrid Acute Renal Failure Study Group. Kidney Int, 50, 811–​18, with permission.

21.5  Acute kidney injury 4811 of dry axillae. If weight rises at any time, then this must be due to positive fluid balance, whatever the input/​output charts may sug- gest. It may not be obvious from clinical examination where the fluid has gone: the possibilities of sequestration in the peritoneal cavity or in the tissue interstitium should be recognized. Prevention of acute kidney injury Many patients develop AKI while in hospital, which can occur despite exemplary care but is more likely if care is deficient. The NCEPOD report into the deaths of over 1000 patients with AKI found that good care (defined as that which you would accept from yourself, your trainees, and your institution) was provided in only 50% of cases, and that in many instances the development of AKI had been both predictable and avoidable. Given that patients who develop AKI are admitted under many specialties, and very few by nephrologists (Fig. 21.5.2), it is im- portant that all doctors caring for sick patients understand those who are at particular risk of developing AKI and implement meas- ures that will reduce the likelihood of this occurring and respond in an appropriate and timely manner if it does. Risk factors and care bundles Risk factors for AKI are shown in Table 21.5.4. Appropriate re- sponses to the development of AKI can be articulated in the form (to use currently fashionable jargon) of a ‘care bundle’ (Table 21.5.5), and guidance disseminated (Fig. 21.5.3). Key elements of this are prompt recognition and treatment of sepsis, optimization of fluid volume status, and avoidance of toxins. Antihypertensives, with the possible exception of β-​blockers when these are prescribed for is- chaemic heart disease, should be stopped if blood pressure is low. A  meta-​analysis of randomized controlled trials has shown that stopping angiotensin-​converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) before coronary angiography or coronary surgery reduces the risk of AKI. There is no such trial evidence for stopping these drugs during intercurrent illness in pri- mary or secondary care, but a longitudinal ecological study sug- gested that up to 15% of the increase in AKI admissions in England over a four-​year time period was potentially attributable to increased prescribing of ACE inhibitors and ARBs. It would therefore widely be regarded as good practice to advise patients to temporarily dis- continue these drugs in the presence of illnesses causing fluid loss (e.g. vomiting, diarrhoea, and high fever) or evidence of volume de- pletion (e.g. postural dizziness or light-​headedness, reduced home-​ measured blood pressure). Glycaemic control Critical illness is associated with stress hyperglycaemia, and in a range of circumstances a linear relationship between blood glucose levels and adverse clinical outcomes has been shown. It has also been shown that maintaining tight glycaemic control by intensive insulin therapy can improve outcomes, including reducing the incidence of severe AKI in both medical and surgical intensive care unit pa- tients. KDIGO recommendations are that the average blood glucose should not be allowed to exceed 150 mg/​dl (8.3 mmol/​litre), but 200 Number of patients 180 160 140 120 100 80 60 40 20 0 Admitting specialty General medicine Care of the elderly Thoracic medicine Gastroenterology Cardiology Endocrinology Nephrology General surgery Diabetic medicine Urology Haematology Trauma & Orthopaedics Critical care medicine Upper GI surgery Vascular surgery Fig. 21.5.2  Admitting specialty of 631 patients who died in hospitals in the United Kingdom with a diagnosis of AKI. Reproduced with permission from Stewart J, et al. (2009). Adding Insult to Injury. A review of the care of patients who died in hospital with a primary diagnosis of acute kidney injury (acute renal failure). National Confidential Enquiry into Patient Outcome and Death. http://​www.ncepod.org.uk/​2009aki.html

section 21  Disorders of the kidney and urinary tract 4812 Table 21.5.5  A care bundle approach to assessment and management of patients who have developed AKI Initial assessment ABCDE assessment Vital signs—​check NEWS score Look for signs of sepsis Physical exam for large bladder (bedside bladder scan) Medication review Stop potentially harmful drugs; check if dose adjustments required in renal impairment Initial management Give fluid challenge if hypovolaemic/​hypotensive Prompt treatment of sepsis Relieve bladder outflow obstruction if present Stop potentially harmful drugs (NSAIDs, ACE inhibitors, ARBs, diuretics) Check if medications require dose adjustments in renal impairment Maintain glycaemic control Indications for immediate referral for specialty input Renal—​complications of AKI refractory to medical treatment (most notably hyperkalaemia or pulmonary oedema as indications for dialysis); likely intrinsic renal disease/​systemic vasculitis; special circumstances (e.g. renal transplant patient) Radiology and/​or urology—​bladder outflow obstruction that cannot be relieved by urinary catheter passed by admitting team; obstructed and infected kidney (pyonephrosis) Critical care—​haemodynamic instability; multiorgan failure Further investigation Urinalysis—​significant haematuria and proteinuria indicate need for immediate renal referral in context of AKI Cultures for sepsis Venous lactate and arterial blood gases (if sepsis or high NEWS score) Imaging with ultrasonography within 24 h to look for obstruction unless AKI improving or other diagnosis established Other tests based on clinical suspicion (see text) Ongoing monitoring Fluid balance charts, daily weights Daily clinical assessment, with particular attention to volume status Daily review of medication charts Regular blood tests (creatinine, electrolytes, glucose) Nutritional assessment Specialty referral within
24 hours Renal—​AKI that is not starting to recover Radiology and/​or urology—​obstruction on ultrasonography not relieved by urinary catheter, or persistent clinical suspicion of obstruction as underlying diagnosis ACE, angiotensin-​converting enzyme; ARBs, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-​inflammatory drugs. Source data from ‘Recommended minimum requirements of a care bundle for patients with AKI in hospital’, published December 2015, www.thinkkidneys.nhs.uk. Copyright © 2018 Think Kidneys, NHS England, UK Renal Registry. Table 21.5.4  Risk factors for AKI in patients admitted to hospital Nonmodifiable risk factors Comment Modifiable risk factors Comment Age >75 years Hypovolaemia Chronic kidney disease eGFR <60 ml/​min Drugs with adverse renal haemodynamic effects in acute illness NSAIDs ACE inhibitors ARBs Diuretics History of AKI Nephrotoxic drugs Aminoglycosides Iodinated radiological contrast agents Diabetes mellitus Sepsis Cardiac failure Glycaemic control Vascular disease Liver disease Cognitive or neurological impairment or disability May limit access to fluids without assistance ACE, angiotensin-​converting enzyme; ARBs, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-​inflammatory drugs.

21.5  Acute kidney injury 4813 that (because of the risk of inducing serious hypoglycaemia) insulin therapy should not be used to reduce the blood glucose to below 110 mg/​dl (6.1 mmol/​litre). Maintaining control within these limits is challenging and, unless the circumstances are such that very close monitoring of blood glucose can be assured 24/7, it is safer for a patient’s blood glucose to be too high rather than too low. Diagnosis of the cause of acute kidney injury The physician must try to make a precise diagnosis of the cause of AKI in all cases. After treatment of life-​threatening complications (see later), the initial assessment of a patient who appears to have AKI must answer three questions. Question 1: is the kidney injury really acute? The only basis for excluding the possibility of pre-​existing chronic kidney disease with absolute confidence is the knowledge of a pre- vious normal measurement of renal function. In cases where there is uncertainty, a diligent search for previous notes and biochemical information may save the patient and the doctor the inconvenience (and occasionally hazard) of unnecessary investigation. The finding of two small kidneys on ultrasound examination indicates the pres- ence of chronic kidney disease. Other clinical features are poor dis- criminators between acute and chronic renal impairment. A history of vague ill health of some months duration, of nocturia, of pruritus, or the findings of skin pigmentation or anaemia, would all suggest chronicity (see Chapters 21.3 and 21.6). However, anaemia is not in- variable in advanced chronic kidney disease (e.g. in polycystic kidney disease the haemoglobin concentration may be normal), and an- aemia can develop over a few days in AKI, as may hypocalcaemia and hyperphosphataemia. Radiological evidence of renal osteodystrophy is only found in patients with obviously long-​standing renal failure. Question 2: is urinary obstruction a possibility? One of the merits of the traditional division of the causes of AKI into prerenal, renal, and postrenal is that it encourages consideration of the possibility of urinary obstruction. It is extremely important that obstruction should not be missed, since most cases are readily treat- able and delayed diagnosis may lead to permanent renal damage. Obstruction is particularly likely to cause AKI in those with a single functioning kidney, in those with a history of renal stones or of Fig. 21.5.3  AKI risk and prevention guidance for secondary care. To the best of our knowledge, the contents of this publication are in line with National Institute for Health and Care Excellence guidance relating to the management and treatment of acute kidney injury. Professional advice should be sought before taking, or refraining from taking, any action on the basis of the content of this publication. We cannot be held responsible for any errors or omissions therein, nor for the consequences of these or for any loss or damage suffered by readers or any third party informed of its contents. The UK Renal Registry disclaims all liability and responsibility arising from any reliance placed on the information contained in this publication by you or any third party who may be informed of its contents. Courtesy of Think Kidneys (https://www.thinkkidneys.nhs.uk/).

section 21  Disorders of the kidney and urinary tract 4814 prostatism, and after pelvic or retroperitoneal surgery, but the possi- bility of obstruction should be seriously considered in all cases where another positive diagnosis cannot be made. The presence of anuria, or of alternating polyuria and oligoanuria, are helpful clues. However, it is not widely appreciated that a patient may pass normal or elevated volumes of urine despite significant obstruction, although this is ex- tremely rare. The mechanism is poorly understood, but three factors present in obstruction tend to impair urinary concentrating ability, thereby leading to the preservation of urinary volume despite ob- structive depression of the filtration rate. These factors are structural damage to the inner medulla and papilla, functional changes in the distal nephron resulting from increased intraluminal or interstitial pressure, and loss of medullary hypertonicity at low filtration rates. Ultrasound examination of the kidneys and bladder is the usual first method of investigation for the presence of obstruction (Fig. 21.5.4). However, it is important to remember that the quality of the image obtained by renal ultrasonography is highly vari- able, depending on the patient, the equipment, and the operator. Furthermore, ultrasonography detects pelvicalyceal dilatation, not obstruction, and the test may be ‘negative’ (because the renal pelvis and calyces fail to dilate, or do so only minimally) in about 5% of cases of acute obstructive renal failure. If, following ultrasound examination, doubt as to the diagnosis of obstruction persists in the clinician’s mind, then the usual next step will be to request CT scanning of the abdomen and pelvis, which generally gives better anatomical definition. If the question is whether or not a dilated renal collecting system, demonstrated by either ultrasonography or CT scanning, is due to functional ob- struction or to a ‘baggy’ renal pelvicalyceal system, then—​if renal function is adequate (creatinine concentration less than about 250 µmol/​litre)—​diethylenetriaminepentaacetic acid (DTPA) or mercaptoacetyltriglycine (MAG3) renography with furosemide in- jection may be helpful, showing delayed excretion and clearance of radionuclide from the obstructed kidney(s). If renal function is severely impaired then imaging modalities that depend on renal excretion (including intravenous pyelography) are not useful, and percutaneous antegrade nephrostomy/​pyelography or cystoscopy with retrograde ureteric catheterization and pyelography should be undertaken. (See Chapters 21.4 and 21.17 for further discussion.) Obstruction, once diagnosed, must be relieved urgently by (as possible and appropriate) insertion of a urethral or suprapubic cath- eter, antegrade percutaneous nephrostomy, or cystoscopic inser- tion of ureteral stents, as a prelude to definitive treatment (where possible) of the underlying obstructive lesion. The most important causes of urinary obstruction are renal calculi, retroperitoneal fi- brosis, and malignant diseases of the uterine cervix, prostate, bladder, and rectum (see Chapter 21.17). Question 3: is there a renal inflammatory cause? Renal inflammatory conditions—​including glomerulonephritis, interstitial nephritis, vasculitis, and other rarities—​together account for fewer than 10% of cases of AKI. To make these diagnoses, which have critically important management implications, stick testing of the urine and microscopy of the urinary sediment is an essential part of the assessment of any patient with unexplained acute renal impairment. If stick testing indicates more than ‘+’ of protein or more than a trace of blood, then a sample of urine should be examined under the micro- scope. This should be done by centrifuging 10 to 15 ml of urine at 1500 to 2500 rev/​min (c.400–​1120 g) for 5 min, carefully discarding all but 1 ml of the supernatant, and then resuspending the pellet. Examination should be made under high power, preferably after staining, which makes the cellular elements of casts more obvious. Urinary casts containing red blood cells (Fig. 21.5.5) are present in acute glomer- ulonephritis, renal vasculitis, accelerated-​phase hypertension, and (sometimes) in interstitial nephritis, but not in other conditions. Their presence indicates the need for urgent specialist renal referral. Clinical features of acute kidney injury The early stages of AKI do not produce any obvious clinical features, and—​as stated previously but worthy of emphasis—​the main clin- ical risk is of hyperkalaemic cardiac arrest arising (apparently) out of the blue. Most patients who are unwell do not drink as much as usual and therefore pass less urine than normal, hence enquiry along the lines of ‘Are you passing less urine than normal?’ is rarely illuminating. Furthermore, as many as 50% of cases of AKI are not oliguric. The clinical picture is likely to be dominated by the primary condition of which AKI is a complication, and by the effects of intravascular volume depletion, with dizziness caused by postural hypotension a common reason for patients being brought to medical attention. Fig. 21.5.5  A cellular urinary cast.   ∗ ∗ Fig. 21.5.4  Ultrasound image of an obstructed left kidney, showing pelvicalyceal dilatation (asterisks). The horizontal dotted line measures the length of the kidney (normal in this case), and the renal cortex is well preserved (not a thin rim), both of which suggest that there is a
high likelihood that function will recover substantially when obstruction is relieved.

21.5  Acute kidney injury 4815 In the later stages of AKI there are manifestations of uraemia with anorexia, nausea, vomiting (or occasionally diarrhoea), mus- cular cramps, and signs of encephalopathy—​including a ‘meta- bolic’ flapping tremor (asterixis), progressing in extreme cases to depressed consciousness and grand mal convulsions. Skin bruising and gastrointestinal bleeding may occur. Uraemic haemorrhagic pericarditis is another potentially fatal complication, but this oc- curs much less frequently in AKI than in (neglected) chronic renal failure. For further discussion see Chapter 21.3. Biochemical changes The diagnosis of renal impairment, acute or chronic, is made when the serum urea and creatinine concentrations rise. Other important biochemical changes include the development of hyperkalaemia, metabolic acidosis, hypocalcaemia, and hyperphosphataemia. Hyperkalaemia is due not only to reduced urinary excretion, but also to potassium release from cells—​either as a consequence of cell death or as a result of metabolic acidosis. Particularly rapid rises are to be ex- pected when there is extensive tissue damage or hypercatabolism, as in rhabdomyolysis, burns, and sepsis. Transfusion of stored blood is sometimes said to cause dangerous rises in serum potassium concen- tration in oliguric patients. However, the transfused blood may not really be to blame, but the circumstances that demand transfusion. Loss of blood into the gastrointestinal tract or body tissues is followed by red cell lysis and the absorption of a considerable potassium load. Protein catabolism produces sulphuric and phosphoric acids. These are normally buffered by bicarbonate and excreted by the kidney. In AKI these systems fail, leading to the development of acidosis. This is usually modest in degree (plasma pH 7.2–​7.35), but can be more severe, manifesting as sighing Kussmaul’s respiration and/​or circulatory compromise. Acidosis is rarely the metabolic ab- normality most obviously necessitating urgent institution of renal replacement therapy, but overzealous administration of bicarbonate should be avoided (see following paragraph). Calcium malabsorption occurs early in AKI and is probably sec- ondary to disordered vitamin D metabolism. Hypocalcaemia can develop with surprising rapidity. It is usually asymptomatic, but tetany and fits may be provoked by injudicious over-​rapid correction of acidosis with resultant depression of ionized calcium. Profound hypocalcaemia and marked hyperphosphataemia, together with hyperuricaemia, is to be expected in rhabdomyolysis. Transient hypercalcaemia is frequently seen during the recovery phase from AKI, and this is particularly common after rhabdomyolysis, prob- ably being caused by secondary hyperparathyroidism related to pre- ceding hypocalcaemia. The hypercalcaemic phase may be prolonged and accompanied by metastatic calcification in patients in whom there has been extensive muscle injury. The serum sodium concentration is usually normal in cases of AKI: any deficit of sodium is usually matched by that of water, thus leading to reduction of the extracellular fluid volume but with an unchanged serum sodium concentration. However, on occasion the intake of water, either drunk in response to thirst or inflicted iatrogenically (typically by 5% dextrose infusion), may exceed the rate of excretion such that hyponatraemia results. The retention of uric acid, sulphate, and magnesium occurs in renal failure, but these biochemical abnormalities are rarely clinically significant, with the exception of the grossly elevated levels of uric acid that can be seen in rhabdomyolysis and following tumour lysis. General aspects of acute kidney injury The immediate management of patients with renal impairment is directed towards three goals. The first is the recognition and treat- ment of any life-​threatening complications of AKI. The second is prompt diagnosis and treatment of hypovolaemia. The third is spe- cific treatment of the underlying condition: if this persists untreated then renal function will not improve. Life-​threatening complications Hyperkalaemia Hyperkalaemia, which is rarely a significant clinical problem in pa- tients who do not have renal failure, is important in the context of AKI or chronic kidney disease because it can cause cardiac arrest. Patients may occasionally notice muscle weakness or paralysis, but the significance of these symptoms is rarely appreciated, and usu- ally there are no symptoms whatsoever. All doctors who work with acutely ill patients should be able to recognize the characteristic ECG appearances, which are a better indicator of cardiac toxicity in the individual patient than the serum potassium level. As serum po- tassium rises, the following changes occur progressively: 1. ‘Tenting’ of the T wave 2. Reduction in size of P waves, increase in the P–​R interval, widening of the QRS complex 3. Disappearance of the P wave, further widening of the QRS complex 4. Irregular ‘sinusoidal’ ECG (Fig. 21.5.6) 5. Asystole Standard definitions are that a serum potassium concentration of 5.5 to 5.9 mmol/​litre is described as mild hyperkalaemia, 6.0 to 6.4 mmol/​litre as moderate, and greater than 6.5 mmol/​litre as severe. Treatment of hyperkalaemia is described in Table 21.5.6, but in determining whether treatment is required, and what that treat- ment should be, it is important to understand the clinical context. It is acute rises in serum potassium that cause cardiac arrest, and la- boratory notification of a serum potassium result of (say) 6.5 mmol/​ litre in a routine blood sample taken in primary care or outpatient practice for monitoring of a patient who is not acutely unwell should not, on the grounds that it is ‘severe’, automatically precipitate a rec- ommendation for hospital admission and management with intra- venous calcium and/​or insulin and dextrose. Many patients with chronic kidney disease have a serum potassium concentration in the range 6.1 to 6.5 mmol/​litre, or even a bit higher (particularly if they are taking ACE inhibitors or ARBs, or have hyporeninaemic hypoaldosteronism, which is most common in those with dia- betes or chronic interstitial renal disease), which they tolerate well, without any significant ECG changes. The appropriate clinical re- sponse in this circumstance is to advise discontinuation of any drug that will exacerbate hyperkalaemia (including ACE inhibitors and ARBs), institution of a low potassium diet (see Table 21.2.2.3), and repeat measurement in a few days’ time. Various drugs can reduce serum potassium by increasing elimination of potassium from the gut. Calcium resonium and patiromer release calcium ions in ex- change for potassium; zirconium cyclosilicate selectively captures potassium ions. Calcium resonium is not suitable for administra- tion for more than a few days because it is unpalatable and causes

section 21  Disorders of the kidney and urinary tract 4816 severe constipation, sometimes to the point of faecal perforation, and the proper uses of patiromer and zirconium cyclosilicate are not yet established. Many physicians will rightly regard giving a drug to counteract the side effect of another drug (one which causes hyperkalaemia) as intuitively unattractive, and doing so will clearly compound hazards of polypharmacy. Pulmonary oedema The most serious complication of salt and water overload in AKI is the development of pulmonary oedema, which is usually iatrogenic, being caused by continued ill-​advised intravenous in- fusion of fluids into patients who are anuric or oliguric. Severe cases are dramatic. The patient is terrified, restless, and confused. Examination reveals cyanosis, tachypnoea, tachycardia, wide- spread wheeze or crepitations in the chest, and a gallop rhythm (if the heart can be heard). Investigation demonstrates arterial hyp- oxaemia and widespread interstitial shadowing on the chest radio- graph. (See Chapter 16.5.2 for further discussion.) The patient should be sat up and supported, and given oxygen by facemask in as high a concentration as possible using a reservoir Table 21.5.6  Treatment of hyperkalaemia Treatment Comment 1 Intravenous calcium (10 ml of 10% calcium chloride or gluconate, over 60 s, repeated until ECG improves) Treatment to be given immediately if hyperkalaemia is associated with ECG changes more severe than tenting of the T wave. Acts instantly to ‘stabilize’ cardiac membranes (mechanism unknown). Does not alter serum potassium concentration 2 Intravenous insulin and glucose (10 units of rapidly acting insulin plus 50 ml of 50% dextrose, over 10 min) Insulin stimulates Na+,K+-​ATPase in muscle and liver, thus driving potassium into cells. Serum potassium falls by 1–​2 mmol/​litre over 30–​60 min. Blood glucose concentration should be monitored at regular intervals for a minimum of 6 h after administration of insulin-​dextrose
(danger of hypoglycaemia) 3 Nebulized salbutamol (10–​20 mg) β2-​agonists stimulate Na+,K+-​ATPase in muscle and liver, thus driving potassium into cells. Serum potassium falls by 1–​2 mmol/​litre over 30–​60 min. Induces tremor and tachycardia, and sometimes nausea and vomiting 4 Intravenous sodium bicarbonate (50–​100 ml of a 4.2% solution, over 10 min) Traditionally thought to act by increasing blood pH, inducing exchange of intracellular protons for extracellular potassium. May not work in this manner since hypertonic saline has been shown to be effective. Only to be used if there is severe acidosis that merits treatment in its own right, and should not be used routinely in the management of hyperkalaemia. Glucose/​insulin and salbutamol are equally effective and do not have the disadvantages of (1) requiring a large sodium load, (2) being severe chemical irritants (‘burns’ requiring surgical debridement and reconstruction can occur if concentrated bicarbonate gets into tissues from peripheral intravenous lines), and (3) carrying a risk of precipitating severe hypocalcaemia 5 Cation exchange resins, e.g. sodium or calcium polystyrene sulphonate (15 g by mouth every 6 h or 15–​30 g per rectum every 6 h), or other oral agents that increase excretion of potassium from the gastrointestinal tract Exchange sodium or calcium for potassium in the gut lumen and thus induce loss of potassium from the body (unlike 1–​3 above in table). Take 4 h to produce an effect and are not to be used in the emergency treatment of severe hyperkalaemia. 6 Haemodialysis/​filtration Except in those rare cases where renal function can be rapidly restored (e.g. relief of obstruction), it is likely that hyperkalaemia will recur and haemodialysis or high-​volume haemofiltration will be required Treatment with insulin/​glucose and with β2-​agonists works in the same way, hence their effects in reducing serum potassium are not additive and there is no benefit in giving both together. The side effects of β2-​agonist treatment mean that insulin/​glucose is to be preferred if it can be administered easily. Fig. 21.5.6  An ECG showing severe hyperkalaemic changes in a patient with a serum potassium level of 9.4 mmol/​litre.

21.5  Acute kidney injury 4817 bag. Furosemide may work as a venodilator but is unlikely to pro- voke a substantial diuresis in a patient with renal failure. Morphine can relieve symptoms rapidly and should be given (along with an antiemetic) in small (2.5–​5 mg) doses, repeated if necessary and if tolerated, and with the opioid antagonist naloxone to hand in the event of respiratory depression. An intravenous infusion of a venodilator such as isosorbide dinitrate may be helpful. Continuous positive airway pressure or noninvasive positive pressure ventilation can be very useful in supporting the patient until such time as fluid can be removed, the definitive treatment for pulmonary oedema caused by renal failure being haemodialysis or haemofiltration. Acute peritoneal dialysis is much less effective in this capacity and should only be considered in circumstances where haemodialysis and haemofiltration are not available. The immediate beneficial ef- fects of venesection of 200 to 400 ml of blood from the patient in extremis should not be forgotten. Recognition and treatment of volume depletion A key part of the immediate assessment and management of any patient who is very ill, which will include many of those with AKI, is to make a correct assessment of their intravascular volume status and to resuscitate rapidly and effectively. The NCEPOD report dis- cussed earlier in this chapter identified that a common failing was that hypovolaemia was not recognized and treated appropriately. Fluid and electrolyte requirements in established
acute kidney injury Fluid Many patients with AKI are volume depleted at the time of presen- tation. An urgent priority is to correct such depletion rapidly. Once this has been achieved—​as judged by an improvement in peripheral perfusion, a fall in pulse rate, loss of postural drop in blood pres- sure, and a rise in jugular venous pressure—​the perspective changes. In the absence of normal renal function, the greatest care must be taken to regulate the intake of fluids and electrolytes to match losses in the urine, from the gastrointestinal tract, and from other ‘insens- ible’ sources. As a working rule, fluid intake is limited to the volume of the previous day’s urine output and gastrointestinal losses, plus 500 ml, but this allocation may need to be substantially increased in the presence of fever or in hot environments, when insensible losses may be much increased. However, as discussed previously, fluid-​ balance charts are frequently inaccurate, hence unthinking adher- ence to the ‘output plus 500 ml’ rule can lead to grief. To keep the patient in the optimal state of fluid balance, there is no substitute for careful, twice-​daily clinical examination for signs of intravas- cular volume depletion or excess, supplemented by accurate daily weighing to gauge the overall net fluid balance, and an intelligent flexible response to the findings. Sodium In patients who are not being dialysed, the intake of sodium must also be matched to output. Requirements are usually very small in those who are oliguric, perhaps only 15 to 30 mmol/​day, but if the patient is polyuric the requirements can be considerable, with a danger of volume depletion if these are not met. The urine of a pa- tient with polyuric renal failure will usually contain sodium at a con- centration of 50 to 70 mmol/​litre; hence, if urine output is 3 litres/​ day then over 200 mmol of sodium may be required. On occasion, the urine output in polyuric AKI can be massive (even up to 1 litre/​ h), and if the response is to administer an even greater quantity of fluid (output plus insensible losses), then it is possible to contrive a vicious cycle whereby an ever-​increasing urinary output is rewarded by ever-​increasing fluid infusion. To avoid this situation in a patient with polyuria, it is best to limit input to urinary output alone, thus al- lowing other fluid losses to establish a mild overall negative balance, only increasing fluid input if the patient develops significant pos- tural hypotension, which should be checked for twice daily. For un- known reasons, an excess of sodium and water in patients with acute tubular necrosis leads to peripheral or pulmonary oedema, whereas in those with glomerulonephritis it tends to produce hypertension. Potassium Because hyperkalaemia is one of the most important problems in the management of patients with AKI, it is essential to check serum potassium levels at least daily, and in those with hypercatabolism or gastrointestinal bleeding, or who require surgery, more frequent estimations are advisable. In oliguric cases, dietary consumption should be limited to the minimum compatible with an adequate in- take of protein and amino acids (20–​30 mmol/​day). Diuretics that work on the distal tubule (e.g. spironolactone, amiloride, and triamterene) promote potassium retention and should be stopped in all patients with AKI, and it is important when reviewing the drug chart to remember that these agents are frequent constituents of tablets containing a combination of di- uretic/​antihypertensive compounds. ACE inhibitors and ARBs similarly increase serum potassium and should be stopped, as discussed previously. Intravenous preparations of antimicrobial agents that contain large amounts of potassium should also be avoided whenever possible. Excretion of potassium can sometimes be enhanced in those who are oliguric by the use of high doses of furosemide (0.5–​1 g daily). Oral potassium-​exchange resins (e.g. polystyrene sulphonate resins, prescribed concurrently with a laxative to avoid very severe consti- pation, even faecal perforation), can be useful in controlling serum potassium for a few days or weeks, but they and other oral agents are not effective treatments for acute severe hyperkalaemia (see Table 21.5.6). By contrast, substantial losses of potassium can occur in polyuric AKI and need to be replaced. Measurement of the urinary potas- sium concentration can be helpful in estimating how much potas- sium is required in this circumstance. Renal replacement therapy Mandatory indications for immediate instigation of renal replace- ment therapy are: • refractory hyperkalaemia • intractable fluid overload • metabolic acidosis producing circulatory compromise • overt uraemia manifesting as encephalopathy, pericarditis, or uraemic bleeding These indications will be present in some patients on their admis- sion to hospital, but in many cases renal function will decline over a period of days or a few weeks when the patient is under observation in hospital, and the literature gives no clear message as to when renal replacement therapy should be initiated. There is no level of nitro- genous waste at which the patient suddenly becomes susceptible to overt uraemic sequelae. Nevertheless, it is clearly not sensible to wait

section 21  Disorders of the kidney and urinary tract 4818 until an obvious uraemic complication (which might be fatal) arises. Some studies have reported better outcomes in patients who were started on renal replacement therapy earlier rather than later, but others have not, and much of the evidence is of low quality. In the ab- sence of an indication such as hyperkalaemia, fluid overload, or se- vere acidosis, modern practice is (whenever possible) to begin renal replacement therapy when the blood urea reaches 25 to 35 mmol/​ litre and the serum creatinine 500 to 700 µmol/​litre, unless there is clear evidence that spontaneous recovery is occurring or other reasons to maintain a conservative approach. There are three basic options for renal replacement therapy: peritoneal dialysis, haemodi- alysis, and haemofiltration. Peritoneal dialysis Peritoneal dialysis is technically the simplest form of renal replace- ment therapy and available in some settings where haemodialysis or haemofiltration is not. Little has been published recently about its use in patients with AKI, but a systematic review in 2017 of six studies with 484 participants concluded that there was probably little or no differ- ence in outcomes produced by peritoneal dialysis or extracorporeal therapy. The principle is the same as that described for the long-​term treatment of patients with chronic renal failure (see Chapter 21.7.2), the main differences being that (1) catheters are used which can be inserted percutaneously using a metal stylet (although some use the same type of catheter as that used for continuous ambulatory treat- ment), and (2) smaller volume exchanges with shorter dwell times are the norm. Details of how to make up fluid suitable for performing peritoneal dialysis from intravenous fluids can be found at https:// ispd.org/ispd-guidelines/. The technique requires an intact peri- toneum and is therefore precluded in the many patients whose renal failure is associated with abdominal surgery. Other problems include difficulties in maintaining dialysate flow, leakage, peritoneal infection, protein losses, and restricted ability to clear fluid and uraemic wastes. Notwithstanding the systematic review reported just mentioned, it is fair to say that peritoneal dialysis is virtually never the first-​choice mo- dality for renal replacement therapy in an adult with AKI in centres that have a range of techniques at their disposal. Haemodialysis and haemofiltration Haemodialysis is an intermittent technique, usually applied three times per week in the context of chronic renal failure (see Chapter 21.7.1), but often used more frequently (up to every day) in the management of patients with AKI. By contrast, haemofiltration is a continuous technique, brief details of which are as follows: a mechanical pump (but sometimes the patient’s own arterial pres- sure) drives blood through a haemofilter of high hydraulic con- ductivity. An ultrafiltrate of plasma is removed, usually at a rate of between 1 and 2 litre/​h. This is replaced, minus the volume of other fluid inputs and the amount of ‘negative balance’ required, using (most commonly) a lactate/​acetate-​based substitution fluid. A large number of technical variations are possible—​for example, a com- bination of filtration and dialysis elements (haemodiafiltration), and use of differing replacement fluids—​but there is nothing to suggest that any one of these is better than another, excepting in those who are unable to metabolize lactate, when bicarbonate-​based substitu- tion fluid is essential. Theoretical advantages of haemofiltration over haemodialysis in the management of patients with AKI include enhanced haemo- dynamic stability, increased ability to remove salt and water (allowing better prevention of volume overload and permitting im- proved nutrition), and greater clearance of inflammatory mediators (which may provide advantage in patients with sepsis). However, meta-​analyses of trials that have compared intermittent with con- tinuous treatments in the context of AKI have not shown important differences in outcomes, and usage depends on local custom and practice. In the same way that there is no evidence on which to make firm recommendations as to when to start renal replacement therapy in those with AKI whose chemistry is gradually ‘going off’, there is also little information on which to base targets for the clearance of metabolic wastes that should be achieved by treatment. For inter- mittent or extended (sustained low efficiency dialysis, where treat- ment typically takes 8 h compared to the usual 3–​4 h for a standard dialysis treatment) renal replacement therapy, KDIGO guidelines recommend delivering a Kt/​V greater than 3.9 per week. Most trials of daily haemodialysis versus thrice-​weekly haemodialysis have not shown advantage of daily treatment, provided that an adequate dialysis dose (Kt/​V >1.2) is delivered thrice weekly. With regard to continuous treatments, the standard of care is to provide an effluent (filtrate/​dialysate) flow rate of 20 to 25 ml/​kg body weight per hour, and exceeding this provides no clearly proven benefit. Other issues in the management of patients
with acute kidney injury Indications for renal biopsy Most cases of AKI are due to prerenal failure or to the clinical syn- drome of acute tubular necrosis. They occur in an appropriate clin- ical setting and follow a typical time course, with recovery of renal function over a few weeks. In such instances, renal biopsy should not be performed since the information gained is exceedingly un- likely to influence management, and the risks of the procedure are therefore not warranted. There are, however, circumstances in which renal biopsy is essential to establish a correct diagnosis, with im- portant implications for both management and prognosis. Biopsy should be considered when: • the history, examination, or laboratory tests suggest a systemic dis- order that could cause AKI and could be diagnosed by renal biopsy • urinalysis shows significant haematuria and proteinuria and/​or the urine sediment contains red cell casts • the case history is atypical • renal failure is unusually prolonged (say beyond 6 weeks), al- though in this context cortical necrosis (see ‘Renal cortical ne- crosis’) is better diagnosed by CT scanning or angiography Nutrition Patients with AKI are invariably catabolic and derive a larger fraction of their energy expenditure from protein breakdown than normal. Insulin resistance, metabolic acidosis, the release of proteinases into the circulation, and changes in the metabolism of branched-​chain amino acids have all been suggested as possible reasons. If nutri- tion is neglected, patients with AKI lose weight very rapidly, and those that lose most have the highest mortality, but it has not been proven in controlled trials that any form of nutritional support can alter mortality. Nevertheless, there is a consensus that early insti- tution of nutritional support probably improves prognosis. Despite this, and almost certainly to the patient’s detriment, action is fre- quently delayed or not taken at all, particularly if it is thought that

21.5  Acute kidney injury 4819 the extra fluid load required will mandate the institution of dialysis or the need for additional dialysis sessions in an already busy unit. There is very little good evidence on which to base recommenda- tions. Enteral nutrition should be preferred to parenteral nutrition whenever possible, with KDIGO recommended daily adult re- quirements for those with AKI being total energy 20 to 30 kcal/​kg body weight, with protein intake of 0.8 to 1.0 g/​kg body weight (non­ catabolic patients not on dialysis), 1.0 to 1.5 g/​kg body weight (patients on dialysis), up to a maximum of 1.7 g/​kg body weight (catabolic patients, and those on continuous renal replacement therapy). If patients with AKI are oliguric, the nutritional support should be given in a restricted fluid volume, with reduced amounts of sodium, potassium, and phosphate. For practical purposes, it is sensible to have enteral and parenteral fluids that satisfy these needs available routinely (a variety of commercial preparations are avail- able): extra water and electrolytes can always be added when re- quired. In the many patients who are too unwell to take adequate food by mouth, commonly those who need it most, tube feeding or parenteral nutrition should be started early. Protein restriction, aimed at moderating the rise of serum urea, is not appropriate man- agement for patients with AKI. Bleeding In uraemia the bleeding time is prolonged, and in AKI this summates with any abnormality of haemostasis that might be simultaneously induced by the precipitating condition. Better control of uraemia and the routine use of H2-​receptor antagonists have been associated with a greatly reduced risk of upper gastrointestinal bleeding, a pre- viously frequent and grave occurrence. Impairment of haemostasis is not a cause of great clinical concern in most patients, but there are some who bleed—​from anywhere and everywhere. Guidelines for the management of such cases are given in Box 21.5.2. Sepsis Sepsis is a common cause of AKI, and outcome can be improved with prompt instigation of basic therapies, as described in the ‘sepsis six’ care bundle that emphasizes the following: • Administering high-​flow oxygen to maintain target oxygen saturations at higher than 94% (unless the patient is at risk of hypercapnia) • Taking blood cultures • Giving intravenous antibiotics • Starting intravenous fluid resuscitation • Checking serum lactate • Monitoring hourly urine output In many more cases, however, the role of sepsis in the patient with AKI is insidious and difficult to diagnose with certainty. There is often a strong clinical feeling, but little in the way of hard proof, that sepsis underlies the slide towards worsening renal and multiorgan failure in patients who have been apparently successfully resusci- tated from major trauma or surgery, and septicaemia is the most common cause of death in those with AKI. The index of clinical suspicion must therefore be very high: if a patient with AKI ap- pears to be deteriorating in any way, the question must be asked: ‘Is this sepsis?’ Unused intravenous lines and urinary catheters should be removed, and those that are necessary but in any way suspicious should be replaced. The patient should be examined regularly for signs of a septic focus. There should be a low threshold for re- peated, thorough microbiological investigation. Proven infection should be treated promptly with appropriate antimicrobial agents (with the dose being modified as required). In many cases, how- ever, it will be necessary to start treatment ‘blind’, having taken specimens for culture and having made an educated guess as to the likely pathogen, with the possibility of Gram-​negative septicaemia high on the list. In patients who appear ‘obviously septic’ or to be ‘going off’, but in whom no cause can be found, attention should be directed to- wards the abdomen, this being the most likely place for hidden mischief, either infective or ischaemic. Radiological investiga- tions, in particular CT scanning, can be very useful in searching for abdominal sepsis or dead bowel, but are not infallible: surgical exploration may be required, both to diagnose and to treat, espe- cially in patients whose renal failure follows previous abdominal surgical procedures. Prescription of drugs Many drugs are excreted by glomerular filtration or tubular secre- tion and must be given in reduced dosage or at longer intervals than normal in patients with renal failure (see Chapter 21.19). For patients with AKI, the following should not be given without very good reason:  nonsteroidal anti-​inflammatory drugs, ACE inhibi- tors, ARBs (all of which have adverse effects on renal perfusion and glomerular filtration), and aminoglycoside antibiotics (these are dis- cussed later in this chapter). A note about two other drugs that may be given to patients with AKI is also appropriate here: both aciclovir and penicillins can cause encephalopathy if given in the doses used to treat severe infection in patients with normal renal function. The dose of aciclovir needs to be reduced from between 5 and 10 mg/​kg every 8 h to between 2.5 and 5 mg/​kg every 24 h in those receiving renal replacement therapy, and physicians should restrain themselves from prescribing the maximum recommended doses of penicillins. If in doubt, consult the manufacturer’s data sheet before prescribing any drug to a pa- tient with AKI. Specific causes of acute kidney injury A list of specific causes of AKI is given in Box 21.5.1: many of these are discussed in other chapters; those that are not are considered here. Box 21.5.2  Practical strategies for the management of bleeding in acute kidney injury 1 Exclude the possibility of a heparin effect 2 Blood transfusion to obtain haematocrit greater than 30% (very occa- sionally erythropoietin is of value) 3 Cryoprecipitate (10 bags) has its maximal effect between 1 and 2 h after administration. Its effect disappears at 24 to 36 h 4 Deamino-​d-​arginine vasopressin (DDAVP) (0.3 µg/​kg intravenously) acts by increasing factor VIII coagulant activity. It has been shown in AKI to shorten prolonged bleeding time. Repeated doses have a lesser effect 5 Conjugated oestrogen: 0.6 mg/​kg per day for 5 days. Shown to reduce bleeding time (for at least 14 days) in patients with chronic renal im- pairment and haemorrhagic tendency

section 21  Disorders of the kidney and urinary tract 4820 Prerenal failure and acute tubular necrosis Between 80 and 90% of the cases of AKI seen by physicians will fall into the categories of prerenal failure and acute tubular necrosis. The term ‘prerenal failure’ is used when renal dysfunction is entirely at- tributable to hypoperfusion, and where restoration of renal perfusion leads to rapid recovery. The term ‘acute tubular necrosis’ describes a clinical entity comprising AKI with three main characteristics: 1. It is seen in specific clinical contexts, frequently involving cir- culatory compromise and/​or nephrotoxins. 2. Urinary abnormalities usually suggest tubular dysfunction. 3. Essentially complete recovery of renal function is expected within days or weeks in most cases if the patient survives the precipitating insult, with a period of polyuria commonly fol- lowing oliguria. The syndrome can be seen after virtually any episode of severe cir- culatory compromise, but not all causes of circulatory derangement are equally devastating to renal function. Primary impairment of cardiac performance, for example, following myocardial infarction, may cause serum creatinine to rise, but rarely causes renal failure of sufficient severity to require renal replacement therapy. By con- trast, an apparently similar haemodynamic upset caused by sepsis frequently does. Multiple insults are the rule rather than the excep- tion. Circumstances associated with a particularly high risk of AKI include repair of a ruptured aortic aneurysm (20%, as opposed to 3% for elective repair), hepatobiliary surgery (10%), cardiac surgery (up to 20%, depending on case mix), pancreatitis (10%), and burns (2–​38%, depending on the series). Pathophysiology The perfusion of the kidney seems to suffer more than that of any other organ when the circulation is compromised. In the face of modest underperfusion, the GFR is relatively preserved by a com- pensatory increase in the filtration fraction. This increase has re- percussions on tubular function which, along with other factors, leads to the increased tubular reabsorption of sodium, water, and urea—​a situation rapidly reversed by restoration of renal perfusion. However, following prolonged circulatory shock, renal function fre- quently deteriorates in a manner that is not immediately reversible, and it is not at all obvious why this should be so. Lack of a clear pathophysiological understanding has bedevilled attempts at the de- velopment of rational therapy. Under normal conditions the kidney enjoys high blood flow, exceeded on a volume/​weight basis only by the carotid body, and oxygen tension in the renal venous effluent is high, suggesting that oxygen supply greatly exceeds demand. Such a situation might be expected to confer protection from the effects of circulatory com- promise, but no such benefit is observed: indeed the kidney appears to be more susceptible to damage than other organs, with the typ- ical histological features of acute tubular necrosis being effacement and loss of the brush border of the proximal tubule (particularly in the S3 segment), patchy loss of tubular cells, and casts in the distal tubule. AKI similar to this can be produced in animal models by ischaemia, and the condition often arises clinically in the setting of profound haemodynamic disturbance, leading to the supposition that—​despite apparently generous blood flow normally—​renal is- chaemia is the cause of renal failure in such circumstances. At the ‘whole-​organ’ level, two main hypotheses, not mutually ex- clusive, have been proposed to explain the kidney’s vulnerability to ischaemic damage. First, the specialized anatomical arrangement of the vasa rectae that is essential for the countercurrent mechanism involved in urinary concentration and dilution leads to arterio- venous shunting of oxygen and the presence of areas of profound hypoxia (Po2 10–​20 mmHg) within the normal kidney. These areas are operating on the verge of anoxia in the normal organ and hence might be susceptible to ischaemic damage in response to a modest compromise of whole-​organ blood flow. Second, there is clinical and experimental evidence of intense constriction of renal vessels during shock, hence very severe reduction in renal blood flow (perhaps only transient) may be responsible for the initiation of ischaemic damage. The justification for many of the interventions proposed in the man- agement of patients at risk of AKI, or with established AKI, is that they might preserve renal blood flow and/​or reduce renal oxygen consumption, thus rendering the development of ischaemic injury less likely. At a cellular level, a wide variety of pathophysiological mech- anisms are involved. Endothelial cell injury arising directly from ischaemia or various inflammatory processes causes disruption of microvascular blood flow. Poor tissue oxygenation leads to epithelial cell injury via mechanisms including intracellular ac- cumulation of calcium, generation of reactive oxygen species, ac- tivation of various proteases and phospholipases, and depletion of ATP. These lead to a range of consequences such as redistribution of tubular membrane proteins, sloughing of viable cells into the tubular lumen, and apoptosis. Recent work has drawn attention to the involvement of immunological factors (complement activa- tion, intercellular adhesion molecules, inflammatory mediators) and receptors on tubular cells (peroxisome proliferator-​activated receptor β, toll-​like receptors, bradykinin receptors), some of which may in the future provide opportunity for therapeutic intervention. Once damage to the kidney has been sustained, a variety of fac- tors may be responsible for the persistence of excretory failure that is characteristic of the clinical syndrome of acute tubular necrosis. These include activation of tubuloglomerular feedback (increased delivery of sodium chloride to the macula densa leads to reduction in GFR), back-​leak of filtrate from damaged tubules, and tubular obstruction by casts. Even in experimental models it is very hard to determine what is happening at any time, and impossible to do so in clinical practice. However, many of the ab- normalities have a structural as well as a functional basis, hence rapid reversal cannot be expected, there being good evidence that recovery from acute tubular necrosis depends on cellular regeneration. Diagnosis The diagnosis of prerenal failure/​acute tubular necrosis is based on the clinical context, which often involves circulatory compromise, and the exclusion of obstruction or renal inflammatory conditions, usually by ultrasound examination of the urinary tract and testing of the urine for blood and protein, respectively. Prerenal failure and acute tubular necrosis can best be regarded as a continuum of renal response to ischaemic injury, in much the same way that stable angina, non-​ST-​elevation myocardial infarc- tion, and ST-​elevation myocardial infarction are a continuum of

21.5  Acute kidney injury 4821 cardiac response to ischaemia. A simple analysis emphasizes that at the prerenal end of the spectrum the biochemical composition of the urine reflects the response of normal tubules to impaired renal perfusion. There is avid retention of sodium and water, leading to low urinary sodium and high urinary urea and creatinine concen- trations, together with a high urinary osmolarity. By contrast, at the acute tubular necrosis end of the spectrum the tubules are damaged and unable to sustain large sodium or osmolar gradients, hence urinary sodium concentration is elevated and the urinary urea and creatinine concentrations and urinary osmolarity are relatively low. However, this simple analysis is flawed and biochemical ana- lysis of the urine is rarely useful in clinical practice, as explained in Table 21.5.7. From a practical point of view, treatment is begun on exactly the same lines whether the expected diagnosis is of prerenal failure or of acute tubular necrosis. The response to resuscitation retrospectively defines the diagnosis—​restoration of renal per- fusion leads to rapid improvement in renal function in prerenal failure—​and determines further management. Over the past 20 years (and more), the measurement of urinary or plasma/​serum levels of a variety of proteins (e.g. urinary kidney injury molecule-​1, plasma and urinary neutrophil gelatinase-​ associated lipocalin (NGAL), and many others) have been explored as possible early markers of acute tubular necrosis. None has yet been found useful in clinical practice. Two uncommon circumstances in which measurement of urinary sodium concentration may be helpful are (1) hepatorenal syndrome, when urinary sodium concentration is typically low (<10 mmol/​ litre), although this is not a major diagnostic criterion of the condi- tion; and (2) acute renal artery occlusion (bilateral or of single func- tioning kidney) when urinary sodium concentration can equal that in serum. Circumstances predisposing to prerenal failure are almost invari- ably associated with raised serum levels of antidiuretic hormone. This acts on the collecting duct to increase the tubular reabsorption of both water and urea, hence the serum concentration of urea rises out of proportion to that of creatinine in prerenal failure. Serum urea may also appear to be disproportionately raised in the presence of sepsis, steroids, tetracycline (catabolic effect), and gastrointes- tinal haemorrhage (protein meal, perhaps inducing catabolism due to absence of the essential branched chain amino acid isoleucine in haemoglobin). Prevention Key elements have been described previously in this chapter in ‘Prevention of acute kidney injury’. Clinical findings There are no specific clinical features of prerenal failure or acute tubular necrosis. There may be symptoms of AKI, as described pre- viously, but these are also not specific and are rarely prominent, hence the clinical picture at presentation is likely to be dominated by signs of volume depletion and those of the precipitating condition. If the patient does not die of AKI, either because the degree of uraemia is modest or renal replacement therapy is provided, then renal recovery occurs in the vast majority of those who survive the precipitating insult. This may begin at any time from a few days to a few months (median 10–​14 days) after the onset of the condition, with a progressive increase in urinary volume typically preceding improvement in the serum levels of creatinine and urea. Due to a relatively persistent defect in renal tubular sodium reabsorption and concentrating ability, a period of polyuria may ensue, placing the patient at risk of sodium and water depletion. Specific treatment The importance of effective treatment of the underlying condition and of rapid correction of hypovolaemia are above clinical dispute, although neither has been subject to controlled trial as regards the outcome of prerenal failure or acute tubular necrosis. There is no strong evidence that any other pharmacological agent is beneficial, and following the publication of a number of randomized controlled trials, the use of agents such as loop diuretics (e.g. furosemide), dopamine (or fenoldopam, a selective dopamine D1 partial agonist), and mannitol cannot be recommended. In experimental models of acute tubular necrosis, the use of growth factors has been shown to speed up renal recovery: this offers some hope for the future, but no benefit has yet been shown in anything other than pilot clinical studies, and such agents (including erythropoietin) should not be given for this indication outside properly conducted clinical trials. Prognosis The prognosis of patients with AKI, most of whom will have prerenal failure or acute tubular necrosis, has been described previously in this chapter in ‘Epidemiology’. Series from intensive care units of patients who require renal replacement therapy for acute tubular necrosis, commonly in the context of respiratory failure requiring mechanical ventilation, typically report mortality rates of 40 to 60%. Death should rarely be attributable to a primary sequel of renal failure (e.g. uraemia or hyperkalaemia) and the incidence of life-​ threatening gastrointestinal haemorrhage is much reduced: sepsis is the major killer. Most patients die with, but not directly of, renal failure. Assuming survival from the precipitating insult, complete re- covery of renal function can be anticipated in almost all patients aged less than 65 years with pre-​existing normal renal function and acute tubular necrosis of short duration. This is not so for older pa- tients, those with pre-​existing chronic kidney disease, or those who have prolonged acute tubular necrosis (>4-​week requirement for renal replacement therapy). In the largest reported series of patients with AKI, 11 to 12% of survivors of ‘medical’ or ‘surgical’ AKI (pre- sumed to have acute tubular necrosis) required long-​term dialysis. Table 21.5.7  ‘Typical’ urinary biochemical indices in prerenal failure and acute tubular necrosis, and why they are rarely useful Index ‘Typical’ prerenal failure ‘Typical’ acute tubular necrosis Urinary sodium (mmol/​litre) <20

40 Urine osmolarity (mOsm/​litre) 500 <350 Urine:serum urea 8 <3 Urine:serum creatinine 40 <20 Fractional sodium excretion <1% 2% There are several reasons why urinary biochemical indices are of very limited clinical use: (1) intermediate values are common; (2) ‘typical’ values do not reliably predict renal prognosis—​it is recognized that cases that are otherwise indistinguishable from ‘typical’ acute tubular necrosis can have a low urinary sodium concentration; (3) diuretics and pre-​existing tubular disease will impair the ability of tubules to retain sodium in prerenal failure; and (4) treatment is not dictated by urinary indices.

section 21  Disorders of the kidney and urinary tract 4822 Nephrotoxins Exogenous nephrotoxins A wide variety of exogenous agents, including therapeutically pre- scribed drugs, can cause AKI (Box 21.5.3). Poisoning by drugs and chemicals are discussed in Chapter 10.4.1; envenoming and poi- soning by animals or plants are discussed in Chapters 10.4.2 and 10.4.3. Other causes listed in Box 21.5.3 that are worthy of par- ticular note are discussed here. Aminoglycosides The nephrotoxicity of particular aminoglycosides is related to the strength of their positive charge. They are freely filtered by the glom- eruli, with 90 to 95% passing into the urine, but 5 to 10% is retained in the renal cortex as a result of binding to negatively charged mem- brane phospholipids in parts S1 and S2 of the proximal tubule (and S3 in the presence of renal ischaemia). Here they are delivered to megalin (the Heymann nephritis autoantigen, a member of the low-​ density lipoprotein receptor family) in coated pits, endocytosed and trafficked to the endosome of proximal tubular cells, where at a con- centration vastly exceeding the serum level they inhibit fusion in vivo and in vitro. Gentamicin is nephrotoxic, as are tobramycin, amikacin, netilmicin and streptomycin to progressively lesser degrees. The risk of nephrotoxicity is increased by old age, chronic kidney disease, high dosage, prolonged treatment, combined treatment with other nephrotoxic drugs, renal ischaemia, and volume depletion. A 50% rise in serum creatinine from baseline is seen in 10 to 20% of patients, even when monitoring optimally controlled drug levels. Parenteral administration is not required for the development of toxicity: AKI can occur as a result of systemic absorption when aminoglycosides are used in irrigating or bowel-​sterilizing solutions. The typical clinical picture is of relatively mild nonoliguric renal failure coming on about 1 week after starting treatment. The urine typically shows low-​level proteinuria, with hyaline or granular casts. Hypokalaemia, hypomagnesaemia, hypocalcaemia, and hypophosphataemia are sometimes seen, and also a Fanconi’s syndrome. Recovery typically occurs over about 3 weeks after the aminoglycoside is stopped, but this may be delayed or incomplete. Differentiating aminoglycoside-​induced AKI from other causes of acute tubular necrosis can be difficult or impossible. Patients are given aminoglycosides because of sepsis, and many will have other significant comorbidities, other acute medical problems, and have been exposed to other potential nephrotoxins (e.g. radiocontrast agents). Aminoglycosides should only be used in the relatively uncommon circumstance that there is no suitable alternative antibiotic that is not nephrotoxic. The risk of nephrotoxicity can be reduced by choosing the least toxic aminoglycoside possible, ensuring that the patient is not volume depleted, correcting hypokalaemia and hypomagnes- aemia, using a once-​daily dosing regimen, adjusting the dose ac- cording to renal function, monitoring serum drug levels, limiting the duration of therapy to 7 to 10 days, and minimizing the use of other nephrotoxic drugs. Anionic polyaminoacids (e.g. polyaspartic acid) can interfere with the binding of cationic aminoglycosides to proximal tubular cell membranes and lysosomes and may be useful in preventing aminoglycoside nephrotoxicity, but this approach is not used clinically. Radiographic contrast media Studies in animal models suggest that radiographic contrast media can cause acute tubular necrosis. The mechanism is uncer- tain: favoured hypotheses include by induction of intramedullary vasoconstriction or by direct cytotoxic effect. The incidence of AKI associated with the use of radiographic con- trast media has been reported to vary between 0 and 50%, reflecting many variables. Patient risk factors include pre-​existing chronic Box 21.5.3  Some nephrotoxins that can cause acute kidney injury (excluding causes of interstitial nephritis) Exogenous • Antibiotics:

—​ Aminoglycosides

—​ Tetracyclines

—​ Cephaloridine

—​ Amphotericin B

—​ Sulphonamides

—​ Polymyxin/​colistin

—​ Bacitracin

—​ Pentamidine

—​ Vancomycin • Radiocontrast media • Anaesthetic agents:

—​ Methoxyfluranea

—​ Enfluranea • Chemotherapeutic/​immunosuppressive agents:

—​ Ciclosporin

—​ Cis-​platinum

—​ Methotrexate • Organic solvents:

—​ Glycols (e.g. ethylene glycola)

—​ Hydrocarbons (e.g. carbon tetrachloride, toluene) • Poisons:

—​ Venoms (snake bite, e.g. Russell’s viper)

—​ Stings

—​ Insecticides/​herbicides/​rodenticides (including paraquat, copper sulphate, and sodium chlorate)

—​ Mushrooms (amanita)

—​ Hemlock

—​ Carp bile

—​ Herbal medicines • Drugs of abuse • Heavy metals Endogenous • Pigments:

—​ Myoglobin

—​ Haemoglobin • Intrarenal crystal deposition:

—​ Urate

—​ Phosphate (tumour lysis syndrome) • Tumour related:

—​ Immunoglobulin light chains In many instances, nephrotoxicity arises both from a direct toxic action on renal tissue and from indirect systemic effects. a May be associated with intratubular precipitation of oxalate crystals.

21.5  Acute kidney injury 4823 kidney disease, diabetic nephropathy, cardiac failure, hypovolaemia, and myeloma. Procedural risk factors include dose and type of con- trast agent, and the type of procedure (interventional procedures are higher risk than diagnostic). As with aminoglycosides, differentiating contrast-​induced AKI from other causes of acute tubular necrosis can be difficult or im- possible, and contrast exposure may be one of many contributing factors to AKI in some patients. In patients who develop AKI after angiography, particular consideration should be given to the dis- tinction between contrast nephropathy and atheroembolic renal disease. Features suggesting the latter include embolic lesions (e.g. ‘trash foot’), eosinophilia, hypocomplementaemia, delayed onset of AKI, and little or no recovery of AKI (see Chapter 16.14.3). When renal impairment does develop, it typically occurs 12 to 24 h after exposure, is nonoliguric and usually mild, and recovery begins within 3 to 5 days. Recent prospective studies, using nonionic contrast media and in which careful attention has been paid to the maintenance of adequate hydration, have shown a very low incidence of significant renal im- pairment, even in groups reported to be at high risk (diabetes, mye- loma). Concern about nephrotoxicity of radiocontrast media should very rarely, if ever, restrict the selection of imaging technique in a particular patient: if there is diagnostic uncertainty, then they re- quire the imaging technique most likely to achieve a diagnosis; if there is no diagnostic uncertainty, then no imaging is needed. With regard to prevention, there is no very strong evidence on which to base recommendations. Standard practice is to advise that patients with an estimated GFR less than 60 ml/​min and additional risk factors (e.g. significant proteinuria, diabetes, heart failure, liver failure, and myeloma) and all patients with an estimated GFR less than 45 ml/​min who are to be given intra-​arterial contrast agents (for nonemergency purposes) should avoid volume depletion, avoid nonsteroidal anti-​inflammatory drugs (NSAIDs), be given a periprocedural infusion of isotonic saline, and be given the lowest effective dose of an iso-​osmolal contrast agent. There is no good evidence to support the use of N-​acetylcysteine or any other agent in attempting to prevent contrast-​induced nephropathy, and a meta-​analysis of 11 studies showed no benefit of haemodialysis or haemofiltration/​haemodiafiltration in preventing the condition. Endogenous nephrotoxins Myoglobin Myoglobinuric AKI, the mechanism of which is incompletely understood (but probably involves a combination of volume de- pletion/​renal ischaemia, tubular injury by free iron/​haem, and tubular obstruction by haem pigment casts), is typically associated with crush injury to muscle, most typically after patients have been trapped under rubble following earthquakes or explosions, but there are a large number of causes of nontraumatic rhabdomyolysis (Box 21.5.4). As might be expected, genetic causes are most likely with young age of presentation: whole-​exome sequencing found mutations that were thought to be pathogenic in 8 of 58 candi- date genes in 9 of 21 (43%) children and adolescents with rhabdo- myolysis in a study in Israel. A high index of suspicion is required to diagnose cases that are not obviously associated with muscle injury, since muscular pain, swelling, and tenderness may not be prominent features and can even be absent. The key to making the diagnosis is to detect myo- globin in the urine, or a very high level of enzymes released from muscle in the plasma. The former is recognized by the combination of dark-​brown (‘Coca-​Cola’) urine that tests positive for ‘blood’ on a reagent strip, but which does not contain red cells on microscopy, although pigmented ‘muddy’ granular casts are seen. The muscle enzyme usually measured in serum is creatine kinase: the normal range of this is up to just below 200 U/​litre; in rhabdomyolysis values above 10 000 U/​litre are typical, a value of only 1000 to 2000 U/​litre not being enough to establish the diagnosis of rhabdomyolytic AKI in the absence of other supporting evidence. Extremely high levels of serum myoglobin, aldolase, and lactic dehydrogenase are also seen, all being released from damaged muscle. Rhabdomyolysis can be associated with very high serum levels of potassium, phosphate (>2.5 mmol/​litre), urate (>750 µmol/​litre), as- partate transaminase (in the many hundreds of U/​litre, exceptionally in the thousands), and alanine transaminase (in the few hundreds of U/​litre), and with an unusually low serum calcium concentration Box 21.5.4  Some causes of rhabdomyolysis • Direct muscle injury • Ischaemic muscle injury:

—​ Compression

—​ Vascular occlusion • Any cause of coma (e.g. opioid overdose, diabetes mellitus, or cere- brovascular accident) or of prolonged restraint/​immobility (e.g. fol- lowing a fall in older people) can be associated with rhabdomyolysis due to a pressure effect • Excessive muscular activity:

—​ Seizures

—​ Sport (e.g. marathon running) • Inflammatory myositis:

—​ Immunological (e.g. dermatomyositis and polymyositis)

—​ Infection (e.g. viral: influenza, coxsackie, and HIV) • Metabolic:

—​ Hypokalaemia, hypophosphataemia • Genetic:

—​ Disorders of fatty acid metabolism (e.g. CPT2)

—​ Disorders of glycogen metabolism and storage (e.g. PFKM, PGAM2, and PYGM—​McCardle’s syndrome)

—​ Disorders of skeletal muscle relaxation and contraction (e.g. CACNA1S, MYH3, RYR1, and SCN4A)

—​ Disorders of purine metabolism (e.g. AHCY) • Endocrine:

—​ Diabetic ketoacidosis/​nonketotic hyperglycaemia

—​ Hypothyroidism • Toxins/​drugs:

—​ Snake bite, carbon monoxide, alcohol, hemlock, and paint/​glue sniffing

—​ Clofibrate, aminocaproic acid, and 3-​hydroxy-​3-​methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) • Others:

—​ Sickle cell trait

—​ Near drowning

—​ Hypothermia

—​ Malignant hyperpyrexia

—​ Neuroleptic malignant syndrome

—​ Phaeochromocytoma ‘storm’

section 21  Disorders of the kidney and urinary tract 4824 (<1.5 mmol/​litre). Any of these findings should lead to serious con- sideration of rhabdomyolysis in any patient with unexplained AKI. Aside from treatment (when possible) of the underlying cause, including decompression of compromised muscle compartments and stopping any drugs that might be contributing to the problem, initial management involves correction of intravascular volume depletion, which may be massive due to sequestration of fluid in damaged muscle, and provocation of a diuresis of around 200 ml/​h while myoglobinuria persists, the intention being both to establish good renal perfusion and ‘wash out’ obstructing casts. This can be achieved by infusion of 0.9% saline or other balanced salt solution (e.g. Hartmann’s), initially at a rate of 1 to 2 litre/​h, titrated down at the first sign of fluid overload (pulmonary oedema) or—​if and when the patient becomes massively polyuric—​to maintain a urinary output of 200 to 300 ml/​h. When this urinary output is achieved, many physicians would recommend additional infusion of bicar- bonate and mannitol to sustain a forced alkaline-​mannitol diuresis, with urinary pH above 6.5, the argument being that this might reduce the renal toxicity of myoglobin. The evidence that this is beneficial is not very substantial, and care must be taken to monitor for (with bicarbonate) hypokalaemia and hypocalcaemia, and (with man- nitol) hypernatraemia and hyperosmolality. The serum potassium concentration can rise by more than 1 mmol/​litre per day, hence hyperkalaemia is the usual indication for renal replacement therapy. Assuming that the patient survives the precipitating insult, hypercalcaemia develops in 20 to 30% of cases during the recovery phase. This is thought to be caused by mobilization of calcium from injured muscle, correction of hyperphosphataemia with improve- ment in GFR, and an increase in 1,25-​dihydroxyvitamin D (mech- anism uncertain). Haemoglobin AKI can be seen in association with massive haemolysis in many circumstances, but these are relatively rare in the developed world, where ABO-​mismatched blood transfusion is probably the most common cause. By contrast, a study in Chandigarh (north India) re- ported in 1977 that haemolysis was found in over 20% of 325 patients receiving dialysis for AKI, but recent reports suggest a lower preva- lence. Haemolysis is most frequently seen in those with glucose-​6-​ phosphate dehydrogenase deficiency, with snake bite and malaria the next most common causes. Copper sulphate poisoning, wasp stings, arsine poisoning, burns, and as a complication of bladder ir- rigation with hypotonic solutions are other causes. In each circumstance it is thought that the development of AKI is exacerbated by (if not solely caused by) the presence of large amounts of free haemoglobin within the circulation. As with rhabdomyolysis, the urine is coloured red to brown, with pigmented granular casts on microscopy, but the findings in the plasma/​serum are different: it is reddish in colour (whereas it is usually clear in rhabdomyolysis), creatine kinase is not elevated, haptoglobin levels are reduced, and the peripheral blood film is abnormal. The approach to renal man- agement is as described previously for rhabdomyolysis. Urate and other endogenous nephrotoxins The tumour lysis syndrome is associated with a rapid rise in plasma uric acid concentration (and almost certainly liberation of other nephrotoxins) as a complication of the treatment of lymphoma, leukaemia, myeloma, or other ‘high-​turnover’ tumours. Hyperuricaemia and renal failure have been described on rare occa- sions after recurrent epileptic seizures. Prevention and management of tumour lysis syndrome are discussed in Chapter 21.10.5, as is AKI associated with myeloma. Vascular causes Renal cortical necrosis Renal cortical necrosis is an uncommon cause of AKI, accounting for around 1% of cases in the developed world, but more in the developing world, although its incidence here appears to be decreasing. A large centre in north India reported it to be the cause of 3.8% of cases of incident AKI. A study of 2405 cases of community-​ acquired AKI in eastern India reported an incidence of 5.8% in 1983 to 1995, falling to 1.3% in 1996 to 2008. However, these figures may be an underestimate, given that investigation is not pursued in many patients who fail to recover from what was presumed to be acute tubular necrosis on the grounds that test results do not reliably pre- dict prognosis or affect management, which is supportive. Renal cortical necrosis presents in the same context as acute tubular necrosis, which is almost always the diagnosis made initially on clinical grounds. Suspicion should arise immediately if a patient without obstruction is anuric, as was found in 79% of 113 patients in the largest study reported, but cortical necrosis is often considered only when renal function fails to improve. Most cases of renal cortical necrosis are the result of obstetric disasters, particularly postpartum haemorrhage, placental abrup- tion, eclampsia, septic abortion, or puerperal sepsis. Snake bite, haemolytic uraemic syndrome, acute gastroenteritis, pancreatitis, septicaemia (often with disseminated intravascular coagulation), trauma, and drug-​induced intravascular haemolysis are risk factors in the nonobstetric population. The pathological findings are of microvascular thrombosis, mainly affecting interlobular arteries, arterioles, and glomeruli, with complete infarction of affected areas of cortex. The medulla and a rim of juxtamedullary tissue are spared. Investigations to establish the diagnosis of renal cortical ne- crosis are renal angiography, contrast-​enhanced CT scanning or dimercaptosuccinic acid (DMSA) scan. Angiography reveals attenu- ation of interlobular arteries, an increase in the subcapsular vessels, and a negative outer cortical nephrogram. CT scanning shows en- hancement of the renal medulla, but no enhancement of the renal cortex and no excretion of contrast. DMSA scanning typically demonstrates small sections of viable cortex surrounded by a wide-​ rimmed photopenic area of cortical loss. Renal biopsy necessarily samples only a very small piece of tissue and may mislead because of the patchy nature of renal damage. In the months or years after an episode of renal cortical necrosis, the kidneys tend to contract:  cortical calcification producing an eggshell or tramline appearance on the abdominal radiograph is a characteristic sequel, but this is not useful in making the diagnosis acutely. Return of renal function in cases of renal cortical necrosis oc- curs very slowly, if at all, and is attributable to the survival of islands of intact cortical tissue. About 50% of patients recover sufficiently to come off dialysis, but the GFR rarely exceeds 10 to 20 ml/​min. Hypertension (including accelerated phase) may be a significant problem, and a subsequent decline in renal function with the neces- sity for a return to dialysis/​transplantation is not uncommon.

21.5  Acute kidney injury 4825 Large-​vessel occlusion Arterial occlusion Occlusion of the main renal arteries—​or of the artery supplying a solitary functioning kidney—​by embolism (usually in the context of atrial fibrillation), trauma, dissection, or thrombosis may rarely be the reason for AKI. A  meta-​analysis of outcomes following endovascular abdominal aortic aneurysm repair found renal in- farcts in 6.6% of cases with suprarenal fixation and 2.3% of cases with infrarenal fixation. Loin or abdominal pain usually occurs, sometimes there is nausea and vomiting, and occasionally fever, but symptoms can be notable by their absence. Suspicion should be aroused by complete, sudden anuria in the absence of urinary obstruction, especially if the clinical setting is appropriate (e.g. atrial fibrillation in an arteriopath). There may be acute elevation of blood pressure. Urinalysis may reveal proteinuria and haematuria. A  useful pointer to the diagnosis is the finding of a urinary sodium concentra- tion similar to that of serum. Serum lactate dehydrogenase is often more than two to four times the upper limit of normal, which sug- gests renal infarction when seen in an appropriate clinical context in conjunction with normal or near-​normal serum aminotransferases. The test that confirms the diagnosis is usually contrast-​enhanced CT scanning, revealing an absence of renal perfusion or a wedge-​shaped defect. Renal angiography and DMSA scanning can also establish the diagnosis, but the latter is rarely undertaken in the acute setting. There is no good evidence on which to base management recom- mendations. Anticoagulation with therapeutic dose low molecular weight heparin followed by warfarin or a nonvitamin K antagonist oral anticoagulant is indicated if there is recognized clinical indica- tion (e.g. atrial fibrillation). If the diagnosis of renal arterial occlu- sion due to thromboembolism or renal artery thrombosis is made within 1 to 2 days of symptom onset, most nephrologists would ad- vise percutaneous endovascular therapy with local thrombolysis, thrombectomy, or stent placement. Surgery is very rarely indicated in the acute setting, but there are reports of surgical bypass restoring renal function and controlling hypertension when undertaken many weeks after arterial occlusion in those with atherosclerotic renovascular disease in whom (prior to occlusion) a collateral blood supply to the renal parenchyma had developed. This should only be considered when the function of the arterially occluded kidney is critical (e.g. there is no contralateral functioning kidney), the affected kidney has preserved volume (not small and shrunken), and imaging suggests that the renal paren- chyma is not infarcted, albeit that perfusion is inadequate to sustain glomerular filtration. Venous occlusion Renal vein thrombosis can cause AKI, most commonly in adults as a complication of nephrotic syndrome, but in infants and children as a result of abdominal sepsis or severe dehydration. Acute renal vein thrombosis typically presents with loin pain, nonvisible or visible haematuria, and (when bilateral or affecting a single functioning kidney) with AKI. Chronic renal vein thrombosis may present with rising serum creatinine but is usually asymptom- atic. As with arterial occlusion, renal venous occlusion often leads to a rise in serum lactate dehydrogenase without concomitant ele- vation of aminotransferases. Definitive diagnosis requires renal imaging, usually with ultrasonography, CT, or magnetic resonance imaging depending on local practice. Selective renal venography is rarely required. Patients with acute renal vein thrombosis associated with AKI should be considered for local thrombolytic therapy with/​without catheter thrombectomy. Other patients with renal vein thrombosis should be offered anticoagulation, as for pulmonary embolism, un- less contraindicated. Small-​vessel occlusion Accelerated-​phase hypertension ‘Accelerated-​phase’ hypertension (a term preferred to ‘malignant’ hypertension because the implication of malignancy is terrifying for patients) occurs when the blood pressure is elevated sufficiently to cause fibrinoid necrosis of blood vessels, leading to the development of haemorrhages and exudates in the ocular fundi. It may develop as a consequence of pre-​existing renal disease and is itself a potent cause of renal damage. AKI is a common complication in those with previously normal renal function, and is associated with proteinuria, haematuria, and the presence of urinary red cell casts. The higher the creatinine at presentation, the poorer the prognosis for both patient survival and renal outcome: in one study, only 9% of those with an initial serum creatinine below 300 µmol/​litre progressed to need renal replacement therapy, compared with two-​thirds of those with a serum creatinine above this level. The ability of the kidney to autoregulate perfusion is disturbed in accelerated-​phase hyperten- sion, hence the therapeutic lowering of arterial pressure may be as- sociated with reduced renal perfusion and an abrupt decline in renal function. Accelerated-​phase hypertension is one of the conditions in which renal function sometimes recovers after a lengthy period on dialysis. Renal failure was the cause of two-​thirds of the deaths in pa- tients with accelerated-​phase hypertension in the days before dialysis was available. See Chapter 16.17.5 for further discussion. Systemic sclerosis A syndrome resembling accelerated-​phase hypertension and termed ‘scleroderma renal crisis’ affects 5 to 20% of patients with diffuse cutaneous systemic sclerosis, use of prednisolone of greater than 15 mg/​day, and presence of RNA polymerase antibodies being additional risk factors. It usually occurs within the first 5 years of the disease, may be the presenting feature, and often appears during the winter months. Rapid worsening of skin manifestations may precede the crisis, but frequently there is no warning. The patient may de- velop headaches, visual disturbance, and convulsions. Arterial pres- sure is usually grossly elevated, but the renal syndrome can occur without extreme hypertension in those with low baseline blood pressure. Haemorrhages and exudates are often seen in the ocular fundi. Urinalysis can be unremarkable or show low-​level proteinuria and/​or nonvisible haematuria. Renal failure develops rapidly. Renal biopsy is not required for diagnosis, but the typical renal histology is of concentric ‘onion skin’ intimal proliferation and thickening that leads to narrowing and occlusion of small arcuate and interlobular arteries. A microangiopathic haemolytic anaemia may complicate the situation. First-​line treatment is with ACE inhibition, which should be con- tinued even in the face of an initial rise in serum creatinine and per- sisted with in the long term. A study of 145 ACE inhibitor-​treated patients reported that 62% required dialysis, but many of these were able to discontinue it, sometimes many months later. By contrast,

section 21  Disorders of the kidney and urinary tract 4826 discontinuation of dialysis was rarely reported in historical pre-​ACE inhibitor series. See Chapter 19.11.3 for further discussion. Glomerulonephritic and vasculitic causes A large number of glomerulonephritic and vasculitic diseases can cause AKI, sometimes in association with pulmonary haemorrhage. These are discussed in detail in the relevant subchapters of Chapter 21.8, and in Chapters 20.10.2 and 20.10.3. Together they form only 5 to 10% of cases of AKI, but making the correct diagnosis is of extreme im- portance because of the management implications. Regrettably, most nephrologists have seen cases where the diagnosis has been much delayed because renal impairment has incorrectly been attributed to acute tubular necrosis, and infiltrates on the chest radiograph to oe- dema or infection. This error, which can be catastrophic, should be avoided in patients in whom the cause of AKI is not obvious by an approach to management as outlined in Box 21.5.5. The possible presence of a rapidly progressive glomerulonephritis/​ vasculitis is a medical emergency. Antiglomerular basement mem- brane disease responds well to immunosuppression with plasma exchange, steroids, and cyclophosphamide, but only if treatment is begun before dialysis is required. Immunosuppressive treatment should be given as early as possible in the course of AKI complicating microscopic polyangiitis/​idiopathic rapidly progressive (crescentic) glomerulonephritis, granulomatosis with polyangiitis (previously known as Wegener’s disease), and systemic lupus erythematosus. The urgency is such that it may well be appropriate to start these treatments while the results of blood tests and renal biopsy are awaited, and to stop them if the findings do not corroborate the ini- tial clinical diagnosis. The management of these patients is complex and patients benefit from the judgement and expertise of specialists. Acute interstitial nephritis Acute interstitial nephritis is discussed in Chapter 21.9.1. Lepto­ spirosis (Chapter 21.11) and hantaviral infection (Chapter 21.10.8) are both associated with AKI and acute interstitial nephritis: the fol- lowing account is to aid the clinician in distinguishing between them. Leptospirosis The diagnosis of leptospirosis should be considered in any patient with unexplained AKI who has myalgias/​muscle tenderness, con- junctival injection, and/​or haemorrhage and/​or jaundice. Direct enquiry must be made as to whether any such patient has been exposed to rats. Blood tests commonly reveal a dramatic conju- gated hyperbilirubinaemia (often >250 µmol/​litre) and thrombo- cytopenia (seen in 40% of cases), and there may also be elevation of serum creatine kinase and a slight increase in serum aspartate aminotransferase. Anaemia may be severe due to intravascular haemolysis. By contrast to most other causes of AKI, serum po- tassium is often normal or low in cases of leptospirosis. Mild ab- normalities of blood clotting tests can be seen, but disseminated intravascular coagulation is not a feature, which is an important point in distinction from bacterial septicaemia. Hantavirus disease In Europe In Europe, the Puumala serotype of hantavirus produces an illness that can have many similarities to that produced by leptospirosis, although serological studies indicate that many patients must have a subclinical infection. In those that are symptomatic, high fever is typically followed within a couple of days by loin/​abdominal pain and often by nausea and vomiting; photophobia and signs of meningeal irritation can also occur. AKI follows when these symptoms have settled and is associated with conjunctival haem- orrhage (20%), proteinuria (almost 100% of cases), nonvisible haematuria (70%), thrombocytopenia (50%), and a transient mild rise in plasma liver enzymes. There may be a small increase in serum bilirubin (maximum 40 µmol/​litre). Mild abnormalities of blood clotting tests are seen, but disseminated intravascular co- agulation is rare. Renal biopsy, performed for the indication of unexplained acute renal impairment, shows interstitial nephritis. This has no pathog- nomonic features, leading in this clinical context to the differential diagnosis of leptospirosis and sometimes (depending on exposure) disease induced by NSAIDs. Leptospirosis is much more likely if the serum bilirubin is markedly elevated. NSAID-​induced disease does not cause conjunctival haemorrhages or thrombocytopenia. The diagnosis of Puumala hantavirus infection is made on the basis of serological evidence. Prognosis is good: no deaths have been re- ported and renal function returns to normal. Box 21.5.5  Diagnosis of glomerulonephritic and vasculitic causes of acute kidney injury 1 A history and examination specifically directed towards determining whether a glomerulonephritic or vasculitic illness might be present. 2 Stick testing of the urine for blood and protein, followed (if positive) by microscopy to look for the presence of cellular casts. 3 The following tests:

—​ Measurement of serum antiglomerular basement membrane anti- bodies—​positive in Goodpasture’s disease (see Chapter 21.8.7).

—​ Measurement of serum antineutrophil cytoplasmic antibodies (ANCA) (screening by indirect immunofluorescence test, specific tests for antiproteinase-​3 and antimyeloperoxidase antibodies)—​ usually positive in microscopic polyangiitis and granulomatosis with polyangiitis (see Chapter 21.10.2).

—​ Estimation of serum complement levels (C3 may be depressed in postinfectious glomerulonephritis, mesangiocapillary glomerulo- nephritis, and systemic lupus erythematosus) (see Chapters 21.8.5, 21.8.6, and 21.10.3).

—​ Measurement of serum antistreptolysin-​O titre—​elevated in poststreptococcal glomerulonephritis) (see Chapter 21.8.5).

—​ Serological tests for systemic lupus erythematosus (see Chapter 21.10.3).

—​ Estimation of serum immunoglobulins and testing for urinary light chains (see Chapter 21.10.5).

—​ Estimation of serum cryoglobulins (see Chapter 21.10.5). 4 Consideration of the possibility that pulmonary infiltrates in a patient with AKI might be due to haemorrhage; the chances of this are in- creased if there is a history of haemoptysis (associated with several forms of rapidly progressive glomerulonephritis), nasal discharge or bleeding (associated with granulomatosis with polyangiitis), or if an- aemia is unusually profound and otherwise unexplained; lung func- tion tests demonstrating an increase in carbon monoxide transfer factor can establish the diagnosis but may be impractical in a patient who is very ill. 5 An urgent renal biopsy in any patient with AKI and an active urinary sediment unless the diagnosis is clear or there is a strong contraindica- tion (e.g. a single kidney or serious bleeding disorder).

21.5  Acute kidney injury 4827 In some areas of eastern and central Europe, there is a more severe form of hantavirus infection, which is similar to that seen in Asia. In Asia The Hantaan and Seoul viruses cause hantavirus disease in Asia: the former causes more severe illness, but both are considerably more dangerous that the Puumala hantavirus seen in Europe. A total of five phases of disease are recognized: • High fever and myalgias, followed by headache and severe ab- dominal/​loin pain, often with an erythematous rash that may be- come petechial, also conjunctival haemorrhages • Severe hypotension • Gradual recovery of blood pressure, but associated with oliguria and renal failure with proteinuria and nonvisible haematuria—​ one-​third of patients in this stage have significant problems with bleeding:  gastrointestinal, intracerebral, or massive purpura (hence the terms epidemic or Korean haemorrhagic fever) • Polyuria • Convalescence Differential diagnosis is from severe leptospirosis and other causes of haemorrhagic fever found in Asia, including dengue and murine typhus. The diagnosis is made serologically. Treatment is supportive. Mortality is between 3 and 7%; survivors recover completely. ‘Haematological’ causes These are discussed in other chapters: haemolytic uraemic syn- drome (Chapter  21.10.6); idiopathic postpartum renal failure (Chapter  14.5); and plasma cell dyscrasias, immunoglobulin-​ based amyloidoses, fibrillary nephropathies, lymphomas, and leu- kaemias (Chapter 21.10.5). Hepatorenal syndrome The hepatorenal syndrome describes the presence of otherwise unexplained AKI in association with acute on chronic liver failure (see Chapter 15.22.5). It is a diagnosis of exclusion, in particular from AKI due to acute tubular necrosis in the context of intravas- cular volume depletion and/​or sepsis. A large single-​centre study of the causes of AKI in 463 patients with cirrhosis reported these to be infection (46% of cases), volume depletion (32%), hepatorenal syndrome (13%), and renal inflammatory disease (e.g. glomerulo- nephritis (9%)). In one study of 229 patients with cirrhosis and as- cites, it developed in 18% at 1 year and 39% at 5 years, and in another study it developed in 28 of 101 patients with acute alcoholic hepatitis. The mechanism of renal failure in hepatorenal syndrome is uncer- tain, but it is associated with splanchnic vasodilatation and markedly reduced renal perfusion. These may be precipitated by acute insults such as gastrointestinal bleeding or infection. Presentation is typic- ally with oliguria, an inactive urinary sediment, proteinuria less than 0.5 g/​day, a very low urinary sodium concentration (<10 mmol/​litre), and a rising serum creatinine. Based on speed of onset, two forms are described: type 1 with rapid deterioration (creatinine clearance falling to <20 ml/​min or serum creatinine rising twofold to >221 µmol/​litre (2.5 mg/​dl) within 2 weeks); type 2 is less rapid. Diagnostic criteria are unsatisfactory because, as described earlier, they depend substantially on exclusion of other conditions. Hepatorenal syndrome may be characterized by ‘prerenal’ urinary biochemistry, in particular a very low urinary sodium concentration (<10 mmol/​litre), but this is not a diagnostic criterion. Histologically, the kidneys are normal, a fact emphasized by the fact that they work normally if transplanted. The best treatment for hepatorenal syndrome is restoration of liver function. This may be achieved if the patient recovers from al- coholic or viral hepatitis, or from acute hepatic failure, or undergoes liver transplantation. Other measures that have been employed and may be helpful are manoeuvres designed to improve renal perfusion, including the combination of intravenous noradrenaline and intra- venous albumin, terlipressin (a vasopressin analogue), octreotide (a somatostatin analogue), and midodrine (a selective α1-​adrenergic agonist). Transjugular intrahepatic portosystemic shunt procedures may provide short-​term benefit. Whether and for how long to provide active treatment are diffi- cult decisions in the patient with hepatorenal syndrome whose liver shows no sign of improving and for whom there is no opportunity for liver transplantation. Prognosis is poor and there is significant risk of prolonging death rather than supporting life. A multicentre study in Canada reported outcomes of 472 patients with cirrhosis who required renal replacement therapy for AKI, 341 of whom were not listed and 131 were listed for a liver transplant. In the nonlisted group, median survival was 21  days for those diagnosed with hepatorenal syndrome and 85% of all patients had died by 6 months. The risk of hepatorenal syndrome can be reduced in patients with spontaneous bacterial peritonitis by administration of intravenous albumin in addition to antibiotics. A randomized trial has dem- onstrated reduced rates of hepatorenal syndrome with norfloxacin (400 mg daily) in selected patients with cirrhosis and ascites. A trial of pentoxifylline showed benefit in alcoholic hepatitis, but a system- atic review has not confirmed this. Urinary obstruction This is discussed in Chapter 21.17. FURTHER READING Abassi ZA, et al. (1998). Acute renal failure complicating muscle crush injury. Semin Nephrol, 18, 558–​65. Ali T, et al. (2011). The changing pattern of referral in acute kidney injury. QJM, 104, 497–​503. Allegretti AS, et al. (2018). Prognosis of patients with cirrhosis and AKI who initiate RRT. Clin J Am Soc Nephrol, 13, 16–​25. Anderson SM, Park ZH, Patel RV (2011). Intravenous N-​acetylcysteine in the prevention of contrast media-​induced nephropathy. Ann Pharmacother, 45, 101–​7. Ash SR (2001). Peritoneal dialysis in acute renal failure of adults: the safe, effective, and low-​cost modality. Contrib Nephrol, 132, 210–​21. Bagshaw SM, et al. 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21.5  Acute kidney injury 4829 Spital A, et al. (1988). Nondilated obstructive uropathy. Urology, 31, 478–​82. Sponsel H, Conger JD (1995). Is parenteral nutrition therapy of value in acute renal failure patients? Am J Kidney Dis, 25, 96–​102. Stather PW, et al. (2018). Meta-​analysis of renal function following in- frarenal EVAR using suprarenal or infrarenal fixation devices. Eur J Vasc Endovasc Surg, 56, 486–​96. Steen VD, Medsger TA Jr (2000). Long-​term outcomes of scleroderma renal crisis. Ann Intern Med, 133, 600–​3. Stewart J, et al. (2009). Adding insult to injury. A review of the care of patients who died in hospital with a primary diagnosis of acute kidney injury (acute renal failure). National Confidential Enquiry into Patient Outcome and Death. http://​www.ncepod.org.uk/​2009aki.htm Torres PA, et al. (2015). Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J, 15, 58–​69. VA/​NIH Acute Renal Failure Trial Network (2009). Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med, 359, 7–​20 ‘Think Kidneys’ (2015). Recommended minimum requirements of a care bundle for patients with AKI in hospital. https://​www. thinkkidneys.nhs.uk/​aki/​wp-​content/​uploads/​sites/​2/​2015/​12/​ AKI-​care-​bundle-​requirements-​FINAL-​12.07.16.pdf (accessed 25 August 2017). ‘Think Kidneys’ (2016). Guidelines for medicines optimisation in patients with acute kidney injury. https://​www.thinkkidneys.nhs.uk/​ aki/​wp-​content/​uploads/​sites/​2/​2016/​07/​Medicines-​optimisation-​ toolkit-​for-​AKI-​MAY17.pdf (accessed 25 August 2017). UK Renal Association (2014). Clinical practice guidelines: treatment of acute hyperkalaemia in adults. www.renal.org/​guidelines (accessed 25 August 2017). van Ypersele de Strihou C, Mery JP (1989). Hantavirus-​related acute interstitial nephritis in western Europe. Expansion of a world-​wide zoonosis. QJM, 73, 941–​50. Wang HE, et al. (2012). Acute kidney injury and mortality in hospital- ised patients. Am J Nephrol, 35, 349–​55. Whiting P, et al. (2017). What are the risks and benefits of temporarily discontinuing medications to prevent acute kidney injury? A sys- tematic review and meta-​analysis. BMJ Open, 7, e012674. Winearls CG, et al. (1984). Acute renal failure due to leptospirosis: clinical features and outcome in six cases. QJM, 53, 487–​95. Xue JL, et al. (2006). Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992–​2001. J Am Soc Nephrol, 17, 1135–​42.

21.6 Chronic kidney disease 4830 Alastair Hutchiso

21.6 Chronic kidney disease 4830 Alastair Hutchison

ESSENTIALS Definition Chronic kidney disease (CKD) is defined as kidney damage lasting for more than 3 months characterized by structural or functional abnor- malities of the kidney, with or without decreased glomerular filtration rate (GFR). Staging CKD has been subdivided into six stages depending on the esti- mated GFR (eGFR) and degree of proteinuria: CKD stage 1 is eGFR greater than 90 ml/​min (per 1.73 m2) with other evidence of renal disease; CKD stage 2 is eGFR 60 to 89 ml/​min, with other evidence of renal disease; CKD stage 3a is eGFR 45 to 59 ml/​min; CKD stage 3b is eGFR 30 to 44 ml/​min; CKD stage 4 is eGFR 15 to 29 ml/​ min; and CKD stage 5 is eGFR less than 15 ml/​min. At each stage the CKD is further categorized according to the degree of pro- teinuria based on the albumin:creatinine ratio (ACR), from A1 (no increase in protein excretion) to A3 (severe proteinuria). The eGFR is least accurate when the serum creatinine is within or near the normal range. Epidemiology Mild CKD is common, with about 10% of the population of the United States of America having CKD stage 1, 2, or 3 (combined), but advanced CKD is relatively rare (about 0.2% are receiving renal re- placement therapy). Patients with CKD stage 1, 2, or 3 are at relatively low risk of progressing to require renal replacement therapy, but are at high risk of death from cardiovascular disease. Aetiology The causes of chronic renal failure recorded in various national registries are diabetes mellitus (22–​45%), glomerulonephritis (10–​23%), hypertension (5–​25%), chronic pyelonephritis (0.5 to 7%), adult polycystic kidney disease (2–​7%), renal vascular disease (2–​7%), other recognized conditions (13–​15%), and un- known causes (4–​26%). However, these data are flawed for many reasons: diagnoses are often allocated as ‘best guesses’ by clin- icians; there is no universal agreement on the meaning of terms such as ‘pyelonephritis’; glomerulonephritis may be diagnosed without histological proof; hypertension is often cited when it may be no more than a consequence of whatever caused the renal failure. Pathophysiology Compensatory mechanisms and their consequences—​as kidney function gradually fails, these generally maintain acceptable health until the GFR is about 10 to 15 ml/​min, and patients will not usually die of renal failure until the GFR is less than 5 ml/​min. Despite a widened range of single-​nephron GFR in damaged or diseased kidneys, glomerular and tubular function remains closely integrated in all individual nephrons (the ‘intact nephron hypothesis’). However, the functional adaptations required to maintain overall homeostasis come at a price (the ‘trade-​off hy- pothesis’), with the ‘hyperfiltration hypothesis’ most clearly ar- ticulating how these adaptive changes lead, in the long run, to glomerulosclerosis and tubulointerstitial fibrosis and progressive decrease in GFR. Pathophysiological changes—​these include impairment in (1) con- centration and/​or dilution of the urine; (2) excretion and/​or con- servation of sodium; (3) excretion of potassium, with hyperkalaemia often the immediate life-​threatening consideration in the manage- ment of patients with renal failure; (4) excretion of acid; (5) calcium/​ phosphate/​vitamin D/​bone homeostasis; (6) erythropoietin produc- tion, leading to renal anaemia; (7) excretion of many substances and metabolites that act as ‘uraemic toxins’; and (8) a wide range of endo- crine functions. The clinical presentation of CKD is discussed in Chapter 21.3 and investigation of patients with renal disease in Chapter 21.4. 21.6 Chronic kidney disease Alastair Hutchison Acknowledgement: Professor E. Ritz, Professor T. Drueke, and Dr J. Firth wrote on chronic kidney disease for the fifth edition of this textbook: some parts of their text and some figures are retained here. Dr C. Winearls wrote on chronic renal failure in the fourth edition of this textbook: a small part of his chapter is also retained.

21.6  Chronic kidney disease 4831 Prevention of progression Specific and general measures—​in some patients, measures to con- serve renal function may be specific to the cause of renal impair- ment (e.g. relief of obstruction), but it is probable that all patients will benefit from good blood pressure control and (when relevant) measures to reduce proteinuria, which is not only a marker but a promoter of progression of CKD. Blood pressure and proteinuria—​there is limited information on
the target blood pressure to be achieved in patients with chronic kidney disease, but the consensus is that the lower the blood pres- sure, the better—​as long as this can be achieved without unaccept- able side effects. The 2013 European Society of Hypertension/​ European Society of Cardiology guidelines recommend a target systolic blood pressure less than 140 mmHg, and state that if there is significant proteinuria, less than 130  mmHg ‘may be pursued’. Proteinuria should be lowered as much as possible, preferably to less than 1 g/​24 h (roughly equivalent to an ACR of <60 mg/​mmol or a protein:creatinine ratio of <100 mg/​mmol). Combination therapy with several antihypertensive agents (including loop diuretics) is usu- ally required, but there is good evidence that the regimen should contain an angiotensin-​converting enzyme inhibitor or angiotensin receptor blocker, which have antiproteinuric effects, if they are tol- erated (hyperkalaemia being the most common reason why they cannot be used in this context). Medical management of the consequences of CKD Diet—​only patients with oliguric endstage renal failure need to re- strict their fluid intake precisely. It is sensible to recommend modest dietary sodium restriction (100 mmol/​day) in most cases. Patients with a tendency to hyperkalaemia should be offered advice re- garding a low-​potassium diet (with particular care taken if they are given medications that induce hyperkalaemia). Chronic acidosis will benefit from treatment with alkali. Malnutrition is common in ad- vanced CKD, can be detected by serial monitoring of body weight and serum albumin concentration, and is best treated by initiating renal replacement therapy. CKD mineral and bone disorders—​these include hyperparathyroid bone disease, mixed lesions, osteomalacia, adynamic bone, and osteopenia/​porosis, the impact of which extends beyond the bones to cardiovascular structure and function, with increased mortality. Pathogenesis is complex but includes phosphate retention, defi- ciency of active forms of vitamin D, hypocalcaemia, and the devel- opment of hyperparathyroidism. Secondary hyperparathyroidism can be prevented by giving (1) cholecalciferol 2000 U/​day if serum 25-​(OH)D3 is low; (2) calcium carbonate 0.5 to 1.0 g with each meal if plasma calcium is decreased and/​or plasma phosphate is increased; (3)  calcium-​free phosphate binder (e.g. sevelamer or lanthanum carbonate) if serum phosphate is increased and plasma calcium is normal or high; or (4) calcitriol 0.25 µg/​day, or equivalent doses of alfacalcidol or other active vitamin D analogues, if serum parathy- roid hormone (PTH) is consistently above target ranges and serum calcium/​phosphate is normal (spontaneously or after intervention). Advanced hyperparathyroidism can be treated by (1) normalizing serum calcium and phosphate levels if serum intact PTH is con- stantly above target range; (2)  reducing serum phosphate, if this is elevated, by using phosphate binders, dietary restriction, and increased dialysis; (3) reducing serum calcium if this is elevated by reducing/​withdrawing calcium-​containing phosphate binders and active vitamin D sterols, and by reducing dialysate calcium concen- tration; (4) if serum calcium and phosphate have been normalized and elevated intact PTH persists, by increasing the dose or fre- quency of calcitriol or other active vitamin D sterols (e.g. alfacalcidol, paricalcitol, and doxercalciferol), or alternatively administering the calcimimetic cinacalcet, which renders the calcium receptor more sensitive to calcium; and (5) if serum intact PTH fails to decrease and/​ or hypercalcaemia/​hyperphosphataemia develops or persist, then consider surgical parathyroidectomy or cinacalcet. Anaemia—​this is common in CKD and is particularly marked in patients with diabetes. Partial correction of such anaemia by use of erythropoiesis-​stimulating agents (ESAs) improves patients’ physio- logical and clinical status, as well as quality of life. If a patient with CKD has a haemoglobin concentration of less than 11 g/​dl and symp- toms that might be attributable to anaemia, then treatment to re- store haemoglobin to the range 11 to 12 g/​dl is warranted, but it has been convincingly shown in randomized studies that correction to a higher level (‘normal or near normal’) is associated with poorer out- comes and should be avoided. Treatment involves (1) exclusion of other causes of anaemia; (2) optimization of iron status, which usually requires administration of intravenous iron; and (3) initiation and ad- justment of dosage/​frequency of administration of ESAs, with regular monitoring to achieve haemoglobin in the target range 11 to 12 g/​dl. Preparation for renal replacement therapy or conservative management of uraemia Once endstage renal failure is inevitable, the patient must be pre- pared physically and psychologically for renal replacement therapy (see Chapters 21.7.1–​21.7.3). In many cases, it is possible to predict approximately when the endstage will be reached from consider- ation of the rate of renal deterioration, most easily demonstrated by plotting the declining eGFR against time. There are patients for whom dialysis may appear inappropriate, or who either choose not to start or to discontinue treatment. In frail patients, usually elderly and with multiple comorbidities, it is not likely that dialysis will greatly prolong life, although it can certainly reduce the quality of it. The ethical and legal issues are complex and require that the patient makes the decision not to start or to discon- tinue treatment when fully informed and able to do so. They must be given a realistic account of what dialysis can achieve, what it cannot achieve, and at what cost—​access, travel, restrictions, and complica- tions. These conversations can be difficult and cannot be hurried, it being critically important that the patient (and their relatives/​friends) does not get the entirely erroneous impression that dialysis means that ‘the doctors care and I’ll live for ever’, whereas no dialysis means that ‘the doctors don’t care and I’ll die soon’. Properly managed, death from uraemia is peaceful and free of suffering. Definition Chronic kidney disease (CKD) is defined as an abnormality of kidney structure or function lasting for more than 3 months. The current classification is presented in the Kidney Disease: Improving

section 21  Disorders of the kidney and urinary tract 4832 Global Outcomes (KDIGO) CKD Work Group (2013). The classi- fication, prognosis, and risk of adverse health-​related outcomes in CKD are assessed using glomerular filtration rate (GFR) category and albuminuria category (Fig. 21.6.1). A decline in GFR and an in- crease in albumin:creatinine ratio increases the risk of adverse renal and cardiovascular outcomes with a combination of the two multi- plying the risk (Fig. 21.6.2). The current classification is based on six stages of kidney func- tion based on GFR and termed G1 to G5 with three categories of albumin:creatinine ratio, A1 to A3. Stage G5 A3 would reflect those with the poorest function, that is, GFR less than 15 and kidney failure with severely increased albuminuria greater than 30 mg/​ mmol (Fig. 21.6.1). The assessment of kidney function and definition of impair- ment should be based on measurements of serum creatinine using standardized assays. Clinical laboratories should report for every serum creatinine result (measured in an ambulatory context) a glomerular filtration rate estimation (eGFR) using a prediction equation such as the Chronic Kidney Disease Epidemiology Collaboration (CKD-​EPI) creatinine equation or an update of the formula used in the Modification of Diet in Renal Disease (MDRD) study. This is based on standardized measurement of serum creatinine (a method which is easily disturbed by numerous confounders) and considers, in addition to serum creatinine, the age, sex, and ethnicity of the patient (see Chapter 21.4 for further discussion). There are pitfalls in the assessment of kidney function and diag- nosis of CKD when using GFR. CKD should not be confirmed if the duration of the impaired function is less than 3 months or unclear. In individuals with extremes of muscle mass, GFR calculated from serum creatinine will be underestimated in those with high muscle mass such as bodybuilders and overestimated in those with low muscle mass, including amputees and patients with muscle wastage. A correction factor, multiplication of the eGFR by 1.14, is also re- quired for those of African or Afro-​Caribbean ethnicity when using the CKD-​EPI creatinine equation. A meal including meat (protein rich) should be avoided in the 12 h before a blood sample is obtained for creatinine and GFR estimation. The estimation of GFR is also inaccurate for those with preserved function and true GFR greater than 60 ml/​min per 1.73 m2. Caution in diagnosing CKD is also needed where eGFR based on serum cre- atinine is 45 to 59 ml/​min per 1.73 m2 and where there are no other markers of structural kidney disease or evidence of albuminuria. In such cases, serum cystatin C may be used to calculate eGFR, and if the value is greater than 60 ml/​min per 1.73 m2, a diagnosis of CKD should not be given (see Chapter 21.4). Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Normal or high ≥90 Normal to mildly increased <30 mg/g <3 mg/mmol

300 mg/g 30 mg/mmol 30–300 mg/g 3–30 mg/mmol Moderately Increased Severely increased 60–89 45–59 30–44 15–29 <15 Mildly decreased Mildly to moderately decreased Moderately to severely decreased Severely decreased Kidney failure Persistent albuminuria categories Description and range GFR categories (mI/min/ 1.73m2) Description and range A1 G1 G2 G3a G3b G4 G5 A2 A3 Fig. 21.6.1  Stages of CKD and risk of adverse outcomes. Prognosis of CKD by GFR and albuminuria category. Green, low risk (if no other markers of kidney disease, no CKD); yellow, moderately increased risk; orange, high risk; red, very high risk. CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes. Reprinted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group (2013). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements, 3, 1–​150. Copyright © 2013, with permission from Elsevier.

21.6  Chronic kidney disease 4833 Prevalence and incidence of chronic kidney disease The high frequency of impaired renal function in the general population has been recognized only recently. Worldwide preva- lence of CKD is estimated to be greater than 10%, with estimates of greater than 50% in some higher-​risk groups. Particularly at risk are prediabetic patients with metabolic syndrome, patients with diabetes mellitus, and individuals with many other conditions, for example, female sex, smokers, or patients receiving potentially nephrotoxic medications such as nonsteroidal anti-​inflammatory drugs (NSAIDs). Advanced age is another risk factor, with preva- lence over 20% of those aged greater than 60 and 35% of those older than 70 in the United States of America. Based on data from the National Health and Nutrition Examination Survey (NHANES) reported in 2003, it has become apparent that—​ in contrast to the relatively modest number of patients on renal re- placement therapy (RRT) in the United States of America (300 000, i.e. <1% of the population of 175 million) —​the estimated number of adults with CKD stages 1, 2, and 3 (combined) was 18.8 million (i.e. 10–​11% of the population). This observation is not only of aca- demic interest, but also of major public health importance. The reason is shown in Table 21.6.1: in individuals with CKD stage 2, the risk of them living long enough to require RRT is 20 times lower than their risk of dying from cardiovascular causes. Even patients in the more advanced stage 4 of CKD are twice as likely to die from cardiovascular causes as they are to end up on RRT. From a public health perspective, there is therefore a great need for early recogni- tion of CKD to allow opportunity for therapeutic interventions, in particular to improve cardiovascular prognosis. These public health implications for CKD are illustrated further in relation to risk of car- diovascular death in Fig. 21.6.3 and loss of life expectancy in relation to age in Table 21.6.1. The prevalence and incidence of endstage renal disease is shown in Table 21.6.2, which gives the total number of patients on RRT worldwide at the end of 2004 (i.e. 1.8 million), of whom 1.4 million were treated by haemodialysis or continuous ambulatory peritoneal dialysis (or other modalities of peritoneal dialysis) and 412 000 were alive with a functioning renal transplant. In Europe, an estimated total of 324 000 patients were on RRT and 149 000 were alive with a functioning renal graft. This gives a prevalence of 400 per million population for patients on dialysis (haemodialysis and peritoneal dialysis combined) and 185 per million population for kidney trans- plant recipients. Between 1990 and 1999, there was a dramatic increase in the adjusted incidence of RRT in Europe, rising from 73 per mil- lion population (range 58–​101  per million population) in 1990 to 1991 to 117 per million population (range 92–​145 per million population) in 1998 to 1999, that is, by 4.8% per year (range 3.1–​ 6.4%). The increase was greater in men than in women and did not flatten out at the end of the decade, except in the Netherlands. Since 2000, annual rises in RRT incidence rates have slowed being 120 per million population in 2000, 125 per million population in 2006, and 133 per million population in 2012. Rates appear to have stabilized for females aged 65 to 74 years, males aged 75 to 84 years, as well as in patients with RRT causes of hypertension and renovascular disease. It is of particular note that the incidence of endstage renal disease due to diabetic nephropathy (the com- monest single cause of requiring RRT) has begun to flatten out in 4 2 1 0.5 4.0 (b) (a) 2.0 1.0 0.5 2.5 5 10 30 300 ACR (mg/g) 1000 15 30 45 60 75 90 105 120 HR for CVD mortality (ACR studies) HR for CVD mortality (ACR studies) Significant values Non-significant values Fig. 21.6.2  Independent associations of kidney function and proteinuria with cardiovascular mortality. (a) Kidney function
(eGFR); reference value of 95 ml/​min per 1.73 m² is shown with a diamond. (b) Albuminuria (ACR); the reference value of 5 mg/​g
is shown with a diamond. Hazard ratios are adjusted for each
other (eGFR or ACR), age, sex, ethnic origin, and traditional cardiovascular risk factors. ACR, albumin-​to-​creatinine ratio; CVD, cardiovascular disease; eGFR=estimated glomerular filtration rate;
HR, hazard ratio. Reprinted from The Lancet, 382, 339–​52. Gansevoort R, et al. (2013). Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Copyright © 2013, with permission from Elsevier. Table 21.6.1  Risk (percentage chance over 5 years) of death from CKD progression towards endstage renal disease (defined as need for renal replacement therapy, RRT) and risk of death from cardiovascular disease in 27 998 American patients with glomerular filtration rate (GFR) less than 90 ml/​min per 1.73 m2
(for the period 1996–​2001) GFR (ml/​min per 1.73 m2) Risk over 5 years (%) RRT Cardiovascular death CKD stage 2 (60–​89) 1.1 19.5 CKD stage 3 (30–​59) 1.3 24.3 CKD stage 4 (15–​29) 19.9 45.7 Reproduced from Keith DS, et al. (2004). Longitudinal follow-​up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med, 164, 659–​63, with permission.

section 21  Disorders of the kidney and urinary tract 4834 the general population of the United States of America. It has also done so in Pima Indians, in whom the cardiovascular risk is less than in whites people, which excludes the possibility that failure to observe more diabetic patients reaching endstage renal disease was due to their more frequent death from cardiovascular causes before reaching endstage renal disease. A similar trend with regard to diabetic nephropathy as a cause of endstage renal failure has also been observed in Denmark, but there have been large differences in overall incidence and prevalence of RRT between European countries. Specifically, in the United Kingdom, the annual accept- ance rate for RRT increased from 20 per million population in 1982 to 101 per million population in 2002, largely due to higher acceptance rates of patients over 65 years of age and of those with comorbidities. Most recent data from the United Kingdom shows RRT incidence rates of 109 per million population in 2013, a rate which appears to have stabilized since 2006. It has long been known that endstage renal disease is much more frequent in older people than in young people. The European Renal Association/​European Dialysis and Transplant Association (ERA/​ EDTA) Registry data showed a four-​ to fivefold increase in the in- cidence and prevalence of RRT over the period 1985 to 1999, and in 1999 no fewer than 48% of new patients were above age 65 years, leading the registry authors to refer to RRT as an epidemic of ageing. In this context, it is also of interest that the long-​term function of kidney grafts obtained from elderly donors, irrespective of whether they were live donors or cadaveric, is inferior to the function of kidney grafts from younger donors. As typical signs of senescence, telomere length is reduced, repair capacity is curtailed, and the kid- neys of older people are generally hypoperfused as a consequence of vascular sclerosis. It is of interest that the incidence of new patients requiring RRT does not parallel the prevalence of CKD stages 3 and 4. Despite similar prevalence of CKD stages 3 and 4, the incidence of CKD pa- tients requiring RRT in Norway is significantly lower than in white patients in the United States of America. This is explained not by high mortality prior to endstage renal disease, but by more effective intervention to prevent progression of CKD to stage 5, an observa- tion that illustrates the great benefit of dedicated nephrological care for patients with advanced CKD. Causes of chronic kidney disease The usual sources for descriptions of the causes of CKD are endstage renal failure databases. These are flawed for many reasons: diagnoses are often allocated as ‘best guesses’ by clinicians; there is no uni- versal agreement on the meaning of terms such as ‘pyelonephritis’; glomerulonephritis may be diagnosed without histological proof; hypertension is often cited when it may be no more than a conse- quence of whatever caused the renal failure. With these important caveats in mind, Table 21.6.3 lists the given causes of endstage renal failure in recent reports from the United Kingdom Renal Registry, the Australia and New Zealand Dialysis and Transplant Registry, and the United States Renal Data Systems. Less common causes of chronic renal failure are given in Box 21.6.1. Note that some causes of chronic renal failure that are uncommon from a global perspec- tive (e.g. Balkan nephropathy and HIV nephropathy) may be very common in some populations. In most countries, diabetic nephropathy has become the single most frequent cause of endstage renal disease. In comparison with previous years, the relative contribution of glomerulonephritis has substantially decreased, and the diagnosis of ‘pyelonephritis’, that is, the concept that chronic bacterial colonization of the kidney and of the urinary tract causes chronic loss of renal function even in the absence of malformation or urological disease, has increas- ingly been abandoned on the basis of follow-​up studies in cohorts of subjects with uncomplicated chronic urinary tract infection who failed to develop CKD in the absence of additional pathologies. It is of note, however, that in aboriginal populations, the spectrum of renal disease is strikingly different, and this is also true for nonwhite immigrant populations, including in the United Kingdom, who Fig. 21.6.3  Loss of life expectancy due to cardiovascular disease, by chronic kidney disease stage (Canadian data). (a) eGFR stages, (b) albuminuria stages. Loss is compared with life expectancy in people with normal or mildly impaired kidney function (stage 1–​2, eGFR 60 ml/​min per 1.73 m² or higher) and normal or mildly increased albuminuria (stage 1, albumin-​to-​creatinine ratio <30 mg/​g). Data are adjusted for sex. eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy. Reprinted from The Lancet, 382, 339–​52. Gansevoort R, et al. (2013). Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Copyright © 2013, with permission from Elsevier.

21.6  Chronic kidney disease 4835 have an excess of diabetic nephropathy and a variety of renal dis- eases which are less frequently or rarely seen in white patients, for example, renal tuberculosis, sickle cell anaemia nephropathy, and HIV nephropathy. Detailed discussion of particular causes of CKD can be found in other chapters. Pathophysiology of chronic kidney disease As kidney function gradually fails, compensatory mechanisms gener- ally maintain acceptable health until the GFR is about 10 to 15 ml/​min per 1.73 m2, and patients will not usually die of renal failure until the GFR is less than 5 ml/​min per 1.73 m2. The remarkable capacity of renal function to adapt to maintain overall homeostasis in the face of such dramatic reduction in glomerular filtration is best understood on the basis of the ‘intact nephron’ hypothesis and the ‘trade-​off’ hypothesis. Table 21.6.2  Global and regional overview of endstage renal disease (ESRD), dialysis, and transplant patient numbers, and prevalence values at year-​end 2004 (numbers rounded) Region Patient numbers Prevalence values (per million population) ESRD Dialysis (HD + PD) Transplant ESRD Dialysis (HD + PD) Transplant Global 1 783 000 1 371 000 412 000 280 215 65 North America 492 000 337 000 154 000 1505 1030 470 Europe 473 000 324 000 149 000 585 400 185 (thereof EU) (387 000) (252 000) (135 000) (850) (550) (295) Japan 261 000 248 000 13 000 2045 1945 100 Asia (excluding Japan) 237 000 196 000 41 000 70 60 10 Latin America 205 000 170 000 35 000 380 320 65 Africa 61 000 57 000 5000 70 65 5 Middle East 54 000 39 000 15 000 190 140 55 HD, haemodialysis; PD, peritoneal dialysis. Reproduced from Grassmann A, et al. (2005). ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends. Nephrol Dial Transplant, 20, 2587–​93, with permission. Table 21.6.3  Percentage distribution of primary renal diagnosis in patients starting on renal replacement therapy Diagnosis UKRRa ANZDATAb USRDSc Uncertain 14.5d 5 Not specified Diabetese 25.4 35 43.8 Glomerulonephritis 14.4f 19g 7.5 Chronic pyelonephritish 6.9 2 Not specified Renal vascular disease 5.1 Not specified Not specified Adult polycystic kidney disease 7.6 6 2.1 Hypertensionj 7.6 14 28.7 Otherk 18.3 15 18l ANZDATA, Australia and New Zealand Dialysis and Transplant Registry (2014 report); UKRR, United Kingdom Renal Registry (December 2014 report); USRDS, United States Renal Data Systems (2015 report). a Data from 6353 patients beginning dialysis in United Kingdom renal units in 2013 for whom a primary renal diagnosis was reported. b Data from all 2544 patients beginning dialysis in Australian renal units in 2013. c Data from116 990 incident patients from 2013. d Also includes ‘glomerulonephritis not proven by biopsy’. e It can be impossible to know whether diabetes is a cause of endstage renal failure or merely an association. f 100% biopsy proven. g 76% biopsy proven. h Patients diagnosed as having ‘reflux nephropathy’ are included under this heading. i Classified as a subgroup of ‘hypertension’. j Reporting practices varied widely and variation in attribution of hypertension as a cause almost certainly does not reflect real differences in causation of endstage renal failure. k Includes urinary obstruction. l Includes ‘uncertain’. Box 21.6.1  Less common causes of chronic renal failure Metabolic Cystinosis, cystinuria (stones), oxalosis, nephrocalcinosis, and urate nephropathy. Hereditary Alport’s syndrome, Fabry’s disease, tuberous sclerosis, sickle cell disease, medullary cystic disease (and the metabolic conditions listed previously). Vasculitides and other multisystem disorders Granulomatosis with polyangiitis (formerly referred to as Wegener’s granulomatosis), microscopic polyangiitis, polyarteritis nodosa, Henoch–​ Schönlein purpura, systemic lupus erythematosus, scleroderma, and sarcoidosis. Malignancy Renal cell cancer, von Hippel–​Lindau disease, and lymphoma. Dysproteinaemias Myeloma, primary (AL) and secondary (AA) amyloid, and cryoglobulinaemia. Structural/​infection/​interstitial Cystic disease other than autosomal dominant polycystic kidney dis- ease, congenital and acquired abnormalities of the lower urinary tract, tuberculosis, schistosomiasis, Balkan nephropathy, Chinese herb neph- ropathy, analgesic nephropathy, nephrotoxic metals, and radiation nephropathy. Other Haemolytic uraemic syndrome, postpartum renal failure, acute cortical necrosis, accelerated (‘malignant’) hypertension, and HIV nephropathy.

section 21  Disorders of the kidney and urinary tract 4836 The intact nephron hypothesis, first articulated by Bricker, states that despite a widened range of single-​nephron GFR in damaged or diseased kidneys, glomerular and tubular function remains closely integrated in all individual nephrons, both normal and damaged. As the GFR of the whole kidney falls, those nephrons that are still functioning produce an increased volume of filtrate (hyperfiltration), and their tubules respond appropriately for overall homeostasis by excreting fluid and solutes in amounts that maintain external balance, although the capacity for adaptation is variable. For sodium and potassium, compensation can occur down to a GFR as low as 5 ml/​min per 1.73 m2, but this cannot be achieved for phosphate and urate, plasma concentrations of which may be elevated when the GFR falls below 20 ml/​min per 1.73 m2 in some patients. The trade-​off hypothesis recognizes that the functional adapta- tions required to maintain overall homeostasis come at a price and that they contribute to changes characteristic of the syndrome of uraemia. The best example of such a trade-​off is the generation of hyperparathyroidism. As GFR falls, leading (if there were no com- pensation) to a reduction in phosphate excretion and a rise in serum phosphate, the serum parathyroid hormone (PTH) concentration rises and serves to maintain homeostasis by reducing tubular re- absorption of phosphate. However, a consequence is secondary (and sometimes tertiary) hyperparathyroidism, with adverse effects on blood vessels and bones. Electrolyte, water, and acid–​base homeostasis An inability to concentrate the urine in the face of dehydration is sometimes the first symptom of chronic renal failure, manifesting as polyuria, nocturia, and thirst. This is particularly likely in condi- tions that predominantly affect the renal medulla (e.g. obstructive uropathy, interstitial nephritides, and medullary cystic disease). By contrast, urinary diluting capacity is preserved until renal failure is advanced, at which time urinary osmolality becomes fixed at around 300 mOsm/​kg (roughly isotonic with plasma) and there is obligatory polyuria. It should be noted, however, that although urinary diluting capacity is maintained until late in chronic renal failure, large water loads are excreted more slowly than in normal subjects and excessive intake (by drinking or ill-​advised iatrogenic infusion of dextrose-​ containing solutions) can lead to symptomatic hyponatraemia (see Chapter 21.2.1). As renal function decreases, sodium balance and extracellular fluid volume are maintained until GFR is less than about 10 ml/​ min per 1.73 m2 by an increase in the fractional excretion of sodium (the amount excreted in the urine as a fraction of that filtered at the glomerulus) from 1% (normal) to 30%. This capacity for adaptation is overwhelmed in advanced chronic renal failure, with sodium re- tention manifest as hypertension and/​or oedema (peripheral and/​or pulmonary). Such patients can also be at increased risk of sodium depletion as they are unable to restrict sodium excretion promptly in response to stimuli that would normally be expected to lead to such restriction (e.g. diarrhoea, vomiting). A  few patients with modest impairment of GFR (e.g. CKD stage 3), usually with diseases affecting the medulla, may present with low blood pressure (often with a postural drop) due to sodium depletion caused by a urinary sodium leak: sodium supplements may be required. Most patients maintain normal external potassium balance until their GFR is less than 5 ml/​min per 1.73 m2, but their capacity to excrete potassium is limited and severe hyperkalaemia may follow a sudden reduction in GFR such as might be caused by intercur- rent illness, excess dietary intake, or prescription of drugs that im- pair potassium excretion (angiotensin-​converting enzyme (ACE) inhibitors, angiotensin receptor blockers, potassium-​sparing di- uretics). Some patients, particularly those with diabetes mellitus and/​or interstitial nephritis, may develop hyperkalaemia due to hyporeninaemic hypoaldosteronism at levels of GFR that would not otherwise be expected to cause problems with potassium homeo- stasis. Hyperkalaemia is often the immediate life-​threatening con- sideration in the management of patients with renal failure. See Chapters 21.2.2 and 21.5 for further discussion. The kidney normally maintains acid–​base homeostasis by re- absorbing filtered bicarbonate, acidifying urinary buffers, and excreting ammonia. Increasing acidosis tends to occur at a GFR of less than 10 ml/​min per 1.73 m2, and is more likely to be an early feature in diseases that primarily affect the tubules and interstitium (aside from the renal tubular acidoses, where there are specific de- fects in acid–​base homeostasis—​see Chapter 21.15). Abnormalities of calcium and phosphate homeostasis are dis- cussed later in this chapter. Endocrine dysfunction In CKD, hormone concentrations may be elevated as a result of re- duced degradation (e.g. insulin) or increased secretion in response to metabolic changes (e.g. PTH), or reduced by impaired production (e.g. 1,25-​dihydroxyvitamin D, erythropoietin, oestrogen, or tes- tosterone). Reductions in hormone-​binding proteins (e.g. through protein losses in patients with nephrotic syndrome or on peritoneal dialysis) are common and may affect levels of free hormones cir- culating in the blood. Effects on vitamin D and erythropoietin are discussed later in this chapter. Total thyroxine (T4) and T3 (tri-​iodothyronine) may be low, with impaired peripheral deiodination of T4 to T3 and preferential di- version to inactive metabolites. However, patients are not clinically hypothyroid, and levels of thyroid-​stimulating hormone are gener- ally normal and can be used in the usual way as a diagnostic test for hypothyroidism. The kidney is the main site of growth hormone degradation and plasma levels of growth hormone are abnormally high in patients with renal failure because of this, and also because of alterations in hypothalamic–​pituitary control. It is not clear whether or not this has any clinical impact in adults with renal failure, but in children with renal failure and growth restriction the impaired production of insulin-​like growth factor 1 can be overcome by treatment with supraphysiological doses of recombinant growth hormone. Decreased insulin clearances seems to be balanced by increased peripheral resistance to the effects of insulin, hence patients with renal failure are not prone to hypoglycaemia or diabetes, but there is a reduced requirement for exogenous insulin in people with diabetes as renal function declines. Prolactin levels are high in renal failure and may contribute to gynaecomastia and sexual dysfunction in men and to infertility in women. Men with CKD may also have testosterone levels that are low to normal, with raised gonadotropins implying that testicular failure is the cause. The pituitary–​ovarian access is disturbed in ad- vanced renal failure, with many cycles anovulatory, causing oes- trogen deficiency.

21.6  Chronic kidney disease 4837 Middle molecules and the uraemic syndrome Many of the clinical manifestations that are seen with progressive decline in renal function are attributable to derangements in fluid balance, electrolyte handling, and endocrine function as previously described. However, these derangements do not provide an ad- equate explanation for all clinical features, and it is assumed that those which are unexplained are due to retention of substances and metabolites that the failing kidney is unable to excrete. The nature of these ‘uraemic toxins’ is uncertain. Accumulation of urea itself has modest effects, and failure to excrete a variety of small water-​ soluble compounds, protein-​bound compounds, and ‘middle mol- ecules’ (meaning those whose molecular weight is in the range 500–​12 000 Da) is held responsible, although incriminating spe- cific toxins has proved difficult. Among the small water-​soluble compounds, those thought to have a role in the uraemic syn- drome include various guanidine compounds, oxalate, phosphates, and polyamines; and among the protein-​bound compounds, p-​cresol and p-​cresylsulphate, homocysteine, various indoles, and furanproprionic acid. The best-​characterized example of a uraemic middle molecule is β2-​microglobulin, which is normally excreted by the kidneys, reaches a blood concentration 30 times higher than normal in dialysis patients, and accumulates as β2-​microglobulin amyloid in joints and bone. Many of the other middle molecules that have been incriminated have a proinflammatory effect, including a variety of advanced glycosylation end products that are probably at- tributable to increased concentrations of small carbonyl precursors in uraemia (and not to hyperglycaemia). Progression of chronic kidney disease Brenner advanced the concept that the adaptive changes (de- scribed in ‘Pathophysiology of chronic kidney disease’) aimed at increasing the excretory capacity of the kidney are maladaptive in the long run, causing deterioration of renal function mainly as a re- sult of glomerulosclerosis and tubulointerstitial fibrosis, the final result being endstage renal disease. The adaptive changes leading to single-​nephron hyperfiltration, which sustains whole-​kidney GFR in the short term, are mediated by a reduction of the resist- ance of the afferent preglomerular arterioles and an increase of the angiotensin-​dependent resistance of the postglomerular efferent ar- terioles, which combine to raise intraglomerular capillary pressure (glomerular hypertension). Over time, however, GFR will decrease, driven by several pathogenic mechanisms, including proteinuria and oxidative stress. This hypothesis led not only to the introduction of remarkably effective therapeutic and preventive approaches aimed at inter­ fering with progression (see later in this section), it also had re- percussions concerning the relation between GFR and metabolic abnormalities in CKD. The Mild and Moderate Kidney Disease (MMKD) study found an increase in the plasma concentration of asymmetric dimethyl l-​arginine (ADMA), even when whole-​ kidney GFR was still normal. The same was true for apolipoprotein abnormalities and sympathetic overactivity. A  plausible explan- ation for these findings, despite normal whole-​kidney GFR, is loss of nephrons with associated loss of metabolic capacity while whole-​kidney GFR is still normal because of single-​nephron hyperfiltration; hence, having a normal GFR does not exclude functional renal abnormalities. The rate of progression of CKD varies considerably depending on age, sex, type of underlying renal disease, genetics (family history of renal disease and cardiovascular disease), and many other fac- tors. For a given primary kidney disease, the risk of progression is lower in premenopausal women than in men. Such a sex difference is not found in children or postmenopausal women. This finding points to the role of sex hormones, which has also been documented in experimental studies. Testosterone aggravates renal disease, pos- sibly by raising blood pressure and activating the renin–​angiotensin system (RAS), whereas oestrogens ameliorate the evolution of renal disease. Some types of renal disease tend to progress slowly and others rapidly:  adult polycystic kidney disease, renal dysplasia, IgA-​ glomerulonephritis, and membranous glomerulonephritis usually progress slowly; rapid progression is anticipated in antiglomerular basement membrane glomerulonephritis and vasculitis; and inter- mediate rates of progression are typical in diabetic nephropathy. Ethnicity also determines the renal risk for currently poorly understood reasons: in Australian aboriginals, Maoris, American Indians, and particularly individuals of African descent, the fre- quency of CKD and the rate of its progression are substantially higher than in white people. This has been particularly well docu- mented in the immigrant population from south Asia living in the United Kingdom. A powerful predictor of the renal risk is a positive family history, not only of CKD but also of cardiovascular events in first-​degree relatives, which is associated with a substantial increase in the risk of developing progressive kidney disease. A history of pre-​eclampsia is associated with a dramatic increase in the risk of developing overt kidney disease later in life. Similarly, faulty prenatal programming in utero plays a role in the onset and progression of CKD. This is part and parcel of the Barker hypothesis, according to which interference with organogenesis in the prenatal period predisposes an individual at adult age to CKD, hypertension, and the metabolic syndrome. Although such nonmodifiable predictors are of some interest, more important clinically are modifiable predictors associated with a higher rate of progression (Box 21.6.2). It has been well documented that blood pressure has an adverse effect on progression of CKD, and this is true even for values below the former definition of hyperten- sion (>140/​90 mmHg). This finding has greatly increased the ability to interfere with progression, and the same is true for measures to interfere with the activation of the RAS to reduce proteinuria. Of major clinical importance is the fact that while renal function tends to deteriorate progressively in many (but not all) patients with CKD, almost exclusively this is true only in patients with albumin- uria/​proteinuria. The increased risk of cardiovascular events and cardiovascular death in patients with albuminuria/​proteinuria has already been emphasized (Table 21.6.1). Clinical presentation The various presentations of renal disease are discussed in Chapter 21.3, but in brief, the clinical presentation of CKD depends on the degree of renal dysfunction at the time that the condition is recognized.

section 21  Disorders of the kidney and urinary tract 4838 Asymptomatic patients At one extreme are patients with no symptoms whatsoever in whom an abnormal eGFR and/​or proteinuria are detected on routine examination, such as a medical examination for insurance purposes. Such patients may be shocked when hearing for the first time that they have lost what might be a substantial amount of their kidney function. Counselling and persuading them to comply with follow-​ up and to take medications occasionally proves difficult. Illnesses known to cause CKD, such as autosomal dominant polycystic kidney disease, other hereditary kidney diseases, or diabetic neph- ropathy, are generally easier to manage because these patients are more likely to understand the progressive nature of CKD and the benefit of treatment to prevent or slow progression. Patients with associated disease The presence of CKD may be diagnosed in many medical contexts in the absence of any symptoms pointing to the kidneys, for example, outpatient clinics for hypertension, diabetes, cardiac disorders, or urological diseases. Symptomatic presentation The diagnosis of CKD is made in relatively few patients on the basis of symptoms or signs pointing to kidney disease, such as nocturia, foaming of the urine, facial or pedal oedema, or haematuria. Symptoms or signs pointing to advanced CKD include (among others) lethargy, personality change, changes in mentation, loss of appetite, nausea (often in the morning), and vomiting. These may or may not be accompanied by evidence of hypervolaemia, such as dyspnoea on exertion or at rest, swollen ankles/​legs, elevated venous pressure, cardiomegaly, or basal crackles, and often only fluid re- moval can decide whether such manifestations are the result of fluid retention caused by renal failure, or by cardiac disease, and not in- frequently they are the result of both. The final stage of uraemia is heralded by bleeding tendency, pericarditis, obtundation, and coma. See Chapter 21.3 for further discussion. A relatively common clinical challenge to renal services is patients who present as an acute emergency requiring urgent RRT. This is not infrequently due to late referral, but it is not uncommon for there to be an acute deterioration of renal function in patients with pre-​existing CKD as a result of intercurrent illness or medical inter- ventions, for example, cardiac decompensation from myocardial infarction or arrhythmia, hypovolaemia, exposure to radiocontrast media, or prescription of particular drugs. Regarding the latter, common culprits would be the new prescription of ACE inhibitors or angiotensin receptor blockers, particularly in patients with ad- vanced CKD in the presence of hypovolaemia, heart failure, or other conditions activating the RAS. NSAIDs are also commonly incrim- inated, with other possibilities being nephrotoxic antibiotics (e.g. aminoglycosides) and cis-​platinum. When a patient arrives in hospital as an ‘acute uraemic emer- gency’, it is important to determine whether the problem is acute kidney injury (acute renal failure, which may be entirely revers- ible), acute-​on-​chronic kidney failure (when recovery to previous baseline renal function may be possible), or the endstage of pro- gressive chronic kidney failure (which by definition is not revers- ible). The only infallible method of determining whether a patient has CKD is to find documentation of previously reduced GFR in- dicated by past measurement of serum creatinine. When this is not available it is sometimes simply not possible to be sure of the situ- ation at the time of presentation, although ultrasonography with documentation of small kidneys is often of great help in indicating chronicity. Features that suggest the presence of chronic renal failure are shown in Box 21.6.3, and causes of acute deterioration of chronic renal failure are shown in Box 21.6.4. Clinical assessment Personal history When taking the personal history, it is important to ask about nocturia (which may be the first, although nonspecific, sign of renal disease), foaming of the urine, past or present periorbital or pedal oedema, episodes of macroscopic haematuria, and whether or not urinary abnormalities (proteinuria, haematuria) have been detected previously, for example, in medical examinations performed before military service or for occupational or insurance purposes. The in- formation that the patient was told that they had ‘a bit of protein/​ blood in the urine’ many years ago (and almost certainly ‘not to Box 21.6.2  Modifiable and nonmodifiable predictors of the rate of progression of CKD Modifiable predictors • Elevated (systolic) blood pressure (particularly during the night) • Activation of the RAS • Proteinuria • Smoking • Salt intake • Obesity/​metabolic syndrome • Protein intake? Nonmodifiable predictors • Age • Sex • History of pre-​eclampsia • Ethnicity • Genetics (family history—​renal and cardiovascular) • Type of renal disease • Prenatal programming (e.g. maternal hyperglycaemia, malnutrition, pre-​eclampsia, low birthweight) Box 21.6.3  Indications of chronic renal failure History More than 6 months of ill health, long-​standing hypertension, protein- uria, nocturia for more than 6 months, sexual dysfunction, abnormalities previously detected during routine medicals and/​or pregnancies, recur- rent illness during childhood. Examination Pallor, pigmentation, pruritus, brown nails, evidence of long-​standing hypertension; the patient often appears ‘well’ for their very abnormal biochemistry. Investigations Normochromic anaemia, small kidneys on ultrasound examination (except in adult polycystic kidney disease, myeloma, amyloid), renal osteodystrophy on radiography.

21.6  Chronic kidney disease 4839 worry about it’) clearly indicates long-​standing renal pathology in the context of a patient presenting with renal impairment. In women, information on proteinuria in pregnancy or pre-​ eclampsia is important. A history of pre-​eclampsia greatly increases the risk of CKD later in life, and pregnancy often leads to the first manifestation or aggravation of pre-​existing renal disease. In elderly men, a history of prostatic disease or related lower urinary tract symptoms (problems with bladder emptying, dribbling, etc.) should raise the suspicion of obstructive nephropathy. Also important when evaluating a patient with CKD are episodes of urinary tract infection before and after puberty, as well as a history of urolithiasis. A history of urinary stones may point to a urological cause of renal failure, and may also very occasionally be an indica- tion of hyperparathyroidism. In proteinuric patients with CKD of unknown origin, one should enquire for a history of chronic bacterial infection (e.g. bronchiec- tasis or osteomyelitis) and for a history of rheumatoid arthritis, all of which are potential causes of secondary amyloidosis. Particularly in older people with CKD of unknown origin, it is also important to ask about symptoms that might indicate multiple myeloma, which can cause renal impairment via a number of mechanisms (see Chapter 21.10.5). The patient should be asked about the use of potentially nephro- toxic drugs, such as NSAIDs, analgesics (if taken regularly in high dose for prolonged periods, particularly compound preparations or those containing phenacetin, which has now been banned in many countries), nephrotoxic antibiotics (e.g. aminoglycosides), antineoplastic agents (cis-​platinum), and herbal/​alternative/​homeo- pathic treatments (e.g. Chinese herbs; see Chapter 21.9.2). Covert drug intake, including laxatives and diuretics with or without sur- reptitious vomiting, may also cause CKD. Since many drugs are ex- creted via the kidney, it is also important to ask patients with CKD for a history of drug side effects. Women with CKD may have menorrhagia or (in advanced CKD) amenorrhoea, and men with CKD not infrequently have erectile failure/​impotence, but few will volunteer this information and it will only be discovered by the physician who asks directly. Symptoms of advanced renal failure (uraemia) With advancing renal failure to CKD stage 5, patients may develop anaemia and fluid retention manifested as breathlessness on exer- cise or even at rest, particularly at night-​time, and they may notice swelling of their ankles and legs. The first symptoms pointing to the uraemic syndrome are anorexia with attendant loss of body weight and nausea and vomiting, frequently in the morning when brushing the teeth. Further symptoms are superimposed if a patient enters the preterminal phase of uraemia, including severe dyspnoea as the combined result of metabolic acidosis and pulmonary congestion, pericarditic and pleuritic chest pains, bleeding tendency (bleeding mouth ulcers, gastrointestinal haemorrhage), numbness of the feet (polyneuropathy), and insomnia, headache, myoclonic jerks, and impairment of consciousness/​coma. Family history It is important to ask for a family history of renal disease, the most common causes of familial nephropathy being autosomal dominant polycystic kidney disease and reflux nephropathy; see Chapter 21.12 for further discussion. If the patient has a history of hypertension, then concomitant proteinuria or diabetes should be sought, because very often these will be undiagnosed. Patients with type 2 diabetes who have a family history of diabetic nephropathy are at higher risk of nephropathy themselves. A patient’s risk of progressive kidney disease is greater if a first-​ degree relative has had any kind of CKD, even if this was not caused by the same kidney disease as that in the patient, suggesting that hereditary mechanisms are involved in the genesis of progression. Furthermore, the renal risk is higher if a first-​degree relative has had essential hypertension or cardiovascular events. Physical examination Except in areas of the world with very poor access to medical services, or in individuals who are severely neglected, the physician will rarely see the desperate case of terminal uraemia with coma, blindness from retinopathy, pericardial rub from uraemic pericar- ditis, massive gastrointestinal ulceration and bleeding, and urea frost covering the face. Patients with CKD stage 5 who are typically seen in Western countries may be pale (anaemic), have severe hyper- tension, and have fluid retention manifested as peripheral oedema and crackles/​effusions in the lungs. As uraemia progresses, patients usually develop progressive hyperpigmentation of the skin, pruritus with excoriations and prurigo, xerosis, brown nails, and evidence of peripheral polyneuropathy. Box 21.6.4  Causes of acute deterioration in patients with chronic renal failure • Renal hypoperfusion:

—​ Dehydration—​diarrhoea, vomiting, excessive diuretics, inadequate fluid replacement (e.g. postsurgical)

—​ Cardiac failure

—​ Drugs—​especially ACE inhibitors, angiotensin receptor blockers, NSAIDs

—​ Systemic infection

—​ Renal vascular disease

—​ Pericardial tamponade (rare) • Obstruction and infection of the urinary tract:

—​ Benign prostatic hypertrophy

—​ Urinary stones

—​ Cancer—​particularly of prostate or bladder

—​ Clot in the ureter

—​ Papillary necrosis and sloughing—​to be considered in patients with diabetes, sickle cell disease, and analgesic nephropathy.

—​ Polycystic cysts (rare) • Metabolic and toxic:

—​ Hypercalcaemia

—​ Hyperuricaemia

—​ Contrast media—​especially in diabetes

—​ Drugs—​especially aminoglycosides • Progression/​relapse of underlying diseases:

—​ Various nephritides and autoimmune/​vasculitic conditions—​look for an active urinary sediment with proteinuria, haematuria, and cellular casts, and also for serological evidence of disease activity • Development of accelerated-​phase hypertension • Renal vein thrombosis—​usually in severely nephrotic patients • Pregnancy: • At the end of the pregnancy or after delivery (e.g. in patients with reflux nephropathy)

section 21  Disorders of the kidney and urinary tract 4840 Further signs are superimposed if a patient enters the preterminal phase of uraemia, including severe tachypnoea (before terminal cessation of breathing) with an acidotic sighing respiratory pat- tern and/​or widespread crackles of pulmonary oedema, jerking movements (metabolic asterixis/​flap/​twitching), pericarditic and/​ or pleuritic rubs, impairment of consciousness/​coma, red eyes, and evidence of bleeding (from mouth or rectum). In routine outpatient practice, all patients presenting with CKD require a thorough general physical examination with particular at- tention to the features described in Table 21.6.4. Rarely there will be manifestations of systemic or genetic disorders associated with renal disease (see Chapters 21.10.1–​21.10.10 and 21.12). Investigation Investigations required in the assessment of patients with CKD are shown in Table 21.6.5. See Chapter 21.4 for further discussion. Management to prevent progression
of chronic kidney disease In some patients, measures to conserve renal function may be spe- cific to the cause of renal impairment, for example, relief of ob- struction, cessation of nephrotoxic drugs (e.g. lithium, ciclosporin, or NSAIDs), relief of renal artery stenosis, and treatment of active autoimmune/​vasculitic disorders. For further details, see the rele- vant specific chapters. However, the mechanisms of progression de- scribed briefly earlier are common to all forms of CKD, and insight into them has provided effective strategies aimed at slowing or—​ when started early—​even halting progression of CKD. Since not all patients with primary kidney disease inevitably progress to endstage renal disease, it is important to identify factors predisposing to an adverse renal outcome in individual patients—​the main ones being high blood pressure (particularly at night-​time), proteinuria, and reduced baseline eGFR—​and to direct particular attention towards such cases. It is recommended that all patients with CKD stages 4 and 5 (also those with CKD stage 3 whose GFR is deteriorating rapidly—​ meaning by >5 ml/​min per 1.73 m2 per year—​or who have signifi- cant proteinuria/​haematuria), excepting those who are terminally ill or for whom it would otherwise be inappropriate, are referred to and managed by or in conjunction with a nephrologist. This is important because appropriate timely intervention can reduce the rate of progression and also because the results of eventual dialysis and/​or transplantation are better if the patient has been properly prepared (including blood pressure normalization, correction of anaemia, hepatitis B vaccination, creation of vascular access, and the search for a living kidney donor that might render pre-​emptive transplantation possible). Interventions to prevent progression of CKD should be initiated as early as possible, which justifies efforts to diagnose renal dis- ease sooner rather than later. The best evidence comes from studies of patients with diabetes. Controlled trials in advanced diabetic nephropathy achieved reduction of progression by no more than about 30%. By contrast, in diabetic patients with early nephrop- athy, mostly at the stage of microalbuminuria, the DETAIL study had achieved by its fifth year a rate of loss of GFR that was virtually indistinguishable from that seen with advancing age. Even if pro- gression is not completely halted, but only attenuated, the gain in years free of RRT is substantially greater if treatment is started early rather than late. Blood pressure control Although the adverse effects of high blood pressure on progres- sion of renal disease had been recognized for many years, the first solid documentation of the importance of achieved blood pressure Table 21.6.4  Features to look for on physical examination of patients with CKD System Feature Comment General Pallor Anaemia is a common feature of advanced CKD Pigmentation, scratch marks, brown nails Indicate long-​standing CKD Cardiovascular/​respiratory Blood pressure Hypertension is a common association (but uncommon cause) of CKD Elevated jugular venous pressure, enlarged heart, gallop rhythm, mitral regurgitant murmur, pulmonary crackles, peripheral oedema Manifestations of fluid overload caused by CKD and/​or cardiac failure associated with hypertension or ‘uraemia’ Aortic systolic murmur Valvular calcification is more common in CKD Peripheral pulses, vascular bruits Absence of pulses and/​or presence of bruits increase the likelihood of renovascular disease as the cause of CKD Abdominal Palpable kidneys Likely to indicate adult polycystic kidney disease in this context Palpable bladder, malignant-​feeling prostate on digital examination Consider urinary obstruction as cause of CKD Hernias Require repair if peritoneal dialysis otherwise preferred as RRT Neurological Peripheral neuropathy Indicates long-​standing CKD Proximal myopathy Indicates long-​standing CKD Rheumatological Arthritis Carpal tunnel syndrome Gout and pseudogout are associated with CKD Ocular fundi Features of hypertension CKD, chronic kidney disease; RRT, renal replacement therapy.

21.6  Chronic kidney disease 4841 Table 21.6.5  Investigations required in the assessment of patients with CKD Type of investigation/​test Comment All patients Urine Dipstick Screening for proteinuria, haematuria, glycosuria, nitrite, pyuria. Heavy proteinuria suggests glomerular disease Microscopy If abnormality on stick testing to detect bacteriuria, quantitate pyuria, look for cellular casts (indicative of renal inflammatory process) Albumin:creatinine ratio (ACR) To quantitate proteinuria Culture To detect urinary tract infection. For tuberculosis if clinically indicated (sterile pyuria) Blood Creatinine To quantitate level of renal function by eGFR Electrolytes Hyperkalaemia is the obvious concern Urea Elevated out of proportion to creatinine in dehydration and catabolism Glucose Exclusion of diabetes mellitus Lipids Assessment of cardiovascular risk Full blood count To detect anaemia Liver and bone profile Routine screen Cardiac assessment ECG Look for changes of ischaemia and/​or left ventricular hypertrophy. Changes in morphology due to hyperkalaemia indicate the level of risk of cardiac arrhythmia and dictate treatment (see Chapter 21.5) Chest radiograph Assessment of heart size and evidence of fluid overload (pulmonary oedema, pleural effusion) Echocardiogram To assess left ventricular function. To exclude pericardial effusion when clinically appropriate Tests for coronary heart disease—​exercise tolerance test, radionuclide stress test, coronary angiography If symptomatic. To assess risk of and fitness for renal transplantation Renal imaging Ultrasonography of urinary tract Expect to find two small and echogenic kidneys in CKD; exclude urinary obstruction; diagnose presence of renal cysts In selected patients to diagnose particular causes of CKD Urine Bence Jones proteinuria To detect myeloma when clinically appropriate Blood Serum protein electrophoresis or free light chains To detect myeloma when clinically appropriate Autoimmune/​vasculitis screen—​ANA, complement, ANCA, anti-​GBM, cryoglobulins To detect autoimmune (systemic lupus erythematosus) and vasculitic (granulomatosis with polyangiitis, microscopic polyangiitis) conditions, also Goodpasture’s disease and cryoglobulinaemia, when clinically relevant Renal imaging Plain abdominal film (KUB) To look for urinary stones and/​or renal calcification CT scan To determine cause of urinary obstruction Renal angiography (direct, CT or MR) If renal artery stenosis is likely DMSA/​MAG3 scan To detect renal scarring Renal biopsy To be performed only in cases where there is diagnostic doubt and there is a reasonable likelihood that the result will affect the management of the particular patient. Should not be done otherwise In patients with significantly impaired renal function (CKD stages 3B, 4, or 5) to look for complications of renal impairment and/​or guide management Blood PTH To diagnose hyperparathyroidism and monitor response to treatment Bicarbonate To detect acidosis and monitor response to treatment Uric acid In patients with gout associated with CKD Haematinics—​iron studies, vitamin B12, folate In patients with anaemia. Optimal response to erythropoietin (see later) requires plentiful iron stores (high normal/​high ferritin)

section 21  Disorders of the kidney and urinary tract 4842 on progression was provided only in 1989, when a study of patients of the Kaiser Permanente cohort in the United States of America who had normal baseline urinary findings found that even within the range of normotensive values the risk of reaching endstage renal disease increased progressively with progressively higher blood pressure values at baseline (more so in patients with than without diabetes). There is limited information on the optimal target blood pres- sure and the role of different antihypertensive agents. One recent high-​quality study in African American patients with hypertensive kidney disease found no benefit of intensive (mean 130/​78 mmHg) compared to standard (mean 141/​86 mmHg) blood pressure con- trol in preventing decline of renal function, excepting in those who had significant proteinuria. Nevertheless, the consensus remains that the lower the blood pressure, the better, as long as this can be achieved without unacceptable side effects. The 2013 guidelines of the European Society of Hypertension/​European Society of Cardiology on treatment of hypertension recommend ‘in patients with diabetic or non-​diabetic renal disease, systolic blood pressure should be lowered to less than 140 mmHg and when overt protein- uria is present values less than 130 mmHg may be pursued, pro- vided that changes in eGFR are monitored’. To achieve the blood pressure goal, combination therapy of several antihypertensive agents (including loop diuretics when the eGFR is <30 ml/​min per 1.73 m2) is usually required, with an ACE inhibitor or angio- tensin receptor blocker used whenever possible to reduce protein- uria (but a combination of these two classes of drug is no longer recommended). It obviously needs to be considered whether such aggressive blood pressure lowering is safe. No excess of cardiovascular events or of mortality has been reported in nondiabetic patients and patients without coronary disease, although in older people limited toler- ance and safety (orthostatic hypotension, falls) of intensive blood pressure lowering have to be taken into account. By contrast, higher mortality in patients with advanced diabetic nephropathy has been found with an achieved systolic blood pressure below 120 mmHg, and in nonrenal patients with coronary heart disease the rate of myo- cardial infarction has been reported to be increased if diastolic blood pressure is lowered to below 70 mm/​Hg, hence caution in pursuit of very low blood pressure targets is indicated in populations at high cardiovascular risk, including those with CKD. The most important predictor of progressive loss of renal func- tion is the systolic blood pressure, not the mean or the diastolic blood pressure. Of particular concern in renal patients is the ten- dency for an attenuated decrease of blood pressure—​or even a para- doxical increase—​at night-​time, recognition of which requires the use of ambulatory blood pressure measurements. Because of the complexity of blood pressure analysis and the limited accuracy of office blood pressure measurements, it is bad advice to stick only to fixed blood pressure targets—​particularly since almost all studies have shown that the proportion of renal patients reaching target blood pressure values is disappointingly low, despite the use of multidrug regimens. Selection of antihypertensive agents There is good evidence from experimental studies that activation of the RAS and of the sympathetic nervous system play a major causal role in the genesis of progression. There has been some controversy over whether the effect of antihypertensive agents interfering with the activity of the RAS is exclusively explained by lowering of blood pressure. Considering controlled interven- tion trials where similar blood pressure lowering was achieved with antihypertensive agents that did and did not block the RAS, it is obvious that a definite but limited contribution to the slowing of progression is achieved by RAS blockade. An example of the finding of such a trial is shown in Fig. 21.6.4. A head-​to-​head comparison, although somewhat underpow- ered, suggested that the effect of ACE inhibition and angiotensin re- ceptor blockade is comparable in magnitude with respect to halting progression of renal disease. The blockade of the RAS is effective and safe, if properly supervised, but the risk of hyperkalaemia has to be taken into consideration, which is caused most frequently by excessive potassium intake and prescription of other drugs interfering with potassium excretion (β-​blockers, potassium-​ sparing diuretics). Patients with CKD are at high cardiovascular risk and, aside from renal benefit, ACE inhibition (if tolerated) has been shown in some trials to reduce cardiovascular mortality more effectively in those with impaired renal function than in those with normal renal function. Reduction of proteinuria Proteinuria is not only a marker, but also an extremely important promoter of CKD progression, and it has therefore become an im- portant additional treatment target. In patients with primary renal disease, the higher the baseline proteinuria, the greater the subse- quent decline in GFR, and also the greater the risk of cardiovascular events. Even a very modest increase in proteinuria within the normal range is associated with increased mortality. A recent meta-​analysis of data collected over more than 700 000 patient years reported that compared with an ACR of 0.6 mg/​mmol (low normal range), an ACR of 1.1 mg/​mmol was associated with a mortality hazard ratio of 1.20, and an ACR of 3.4 mg/​mmol (upper limit of normal range for men) with a mortality hazard ratio of 1.63. Type of investigation/​test Comment Virology—​screen for hepatitis C, hepatitis B, HIV Relevant to RRT with dialysis or by transplantation Virology—​screen for CMV, HSV, HZV, EBV Relevant to RRT by transplantation Blood group Relevant to RRT by transplantation ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; anti-​GBM, antiglomerular basement membrane antibody; CKD, chronic kidney disease; CMV, cytomegalovirus; DMSA, dimercaptosuccinic acid; EBV, Epstein–​Barr virus; ECG, electrocardiogram; HSV, herpes simplex virus; HZV, herpes zoster virus; KUB, kidneys, ureter, and bladder; MAG3, mercaptoacetyltriglycine; PTH, parathyroid hormone; RRT, renal replacement therapy. Table 21.6.5  Continued

21.6  Chronic kidney disease 4843 Current guidelines recommend that proteinuria should be lowered as much as possible, preferably to less than 1 g/​24 h (roughly equivalent to an ACR <60 mg/​mmol or a protein:creatinine ratio <100 mg/​mmol). When this goal is not achieved, it is wise to check whether modifiable factors explain the limited efficacy of blood pres- sure lowering with RAS blockers, such as patient noncompliance, high sodium intake (which abrogates the antiproteinuric action of RAS blockade), high protein intake (which increases proteinuria), smoking, and poor glycaemic control in people with diabetes. If these factors have been excluded, there are two strategies. First, one can attempt dose escalation of the ACE inhibitor or angiotensin re- ceptor blocker above the dose licensed for blood pressure lowering. This strategy has been shown to be effective in slowing the progres- sion of CKD, with angiotensin receptor blockers often preferred in this situation because of their better side effect profile. Second, consider blockade of the mineralocorticoid receptor: aldosterone levels decrease immediately after the start of RAS blockade, but in many patients they subsequently rise again, a phenomenon known as ‘aldosterone escape’, which can be accompanied by failure to restrain proteinuria. Several studies have shown that, without further lowering of blood pressure, blockade of the mineralo- corticoid receptor by low doses of spironolactone (25 mg/​day) or eplerenone can prevent such relapse. There is, however, a danger of precipitating hyperkalaemia, a risk that is justifiable only in patients who have received and accept appropriate dietary education and agree to close follow-​up. Giving a combination of an ACE inhibi- tors and an angiotensin receptor blocker is no longer recommended following studies that demonstrated risks including worsening of kidney function. Other interventions Dietary protein restriction Reducing dietary protein intake may protect against progression of CKD by haemodynamically mediated reduction in intraglomerular pressure, by changes in cytokine profile, and/​or by changes in matrix synthesis in the renal interstitium. It has been shown to be effective in attenuating progression of renal failure in several well-​conducted animal studies. In clinical trials, numerous uncon- trolled studies have also shown an apparently beneficial effect of low dietary protein intake on CKD progression, but the only major controlled prospective trial (the MDRD study) failed to docu- ment a significant effect. Although subsequent post hoc analyses were consistent with some benefit from dietary protein restriction, its magnitude does not compare with what can be achieved by lowering blood pressure and RAS blockade, and it is important to recognize that drastic lowering of protein intake carries the risk of malnutrition. In routine practice, most nephrologists do no more than to advise against high-​protein diets, recommending limita- tion of protein (but not energy) intake only in CKD patients who have a gross excess of protein intake, for example, more than 2 g/​kg body weight per day, documented by urinary urea measurements. Those of a more interventionist persuasion may recommend a daily protein intake of 0.8 to 1 g/​kg per day (and some even 0.7 g/​ kg per day), with careful monitoring to ensure that protein mal- nutrition does not develop and that there is an adequate intake of calories. Other dietary and lifestyle measures As shown in Box 21.6.2, other modifiable progression promoters are smoking, high salt intake, obesity, and the metabolic syn- drome. In diabetic patients, the risk of onset of microalbuminuria, and the progression from microalbuminuria to overt diabetic nephropathy, is higher in smokers, as is the rate of loss of GFR in smokers with advanced diabetic nephropathy. At least in dia- betic patients, some evidence suggests that cessation of smoking slows the progression of CKD. Thus, in addition to the aim of re- ducing cardiovascular risk, this finding is another strong reason for patients with renal disease to stop smoking. Recent evidence even indicates that passive smoking increases albuminuria and is injurious to the kidney. There is scant evidence in humans, in contrast to convincing evi- dence in animals, for an adverse effect of high salt intake on the progression of primary renal diseases. It is, however, important to recognize that high salt intake militates against control of hyper- tension and interferes with the antiproteinuric action of ACE inhibition, hence it seems sensible—​in line with general recom- mendations accepted for the treatment of hypertension—​to advise a reduction in sodium intake from the usual (in developed countries) 150 to 200 mmol/​day to 100 mmol/​day (6 g of sodium chloride). In practice, this means the patient reducing the amount of processed food that they consume. A further risk factor for the onset and promotion of CKD progres- sion is visceral obesity and the metabolic syndrome. As shown in Fig. 21.6.5, the worse the metabolic syndrome, the greater the preva- lence of CKD and of microalbuminuria in the general (American) population, and the degree of obesity at which renal risk increases Placebo Treatment < 134 < 149 134–140 Quartile of ave systolic BP 141–149 Irbesartan Amlodipine Relative risk of renal endpoint 0.600 1.200 1.800 Fig. 21.6.4  The contribution of achieved blood pressure (BP) lowering and renin–​angiotensin system (RAS) inhibition on the relative risk of reaching a renal endpoint (doubling of serum creatinine or endstage renal disease). At any given blood pressure level, patients on irbesartan (an angiotensin receptor blocker) had a lower renal risk than those on amlodipine (which does not block the RAS). Reproduced with permission from Pohl MA, et al. (2005). Independent and additive impact of blood pressure control and angiotensin-​II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am Soc Nephrol, 16, 3027–​37. Copyright © 2005 American Society of Nephrology.

section 21  Disorders of the kidney and urinary tract 4844 is surprisingly low (Fig. 21.6.6). Overweight patients with early CKD should therefore try to reduce their body weight, since this has proven to be effective in several studies. However, in more ad- vanced stages of CKD—​namely at an eGFR of approximately 30 to 50 ml/​min—​the situation is more complex, with higher body weight (even in the range of morbid obesity) lowering the risk of death for unknown reasons. Other pharmacological interventions Other interventions in addition to ACE inhibition or angiotensin receptor blockade to attenuate CKD progression that are under evaluation include renin inhibitors, endothelin I  blockers, glyco- saminoglycans (increasing the electronegativity of the charge of the glomerular basement membrane), erythropoietin (effective in experimental studies), NSAIDs (potentially dangerous because of overshooting reduction of GFR), vitamin D analogues, and statins. Cochrane meta-​analysis data suggests the use of statins in CKD may reduce the risk of death and cardiovascular events in nondialysis pa- tients. Evidence in support of statin therapy delaying progression of CKD is not yet convincing although recent data suggest high-​ intensity statins may have benefit. The latest KDIGO guidelines on lipid management now recommend use of statins in all nondialysis patients with CKD over the age of 50, and treatment for younger patients with coronary disease, diabetes, previous stroke, or risk of cardiovascular events greater than 10% over 10 years. Medical management of the consequences of chronic kidney disease Water, electrolytes, acidosis, and nutrition Only patients with oliguric endstage renal failure need to restrict their fluid intake precisely, when the usual recommendation is that the patient’s daily intake should be a volume equal to their daily urinary output plus 500 ml for insensible losses. This is difficult to adhere to unless sodium intake is carefully discussed and min- imized, and a diet with ‘no added salt’ is essential. However, most   Prevalence CKD (%) Prevalence Microalbuminuria (%) Metabolic syndrome risk factors Metabolic syndrome risk factors 0 0 5 10 20 15 2 4 6 8 10 0 1 2 3 4 5 0 1 2 3 4 5 Fig. 21.6.5  The prevalence of CKD (GFR <60 ml/​min per 1.73 m2) and of microalbuminuria (ACR 30–​300 mg/​g, approximately 3–​30 mg/​mmol) in relation to the number of metabolic risk factors that a patient has. The five metabolic risk factors considered were (1) waist circumference greater than 102 cm (men); (2) fasting glucose greater than 110 mg/​dl (>6.1 mmol/​litre); (3) high-​density lipoprotein cholesterol (HDL-​C) less than 40 mg/​dl (<1.03 mmol/​litre); (4) triglycerides greater than 140 mg/​dl (>1.58  mmol/​litre); and (5) blood pressure greater than 130/​80 mmHg. Reproduced with permission from Chen et al. Ann Int Med 2004; 140; 167–​74. http://​www.annals.org/​content/​vol140/​issue3/​ Copyright © 2004, The American College of Physicians. BMI (kg/m2) <18.5

40.0 35.0–39.9 18.5–24.9 25.0–29.9 RR 0.44 1.00 1.87 3.57 6.12 7.07 Adjusted relative risk ESRD 0.1 1.0 10.0 30.0–34.9 Fig. 21.6.6  Body mass index (BMI) is an independent predictor of endstage renal disease in the United States of America. Reproduced with permission from Hsu et al. Ann Int Med 2006; 144: 21–​28 http://​www.annals.org/​cgi/​content/​ full/​144/​1/​21 Copyright © 2006, The American College of Physicians.

21.6  Chronic kidney disease 4845 patients with CKD pass a normal volume of urine, but they need to avoid binge drinking because their ability to excrete free water is impaired. They should be aware that they will need to drink more if they have other significant fluid losses, for example, vomiting, diarrhoea, or excessive sweating, because their kidneys will not be able to produce appropriately concentrated urine. They should be informed of the importance of temporarily stopping diuretics and possibly antihypertensive medication if increased oral intake is not possible during intercurrent illness to minimize the likelihood of developing acute (on chronic) kidney injury. Dietary sodium restriction (100 mmol/​day) is important to min- imize thirst and fluid retention in patients with CKD, with no salt added to food after cooking. Reduction of sodium intake to around 60 mmol/​day can be helpful in patients with fluid retention in the context of advanced CKD, but many patients find this unacceptable. Using loop diuretics to encourage sodium excretion is more effective in most cases, but excessive salt intake will negate the diuretic effect. Hyperkalaemia is most commonly seen in the context of renal failure (acute or chronic) and can be life-​threatening. Emergency management is discussed in Chapter 21.5, but an important aim of medical management of patients with CKD is to avoid such prob- lems. Monitoring of the serum potassium must be routine whenever the creatinine is checked, and especially after introduction of drugs that are known to cause hyperkalaemia (including ACE inhibitors, angiotensin receptor blockers, and potassium-​sparing diuretics). The patient should be offered dietary advice (see Chapter 21.2.2) if serum potassium is found to be in the range 5.5 to 6.5 mmol/​litre, and the measurement should be repeated a few days later (unless they are known to have a stable potassium in this range). Dietary advice combined with stopping of all medications that might pre- cipitate hyperkalaemia is appropriate if potassium is in the range 6.5 to 7 mmol/​litre, again with repeated measurement a few days later. If the potassium is above 7 mmol/​litre, the patient should be reviewed in hospital, with checking of the ECG for hyperkalaemic mani- festations being an immediate priority, followed by consideration of possible precipitants, which include dietary indiscretion (fruit, chocolate, coffee) and gastrointestinal haemorrhage as well as more obvious intercurrent illness. Chronic acidosis with serum bicarbonate in the range 12 to 20 mmol/​litre is most common in patients with interstitial renal dis- ease and will aggravate hyperkalaemia, inhibit protein anabolism, and accelerate calcium and phosphate loss from bone. Treatment with alkali to maintain the serum bicarbonate above 22 mmol/​litre is recommended. Sodium bicarbonate (1.0–​2.0 g twice day) is the first-​line treatment, with sodium citrate an alternative for those who cannot tolerate bicarbonate (usually because of abdominal bloating) as long as they are not taking aluminium-​containing antacids (cit- rate enhances aluminium absorption). Malnutrition is common in advanced chronic renal failure because of anorexia, impaired gut function, and acidosis. The most practical ways of detecting its insidious development is by serial monitoring of body weight and serum albumin concentration. Standard advice is that patients with CKD should have a diet containing about 30 to 35 kcal/​kg body weight per day. Dietary supplements may be helpful in achieving this, but they are not a cure for the problem: a patient that is becoming malnourished probably needs to start RRT sooner rather than later. Mineral and bone disorder The mineral and bone disorder (MBD) associated with CKD is a major cause of disability in patients with endstage renal failure (Box 21.6.5). The term was coined to describe the threefold elements of biochemical, vascular, and skeletal abnormalities which develop with progressive CKD. The term renal osteodystrophy refers solely to the skeletal abnormalities, but it has become clear that the bio- chemical, skeletal, and vascular problems are all intimately linked. This is mainly, but not exclusively, the consequence of abnormalities in the metabolism of calcium, phosphorus, PTH, and vitamin D, and also the more recently discovered phosphaturic hormone FGF23, produced by osteocytes in bone. The biochemical and metabolic abnormalities that make up CKD-​MBD are complex and incompletely understood, but begin to develop as early as CKD stage 3. The initial sequence of events is unclear but involves progressive reduction in the kidneys’ ability to excrete phosphate, to produce the active form of vitamin D3 (1,25-​ (OH)2D3 or calcitriol), to maintain normal calcium levels, and therefore to prevent PTH rising. Consequently, secondary hyper- parathyroidism is common in unmanaged CKD patients, but now that oral vitamin D replacement, phosphate binders, and calcium supplements are widely prescribed to control parathyroid over- activity, patients with advanced stages of CKD are now more likely to develop relative hypoparathyroidism. This results in low bone turnover (adynamic bone on iliac crest biopsy) in which the skeleton is unable to absorb excess calcium and phosphate resulting in epi- sodes of hypercalcaemia, hyperphosphataemia, and an association with increased likelihood of vascular calcification for reasons which are uncertain. A degree of controlled secondary hyperparathyroidism appears to be required to maintain normal bone turnover, whilst trying to pre- vent PTH rising beyond nine times the upper limit of normal (ULN), which is associated with an increased risk of arterial and valvular calcification, and increased cardiovascular and all-​cause mor- tality. Current guidelines (based on very limited evidence) suggest maintaining serum PTH in the range between two and nine times the ULN, which is a difficult task attempted by control of serum cal- cium, phosphate, and use of oral vitamin D supplements, with use of an oral calcimimetic (cinacalcet) if PTH appears to be rising uncon- trollably. This drug blocks production of PTH by mimicking a state of extreme hypercalcaemia at the calcium-​sensing receptor (CaR) on parathyroid cells. Box 21.6.5  Definition of CKD–​MBD A systemic disorder of mineral and bone metabolism due to CKD mani- fested by either one or a combination of the following: • Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism • Abnormalities in bone turnover, mineralization, volume, linear growth, or strength • Vascular or other soft-​tissue calcification Definition of renal osteodystrophy • Renal osteodystrophy is an alteration of bone morphology in patients with CKD • It is one measure of the skeletal component of the systemic disorder of CKD–​MBD that is quantifiable by histomorphometry of bone biopsy.

section 21  Disorders of the kidney and urinary tract 4846 Pathogenesis Phosphate excess In the early stages of CKD, the plasma phosphate concentration re- mains normal or may be even low, which is achieved at the price of increased fractional clearance of phosphate. Hyperphosphataemia begins to develop once the GFR has decreased to between 60 and 30 ml/​min per 1.73 m2 (CKD stage 3). Hyperphosphataemia ag- gravates secondary hyperparathyroidism by indirect mechanisms, such as inhibition of the synthesis of the active vitamin D metabolite 1,25 dihydroxyvitamin D3 (1,25-​(OH)2D3 or calcitriol) in tubular epithelial cells, and possibly also by inducing a tendency for hypo- calcaemia. Phosphate also directly stimulates PTH synthesis and se- cretion as well as parathyroid cell proliferation, independent of low serum 1,25-​(OH)2D3 and hypocalcaemia. Increased PTH secretion reduces tubular phosphate reabsorption and therefore increases urinary phosphate excretion. In parallel, plasma FGF23 increases as it attempts to increase phosphate excretion, but as renal impairment progresses, this eventually becomes an impossible task because the feedback loop is broken, so that FGF23 and PTH rise uncontrollably. The relative roles of PTH and FGF23 in the control of phosphate re- absorption are currently unclear. 1,25-​dihydroxyvitamin D3 deficiency The hepatic vitamin D metabolite, 25-​hydroxyvitamin D3 (25-​(OH) D3 or cholecalciferol), is further hydroxylated, mainly in renal tubular epithelial cells, to the most active vitamin D metabolite, 1,25-​dihydroxyvitamin D3 (1,25-​(OH)2D3 or calcitriol), which acts as a circulating hormone (apart from paracrine actions of locally synthesized 1,25-​dihydroxyvitamin D3 in tissues such as activated macrophages, vascular cells, and others). Its synthesis is stimulated by PTH but inhibited by phosphate and FGF23. Even in early stages of CKD there is a tendency for 1,25-​dihydroxyvitamin D3 concen- tration to decrease, although this is counteracted to some extent by simultaneous increases in PTH. Nevertheless, average concentra- tion of 1,25-​dihydroxyvitamin D3 tends to fall progressively, unless treated, as CKD advances (Fig. 21.6.7). The renal 1α-​hydroxylase reaction is normally substrate inde- pendent, but with progression of CKD it becomes increasingly dependent on the availability of the substrate 25-​hydroxyvitamin D3, with deficiency of this form of vitamin D further aggravating the impairment of synthesis of 1,25-​dihydroxyvitamin D3. For this reason some renal units prescribe weekly oral 25-​hydroxyvitamin D3 supplements (cholecalciferol) routinely to all their CKD stage 5 and stage 5d patients. 1,25-​dihydroxyvitamin D3 increases calcium (and phosphate) uptake from the gastrointestinal tract and reduces calcium loss in urine by increasing renal tubular calcium reabsorption, both effects raising serum calcium levels. In times of dietary calcium deficiency it can also stimulate calcium release from bone to correct hypocal- caemia. In patients with heavy proteinuria or nephrotic syndrome, circulating vitamin D metabolites bound to vitamin D-​binding pro- tein may be lost in the urine, so that deficiency of vitamin D me- tabolites, such as 25-​hydroxyvitamin D3 and 1,25-​dihydroxyvitamin D3, may ensue. As also shown in Fig. 21.6.7, average serum levels of PTH increase progressively as average serum 1,25-​dihydroxyvitamin D3 levels de- crease with decreasing GFR in patients with various stages of CKD. Hypocalcaemia On average, plasma (total and ionized) calcium concentrations are maintained in the normal range until CKD stage 5. Nevertheless, in the untreated state there is a tendency towards hypocalcaemia, mainly because of reduced active intestinal calcium absorption as a result of insufficient active vitamin D generation and diminished release of calcium (skeletal resistance) in response to PTH and 1,25-​dihydroxyvitamin D3. Skeletal resistance to normal serum levels of PTH is not under- stood at all, but may well play an important role in the pathogen- esis of secondary hyperparathyroidism, with another mechanism being impaired inhibition of the parathyroid gland, which senses this calcium levels via the CaR, expression of which is decreased GFR(ml/min) 60–90 20–40 Normal 40–60 GFR(ml/min) 60–90 20–40 Normal 40–60 60 50 40 30 20 10 (a) (b) 70 80 1,25 (OH)2D3 (ng/L) 60 50 40 30 20 10 1-84 iPTH (pmol/l) Fig. 21.6.7  1,25-​(OH)2vitamin D3 (a) and intact plasma parathyroid hormone (b) values as a function of glomerular filtration rate (GFR) in patients with various stages of CKD. Reproduced with permission from Reichel et al. (1991). Calcium metabolism in early chronic renal failure: implications for the pathogenesis of hyperparathyroidism. NDT, 6, 162–​9. Copyright © 1991, Oxford University Press.

21.6  Chronic kidney disease 4847 in parathyroid tissue in CKD-​MBD. Some reports have showed abnormal Ca2+ sensing even in early stages of CKD. CaR down-​ regulation in the parathyroid gland can be reversed by a low phos- phate diet, calcimimetics, and other compounds. Types of bone lesions (renal osteodystrophy) in CKD The bone lesions discussed in the following sections, collectively known under the term renal osteodystrophy, are found in the skel- eton of patients with CKD, in isolation or often in combination (Box 21.6.6). They are the result of the variable effect of PTH on uraemic bone, and in particular on the two main types of bone cells—​osteoblasts and osteoclasts. Osteoblasts are responsible for deposition of bone matrix, which is then calcified under the influ- ence of vitamin D3. During this process, some osteoblasts become incorporated into the calcified matrix within lacunae, and become osteocytes able to produce FGF23. Osteoclasts are multinucleate giant cells which are able to resorb mineralized bone, thereby starting a remodelling process. Severe hyperparathyroidism This is characterized histologically by an enormous increase in both osteoclastic bone resorption and osteoblastic bone apposition rates with (1) intense and disorganized remodelling of bone trabeculae in the spongiosa, and (2) uncontrolled resorption and tunnelization of cortical and cancellous bone by groups of osteoclasts, with or without deposition of fibrous tissue (endosteal fibrosis) (Fig. 21.6.8). The de- position of disorganized fibrous tissue gave rise to the descriptive name of osteitis fibrosa, but in reality there is no inflammatory pro- cess at work, just excessive stimulation of bone turnover by very high levels of PTH. The end result of this process is significant weakening of the bone’s mechanical strength. Typical radiological appearances are shown in Fig. 21.6.9, but it should be noted that it is uncommon to see such extreme changes since the introduction of accurate PTH monitoring. Osteomalacia Osteomalacia is characterized by a disparity between the rate of bone matrix synthesis and bone matrix mineralization, leading to widening of the seam of unmineralized bone matrix (osteoid), usually associated with signs of diminished numbers and activities of cells at the bone surface. Pure osteomalacia is rarely seen now- adays: 30 years ago it was mainly due to aluminium intoxication, and before that to overt vitamin D (cholecalciferol) deficiency. Mixed lesions In many patients with advanced stages of CKD, a combination of os- teitis fibrosa and osteomalacia is present, which is commonly called mixed lesions or mixed renal osteodystrophy. This is the commonest lesion found in recent series of bone biopsies, present in up to 50% of prevalent dialysis patients. Adynamic bone In patients with low or normal serum intact PTH concentrations (less than twice the ULN), the number and activity of cells on the bone surface is strikingly reduced, as is bone turnover. This condi- tion is most common in patients with CKD due to diabetes, those with poor nutritional status, and those who have been overtreated with active vitamin D and/​or calcium-​containing phosphate binders. Box 21.6.6  Bone lesions in patients with CKD Bone lesions that may be found either in isolation or in combination • High turnover Severe hyperparathyroidism (PTH usually > 15 × ULN) Moderate hyperparathyroidism (PTH usually 2–​9 × ULN) • Normal turnover Relatively uncommon in CKD stage 5 and stage 5d patients • Mixed lesions High and low turnover lesions evident in same biopsy • Low turnover Adynamic bone, oversuppression of PTH with
calcium/​vitamin D3 Osteomalacia, uncommon since advent of oral vitamin D3 Further pathologies that must be considered in atypical cases • β2-​Microglobulin-​related amyloidosis • Sequelae of preceding corticosteroid therapy—​fractures, femoral osteonecrosis • Osteopenia and osteoporosis, particularly in postmenopausal patients • Reflex sympathetic dystrophy • Bony problems caused by primary disease leading to CKD (e.g. oxalosis) (b) (a) Fig. 21.6.8  Light microscopic images of severe secondary hyperparathyroidism in a patient with CKD stage 5 (transiliac bone biopsy, Masson trichrome stain). (a) Increased osteoclastic bone resorption (arrows) and osteoblastic bone apposition with deposition of fibrous tissue (endosteal fibrosis). Widened osteoid seams (between large arrow heads). (b) Greatly enhanced mineralization activity, as evidenced by double fluorescent tetracycline bands (tetracycline stain). Courtesy of ALM de Francisco MD.

section 21  Disorders of the kidney and urinary tract 4848 It predisposes to hypercalcaemia, hyperphosphataemia, and soft tissue calcification because the capacity of the skeleton to sequester calcium and phosphate is reduced because most bone turnover has ceased. There is some evidence that adynamic bone may contribute to skeletal fractures in patients on dialysis through accumulation of unrepaired microfractures, but it is not known whether there are more far-​reaching clinical implications. Although often referred to as adynamic bone ‘disease’ there is no reason for this lesion to be considered in this way. Osteopenia and osteoporosis Diminished bone mass is possibly more common in patients with CKD stages 4, 5, and 5d than in the general population, and frac- ture rates per 1000 patient years are around four times higher. Furthermore, death rates in the days following a major fracture are at least three times higher for such patients. Contributory factors are underlying renal osteodystrophy, a history of treatment with ster- oids, and (premature) menopause. It is not known whether the risk is aggravated by smoking and low-​calcium diets, or whether it can be prevented by substitution of oestrogens/​gestagens or selective oes- trogen receptor modulation. In CKD stage 3, osteoporosis can be treated in the same way as the general population, including bisphosphonates where neces- sary. However, in CKD stages 5 and 5d it is important to consider the possibility of underlying renal osteodystrophy. In particular, the combination of osteoporosis and adynamic bone could result in bisphosphonates making matters worse, by reducing bone turnover to zero and preventing any improvement. Bisphosphonates prob- ably remain within such bone for many years. Bone biopsy is re- quired before commencing any treatment if there is doubt about the underlying renal osteodystrophy. In CKD stage 4, there are so few published data that treatment re- commendations are not possible, but anecdotal reports of treatment with denosumab are published. Other bone-​related pathologies In patients with CKD, several bone pathologies unrelated to calcium metabolism may coexist with CKD-​MBD (Box 21.6.5). Specifically, dialysis-​associated amyloidosis with preferential osteoarticular involvement, called β2-​microglobulin-​related amyloidosis, must be considered in the differential diagnosis of bone pain and osteoarticular destruction. Symptoms and signs MBD in CKD is usually asymptomatic. Bone pain is not common, even in advanced osteitis fibrosa, although bones subjected to mech- anical stress (spine, calcaneus, foot) may be painful. While fractures are uncommon, skeletal deformity, facial leontiasis, and avulsion of the patella may occur. By contrast, osteomalacia, particularly that secondary to aluminium intoxication, may be very painful, espe- cially when Looser’s zones (fatigue fractures) are present. Again, it is important to exclude alternative causes of bone pain, particularly myeloma and metastases (Box 21.6.7). Severe extraosseous calcifications (Figs. 21.6.9–​21.6.11), specif- ically periarticular, bursal, and visceral calcifications, are usually the consequence of severe hyperphosphataemia and high-​normal serum calcium, with either very high or low serum PTH concentra- tions. Tumoural tissue calcification is often triggered by trauma with haematoma formation and favoured by low bone turnover, which diminishes the capacity of the bone to sequester calcium and phos- phate from the extracellular space. Slowly progressing arterial and cardiac valvular calcifications may be associated with clinical evidence of cardiovascular disease, indeed cardiovascular mortality in dialysis patients is strongly pre- dicted by the presence of coronary artery calcification detected by cardiac CT scanning. (b) (a) Fig. 21.6.9  Radiographs of the hand. (a) Reduced mineral density as well as fluffy and mottled texture of the bones. Note (1) subperiosteal resorption zones at the radial side of the middle phalanges; (2) erosion cavities at the periosteal surface with overlying areas of calcification, so-​called periosteal neostosis; (3) longitudinal striation of cortical bone (corresponding to enlarged Haversian channels); (4) thinning of cortical bone by endosteal bone resorption; (5) loss of the terminal lamella of the terminal phalanx; and (6) vascular calcification above the first digit and along the side of the radius. (b) A detail of the second digit, the terminal phalanx of which has collapsed such that the patient had ‘pseudo-​clubbing’. Box 21.6.7  Differential diagnosis of bone pain in patients with advanced CKD or on dialysis Mineral and bone disorders related to CKD • Severe hyperparathyroidism—​pain relatively rare • Osteomalacia—​secondary to vitamin D deficiency, or exceptionally aluminium accumulation • β2-​Amyloidosis Bone pathologies not directly caused by CKD • Skeletal metastases, myeloma • Osteomyelitis, mostly spondylodiscitis—​may be related to infected vascular access • Neuromelic pain after creation of arteriovenous fistula • Bone infarction, osteonecrosis—​related to corticosteroid treatment, sickle cell anaemia • Osteopenia-​associated infarctions and fractures

21.6  Chronic kidney disease 4849 Calciphylaxis, more correctly called calcific uraemic arteriolopathy, is a rare medical emergency characterized by is- chaemic eschars of the skin secondary to calcification of cuta- neous arterial vessels. Predisposing factors, apart from secondary hyperparathyroidism, include diabetes, obesity, female sex, and (probably) treatment with warfarin. It can produce gangrene and may be fatal in up to 40% of cases. It may respond to tight control of serum phosphate levels with a noncalcium-​containing phos- phate binder, and parathyroidectomy (or cinacalcet treatment) if serum PTH levels are elevated. Biochemical abnormalities While patients with advanced stages of CKD left untreated usu- ally have hypocalcaemia and hyperphosphataemia, patients with advanced secondary hyperparathyroidism are characterized by hypercalcaemia and hyperphosphataemia associated with an in- crease in serum total alkaline phosphatase and its bone-​specific isoenzyme. The findings on serum biochemistry in patients with CKD-​MBD are shown in Table 21.6.6, with the findings in the two main contrasting forms of MBD compared in Table 21.6.7. In pa- tients with hypercalcaemia, it is important to consider causes other than secondary hyperparathyroidism which necessitate specific treatment, as listed in Box 21.6.8. Prophylaxis and management of secondary hyperparathyroidism Secondary hyperparathyroidism is the combined result of failing ex- cretory function of the kidney (leading to phosphate retention) and failing endocrine function of the kidney (leading to calcitriol de- ficiency). Appropriate management requires prevention (whenever possible) and treatment of both abnormalities. Approach to serum phosphate control It is usually recommended that phosphate-​lowering interventions should begin once plasma phosphate concentrations exceed the upper limit of the normal range, that is, 1.45 mmol/​litre. This is generally the case when GFR has decreased to less than 30 ml/​min per 1.73 m2 and persists even when patients with CKD are on dia- lysis, which cannot (on a conventional 3 × 4 h weekly haemodialysis regimen, or by peritoneal dialysis) clear the phosphate consumed in a standard Western diet (50–​100 mmol/​day, of which 50–​70% is absorbed). However, slow continuous therapies (e.g. peritoneal dialysis) will clear on average around 30% more than conventional haemodialysis. Phosphate is present in virtually all foods, hence reduction of dietary intake is difficult without incurring the risk of malnutrition, especially in the elderly. Patients should be reviewed by a renal diet- ician and may need to avoid food items with very high phosphate content (e.g. some dairy products) and those to which phosphate is added, such as sausages and phosphate-​rich soft drinks. A protein-​ restricted diet will reduce phosphate intake, but the merit or other- wise of protein restriction is debatable (see previous discussion). However, given that sufficient dietary restriction of phosphate is usually not feasible, patients with advanced CKD remain in positive phosphate balance unless oral phosphate binders are administered. All oral phosphate binders trap phosphate in the gastric and small intestinal lumen by forming insoluble complexes, hence they must be taken at meal times, after which the phosphate concen- tration in the gut is highest. The agents most commonly used in Europe are calcium carbonate and calcium acetate, with magne- sium carbonate sometimes used if total calcium intake needs to be reduced. Although very effective in controlling serum phos- phate, the prescription of aluminium-​containing compounds has been abandoned by almost all nephrologists because of the risk of aluminium intoxication, except for short-​term use. However, calcium-​containing phosphate binders cause positive calcium balance and perhaps promote vascular calcification, although this remains controversial. Over the past decade, the calcium-​free and Fig. 21.6.10  Calcification of the popliteal artery in a patient with diabetes, CKD, and severe secondary hyperparathyroidism. Fig. 21.6.11  Tumoural calcification around the left shoulder in a chronic haemodialysis patient with severe low-​turnover bone disease.

section 21  Disorders of the kidney and urinary tract 4850 aluminium-​free phosphate binders sevelamer (an anion-​exchange resin) and lanthanum carbonate have been introduced into clinical practice. These allow similar control of plasma phosphate, while avoiding calcium and aluminium overload. Use of these binders may be associated with reduced progression of vascular calcifica- tion in animal models and a few small randomized trials. However, no randomized trial has shown that selecting a particular phos- phate binder improves any clinically relevant outcome, and the more important question remains—​does controlling phosphate to any specific target result in improved patient outcomes? If hyperphosphataemia does not respond to medical intervention, then issues to consider include nonadherence to prescribed binders or dietary measures, increased phosphate release from the skeleton (e.g. in severe hyperparathyroidism), stimulation of intestinal phos- phate absorption by excessive amounts of active vitamin D sterols, and (in patients on RRT) inadequate dialysis. Approach to serum calcium control The target range for serum total calcium (corrected for albumin) is 2.20 to 2.60 mmol/​litre (8.8–​10.4 mg/​litre). If the corrected total serum calcium level exceeds 2.60 mmol/​litre (10.4 mg/​litre), then therapies that cause a rise in serum calcium should be adjusted and other potential causes of hypercalcaemia should be considered, in particular an inappropriately high dialysate calcium concentration and immobilization (Box 21.6.8). Reversal of  deficiency of  native vitamin D3  Deficiency of the parent compound vitamin D3 (cholecalciferol) is common among patients with CKD stages 3, 4, 5, and 5d as a result of al- tered lifestyle, with insufficient sun exposure, dark skin, and loss of protein-​bound vitamin D (metabolites) into proteinuric urine or peritoneal dialysis fluid. Vitamin D deficiency can be diagnosed using the same criteria as in the general population, when plasma 25-​hydroxyvitamin D3 concentrations are less than 30 nmol/​litre (12 ng/​ml), and vitamin D insufficiency when they are between 30 and 50 nmol/​litre (12–​20 ng/​ml). However, current practice in patients with CKD is hindered by uncertainties regarding the Table 21.6.6  Serum biochemistry in the evaluation of CKD-​MBD Analyte Comments Normal range Calcium Low, normal, or elevated (elevated in severe HPT, vitamin D excess, therapy with calcium-​ containing phosphate binders, inappropriately high dialysate calcium, immobilization) 2.2–​2.6  mmol/​litre or 8.8–​10.4 mg/​dl Phosphate Elevated in advanced CKD (GFR <30 ml/​min) 0.8–​1.4  mmol/​litre or 2.4–​4.2 mg/​dl Intact PTH Elevated in HPT; can be normal or even low (mostly in cases of aluminium intoxication, adynamic bone disease, overtreatment with calcitriol, after parathyroidectomy); beware of interassay variations of intact PTH measurements 1–​7 pmol/​litre or 10–​65 pg/​ml 25-​(OH)D3 (calcidiol) Often low because of reduced sun exposure or low dietary intake; seasonal variation; if increased, check for exogenous source 50–​200 nmol/​litre or 20–​80 ng/​mla 1,25-​(OH)2D3 (calcitriol) Usually low (if increased, check for calcitriol ingestion; rarely endogenous overproduction (granulomatous disease)) 50–​120 pmol/​litre or 25–​50 pg/​mla Total alkaline phosphatases (AP) Normal or increased; elevated in severe HPT (exclude concomitant liver disease by determination of γ-​GT or bone-​specific AP isoenzyme) 60–​170 IU/​litre Osteocalcin Diagnostic information analogous to AP; fragments accumulate in advanced CKD; probably no extra information in addition to intact PTH and bone isoenzyme of AP c.3–​8 µg/​litreb (may depend on assay) Magnesium Normal or elevated (decreased renal excretion) 0.8–​1.3  mmol/​litre Aluminium Normal; elevated if aluminium-​containing phosphate binders are taken or if dialysate is aluminium contaminated <10 µg/​litre AP, alkaline phosphatase; CKD, chronic kidney disease; GFR, glomerular filtration rate; γ-​GT, γ-​glutamyl transferase; HPT, hyperparathyroidism; MBD, mineral and bone disorder; PTH, parathyroid hormone. a Normal range varies depending on season (consult local laboratory guidance). b In individual with normal renal function. Table 21.6.7  Typical serum biochemistry in the two main contrasting forms of renal bone disease Analyte Severe hyperparathyroidism Adynamic bone Calcium Variable, high normal or elevated in advanced secondary hyperparathyroidism Tendency to hypercalcaemia Phosphate Marked increase (dissolution of bone mineral) No typical pattern, often elevated Intact PTH Markedly elevated Normal or low Total alkaline phosphatases Usually elevated Tend to be low Box 21.6.8  Differential diagnosis of hypercalcaemia in patients with advanced CKD or on dialysis Related to CKD • Severe hyperparathyroidism • Intoxication with vitamin D sterols—​cholecalciferol, ergocalciferol, calcidiol, calcitriol or active vitamin D derivatives • Excessive dose of calcium-​containing phosphate binders • Inappropriately high dialysate calcium concentration Not directly related to CKD • Immobilization • Cancer with bone metastases • Myeloma • Granulomatous disease (e.g. sarcoidosis, tuberculosis) • Other rare causes of hypercalcaemia—​see Chapter 13.4 • Pseudohypercalcaemia—​elevated of total protein concentration

21.6  Chronic kidney disease 4851 appropriate threshold for intervention and by a lack of evidence that supplementation will impact on endpoints beyond the serum 25-​hydroxyvitamin D3 level. Furthermore, it is known that there is significant variation between different assay systems, adding fur- ther uncertainties to published guidelines. In the presence of symptoms and very low plasma levels, a loading regimen to provide a total of approximately 300 000 IU vitamin D (given either as separate weekly or daily doses over 6 to 10 weeks) can be used, with the exact regimen depending on the local availability of vitamin D preparations and guidelines. For example, 20 000-​IU capsules, two given weekly for 7 weeks (280  000 IU), or 800-​IU capsules, five a day given for 10 weeks (280 000 IU). Maintenance therapy then comprises vitamin D in doses equivalent to 800 to 2000 IU daily (occasionally up to 4000 IU daily), given daily or alterna- tively weekly at higher doses. In CKD, the synthesis of 1,25-​dihydroxyvitamin D3 depends on the concentration of the precursor substance 25-​hydroxyvitamin D3. This explains why administration of up to 2000 IU cholecalcif- erol per day (which is two to three times the average daily intake with vitamin D-​fortified food) leads to an increase of serum calcitriol and a decrease of serum intact PTH in many patients with CKD stages 3 and 4. Serum 25-​hydroxyvitamin D3 levels can usually be raised to a target of at least 50 nmol/​litre (20 ng/​ml) by supplementation with cholecalciferol or (less reliably) by sufficient sun exposure. It is important to note, however, that treatment with pharmaco- logical doses of cholecalciferol (‘native’ vitamin D) is potentially haz- ardous in CKD, especially if a patient confuses a weekly for a daily prescription. Cholecalciferol is less effective than its dihydroxylated and more active metabolites in terms of PTH reduction (see fol- lowing section on active vitamin D sterols), and carries a substantial risk of inducing prolonged increases in serum calcium and phos- phate that may damage residual renal function and possibly exacer- bate soft tissue calcification. Administration of  active vitamin D sterols  Current practice is hindered by uncertainties regarding the appropriate threshold for intervention and by a lack of evidence that supplementation will im- pact on endpoints beyond the serum 25-​hydroxyvitamin D level. If serum 25-​hydroxyvitamin D3 levels are higher than 50 nmol/​ litre (20 ng/​ml) and intact PTH levels remain elevated, treat- ment with low doses of active vitamin D sterols calcitriol and alfacalcidol should be considered (paricalcitol and doxercalciferol can also be used at greater expense). In patients with CKD stage 5, whether on dialysis or not, complete return of intact PTH concentrations to normal is not desirable. In advanced CKD, maintenance of normal bone turnover requires measured intact PTH concentrations to be around twice the ULN. It is uncertain whether this reflects PTH resistance of the skeleton, or problems with the second-​generation intact PTH assay which also meas- ures probably inactive fragments of PTH. However, in reflection of these uncertainties, the current KDIGO guidelines advise that in patients with CKD stages 3–​5 not on dialysis, the optimal PTH level is not known, but suggest that patients with levels of in- tact PTH above the ULN of the local assay are first evaluated for hyperphosphataemia, hypocalcaemia and vitamin D deficiency. Any abnormalities found should be corrected and the effect on PTH assessed. If PTH continues to rise, then oral alfacalcidol or calcitriol should be introduced. Box 21.6.9 provides an algorithm for the prophylaxis of secondary hyperparathyroidism. In experimental studies, daily administration of calcitriol or alfacalcidol lowers intact PTH concentration and prevents parathyroid hyperplasia. Higher-​dose intermittent therapy (1–​2 µg twice weekly) may decrease the likelihood of inducing hypercalcaemia, but there is no published evidence that this is more effective in the long term. Medical management of advanced hyperparathyroidism Hypocalcaemia is the most potent driver of PTH in both normal physiology and in CKD, hence this must be corrected before any other measures are likely to be effective. Once this has been done, other measures such as higher-​dose vitamin D sterols can be introduced. The main side effects of treatment with active vitamin D sterols are hypercalcaemia and hyperphosphataemia. There has therefore been an intense search for new analogues that suppress parathyroid activity while causing less hypercalcaemia and hyperphosphataemia. Some of these—​including paricalcitol (19-​nor-​1α,25-​dihydroxyvitamin D2) and doxercalciferol (1α-​hydroxyvitamin D2)—​are available in some countries, but no clinical trials have provided convincing evidence that they are better than the parent compound, calcitriol. Observational studies in large dialysis patient cohorts suggest that treatment with any active vitamin D compound is associated with better outcome than no vitamin D treatment, and that treatment with novel active vitamin D derivatives may lead to better patient outcome than treatment with calcitriol. However, in observational studies it is impossible to know whether such associations are due to bias, confounding, chance, or cause, and hence such results cannot be relied on. Another important method of influencing calcium balance in patients on dialysis is to manipulate the concentration of ionized calcium in the dialysate. Normal serum ionized calcium is around 1.1 to 1.2  mmol/​litre, and in the past a dialysate calcium con- centration of 1.75 mmol/​litre (7 mg/​100 ml) was recommended, such that net uptake of calcium occurred during the dialysis ses- sion. However, if calcium-​containing phosphate binders or active Box 21.6.9  Algorithm for prophylaxis of secondary hyperparathyroidism Monitoring (serum biochemistry) • Calcium, albumin, phosphate, intact PTH, 25-​hydroxyvitamin D3, aluminium Prophylactic measures If serum 25-​hydroxyvitamin D3 is low, i.e. below 50 nmol/​litre (20 ng/​ml): • Consider cholecalciferol 2000 U/​day or 20 000 U/​week If plasma calcium is decreased and/​or plasma phosphate is increased: • Give calcium acetate 0.5–​1.0 g with each meal If serum phosphate is increased and plasma calcium is normal or high: • Consider calcium-​free phosphate binder (e.g. lanthanum or sevelamer carbonate) If serum intact PTH is consistently above target ranges (see text) and serum calcium/​phosphate is normal (spontaneously or after intervention): • Give alfacalcidol/​calcitriol 0.25 µg/​day or equivalent doses of other analogues

section 21  Disorders of the kidney and urinary tract 4852 vitamin D sterols are administered, then intestinal uptake of cal- cium is increased and patients may develop a strongly positive calcium balance, with or without hypercalcaemia. The standard concentration of calcium in dialysate currently in use is usually 1.50 mmol/​litre (6 mg/​100 ml). This may be reduced further to 1.25 mmol/​litre (5 mg/​100 ml) if hypercalcaemia develops, but it is important to ensure that careful monitoring is in place since if calcium carbonate and/​or active vitamin D derivatives are omitted, then a negative calcium balance may result with exacerbation of secondary hyperparathyroidism. In peritoneal dialysis fluids, a calcium level of 1.25 mmol/​litre is widely used since the risk of inducing hypercalcaemia is much less because the volumes of fluid in use are so much lower. Another effective treatment for hyperparathyroidism is to use a calcimimetic, only one of which—​cinacalcet—​is in clinical use at present. This renders the CaR more sensitive to extracellular Ca2+ and has been shown to reduce elevated serum intact PTH concen- trations in dialysis patients with moderate or severe hyperparathyr- oidism. Its beneficial effect on serum biochemistry is maintained over prolonged time periods, but it is not licensed for use in patients with CKD who are not on dialysis, and some experts—​including the KDIGO working group—​do not recommend its use in such cases because of lack of data on long-​term efficacy and safety in this population. In any patient with significant residual renal function, including a transplanted patient, the risk of inducing symptomatic hypocalcaemia is significant and therefore initial weekly monitoring of serum calcium is essential. Tumour-​like parathyroid growth and parathyroidectomy Uncontrolled severe secondary hyperparathyroidism can become an adenomatous process that bears similarities to tumour growth. Nodular hyperplasia is usually found in patients whose estimated parathyroid mass exceeds 1 to 1.5 g, with the nodules exhibiting clonal growth, with microsatellite analysis showing loss of hetero- zygosity for many alleles, including putative tumour suppressor genes. The parathyroid tissue within these nodules is also charac- terized by reduced expression of vitamin D receptors and CaRs, which could explain—​at least in part—​the eventual lack of response to medical management, at which point the condition is referred to as tertiary hyperparathyroidism. It appears that continuous stimu- lation of the parathyroid gland selectively favours cells with higher proliferative potential so that the gland progressively escapes from growth-​inhibitory control mechanisms. This is illustrated by the fact that regrowth, including locally invasive regrowth, occurs in many patients after subtotal parathyroidectomy or autotransplantation of parathyroid tissue. Tertiary hyperparathyroidism is by definition uncontrollable by manipulation of calcium and phosphate levels, and it tends to be associated with high levels of both, plus increased serum alkaline phosphatase. It is also generally unresponsive to vitamin D therapy, which may be impossible to deploy because of high calcium levels. The patient may have a variety of symptoms including general mal- aise, pruritus, muscle and bone aches, depression, and anaemia due to PTH-​induced unresponsiveness to erythropoietin. Before the introduction of cinacalcet treatment, parathyroidectomy was generally considered in symptomatic patients with marked ele- vation of serum intact PTH (>100 pmol/​litre or 950 pg/​ml) who failed to respond to medical treatment within 8 to 12 weeks. Such patients almost certainly have tertiary hyperparathyroidism, and imaging will usually show significant parathyroid enlargement (es- timated mass >1.0–​1.5 g). Over the past decade, oral cinacalcet has been used more commonly in this situation, and will effectively re- duce PTH levels if carefully monitored and the dose appropriately titrated according to response. The National Institute for Health and Care Excellence (NICE) published guidance on its use in this situ- ation (Box 21.6.10). An indication for urgent parathyroidectomy is calcific uraemic arteriolopathy (also called calciphylaxis), namely ischaemic skin ne- crosis secondary to calcification of skin arteries, but only if associ- ated with elevated serum intact PTH levels. There has been a long-​standing debate as to whether total parathyroidectomy or subtotal parathyroidectomy should be pre- ferred, the latter with a remnant left in situ or autotransplanted into the subcutaneous abdominal fat or forearm musculature. There are no trial data to inform decision-​making, and autotransplantation has become generally less usual over recent years. Leaving parathy- roid tissue behind is associated with a relatively high risk of local recurrence, presumably because of the increased growth potential of parathyroid cells, although the risk can be reduced if only non-​ nodular parts of the gland are autotransplanted. Alcohol injection into the enlarged parathyroids under ultrasonographic guidance has been tried as an alternative to surgery, but this procedure has not found wide application, except in Japan. Box 21.6.11 summarizes the approach to the management of pa- tients with advanced renal secondary hyperparathyroidism. Anaemia Pathogenesis The physiological mechanisms controlling red cell mass are shown in Fig. 21.6.12. The maintenance of a normal red cell mass requires an appropriate rate of red cell production by the bone marrow, with no substrate limitations and under the influence of an adequate amount of erythropoietin. The production rate should balance red cell loss and destruction. All elements are disturbed in uraemia, and anaemia is one of the most obvious manifestations of the uraemic syndrome. Red cell lifespan is shortened by accelerated destruction. Erythropoietin secretion is enhanced, but not to a sufficient level (Fig. 21.6.13). Box 21.6.10  NICE guidance on the use of oral cinacalcet 1 Cinacalcet is not recommended for the routine treatment of sec- ondary hyperparathyroidism in patients with endstage renal disease on maintenance dialysis therapy 2 Cinacalcet is recommended for the treatment of refractory secondary hyperparathyroidism in patients with endstage renal disease (including those with calciphylaxis) only in those:

—​ who have ‘very uncontrolled’ plasma levels of intact parathyroid hormone (defined as greater than 85 pmol/​litre (800 pg/​ml)) that are refractory to standard therapy, and a normal or high adjusted serum calcium level, and

—​ in whom surgical parathyroidectomy is contraindicated, in that the risks of surgery are considered to outweigh the benefits 3 Response to treatment should be monitored regularly and treatment should be continued only if a reduction in the plasma levels of intact parathyroid hormone of 30% or more is seen within 4 months of treat- ment, including dose escalation as appropriate

21.6  Chronic kidney disease 4853 Epidemiology and clinical significance Anaemia (defined as a haemoglobin concentration <130 g/​litre in adult men and postmenopausal women, and <120 g/​litre in pre- menopausal women) is common in CKD, particularly in those with diabetes, and affects nearly 90% of all with CKD stages 4 and 5, many of whom will have haemoglobin concentrations less than 100 g/​litre. Renal anaemia, which is normochromic and normocytic, accounts for many of the symptoms that previously were attributed to uraemia, including lethargy, cold intolerance, and general fatigue. Population studies and registry data generally report higher mor- tality for dialysis patients with haematocrit 30 to 33% compared with those with haematocrit 33 to 36%, or for haemoglobin levels less than 110 g/​litre or 115 g/​litre than above. Management As a result of many trials of erythropoietin and other erythropoiesis-​ stimulating agents (ESAs), there is now general agreement that partial correction of anaemia in patients with CKD improves physiological and clinical status, as well as quality of life. This agree- ment has manifested itself in a plethora of clinical practice guide- lines, including those produced by the National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) in the United States of America, the ERA/​EDTA, the Canadian Society of Nephrology, and the Japanese Society for Dialysis Therapy. There are minor differences between the particular guidelines, but they are all essentially similar. There is no particular haemoglobin concentration at which symptoms become manifest in all patients, hence the decision to start treatment in a particular patient is always a matter of judge- ment. As a rule of thumb, if a patient with CKD has a haemoglobin concentration of less than 110 g/​litre and symptoms that might be attributable to anaemia, then treatment to restore haemoglobin to the range 110 to 120 g/​litre is warranted if available, but it has been convincingly shown in randomized studies that full correction to a higher level (‘normal or near normal’) is associated with poorer outcomes and should be avoided. Before starting treatment with ESAs it is important to exclude other causes of anaemia: serum vitamin B12, red cell folate, and in- dices of iron status should be assessed in all patients, with other tests ( O 2 de li ve ry in u ra e mi a) All tissues Bone marrow (Shortened red cell survival in uraemia) Red cell mass Sense O2 delivery (abnormal in uraemia) Hypoxia-inducible factor (HIF) Epo gene in interstitial fibroblasts Epo synthesis O x y g e n d el i v e r y EPO ( in uraemia) ( Red cell production in uraemia) Kidney Fig. 21.6.12  The relationship between red cell mass, oxygen delivery, erythropoietin synthesis, and red cell production in the bone marrow. Erythropoietin production is reduced in uraemia because of defective sensing, reduced synthesis, or both. 1000 10 Haematocrit (%) Log Epo concentration Spread of values in renal anaemia Spread of values in nonrenal anaemia 10 20 30 40 50 Fig. 21.6.13  In renal anaemia, the erythropoietin concentration rises in response to anaemia, but to a much lower level than in comparably severe nonrenal anaemia. Box 21.6.11  Treatment of advanced hyperparathyroidism If serum intact parathyroid hormone (PTH) is constantly above target range (see text): • normalize serum calcium and phosphate levels If serum phosphate is elevated: • give calcium carbonate, calcium acetate, or calcium-​free phosphate binders with meals • reduce excessive intake of dietary phosphate • increase efficacy of dialysis (higher blood flow, longer dialysis sessions, more frequent dialysis sessions) If serum calcium is elevated: • reduce dialysate calcium to 1.5 mmol/​litre (6 mg/​dl) or—​transiently—​to 1.25 mmol/​litre (5 mg/​dl) • reduce or withdraw calcium-​containing oral phosphate binders or active vitamin D sterols If serum calcium and phosphate have been normalized and elevated intact PTH persists: • increase dose of calcitriol (0.5–​3 µg) or alternative active vitamin D sterols (e.g. alfacalcidol, paricalcitol, doxercalciferol)—​these can be given one to three times per week, or daily, with dose and time interval depending on degree of elevation of serum intact PTH; alternatively, administer cinacalcet (initial dose 30 mg/​day) • monitor serum calcium, phosphate, intact PTH, and total alkaline phosphatases If serum intact PTH decreases below approximately 16.5 pmol/​litre (150 pg/​ml): • interrupt administration of calcitriol, measure intact PTH again, and decide whether low-​dose, long-​term prophylaxis is necessary If serum intact PTH fails to decrease and/​or hypercalcaemia/​ hyperphosphataemia develop or persist: • monitor parathyroid gland size (ultrasonography; MIBI scan before surgery to localize ectopic glands) • consider cinacalcet (initial dose 30 mg/​day) or surgical parathyroidectomy Note: increased active vitamin D dose is contraindicated as long as plasma phosphate or calcium is elevated.

section 21  Disorders of the kidney and urinary tract 4854 on the basis of clinical suspicion, for example, an elderly patient presenting with renal impairment and marked anaemia may have myeloma. If a patient is significantly iron deficient, then standard clinical methods of history and examination followed by appropriate investigation may be required to determine the cause, but otherwise it is important to recognize that an optimal response to ESAs re- quires plentiful iron (ferritin >200 μg/​litre), not simply a level that is not deficient. It is also important to ensure that blood pressure is reasonably controlled before ESAs are given. In the early days of erythropoietin treatment, rapid increases in haemoglobin concen- tration in combination with poorly controlled blood pressure pre- cipitated hypertensive encephalopathy in some patients. Therefore ESAs should not be started (or a dose should be omitted) if blood pressure is higher than 160/​100 mmHg. Box 21.6.12 shows an algorithm whereby the patient’s iron status is optimized before ESAs are administered. A variety of ESAs are available:  all are clinically effective, many can be administered intravenously or subcutaneously, patients may prefer one rather than another because of the particular method of delivery and fre- quency of administration (variable from once or twice a week to monthly), and those paying may wish to choose the cheapest. If the haemoglobin fails to respond, or falls after initially responding, then causes given in Table 21.6.8 need to be considered. An orally active inhibitor of hypoxia-inducible factor (HIF, see Fig. 21.6.12) prolyl hydoxylase, roxadustat, has recently been shown to be effective in correcting anaemia in patients with chronic kidney disease (both on and not on dialysis). The place of this and other similar agents in the management of renal anaemia has not yet been established. Complications of chronic renal failure Chronic renal failure affects all parts of the body. Many of its compli- cations have been discussed in this chapter, but a more complete—​ although not exhaustive—​list is given in Table 21.6.9. Preparation for renal replacement therapy In any patient with progressive CKD who is likely to require fu- ture dialysis, it is important to preserve the superficial veins of the forearm for creation of an arteriovenous fistula. Whenever possible, blood should only be taken from the veins on the dorsal surface of the hand, or—​if veins in the forearm or elbow must be punctured or cannulated—​the nondominant arm must be kept free from assault for later formation of an arteriovenous dialysis fistula. Once endstage kidney failure is inevitable, and progression of the underlying disease process cannot be halted, the patient must be prepared physically and psychologically for RRT or conserva- tive management. The length of time needed for this preparation process, which requires contact with a variety of members of the renal multidisciplinary team, will vary from patient to patient, but usually needs 9–​12 months in total, hence an approximate predic- tion of the point at which RRT will become necessary, and when symptoms are likely to begin to become troublesome, is essen- tial (Box 21.6.13). This can be established by consideration of the Box 21.6.12  Treatment of renal anaemia Is anaemia due to CKD? • Consider other causes Determine iron status: • Iron deficiency is defined by serum ferritin less than 100 µg/​litrea • Functional iron deficiency is defined by serum ferritin greater than 100 µg/​litre with hypochromic red cellsb greater than 6% or transferrin saturation less than 20% Optimize iron status: • Aim to maintain serum ferritin greater than 200 µg/​litre with hypochromic red cells less than 6% (unless ferritin >800 µg/​litre) or transferrin saturation greater than 20% (unless ferritin >800 µg/​litre) • It is likely that this will require intravenous iron (usually 600–​1000 mg for adults) Initiate ESAs and adjust dose and frequency: • To maintain stable haemoglobin (Hb) in range 100–​120 g/​litre (adjustments to ESA doses should be considered when Hb is <105 or >115 g/​litre) • To keep the rate of increase of Hb between 1 and 2 g/​litre per month Maintain adequate iron levels: • Keep serum ferritin in the range 200–​500 µg/​litre with hypochromic red cells less than 6% (unless ferritin >800 µg/​litre) or transferrin satur- ation greater than 20% (unless ferritin >800 µg/​litre) • It is likely that this will require regular but infrequent intravenous iron Monitor: • Hb every 2 to 4 weeks (induction phase, or after ESA dosage change) or every 1 to 3 months (maintenance phase) • Iron status every 1 to 3 months (but not within a week of receiving intravenous iron) • Keep serum ferritin less than 800 ug/​litre • Aim to increase haemoglobin by 10 to 20 g/​litre per month Review: • Patient’s clinical response • If there is any unexpected change in Hb level a The ‘normal’ range for ferritin is usually quoted as 15–​200 µg/​litre. b Percentage of hypochromic red cells directly reflects the number of red cells with suboptimal haemoglobin content and may be determined by some automated analysers: less than 2.5% is normal and greater than 10% indicates definite iron deficiency. Table 21.6.8  Causes of failure to respond to
erythropoiesis-​stimulating agents Cause Comment Is the patient receiving the injections? Absolute or functional iron deficiency Hypochromic red cells, reticulocyte haemoglobin, or transferrin saturation with serum ferritin Acute or chronic inflammatory states These reduce the efficacy of ESAs Other haematological conditions Consider myeloma, other malignant diseases affecting the bone marrow, thalassaemia, vitamin
B12 or folate deficiency Chloramine in dialysis water Can cause haemolysis presenting as apparent resistance to ESAs Aluminium overload Rare Antierythropoietin antibodies Rare, but a significant concern with one ESA preparation that led to its temporary withdrawal

21.6  Chronic kidney disease 4855 Table 21.6.9  Complications of chronic renal failure Complication Comment Cardiovascular system Hypertension Discussed in text Left ventricular hypertrophy Found in 75% of dialysis patients Coronary atherosclerosis Cardiovascular disease is responsible for about 50% of deaths of patients receiving RRT. High risk of acute myocardial infarction, but sudden arrhythmic death is the most common fatal cardiac event Pericarditis A feature of neglected uraemia, including inadequate dialysis; can lead to tamponade and death Calcific valvular disease Mitral valve calcification found in one-​third of dialysis patients. Calcific aortic stenosis can progress very rapidly Respiratory system Pulmonary oedema Feature of fluid retention Pleural effusion Feature of fluid retention Gastrointestinal system Anorexia, nausea and vomiting Poor oral hygiene Haemorrhage Due to nonspecific gastric ulceration and/​or angiodysplasia anywhere in the gastrointestinal tract; CKD renders normal bone marrow compensatory mechanisms less effective Pancreatitis Can be provoked by hypercalcaemia; long-​term dialysis patients develop pancreatic fibrosis, but this does not seem to affect pancreatic function Nervous system Encephalopathy Typically presents with confusion, myoclonic muscular twitching, and impairment of consciousness; seizures are rare unless there is accelerated hypertension Sensorimotor peripheral polyneuropathy Presents as dysaesthesias, restless legs, eventually weakness with foot drop; dialysis leads to slow improvement, but patients are often left with motor disability Autonomic neuropathy Manifests as abnormal cardiovascular reflexes, particularly on dialysis Carpal tunnel compression Caused by β2-​microglobulin amyloid deposition; a feature in almost all patients who have been on dialysis for more than 10 years Dialysis dementia Presents as gradual deterioration in intellectual performance, progressing to dementia with abnormal movements. Due to aluminium intoxication. Should be of historical interest only Musculoskeletal system Mineral and bone disorder Discussed in text Proximal myopathy Crystal arthropathy Gout and pseudogout (pyrophosphate arthropathy) are common. Management of gout can be difficult: NSAIDs are best avoided if possible in patients with advanced CKD who are not on dialysis, although very short-​term use is acceptable; diarrhoea caused by colchicine can lead to acute deterioration of CKD; a short course of oral prednisolone (20 mg/​day) may be the best treatment for an acute attack; reduced dose of allopurinol required Skin Pigmentation Pruritus Can be a cause of significant distress. Associated with dry skin (xerosis), and worse when the skin is warm. Cause is uncertain—​raised calcium × phosphate product, histamine sensitivity, and ‘uraemia’ have been blamed. Scratching can lead to infection and nodular prurigo. Treatments include starting/​increasing dialysis, emollient lotions/​creams, controlling plasma phosphate, keeping cool, antihistamines (e.g. chlorphenamine 4 mg at night), naltrexone, and ultraviolet phototherapy Calciphylaxis Discussed in text Bullous eruptions Pseudoporphyria, affecting sun-​exposed areas. Thought to be due to accumulation of porphyrins in high molecular weight protein-​bound complexes that are not removed by haemodialysis. Treatment is by avoidance of sun exposure, phlebotomy (for patients who are not anaemic and who have increased iron stores) and ESAs (which remove iron from stores by enhancing production of red blood cells) Sexual function Men Loss of libido and erectile impotence are common and of multifactorial cause. Sperm counts may be low leading to reduced fertility. Priapism is a rare complication of haemodialysis treatment Women Most women with severe CKD develop irregular periods or amenorrhoea and are infertile, with rare pregnancies almost always ending in miscarriage. For general discussion of pregnancy in women with kidney disease, see Chapter 14.5 (continued)

section 21  Disorders of the kidney and urinary tract 4856 rate of renal deterioration, most easily demonstrated by plotting the reciprocal creatinine or eGFR against time and extrapolating forward to the month when eGFR is likely to reach 10 ml/​min or less (Fig. 21.6.14). This information is useful for the patient and those planning care, providing a guide for the timing of the cre- ation of permanent vascular access (thereby avoiding the perils of temporary lines), placement of peritoneal dialysis catheters, or activating the patient on to a transplant waiting list. If the process is planned sufficiently well then the transition to RRT should be possible without requiring hospital admission. Complication Comment Psychological Anxiety and depression are predictable and understandable consequences of loss of health, control, and pleasure. They tend to be most prominent in young patients. The best treatment is by sympathetic support of the dialysis multidisciplinary team. Psychotherapy/​counselling can be helpful, but psychiatrists and/​or medication have little to offer unless there is a specific mental illness Metabolic Glucose intolerance CKD causes resistance to insulin-​mediated glucose uptake in skeletal muscle Complex effects on lipids Increased very-​low-​density lipoproteins; increased high-​density lipoproteins Enhanced protein catabolism Risk of malnutrition discussed in text Haematological Anaemia Discussed in text Impaired platelet function Platelet numbers are normal, but function impaired at the level of endothelial contact Impaired T-​cell immunity Mechanism uncertain, but puts patients with advanced CKD at higher risk of reactivation of tuberculosis and herpes zoster, of failure to clear some viral infections (e.g. hepatitis B), and of failure to generate normal responses to immunization (e.g. hepatitis B vaccine) Impaired neutrophil function Mechanism uncertain, but may in part explain high incidence and severity of bacterial infections Infective Blood-​borne viruses Dialysis is a risk factor for hepatitis C, hepatitis B, and HIV Methicillin-​resistant Staphylococcus aureus (MRSA) Dialysis patients are at high risk of acquiring MRSA because of their frequent contact with medical services, common requirement for invasive procedures/​indwelling lines, and (perhaps) susceptibility to infection Clostridium difficile infection A problem on many renal units Endocarditis Bacteraemias in dialysis patients are often attributable to infection of vascular access sites, which, combined with high prevalence of calcific valvular disease, creates high risk of endocarditis, usually (70%) due to S. aureus CKD, chronic kidney disease; ESA, erythropoiesis-​stimulating agent; NSAID, nonsteroidal anti-​inflammatory drug; RRT, renal replacement therapy. Table 21.6.9  Continued Box 21.6.13  Recommended standards to improve choice and quality in dialysis and kidney transplantation (from UK Renal National Service Framework (2004)) Standard one: a patient-​centred service All children, young people, and adults with CKD are to have access to information that enables them with their carers to make informed de- cisions and encourages partnership in decision-​making, with an agreed care plan that supports them in managing their condition to achieve the best possible quality of life. Standard two: preparation and choice All children, young people, and adults approaching established renal failure are to receive timely preparation for RRT so the complications and progression of their disease are minimized, and their choice of clinically appropriate treatment options is maximized. Standard three: elective dialysis access surgery All children, young people, and adults with established renal failure are to have timely and appropriate surgery for permanent vascular or peri- toneal dialysis access, which is monitored and maintained to achieve its maximum longevity. Standard four: dialysis Renal services are to ensure the delivery of high-​quality, clinically appro- priate forms of dialysis which are designed around individual needs and preferences and are available to patients of all ages throughout their lives. Standard five: transplantation All children, young people, and adults likely to benefit from a kidney transplant are to receive a high-​quality service which supports them in managing their transplant and enables them to achieve the best possible quality of life. 10.0 100 15 9.0 8.0 7.0 6.0 Nephrotic syndrome Bx: MCGN Transplant from mother UNIVERSITY Starts Epo eGFR Established career CAPD 1/creatinine (μmol/l) × 1000 5.0 4.0 3.0 2.0 1.0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 eGFR ml/min Fig. 21.6.14  A graph showing the progressive decline in renal function in a patient with glomerulonephritis. The timing of the need to start dialysis could be predicted sufficiently well to allow advance planning of treatment.

21.6  Chronic kidney disease 4857 The temptation to delay starting dialysis for as long as possible should be avoided: severe uraemia puts the patient at risk and is likely to result in a prolonged inpatient admission to deal with un- foreseen problems and potentially life-​threatening complications. However, there is no evidence that starting dialysis early in an asymptomatic patient (eGFR 10–​14 ml/​min) is better than starting when they begin to develop their first uraemic symptoms. The absolute indications for dialysis, other than in patients for whom such treatment would be inappropriate, are the develop- ment of complications that cannot be treated by conservative and pharmacological means. These are hyperkalaemia, fluid overload, acidosis, severe hypertension, pericarditis, encephalopathy, and neuropathy. To wait for these to develop puts the patient at risk, and makes hospital admission more likely. However, if plans for RRT are in place and dialysis access is prepared, then many patients and their nephrologists will opt to wait until some uraemic symptoms such as anorexia, lassitude, and pruritus develop, if only because their relief reinforces the need to adjust to regular dialysis. Apart from the serum potassium concentration and the degree of acidosis, blood tests such as urea and creatinine do not provide a safe guide as to when to RRT should commence. Nevertheless, it is advis- able to start dialysis, even in the absence of symptoms, when eGFR falls below about 7–​8 ml/​min. In small patients with little muscle bulk, the urea concentration is often between 25 and 35 mmol/​litre and the creatinine concentration between 650 and 800 µmol/​litre; in larger patients, the blood urea concentration is typically 40 to 50 mmol/​litre and that of creatinine above 800 µmol/​litre. Initiation of dialysis at lower blood levels of urea and creatinine is recom- mended in patients with diabetes as the primary cause of CKD. Pre-​emptive transplantation In choosing a modality of RRT, the first question for discussion should be whether the patient is suitable for kidney transplantation and whether there are any suitable live donors within the family. Pre-​ emptive kidney transplant is the treatment of choice for CKD stage 5 as successful transplantation provides increased patient survival time, improved quality of life, and reduced costs compared to dia- lysis. Activation on the transplant waiting list should occur at least 6 months prior to need for dialysis, typically when eGFR falls below 15 ml/​min/​1.73 m2, and in view of both better transplant outcomes and the shortage of deceased donors, the possibility of a living donor should be explored early with all potential recipients. The treatment of choice for all patients with a living donor is a pre-​emptive transplant occurring before dialysis commences. This strategy results not only in avoidance of dialysis but improved pa- tient survival and also improved graft survival. The pre-​emptive approach shows survival benefits in those being considered for their first transplant and also in those with failing grafts requiring retransplantation. Current pre-​emptive transplant rates in the United Kingdom (2014) are 37% for living donors and 16% for de- ceased donors, with rates in the United States of America (2012) being 18% and 11% respectively. There is potential to improve pre-​ emptive rates as 40% of all transplant recipients are predialysis at the time of wait-​listing (United Kingdom), while recent data from the United States of America suggest a third of nonpre-​emptive living donor recipients had dialysis for less than one year prior to trans- plantation. See Chapter 21.7.3 for further discussion. Home dialysis The second question to discuss is does the patient wish to dialyse at home (home haemodialysis or peritoneal dialysis) or in-​centre (haemodialysis)? The answers to these two questions depend on many factors, but availability of all treatment modalities should not be a factor (see Chapters 21.7.1 and 21.7.2 for further discussion). If haemodialysis (either at home or in-​centre) is chosen, vascular access should be created at least 2 months before it is needed. If con- tinuous ambulatory peritoneal dialysis is to be used, the Tenckhoff catheter should be placed 2 to 3 weeks before dialysis needs to be started to allow it to seal. Conservative kidney management of terminal uraemia Few treatments demand as much of a patient’s endurance and deter- mination as peritoneal or haemodialysis, with hospital admissions, dietary restrictions, multiple invasive procedures, and polypharmacy. It is therefore particularly important that patients with progressive CKD are enabled to understand all that will be involved, and the im- plications for both their quantity and quality of life. For those over the age of 75 years with significant co-​morbidities, survival on dia- lysis is relatively short (50% survival, <2 years), and 3 days in every week are consumed by travel, dialysis, and recovery. Consequently, many such people may opt for reduced quantity but better quality of life, and reject dialysis treatment. Because intuitively many people expect that instituting dialysis in a patient with kidney failure and other comorbid conditions will result in some improvement of their clinical condition, it is common to find that friends and relatives find it hard to understand why someone may decide not to have dialysis. It is therefore important that the multidisciplinary team supports the patient to make their own decision wherever possible, and to understand fully its implications. These difficult decisions can only be made once the patient and relatives or carers have a full understanding of both dialysis and con- servative kidney management. This takes time, effort and patience from both the renal multidisciplinary team and the patient. The patient’s capacity to determine their own treatment must be con- sidered, and any advance treatment directives taken into account. In the United Kingdom, many of these aspects are now legally en- shrined within the Mental Capacity Act. Equally there are patients for whom dialysis may appear inappro- priate to the clinical team, but who wish to commence for a variety of personal and family reasons, and others who choose to discon- tinue dialysis after a certain point. Under occasional circumstances, a 3-​month trial of dialysis might be appropriate, but this may sug- gest a failure of the planning process. In-​centre haemodialysis is usually the treatment modality offered in such circumstances, but establishing access and the requirement for thrice-​weekly transport to a dialysis facility which the frail body may find difficult to tolerate, recovering only in time for the next dialysis session, can be truly miserable for the patient and all others concerned. Home dialysis by means of assisted automated peritoneal dialysis may be more appro- priate and less intrusive. In frail patients, it is not likely that dialysis will greatly prolong life, although it can certainly reduce its quality. There have been no

section 21  Disorders of the kidney and urinary tract 4858 trials that have randomized such patients to treatment with RRT or to conservative (palliative) management, but one observational study reported the outcome of 63 patients who were recommended to receive palliative care after multidisciplinary assessment and counselling about treatment options. Ten of these patients opted for and received dialysis treatment, but their median survival after initiation of dialysis (8.3 months) was not significantly longer than survival beyond the putative date of dialysis initiation in the pal- liatively treated patients (6.3 months), and 65% of those treated with dialysis died in hospital, compared with 27% of those re- ceiving palliative care. A study of 3702 nursing home residents in the United States of America who started on dialysis treatment be- tween June 1998 and October 2000 revealed that 12 months later most (58%) had died and only 13% had maintained their predialysis functional state. The process of dialysis withdrawal and dying can be traumatic for the patient, the patient’s family and friends, and for staff if careful discussion and planning is not in place. With appropriate prep- aration it should be a peaceful, painless, and dignified end to life. Around 10% of deaths in dialysis programmes follow withdrawal of treatment. If one takes the view that dialysis is a treatment to allow a patient to continue living with a reasonable quality of life, as opposed to delaying death in the short term, then it will rarely be taken up by patients with other immediately life-​limiting conditions. However, the ethical and legal issues are complex and it is essential that the patient makes the decision for conservative management when fully informed and able to do so. The various members of the multidis- ciplinary team should discuss with the patient the option of conser- vative management well before dialysis is actually needed. If this is not possible because of an acute presentation, the discussion process may need to be rapid but must not be avoided. The patient must be given a realistic account of what dialysis can achieve, what it cannot achieve, and at what personal cost—​ access, travel, restrictions, and complications. One could argue that it should not be started when survival beyond 3 months outside hospital is unlikely, but a patient who is looking forward to a par- ticular event (birth of a grandchild, a graduation ceremony, a final holiday) may wish to commence dialysis (perhaps on a temporary basis) against all expectations. These conversations can be difficult and ideally should not be hurried. They should routinely be aided by offering arrangements for the patient (and relative/​friend) to visit the dialysis unit, and in particular to meet other patients and carers outside the hospital environment. Without careful and timely dis- cussions it is possible for the patient (and their relatives/​friends) to be left with the impression that dialysis means that ‘the staff care, and I’ll be well looked after’, whereas no dialysis means that ‘the staff don’t care, and I’ll be left at home to fend for myself’. Properly managed, death from uraemia is peaceful and free of pain or suffering. It is important to ensure that the patient has peace of mind, that they are comfortable with their decision, and that their family members are understanding and supportive. They will be comforted to know that their doctor respects their decision. A late change of mind can occasionally occur and must similarly be respected. The preferred place of death should be discussed and decided. Clearly a hospital ward is a possibility, but the patient may never have been an inpatient and therefore have no relationship with the staff. Hospices will admit terminally ill uraemic patients, but most people prefer to die at home if at all possible. This requires close liaison with appropriate primary care staff and continuing sup- port from the renal multidisciplinary team. Several distressing symptoms may need to be controlled in the final 2 or 3 weeks of life. Breathlessness from pulmonary oedema and acidosis is best controlled with a subcutaneous morphine in- fusion. Nausea and anorexia can be helped with regular chlorpro- mazine 25 mg four times daily, and ondansetron 8 mg twice daily can also be effective. Food and fluid should be offered in small, palatable helpings, with no pressure to eat or drink exerted on the patient. The mouth can become dry and crusted from mouth breathing and will smell foul from uraemic saliva, for which regular mouth washes and gum care will help. Pruritus is managed by keeping the skin cool, and soft with emollients. The patient may not be aware of myoclonic jerks, but these may distress the family—​benzodiazepines, such as clonazepam, can be prescribed if needed. FURTHER READING Combs SA, Davison SN (2015). Palliative and end-​of-​life care issues in chronic kidney disease. Curr Opin Support Palliat Care, 9,
14–​19. Cooper BA, et al. (2010). A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med, 363, 609–​19. Coresh J, et  al. (2003). Prevalence of chronic kidney disease and decreased kidney function in the adult US population:  Third National Health and Nutrition Examination Survey. Am J Kidney Dis, 41, 1–​12. Davison R, Sheerin NS (2014). Prognosis and management of chronic kidney disease at the end of life. Postgrad Med J, 90, 98–​105. Eckardt KU, et al. (2013). Evolving importance of kidney disease: from subspecialty to global health burden. Lancet, 382, 158–​69. Hallan SI, et al. (2006). International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol, 17, 2275–​84. Hallan S, et al. (2007). Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: the HUNT II Study. Arch Intern Med, 167, 2490–​6. Hsu CY, et al. (2005). Elevated blood pressure and risk of end-​stage renal disease in subjects without baseline kidney disease. Arch Intern Med, 165, 923–​8. Hsu CY, et al. (2006). Body mass index and risk for end-​stage renal disease. Ann Intern Med, 144, 21–​8. Jha V, et al. (2013). Chronic kidney disease: global dimensions and perspectives. Lancet, 382, 260–​72. Keith DS, et al. (2004). Longitudinal follow-​up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med, 164, 659–​63. Kheder-​Elfekih R, et al. (2015). Hypertension and chronic kidney dis- ease: respective contribution of mean and pulse pressure and arterial stiffness. J Hypertens, 33, 2010–​15. Kurella-​Tamura M, et al. (2009). Functional status of elderly adults be- fore and after initiation of dialysis. N Engl J Med, 361, 1539–​47. Matsushita K, et al. (2010). Association of estimated glomerular filtra- tion rate and albuminuria with all-​cause and cardiovascular mor- tality in general population cohorts: a collaborative meta-​analysis. Lancet, 375, 2073–​81. Pippias M, et al. (2016). The changing trends and outcomes in renal replacement therapy: data from the ERA-​EDTA Registry. Nephrol Dial Transplant, 31, 831–​41.

21.6  Chronic kidney disease 4859 Rossing P (2006). Diabetic nephropathy:  worldwide epidemic and effects of current treatment on natural history. Curr Diab Rep, 6, 479–​83. Singh AK, Kari JA (2013). Metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens, 22, 198–​203. Turin TC, et al. (2013). Proteinuria and life expectancy. Am J Kidney Dis, 61, 646–​68. Van der Velde M, et al. (2011) Lower estimated glomerular filtration rate and higher albuminuria are associated with all-​cause and car- diovascular mortality. A  collaborative meta-​analysis of high-​risk population cohorts. Kidney Int, 79, 1341–​52. Progression of CKD and its prevention Appel LJ, et al. (2010). Intensive blood-​pressure control in hyperten- sive chronic kidney disease. N Engl J Med, 363, 918–​29. Baigent C, et al. (2011). The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):  a randomised placebo-​ controlled trial. Lancet, 377, 2181–​92. Barnett AH, et  al. (2004). Angiotensin-​receptor blockade versus converting-​enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med, 351, 1952–​61. Brenner BM, Meyer TW, Hostetter TH (1982). Dietary protein in- take and the progressive nature of kidney disease: the role of hemo- dynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and in- trinsic renal disease. N Engl J Med, 307, 652–​9. Casas JP, et al. (2005). Effect of inhibitors of the renin–​angiotensin system and other antihypertensive drugs on renal outcomes: sys- tematic review and meta-​analysis. Lancet, 366, 2026–​33. Chronic Kidney Disease Progression Consortium (2010). Association of estimated glomerular filtration rate and albuminuria with all-​ cause and cardiovascular mortality in general population cohorts: a collaborative meta-​analysis. Lancet, 375, 2073–​81. Gansevoort RT, et al. (2013). Chronic kidney disease and cardiovas- cular risk: epidemiology, mechanisms, and prevention. Lancet, 383, 339–​52. Jay CL, et al. (2016) Reassessing pre-​emptive kidney transplantation in the United States: are we making progress. Transplantation, 100, 1120–​7. Kasiske BL, et al. (2002). Pre-​emptive kidney transplantation: the ad- vantage and the advantaged. J Am Soc Nephrol, 5, 1358–​64. Kidney Disease:  Improving Global Outcomes (KDIGO) Lipid Work Group (2013). KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Int Suppl, 3, 259–​305. Klahr S, et al. (1994). The effects of dietary protein restriction and blood-​pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med, 330, 877–​84. Lewis EJ, et  al. (2001). Renoprotective effect of the angiotensin-​ receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med, 345, 851–​60. Muntner P, et al. (2009). Hypertension awareness, treatment, and con- trol in adults with CKD: results from the chronic renal insufficiency cohort (CRIC) study. Am J Kidney Dis, 55, 441–​51. National Institute for Health and Care Excellence (2014). Cardiovascular disease:  risk assessment and reduction, including lipid modification. Clinical guideline [CG181]. NICE, London. Palmer SC, et al. (2014). HMG CoA reducatase inhibitors (statins) for people with chronic kidney disease not receiving dialysis. Cochrane Database Syst Rev, 5, CD007784. Peterson JC, et  al. (1995). Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med, 123, 754–​62. Pohl MA, et  al. (2005). Independent and additive impact of blood pressure control and angiotensin-​II receptor blockade on renal out- comes in the irbesartan diabetic nephropathy trial: clinical implica- tions and limitations. J Am Soc Nephrol, 16, 3027–​37. Remuzzi G, Chiurchiu C, Ruggenenti P (2004). Proteinuria predicting outcome in renal disease:  nondiabetic nephropathies (REIN). Kidney Int Suppl, 92, S90–​6. Sarnak MJ, et al. (2005). The effect of a lower target blood pressure on the progression of kidney disease: long-​term follow-​up of the modi- fication of diet in renal disease study. Ann Intern Med, 142, 342–​51. Wanner C, Tonelli M (2014). KDIGO Clinical Practice Guideline for Lipid Management in CKD: summary of recommendation state- ments and clinical approach to the patient. Kidney Int, 85, 1303–​9. Mineral and bone disorder Arnold A, et  al. (1995). Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest, 95, 2047–​54. Block GA, et al. (2007). Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int, 71, 438–​41. Bover J, et al. (2016). Clinical and practical use of calcimimetics in dia- lysis patients with secondary hyperparathyroidism. Clin J Am Soc Nephrol, 11, 161–​74. Briet M, et al. (2012). Arterial stiffness and pulse pressure in CKD and ESRD. Kidney Int, 82, 388–​400. Cunningham J, Locatelli F, Rodriguez M (2011). Secondary hyper- parathyroidism: Pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol, 6, 913–​21. Eknoyan G, Levin A, Levin NW (2003). Bone metabolism and disease in chronic kidney disease. Am J Kidney Dis, 42, 1–​201. EVOLVE Trial Investigators (2012). Effect of cinacalcet on cardio- vascular disease in patients undergoing dialysis. N Engl J Med, 367, 2482–​94. Greeviroj P, et al. (2018). Cinacalcet for treatment of chronic kidney disease-mineral and bone disorder: a meta-analysis of randomised controlled trials. Nephron, 139, 197–210. Hollis BW (2005). Circulating 25-​hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr, 135, 317–​22. Hutchison AJ, Smith CP, Brenchley PE (2011). Pharmacology, efficacy and safety of oral phosphate binders. Nat Rev Nephrol, 7, 578–​89. Kazama JJ, et al. (2015). Chronic kidney disease and bone metabolism. J Bone Miner Metab, 33, 245–​52. Ketteler M, Gross ML, Ritz E (2005). Calcification and cardiovascular problems in renal failure. Kidney Int, 67, S120–​7. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-​MBD Work Group (2017). KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—​mineral and bone disorder (CKD-​MBD). Kidney Int Suppl, 7, 1–59. National Institute for Health and Care Excellence (2007). Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-​stage renal disease on maintenance dialysis therapy. Technology appraisal guidance [TA117]. NICE, London. Navaneethan SD, et  al. (2009). Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am J Kidney Dis, 54, 619–​37.

section 21  Disorders of the kidney and urinary tract 4860 Razzaque MS (2009). The FGF23-​Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol, 5, 611–​19. Rodriguez M, et al. (2015). The use of calcimimetics for the treatment of secondary hyperparathyroidism: a 10 year evidence review. Semin Dial, 28, 497–​507. Schmitt CP, Odenwald T, Ritz E (2006). Calcium, calcium regulatory hormones, and calcimimetics: impact on cardiovascular mortality. J Am Soc Nephrol, 17, S78–​80. Tonelli M, Pannu N, Manns B (2010). Oral phosphate binders in pa- tients with kidney failure. N Engl J Med, 362, 1312–​24. Urena-​Torres P, et al. (2007). Klotho: an antiaging protein involved in mineral and vitamin D metabolism. Kidney Int, 71, 730–​7. Renal anaemia Besarab A, et al. (2000). Optimization of epoetin therapy with intra- venous iron therapy in hemodialysis patients. J Am Soc Nephrol, 11, 530–​8. Chen N, et al. (2019). Roxadustat treatment for anemia in patients with kidney disease not receiving dialysis. N Eng J Med, 381, 1001–10. Chen N, et al. (2019). Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Eng J Med, 381, 1011–22. Drueke TB, et al. (2006). Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med, 355, 2071–​84. Hsu CY, Mcculloch CE, Curhan GC (2002). Iron status and hemo- globin level in chronic renal insufficiency. J Am Soc Nephrol, 13, 2783–​6. Kaufman JS, et al. (2001). Diagnostic value of iron indices in hemodi- alysis patients receiving epoetin. Kidney Int, 60, 300–​8. Kazmi WH, et al. (2001). Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis, 38, 803–​12. Li S, Collins AJ (2004). Association of hematocrit value with cardio- vascular morbidity and mortality in incident hemodialysis patients. Kidney Int, 65, 626–​33. MacDougall IC, et  al. (2009). A peptide-​based erythropoietin-​ receptor agonist for pure red-​cell aplasia. N Engl J Med, 361, 1848–​55. National Collaborating Centre for Chronic Conditions (2006). Anaemia management in chronic kidney disease:  national clinical guideline for management in adults and children. Royal College of Physicians, London. National Institute for Health and Care Excellence (2014). Chronic kidney disease. Managing anaemia. NICE guideline [NG8]. NICE, London. Van Wyck D, et al. (2005). A randomized, controlled trial comparing IV iron sucrose to oral iron in anaemic patients with nondialysis-​ dependent CKD. Kidney Int, 68, 2846–​56.

21.7 Renal replacement therapy 4861 21.7.1 Haemodi

21.7 Renal replacement therapy 4861 21.7.1 Haemodialysis 4861

CONTENTS 21.7.1 Haemodialysis  4861 Robert Mactier 21.7.2 Peritoneal dialysis  4874 Simon Davies 21.7.3 Renal transplantation  4879 Nicholas Torpey and John D. Firth 21.7.1  Haemodialysis Robert Mactier ESSENTIALS Maintenance haemodialysis (HD) is a highly successful treatment for patients with established renal failure and is the default therapy when other renal replacement therapy options are not available. In the developed world, the HD population continues to increase and is becoming more elderly and dependent. Principles—​HD uses the countercurrent flow of blood and di- alysate through a hollow fibre dialyser to maximize the concentra- tion gradient for diffusive transport of solutes. A hydrostatic gradient across the dialyser membrane induces ultrafiltration (UF) of water and convective transport of solutes by solvent drag. Dialysers and types of dialysis—​high-​flux membranes are standard in most HD centres and are needed to achieve significant re- moval of middle molecules, of which β2-​microglobulin (the cause of dialysis-​related amyloid) is the prime example. The technique of haemodiafiltration (HDF) contributes additional convective removal of fluid and better clearance of middle molecules. Vascular access—​the need to secure and maintain reliable vas- cular access is fundamental to achieving adequate dialysis and maintaining health. An arteriovenous fistula is the preferred option, with fewer complications and longer survival than other access op- tions. Dependence on tunnelled central venous access lines con- tributes to morbidity and excess mortality, mainly from line-​related sepsis, and often represents a failure in access provision. Dialysis adequacy—​for historical and pragmatic reasons, HD is normally provided three times per week. Working definitions of adequacy are based on small-​solute—​typically urea—​removal. The optimal dialysis dose has not been well defined, but minimum tar- gets of delivered dose measured by urea reduction ratio (URR) and normalized urea clearance (Kt/​V) have been established. Current guidelines recommend targeting a URR of 65% or normalized urea clearance (Kt/​V) in excess of 1.2 per session for thrice-​weekly treat- ment. Higher doses of dialysis delivered thrice weekly (as judged by Kt/​V) do not produce a significant improvement in outcomes, but a longer duration of dialysis delivered thrice weekly does, as do short daily HD or nocturnal daily HD treatments. The technique of HDF provides a survival benefit over HD. Complications—​the main acute complication of HD is intradialytic hypotension, resulting from an imbalance between the UF rate and the rate of vascular refill. Underlying cardiovascular disease, antihypertensive drugs, autonomic dysfunction, shortened dialysis times, large interdialytic fluid gains, and inaccurate dry-​weight as- sessment all predispose. Other acute complications include dialysis-​ related haemorrhage, acute haemolysis, air embolism, dialyser reactions, and dialysis disequilibrium. In the longer term, dialysis-​ related amyloidosis is a disabling, progressive condition caused by the polymerization of β2-​microglobulin within tendons, synovium, and other tissues. The incidence and prevalence of a wide range of comorbid medical conditions is increased in HD patients, including ischaemic heart disease, cerebrovascular disease, and peripheral vas- cular disease. Introduction An ever increasing number of patients with established renal failure are dependent on haemodialysis (HD) to sustain their lives. HD has very few absolute contraindications and so is the default therapy of all forms of renal replacement therapy (RRT). Ninety days after commencing RRT 65% of incident patients in the United Kingdom in 2017 were receiving HD, compared with 19% on peritoneal dialysis (PD) and 10% with a functioning kidney transplant (6% had died or stopped treatment). Kidney transplantation is recognized as the best mode of RRT, and 55% of the prevalent patients at the end of 2017 in the United Kingdom had a functioning kidney transplant while 37% were on centre HD and 7% were on home dialysis modalities (5% PD and 2% 21.7 Renal replacement therapy

section 21  Disorders of the kidney and urinary tract 4862 home HD). There has been a dramatic expansion in the number of prevalent patients receiving these different forms of RRT in all de- veloped countries over the past four decades, which is exemplified by Fig. 21.7.1.1 which shows the RRT modality of all established renal failure patients in Scotland from 1973 to 2013. Long-​term patient survival in incident HD patients of all age groups has increased gradually during the past 20 years along with progressive improvements in delivered dialysis dose and supportive medical care. There also has been progressive expansion in the number of satellite HD units to make centre HD available more lo- cally. The small rise in home HD observed in the United Kingdom and North America has been prompted by recognition of the ad- vantages of home HD, particularly if this provides more frequent HD sessions than the traditional three sessions per week provided in HD units. Nevertheless, HD provision faces many ongoing challenges. Reliable vascular access is the cornerstone of adequate HD and most renal units fail to achieve the audit measure of 80% of preva- lent HD patients using a functioning arteriovenous fistula or graft for vascular access. Within the UK 14–18% of patients each year still present to the local renal service within 3 months of needing to commence RRT and so have little opportunity for arteriovenous fistula creation and its maturation for use for vascular access prior to starting HD. The prevalent HD population is ageing and has major comorbidity, particularly from coexisting vascular disease, diabetes, depression, and cognitive impairment. Concomitant comorbidity has led to optimum medical conservative care being considered a better option than RRT for an increasing proprotion of patients with progressive stage 5 chronic kidney disease (see Chapter 21.6). Worsening quality of life associated with progressive coexisting or new comorbidity may lead to some patients wishing to withdraw from ongoing HD in the knowledge that without HD they will not survive for long. Consequently, the prevalent HD population within the United Kingdom is growing very slowly, whereas the kidney transplant population continues to expand every year (Fig. 21.7.1.1). This chapter outlines the main issues required for delivering high-​ quality HD and maintaining patient safety on HD and highlights the randomized clinical trials that have influenced current medical practice. Principles of haemodialysis HD requires an integrated machine with the following essential components (Fig. 21.7.1.2): • A pump to deliver blood from the vascular access to the dialyser • A dialysate concentrate proportionating system to prepare dialysis fluid from treated water and then deliver the dialysis fluid to the dialyser • Volumetric control of fluid removal (ultrafiltration (UF)) • A range of patient safety monitors and alarms HD uses the countercurrent flow of the blood and dialysate path- ways in the dialyser to maximize the concentration gradient for diffusive transport. Diffusive transport is greater for smaller and uncharged solutes. HD also uses a hydrostatic gradient across the dialyser membrane to induce UF of water and convective trans- port of solutes by solvent drag. The diffusive and convective trans- port of solutes leads to net removal of urea, creatinine, potassium, and phosphate in the dialysate and uptake of bicarbonate from the dialysate (Fig. 21.7.1.3). The permeability of the membrane to larger solutes, such as vitamin B12 or β2-​microglobulin, is used to

218 343 545 1006 1441 384 438 351 426 774 1132 1406 1724 0 500 1000 1500 2000 2500 3000 3500 4000 4500 1973 1978 1983 1988 1993 1998 2003 Number of patients Year 1773 1810 2044 2505 2008 2013 Transplant APD CAPD Home HD Hospital HD Fig. 21.7.1.1  Renal replacement therapy modality of all established (chronic) renal failure patients in Scotland from 1973 to 2013. APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; HD, haemodialysis. Reproduced from Scottish Renal Registry Report 2013. © NHS National Services Scotland/​Crown Copyright 2014.

21.7.1  Haemodialysis 4863 categorize dialyser membranes into low, mid, or high flux. Dialyser membranes have widely different capacity to permit flow of water across the membrane and the UF coefficient of dialysers range from 3 to greater than 60 ml/​min per hour per mmHg transmembrane hydrostatic pressure. Prescription of haemodialysis Small solute clearance rates The urea clearance rate will depend on whichever of the following prescription variables is the lowest (Fig. 21.7.1.3): • blood flow rate (250–​500 ml/​min) • dialyser urea mass transfer coefficient (300–​1100 ml/​min) • dialysate flow rate (500–​800 ml/​min) There has been a trend to prescribe higher blood flow rates (300–​ 450 ml/​min) and to use dialysers with higher urea mass transfer co- efficients to provide higher efficiency HD than in the past. The blood flow rate that can be achieved from the patient’s vascular access is the commonest rate-​limiting factor of urea clearance rates. The di- alysate flow rate should be at least 50% greater than the blood flow rate in single pass countercurrent flow HD. Increasing the dialysate flow rate to greater than 150% of the blood flow rate results in a rela- tively small increase in urea clearance rates, for example, a 60% rise in dialysate flow rates from 500 ml/​min to 800 ml/​min increases the rate of urea clearance by only 5 to 10% when the blood flow rate is 350 ml/​min. Choice of dialyser Hollow fibre dialysers are the only type of dialysers now being used. This type of dialyser permits blood flow within fibres made from a variety of membrane materials with countercurrent flow of the dia- lysis fluid enclosed within a rigid casing. Artery Vein Pressure monitor Pressure monitor Pump Anticoagulant Dialyser Air trap and detector Fig. 21.7.1.2  Schematic representation of the key components of the haemodialysis system. Direction of solute concentration gradient Direction of hydrostatic pressure gradient Semipermeable membrane Frequently used dialysate concentrations (mmol/L) Urea Potassium 1–2 135–140 1.25–1.50 35–40 Phosphate Sodium Blood flow rate 250–400 ml/min Dialysate flow rate 500–800 ml/min Calcium Bicarbonate Plasma water Fig. 21.7.1.3  Schematic representation of transmembrane solute and water transport in a haemodialyser.

section 21  Disorders of the kidney and urinary tract 4864 Biocompatible dialysis membranes Synthetic and modified cellulose membranes have been shown to be more biocompatible than unmodified cellulose membranes (Box 21.7.1.1). A systematic Cochrane review found no reduction in either mortality or dialysis-​related adverse symptoms when synthetic membranes were compared with cellulose/​modified cellulose mem- branes. Nevertheless, the use of biocompatible instead of unmodi- fied cellulose dialysers has been justified on the basis of the former dialysers’ biological benefits and equivalent costs. High-​ or low-​flux biocompatible dialysers The key decision when using more biocompatible, modified cel- lulose or synthetic membranes is whether to prescribe a low-​, mid-​, or high-​flux dialyser. A  multicentre, randomized con- trolled trial failed to show improvement of anaemia in stable HD patients treated over a 12-​week study period with high-​flux bio- compatible membranes instead of conventional cellulose mem- branes. One small prospective randomized study showed better preservation of residual renal function when using high-​flux membranes combined with ultrapure water. The proven benefits of high-​flux membranes in randomized trials are limited to ad- vantages arising from improved biocompatibility and enhanced removal of middle molecules, such as β2-​microglobulin, rather than better survival rates in patient groups. Evidence of improved patient survival with the use of high-​flux membranes is restricted to prevalent patients in the HEMO study who had been on HD for more than 3.7 years and incident patients in the Membrane Permeability Outcome (MPO) study who had lower serum albumin concentrations (<40 g/​litre) or had diabetes mellitus (Table 21.7.1.1). High-​flux dialysers are now used as standard in most HD centres. Risk of hypersensitivity reactions Dialysers sterilized with ethylene oxide have been associated with hypersensitivity or hypersensitivity-​like reactions. This risk can be avoided by using dialysers that have been sterilized using steam or gamma radiation. Treatment time on haemodialysis per week Weekly solute removal rates may be increased by either increasing the frequency and/​or duration of HD sessions per week. Frequency of haemodialysis HD frequency is a more powerful determinant of weekly solute re- moval than the duration of each session. Twice per week HD is not regarded as an adequate long-​term form of chronic RRT and should be avoided, although it may be acceptable provided: • the patient has a significant level of residual renal function (e.g. a mean of combined urinary urea and creatinine clearance above 5 ml/​min per 1.73 m2) • the patient’s residual renal function is monitored at least every 3 months • the frequency of dialysis is increased when renal function decreases The routine use of a three times per week HD schedule evolved from empirical considerations in the belief that it reconciled adequate treatment with adequate breaks between treatments to provide the patient with a reasonable quality of life within a 7-​day treatment cycle. It is common practice to prescribe daily HD in the short term when patients with chronic renal failure develop an acute intercur- rent illness or (rarely) pericarditis. Two forms of more frequent, long-​term HD have been advocated recently: • Short daily HD is usually prescribed as six ‘daily’ sessions of dia- lysis of 2 to 3 h duration with one rest day per week Box 21.7.1.1  Beneficial effects of biocompatible haemodialysis membranes • Lower activation of complement and leucocytes • Greater adsorption of cytokines • Greater adsorption of β2-​microglobulin • Higher flux and removal of middle molecules (e.g. β2-​microglobulin) Table 21.7.1.1  Randomized controlled trials of mortality rates with high-​ and low-​flux dialysers Study HEMO study MPO study Study design Prospective, multicentre, randomized controlled trial 1846 prevalent patients on HD for a median of 3.7 years 2 × 2 factorial study design: high-​ vs low-​flux and high-​ vs standard-​dialysis dose 10-​fold increase in β2-​microglobulin clearances in the high-​flux vs low-​flux groups Dialyser reuse permitted Prospective, multicentre, randomized controlled trial 738 incident HD patients Comparison of high-​ and low-​flux HD Stratified into two groups with serum albumin < or >40 g/​litre Few exclusion criteria No dialyser reuse Outcomes No differences were observed in all-​cause mortality between the high-​ and low-​flux groups or the high-​ and standard dialysis dose groups No difference was observed in all-​cause mortality in the high-​ and low-​flux groups Secondary analysis In the patient subgroup which had been on HD for longer than a median of 3.7 years before enrolment: a) use of high-​flux dialysis membranes was associated with a 32% reduction in all-​cause mortality (P = 0.001) b) use of high-​flux dialysis membranes was associated with a 37% reduction in cardiac death (P = 0.016) Survival rates in women randomized to the higher-​dose group were higher than women in the lower-​dose group (relative risk 0.81; P = 0.02) after adjusting for different indices of body size In the patient subgroup with serum albumin <40 g/​litre on enrolment: a) use of high-​flux dialysis membranes was associated with a reduction in all-​cause mortality (P = 0.032)

21.7.1  Haemodialysis 4865 • Nocturnal daily HD is usually prescribed as slow overnight treat- ment for 5 to 7 nights per week while the patient is sleeping Both forms of daily HD have been shown to provide a number of medical advantages compared with standard-​duration, thrice-​ weekly HD (Box 21.7.1.2). Short daily HD offers the additional benefit of higher weekly re- moval of small and large molecular weight solutes for the same total time on HD per week, while daily nocturnal daily HD provides: • very large doses of dialysis • greatly reduced need for phosphate binders • reduction in sleep disturbance and sleep apnoea The Frequent Haemodialysis Network daily study showed that the composite endpoints of death and change in left ventricular mass or death and change in physical health in 245 patients were im- proved on HD six days per week compared with thrice-​weekly HD. However, both the Frequent Haemodialysis Network daily and nocturnal trials showed that there was an increased risk of a first access event in the groups receiving HD on 6 days per week, presumed related to more frequent cannulation of the vascular access. Duration of haemodialysis It is difficult to separate the influence of dialysis duration and dose on patient outcomes. The National Co-​operative Dialysis Study (NCDS), an historical randomized trial in the United States of America when cellulose membranes and acetate dialysate were used, is the only randomized study so far to address the issue of optimal dialysis time. This two-​by-​two factorial design study randomized nondiabetic patients into one of four dialysis regimens: • Two with short (2.5–​3.5 h) dialysis times • Two with longer (4.5–​5.0 h) dialysis times • Two with different time-​averaged urea concentrations Longer dialysis times gave better but statistically insignificant sur­ vival rates. However, several observational studies have shown an association between risk of death and shorter dialysis duration (Box 21.7.1.3). These observations suggest that the duration of thrice-​weekly HD should not be reduced below 4 h unless the patient has significant residual renal function. A randomized controlled study of longer dialysis sessions in thrice-​weekly HD is needed. Dialysate composition Bicarbonate should be used as the buffer base. The concentration of components of dialysate may be altered, and an example of the components of a standard dialysis fluid is shown in Table 21.7.1.2. The potential for developing dialysis-​induced hypoglycaemia can be avoided if the dialysate contains glucose. Individualization of di- alysate potassium concentrations may be required in patients with a tendency to hypokalaemia, and adjustment of the dialysate sodium concentrations during HD (sodium profiling) may be beneficial in patients with haemodynamic instability. Ultrafiltration on haemodialysis The interdialytic fluid (weight) gain is removed under volumetric control by the HD machine making adjustments to the transmem- brane pressure to achieve the prescribed UF rate. Treatment time and UF rates are related inversely in HD. Higher rates of UF may be poorly tolerated and were associated with a greater risk of death in the Dialysis Outcomes and Practice Patterns Study (Table 21.7.1.3). Long-​term observational data from Tassin, France, have dem- onstrated that target ‘dry’ body weight and good control of blood pressure without antihypertensive medication are more likely to be achieved with long duration HD sessions and lower rates of UF. It is recommended that the UF rate should not exceed 10 ml/​kg body weight per hour. Box 21.7.1.2  Medical advantages of daily HD versus standard duration thrice-​weekly HD • Improved well-​being and better quality of life • Improved fluid balance and blood pressure control • Regression of left ventricular hypertrophy • Higher dietary protein intake and better nutritional status • Lower hospital admission rate • Reduced need for erythropoietin Box 21.7.1.3  Observational studies showing better patient outcomes with longer-​duration HD • Very low mortality rates were observed in patients treated with long-​ duration thrice-​weekly HD with mean Kt/​V of 1.67 ± 0.41 in Tassin, France. • Increments in dialysis duration up to 5.5 h were associated with im- proved patient survival rates in a large Japanese population after adjusting for dialysis dose. • Patients in the United States of America who received dialysis for less than 3.5 h per session three times per week had approximately twice the risk of death of patients on HD for more than 4 h three times per week. • The Dialysis Outcomes and Practice Patterns Study (DOPPS) has shown that patient survival, independent of dialysis dose, was greater in patients with treatment times above 4 h. • The Australian and New Zealand Dialysis and Transplant Registry has shown that patient survival, independent of dialysis dose, was greater in patients with treatment times above 4.5 h. Table 21.7.1.2  Representative concentrations of components of bicarbonate dialysis fluid Dialysate component Concentration in dialysis fluid (mmol/​litre) Chloride 108 Bicarbonate 35 Acetate 3 Sodium 138 Potassium 2 Calcium 1.25 Magnesium 0.5 Glucose 1

section 21  Disorders of the kidney and urinary tract 4866 Planning and initiating haemodialysis for established renal failure Patient education and patient choice are important aspects of predialysis care to ensure that patients are well prepared to start the RRT modality that is most suited to them in a timely fashion. United Kingdom Renal Registry data demonstrate that the mean estimated glomerular filtration rate (eGFR) at dialysis initiation increased linearly from 6.2 to 8.7 ml/​min per 1.73 m2 between 1997 and 2009, but this trend reversed after the publication in 2010 of the IDEAL (Initiation of Dialysis Early and Late) study, which randomized 828 incident adult patients commencing dialysis in 32 centres in Australia and New Zealand to receive dialysis early (eGFR 10–​12 ml/​min per 1.73 m2 based on the Cockcroft and Gault formula) or late (eGFR 5–​7 ml/​min per 1.73 m2) and showed no survival benefit from starting dialysis early before the onset of symptoms. Previous studies from Scotland and the Netherlands had suggested that any survival advan- tage from commencing dialysis earlier may be attributed to lead time bias. HD and other forms of RRT are usually now commenced when patients with progressive chronic kidney disease stage 5 (eGFR <15 ml/​min per 1.73 m2) develop persistent fluid overload despite diur- etics, persistent hyperkalaemia despite dietary potassium restriction, acidosis despite bicarbonate supplementation, or symptoms sug- gestive of uraemia such as poor appetite and gastrointestinal symp- toms. Progressive decreases in dietary protein intake and nutritional status as residual renal function declines may also be an indication to initiate dialysis. Based on this rationale the United Kingdom Renal Association Clinical Practice Guidelines recommend that the deci- sion to start RRT in patients with chronic kidney disease stage 5 (eGFR <15 ml/​min per 1.73 m2) should be based on ‘a careful discussion with the patient of the risks and benefits of RRT, taking into account the patient’s symptoms and signs of renal failure, nutritional status, comorbidity, functional status, and the physical, psychological and social consequences of starting dialysis in that individual’. The 2018 NICE guideline on renal replacement therapy and conservative man- agement recommends considering starting dialysis ‘when indicated by the impact of symptoms of uraemia on daily living, or biochemical measures or uncontrollable fluid overload, or at an estimated eGFR of around 5 to 7 ml/min/1.73 m2 if there are no symptoms’. Vascular access for haemodialysis Reliable and safe vascular access is a prerequisite for adequate HD. A native arteriovenous fistula is the preferred access in the great majority of HD patients as it provides the highest blood flow rates, minimizes the risk of sepsis, and has the greatest longevity. An ar- teriovenous graft is the second-​best option for long-​term vascular access. Tunnelled and nontunnelled central venous access are in- ferior options. The rate of vascular access-​related infection was 2.5 per 1000 dialysis sessions for patients with native fistulae or grafts, 13.6 per 1000 dialysis sessions for tunnelled central venous catheters, and 18.4 per 1000 dialysis sessions with temporary cen- tral venous catheters. The CHOICE study of 616 incident patients showed that the adjusted relative risk of death was 1.2 for an arterio- venous graft and 1.5 for a central venous catheter compared with the reference group with an arteriovenous fistula. Central venous catheters may, however, be the only option for some patients: some may have a needle phobia; others may have ves- sels unsuitable for creation of a functioning arteriovenous fistula or graft able to provide adequate blood flow rates and adequate HD. Patients may also run out of options for further fistula or graft cre- ation if the current fistula or graft fails and then need to rely upon a tunnelled central venous catheter to allow them to remain on HD or switch to PD. Many HD patients require multiple access procedures to enable them to stay on HD, hence vascular access continues to be HD’s Achilles’ heel. Adequacy of haemodialysis Adequacy of haemodialysis dose The molecular weights of the solutes to be cleared by dialysis range over three orders of magnitude, from small (water, urea) to large (β2-​microglobulin). Adequate clearance of the whole range of mol- ecules by dialysis is important and in the future monitoring of β2-​microglobulin levels may be used to assess dialysis adequacy. For practical reasons, adequacy of HD dosage thus far has been measured using small, easily measured solutes such as urea. Three methods of assessing urea removal on HD are in current use (Table 21.7.1.4): 1. The URR is the percentage fall in blood urea achieved by a dia- lysis session, is easy to perform, and is the most widely employed index of dialysis dose used in the United Kingdom. URR does not take into account solute removal via UF or residual renal function or urea generation during dialysis. However, this is un- important clinically if the main aim of measuring small solute removal by HD is to ensure that a minimum target dialysis dose is delivered consistently. A number of large observational studies in populations of HD patients have shown that variations in URR are associated with major differences in mortality and have led to recommendations that the URR should be at least 65%. 2. Kt/​V urea can be predicted from several simple formulae and, if Kt/​V is being used for comparative audit, it is important that the raw data are collected to allow calculation of estimated Kt/​ V using a single formula. The formula validated and reported by Daugirdas is recommended (Table 21.7.1.4). 3. Urea kinetic modelling (UKM), the most complex measure, in- volves analysis of the fall in blood urea concentration during HD, the rise in blood urea in the interdialytic period, clearance of urea by residual renal function, and the total clearance pre- dicted from the dialyser clearance, blood and dialysate flow, time on dialysis, and fluid removal during dialysis. Kt/​V measured by Table 21.7.1.3  Ultrafiltration rate and survival rates in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Study design Observational international study of risk of death in 22 000 HD patients Outcomes adjusted for demographics, comorbidity, dialysis dose (including RRF) and body size Outcomes UFR >10 ml/​h per kg was associated with higher risk of intradialytic hypotension (RR = 1.3; P = 0.045) UFR >10 ml/​h per kg was associated with higher risk of death (RR = 1.1; P = 0.02) RR, relative risk; RRF, residual renal function; UFR, ultrafiltration rate.

21.7.1  Haemodialysis 4867 formal UKM is more accurate than URR, particularly at high values of URR and Kt/​V. Its use allows accurate prediction of the effects of changing one particular component of the dialysis pre- scription (e.g. dialyser size, dialysis duration, blood flow rate) on the delivered dialysis dose, although this benefit has been over- stated given the limited number of practical options for chan- ging the dialysis prescription. Most United Kingdom HD units only collect pre-​ and postdialysis urea concentration, and only a few perform UKM. For comparative audit, the choice therefore currently lies between calculation of URR and estimation of Kt/​V urea from such data. All methods of assessing urea removal depend upon an accurate measurement of the blood urea concentrations after HD. Postdialysis rebound in blood urea concentration results from cardiopulmonary recirculation of treated blood returning from the extracorporeal cir- cuit and from continuous return of blood from poorly dialysed body ‘compartments’. Accurate comparison of delivered dialysis dose therefore requires estimation of the equilibrated blood urea concen- tration, allowing calculation of URR and ‘equilibrated’ Kt/​V (eKt/​ V). Full re-​equilibration takes about 30 min, but it is impractical to ask patients to wait this long for postdialysis blood sampling on a routine basis. The amount of rebound is determined by several fac- tors including the efficiency of dialysis and the size of the patient. Formulae have been validated for predicting 30-​min postdialysis or ‘equilibrated’ blood urea from blood samples using either the stop dialysate flow method (or similar sampling methods) or the slow flow method. Utilizing one of these methods was recommended in the latest updates of the United Kingdom Renal Association and Kidney Disease Outcomes Quality Initiative (KDOQI) clinical prac- tice guidelines on HD. Doubts have been raised about Kt/​V being a good index of dialysis dose since survival rates on HD are higher in patients with larger body size and better nutrition, even though this patient group tends to have lower Kt/​V values. Non-​normalized dialysis dose (Kt) has been proposed as an alternative and a better index of dialysis dose to Kt/​V since the former index obviates the trend for smaller pa- tients with poorer nutritional status to be accorded a higher dialysis dose. In a large cross-​sectional analysis using Kt as the index of dia- lysis dose, mortality risk was observed to fall if the delivered dialysis dose was a minimum Kt of 42 litres in women and 48 litres in men. A further difficulty with the use of the Kt/​V index for other than thrice-​weekly HD is that the significance of any weekly Kt/​V value depends on the frequency of dialysis since more frequent dialysis therapies, such as daily HD, will deliver greater small solute removal at the same weekly Kt/​V. Minimum and target dialysis dose The optimal dialysis dose has not been well defined, but minimum targets of delivered dose measured by URR and Kt/​V have been es- tablished. Observational studies have shown a reduction in mor- tality rates with increases in dialysis dose or no further reduction in mortality above Kt/​V of 1.3 or URR of 70%. These studies led to the HEMO trial (Table 21.7.1.1) which showed no difference in patient survival or secondary endpoints between the high-​ and standard-​ dose groups, even though dialysis doses were well separated with achieved eKt/​V of 1.16 in the standard-​dose group (URR 66.3 ± 2.5%) and eKt/​V of 1.53 in the high-​dose group (URR 75.2 ± 2.5%). Based upon this evidence, the minimum dialysis dose delivered thrice weekly should have a URR of 65% or an eKt/​V of 1.2 (cal- culated from pre-​ and postdialysis urea values, duration of dialysis, and weight loss during dialysis). To achieve a URR above 65% or eKt/​V above 1.2 consistently in most patients, the minimum target doses should be a URR of 70% or eKt/​V of 1.4 in individual patients. An association between higher dose and lower mortality rates was observed in women but not in men in the HEMO study and was confirmed using the URR of incident patients in the United States of America and eKt/​V of patients in the DOPPS data from seven countries. Aiming for these target doses also addresses the concerns raised by recent data that suggest that women and patients of low body weight may have improved survival rates if the URR is main- tained above 70% or eKt/​V is at least 1.4. Definition of adequacy of dialysis In addition to measurement of dialytic clearance of urea, global as- sessment of the adequacy of all aspects of the HD treatment is re- quired to optimize patient outcomes. This should include a clinical assessment of the patient’s general well-​being, nutritional status, monitoring of biochemical and haematological parameters, quality of life, blood pressure, and fluid status. Large observational studies have shown that patient survival in patients on thrice-​weekly HD is highest when predialysis biochem- ical and haematological measurements are maintained within the Table 21.7.1.4  Methods of measuring urea removal on haemodialysis to assess adequacy of dialysis Method Required input data Calculations Urea reduction ratio (URR) Pre-​HD urea concentration Post-​HD urea concentration (Pre-​HD urea − post-​HD urea) /​pre-​HD urea × 100% Kt/​V urea Pre-​HD urea concentration Post-​HD urea concentration Duration of HD Weight loss during HD See: Daugirdas JT (1993). Second generation logarithmic estimates of single-​pool variable volume Kt/​V; an analysis of error. J Am Soc Nephrol, 4, 1205–​13 Urea kinetic modelling (UKM) Pre-​HD urea concentration Post-​HD urea concentration Duration of HD Weight loss during HD Dialyser clearance Interdialytic urine collection for measurement of urea concentration and volume Pre-​HD urea concentration in the subsequent dialysis Data are uploaded on a computer programme which, assuming steady state, calculates Kt/​V urea and normalized protein catabolic rate

section 21  Disorders of the kidney and urinary tract 4868 target ranges shown in Table 21.7.1.5, and these parameters are audited routinely by local renal units and nationally by the United Kingdom Renal Registry in ongoing efforts to improve the quality of delivered HD. Observational studies have shown an association between ex- cessive interdialytic fluid gains and reduced survival rates. The im- pact of blood pressure control on HD patient survival is uncertain as patients with hypotension have lower life expectancy than pa- tients with uncontrolled hypertension. In particular, the frequency of dialysis-​related hypotension, defined as an acute symptomatic fall in blood pressure during dialysis requiring immediate inter- vention to prevent syncope, is an indicator of poor prognosis for survival in HD patients. This may reflect underlying overt or occult cardiac disease in patients with dialysis-​related hypotension. The achievement of clinical practice guidelines is dependent on patients’ concordance with treatment. Increasing patients’ under- standing of the benefits of delivering all aspects of optimal dialysis, including adequate dialysis dose and creation of native vascular ac- cess, may help to improve outcomes. Patients are often reluctant to increase HD duration if the delivered dialysis dose is inadequate des- pite increasing the dialyser blood flow rate, dialysate flow rate, and dialyser performance to the maximum that can be achieved, and pa- tients with a central venous catheter may be unwilling to have an ar- teriovenous fistula created. Data from the DOPPS have evaluated the relative risk of death of HD patients who fail to meet clinical practice guidelines for five modifiable clinical variables (Table 21.7.1.6). This observational data suggests that the use of central venous catheters for vascular access and nutrition/​inflammation are at least as im- portant as adequate dialysis dose or control of hyperphosphataemia in influencing patient survival rates. Factors affecting patient safety on haemodialysis Haemodialysis machine monitors and alarms HD machines must be serviced and maintained in full working order at all times to ensure that all of the safety monitors and alarms shown in Box 21.7.1.4 are functional. Table 21.7.1.5  United Kingdom Renal Association clinical practice guidelines for haemodialysis Audit variable Recommendation Nondialytic measures Urea clearance by HD Minimum target URR 70% or minimum target eKt/​V 1.3 Fluid removal rate by HD Less than 10 ml/​kg/​h Dietary fluid and sodium restriction Pre-​HD serum potassium concentration Less than 6 mmol/​litre Dietary restriction Pre-​HD haemoglobin concentration in patients receiving erythropoietin stimulating agents 10–​12 g/​dl Erythropoietin, iron supplementation Pre-​HD serum phosphate concentration 1.1–​1.7 mmol/​litre Dietary restriction, phosphate binders, calcimimetic medication Pre-​HD serum calcium concentration (adjusted for serum albumin) 2.2–​2.5 mmol/​litre Alfacalcidol, calcimimetic medication Serum parathyroid hormone 2–​9 times the upper limit of the normal range of the assay Control of serum phosphate and calcium, parathyroidectomy Pre-​HD serum bicarbonate concentration 20–​26 mmol/​litre Vascular access in incident HD patients 60% should have functioning arteriovenous accessa Vascular access in prevalent HD patients 80% should have functioning arteriovenous accessa a Arteriovenous fistula or arteriovenous graft. Table 21.7.1.6  Adjusted relative risk of mortality of patients who fail to achieve clinical practice guidelines (DOPPS I and DOPPS II; international) and percentage of British patients outside each guideline or practice pattern (United Kingdom DOPPS II data only) Modifiable practice pattern Level at which clinical practice guideline parameter was achieved Mortality relative risk (RR) Patients outside range (%) RR P-​value Dialysis dose Single pool Kt/​V <1.2 1.13 0.0023 17.8 Anaemia management Haemoglobin <10 g/​dL 1.21 <0.0001 21.5 Mineral metabolism PO4 >1.8 mmol/​litre 1.11 0.001 41.6 Nutrition/​inflammation Albumin <35 g/​litre 1.48 <0.0001 36.6 Vascular access Facility catheter use >10% 1.20 <0.0001 76.8

21.7.1  Haemodialysis 4869 Vascular access Integrity of the extracorporeal blood circuit is paramount for patient safety on HD. Dislodgement of vascular access needles or catheters and disconnection of the HD lines should be very uncommon com- plications of HD and should be detected promptly if they do occur. Patients are at risk of exsanguination following dislodgement of the venous needle or line as the patient will continue to lose blood at the rate of the blood pump speed unless the HD venous pressure alarm or blood detect device is activated. Anticoagulation during haemodialysis Extracorporeal anticoagulation is usually required to prevent thrombosis of the dialyser and extracorporeal circuit (Box 21.7.1.5). Reuse of dialysers Dialysers are generally marked for ‘single use only’, although some are designed for multiple use in an individual patient. Reprocessing of dialysers for reuse is a combination of cleaning, disinfection, and sterilization processes. Changing from multiple to single use of dialysers has been reported to result in a reduction in the mor- tality rate in a large population in the United States of America, and the cost of high-​flux dialysers has fallen gradually such that the use of high-​flux biocompatible dialysers is now cost-​effective without reuse. Water quality for haemodialysis Quality assurance of the water used in the preparation of dialysis fluid is of paramount importance as HD exposes the blood of the pa- tient to more than 300 litres of water per week through a nonselective dialyser membrane, in contrast to an average of 12 litres per week through a highly selective membrane (intestinal tract) in healthy in- dividuals. Intact dialyser membranes have been shown to be perme- able to bacterial contaminants as well as permitting backdiffusion and backfiltration of chemical contaminants from the dialysate. Table 21.7.1.7 summarizes the quality standards for testing for chemical and microbiological contaminants in the water used in the preparation of dialysate that have been endorsed by the Association of Renal Technologists and United Kingdom Renal Association. Achieving this standard of treated water purity usually requires soft- ening, carbon filtration, reverse osmosis, and an effective disinfec- tion programme for all pipework between the treatment plant and dialysis machines. Sodium is included in the ‘mandatory’ group be- cause, although the drinking water limit is 200 mg/​litre, additional sodium is introduced by softening. Ultrapure water (defined as <0.1 cfu/​ml and bacterial endo- toxins <0.03 IU/​ml) is readily achievable using modern water treat- ment techniques and should be regarded as the standard for all newly installed water treatment plants. The European Best Practice Guidelines recommend the use of ultrapure water for conventional as well as high-​flux HD. Reinfusion fluid, used in haemofiltration (HF) and haemodiafiltration (HDF), must be sterile (<1 cfu/​1000 litres) and, particularly where large exchange volumes are required, have an endotoxin level of less than 0.03 IU/​ml. Even with ultrapure water, this standard of purity can only be achieved by ‘online’ fluid production with multiple filtration of the dialysis fluid. Machines designed to produce reinfusion fluid usually require a water supply that meets the microbiological requirements of Table 21.7.1.7. Patient safety on HD has been jeopardized when the water supply used in the preparation of dialysis fluid has been inadvertently Box 21.7.1.4  Haemodialysis machine monitors and alarms • Blood pump speed (nominal dialyser blood flow rate) • Arterial pressure monitor and alarm • Dialysate conductivity monitor and alarm • Dialysate temperature monitor and alarm • Venous air detect alarm and air trap • Venous pressure monitor and alarm • Temperature and conductivity monitor • Ultrafiltration rate and volume • Heparin infusion pump • Dialysate blood leak detector and alarm • Blood pressure monitor (optional) • Ionic dialysance or online urea clearance for dialysis dose (optional) Box 21.7.1.5  Anticoagulation used for haemodialysis • Unfractionated heparin (with a mean half-​life of 1.5 h) is best admin- istered as a loading dose followed by a continuous or bolus infusion of 500–​1500 units/​h that is discontinued approximately 30 min before the end of the dialysis session in patients using an arteriovenous fistula or graft. • Low molecular weight heparin is a commonly used alternative agent that has been associated with less frequent episodes of hyperkalaemia and an improved lipid profile than standard heparin. • A systematic review of 11 trials comparing the use of low molecular weight heparin and unfractionated heparin in HD patients concluded that there was no difference in the incidence of bleeding complica- tions, bleeding from the vascular access after HD, or thrombosis of the extracorporeal circuit. • The dosage of heparin may need to be increased if there has been a substantive rise in the haematocrit or reduced if the patient is on war- farin or antiplatelet drugs. • For patients with heparin-​induced thrombocytopenia either heparinoids (danaparoid) or hirudin should be utilized instead of heparin. Table 21.7.1.7  Maximum recommended concentration of chemical and microbial contaminants in water for dialysis for which routine testing is mandatory Contaminant Maximum recommended concentration (mg/​litre = ppm) Initial test frequency Aluminium 0.01 3-​monthly Calcium 2 (0.05 mmol/​litre) 3-​monthly Total chlorine 0.1 Not less than weekly Copper 0.1 3-​monthly Fluoride 0.2 3-​monthly Magnesium 2 (0.08 mmol/​litre) 3-​monthly Nitrate (as N) 2 (equates to 9 mg/​litre NO3) 3-​monthly Potassium 2 (0.05 mmol/​litre) 3-​monthly Sodium 50 (2.2 mmol/​litre) 3-​monthly Bacteria (TVC) 100 cfu/​ml Not less than monthly Endotoxin 0.25 IU/​ml Not less than monthly

section 21  Disorders of the kidney and urinary tract 4870 contaminated by aluminium, fluoride, chlorine (or chloramine), or hydrogen peroxide. Haemofiltration HF is an alternative form of extracorporeal dialysis that removes solutes by convection rather than diffusion (as in HD). The highly permeable membrane in the haemofilter allows UF of large volumes of fluid that is measured gravimetrically and replaced by infusion of the substitute fluid either into the arterial line (predilutional HF) or the venous line (postdilutional HF). HF is not commonly used as a mode of chronic RRT because ad- equate intermittent HF requires large exchange volumes (40% of body weight three times per week), high blood flow rates (350–​450 ml/​min), and additional costs. However, continuous or daily HF is often performed instead of daily HD for management of acute kidney injury (AKI) in many critical care settings since continuous HF can maintain fluid balance and may promote cardiovascular stability. Haemodiafiltration HDF is a hybrid of HD and HF in which a convective volume of ap- proximately 24 litres/​session is removed through the haemodiafilter and physiological ‘replacement’ fluid equal to the removed volume minus the desired weight reduction (usually the interdialytic fluid gain) is returned to the blood before (predilutional) or after (postdilutional) the haemodiafilter (Fig. 21.7.1.4). HDF offers the advantage of increasing middle-​molecule clearances without the need for an increase in treatment time by superimposing convective removal of middle molecules onto the diffusive removal of the HD technique. As well as removal of ‘unwanted’ larger solutes, such as β2-​microglobulin, HDF removes ‘wanted’ solutes, such as amino acids and small proteins. Vitamin B12 supplements are often re- quired in patients receiving long-​term HDF. Several randomized controlled trials have compared mortality rates on HD and HDF (Table 21.7.1.8). The Turkish and CONTRAST studies failed to show a beneficial effect of HDF on all-​cause mor- tality and cardiovascular events, but the ESHOL study showed that high efficiency online HDF is associated with a 30% reduction in all-​ cause mortality compared with high-​flux HD and a 46% mortality reduction for the subgroup of HDF patients removing convection volumes of greater than 25 litres/​session. A post hoc analysis of these three studies suggested a dose–​effect relation: the higher the con- vection volume, the lower the mortality risk. The EUDIAL working group’s systematic review of six randomized controlled trials from 1996 to 2013 concluded that current evidence suggests that online HDF provides lower all-​cause and cardiovascular mortality rates than HD. At present, HDF is mainly performed in Europe and is performed infrequently in the United States of America. Renal replacement therapy for acute kidney injury and poisoning When to start RRT? HD may need to be performed as an emergency in patients with life-​threatening AKI or poisoning, or in patients with chronic renal failure who present late and in extremis. The typical indications for emergency HD are severe hyperkalaemia, severe metabolic acid- osis, fluid overload refractory to diuretics, and/​or symptoms of renal failure. Patients with a dialyzable poisoning (lithium, sali- cylate, methanol, ethylene glycol) who are at risk of death or ser- ious complications if treatment is limited to full supportive care and medical therapy may also require emergency HD. It is unproven if early initiation of HD offers clinical or survival benefits in pa- tients with gradually progressive chronic renal failure and so there is no specific level of residual renal function at which HD should be commenced. Which modality of RRT? Currently there is no evidence to show if continuous or intermit- tent dialysis therapies provide better survival in patients with AKI. In a randomized dose-equivalent, prospective study of continuous venovenous HD versus intermittent HD in 80 intensive care unit patients with AKI, the continuous venovenous HD group had no improvement in patient survival or recovery of renal function. Extended daily HD and postdilutional continuous venovenous HF are commonly utilized in the management of AKI. Both provide long duration therapy to help maintain adequate fluid balance and minimize adverse haemodynamic effects in this critically ill group, and the choice of modality of RRT should be based on local experi- ence and expertise in the technique and clinical needs of the indi- vidual patient. Which dialyser membrane to use? Initial randomized studies showed that the use of high-​flux biocom- patible membranes was associated with improved patient survival rates in AKI, but this was not confirmed in follow-​up studies. Fig. 21.7.1.4  Comparison of high-​flux haemodialysis and haemodiafiltration. Flow rates indicated in red and blue are ml/min

21.7.1  Haemodialysis 4871 Which dialysis dose to prescribe? There have been two large, prospective, multicentre, randomized trials comparing dialysis dose in AKI: these showed no benefit from higher dialysis doses (Table 21.7.1.9). The intensive dialysis doses used in these studies were the same as an earlier randomized study of continuous venovenous HF which had shown improved survival in patients prescribed at least 35 ml/​h per kg body weight. Centre haemodialysis versus home haemodialysis The National Institute for Health and Care Excellence (NICE) guide- line NG107 (2018) recommended that all suitable patients should be offered the choice between home and in-centre dialysis. Home HD also offers the medical advantages arising from performing home HD more frequently than three times per week Home haemodialysis versus peritoneal dialysis In most countries, patient choice of dialysis modality is limited to patients who are able to perform dialysis at home. Observational studies have shown that short-​term survival rates of patients on home HD and PD are similar, but technique survival is much poorer on PD, mainly because of catheter-​related infections and inadequate dialysis. Home HD has several advantages in comparison with PD tech- niques (Table 21.7.1.10). Provided the above-​mentioned requirements are met, home HD may be considered more suitable for patients with large body weight or body mass index, low residual renal function, heavy pro- teinuria and/​or hypoalbuminaemia, or previous major abdominal surgery. Complications of haemodialysis Access-​related infections The relative risk of bacteraemia in a large prospective cohort of in- cident HD patients was 1.95 for HD with tunnelled catheters and 1.05 for HD with grafts when compared to patients with an arterio- venous fistula. Infection-​related hospitalization in the HEMO study was also shown to be more frequent in patients relying on central venous catheters for vascular access, and was not reduced by the use of high-​flux dialysers or a higher dialysis dose. Vascular access using central venous dialysis catheters is also associated with a higher risk of central venous stenoses and lower blood flow rates. Loss of pa- tency of central venous catheters is common. The incidence of bacteraemia in a prospective study of nontunnelled HD catheters was 5% after 3 weeks of placement in the internal jugular vein. Cuffed, tunnelled rather than nontunnelled central venous catheters are preferred if vascular access is likely to be required for more than 3 weeks since tunnelled catheters are as- sociated with a lower rate of infection and can provide higher blood flow rates. Dialysis-​related symptomatic hypotension Hypotension is the most frequent complication of HD and can shorten treatment times, thus reducing the delivered dialysis dose. It is important to exclude a range of uncommon alternative Table 21.7.1.8  Randomized controlled trials of mortality rates in HDF and HD Study CONTRAST study ( J Am Soc Nephrol, 2012, 23, 1087–​96) TURKISH study (Nephrol Dial Transplant, 2013, 28, 192–​202) ESHOL study ( J Am Soc Nephrol, 2013, 24, 487–​97) Enrolled patients (N) 714 782 906 Follow-​up (years) 3 2 1.9 Blood flow rate (ml/​min) 300 310 387 Treatment time (min) 226 236 236 HDF convective volume (litres) 20.7 20.7 23.7 HD membrane flux Low flux High flux Mainly high flux All-​cause mortality rate (HDF vs HD) 12.1% vs 12.8%; n.s. 7.0% vs 8.8%; n.s. 6.2% vs 9.0%; P <0.05) Table 21.7.1.9  Randomized controlled trials of the effect of intensity of dialysis dose on mortality rates in AKI Study Veterans Affairs/​National Institutes of Health Acute Renal Failure Trial Network (ATN) study Randomized Evaluation of Normal versus Augmented Level (RENAL) study Study Design 1124 patients High-​dose (HD 6 days per week with Kt/​V 1.2–​1.4 or CRRT with effluent flow 35 ml/​kg per hour vs Standard dose (HD 3 days per week with Kt/​V 1.2–​1.4 or CRRT with effluent flow 20 ml/​kg per hour) 1508 patients High dose (CRRT with effluent flow 35 ml/​kg per hour vs Standard dose (CRRT with effluent flow 20 ml/​kg per hour) Outcome 60-​day mortality was the same in both groups (53.6% with high-​dose and 51.5% with low-​dose therapy) 90-​day mortality was the same in both groups (44.7% with high-​dose and 44.7% with low-​dose therapy)

section 21  Disorders of the kidney and urinary tract 4872 causes whenever a patient develops hypotension on dialysis. These include cardiac disease (arrhythmias, myocardial infarction, pericardial tamponade), autonomic neuropathy, occult haemor- rhage, septicaemia, dialyser reactions, air embolism, and acute haemolysis. Dialysis-​related hypotension is an independent predictor of poor patient survival and patients experiencing frequent dialysis-​related hypotension are at higher risk of death, probably because dialysis-​ related hypotension is a marker of severe cardiac disease. The risk of dialysis-​related symptomatic hypotension can be reduced by several strategies (Box 21.7.1.6). A systematic review of 22 studies concluded that a reduction in dialysate temperature is effective in decreasing the incidence of intradialytic hypotension without af- fecting dialysis adequacy. An increase in the dialysis treatment time combined with a reduction in the fluid UF rate or a decrease in the dialysate fluid temperature are the most reliable methods of redu- cing intradialytic hypotension. Dialysis-​related haemorrhage Bleeding from an arteriovenous fistula or graft or from the gastro- intestinal tract is not uncommon in HD patients. Caution is required with the use of anticoagulants during HD and heparin locking solu- tions in patients with central venous catheters. Anticoagulation can be avoided or kept to a minimum by using a high blood flow rate and regular flushing of the extracorporeal circuit with saline every 15 to 30 min. Alternatively, heparin may be replaced by regional cit- rate anticoagulation, but this requires monitoring of serum calcium levels and replacement of calcium during HD, which is too complex for routine use. Thrombocytopenia is common in patients on heparin and usu- ally mild and transient (HIT-​I). True heparin-​induced thrombo- cytopenia (HIT-​II) is a rare (1–​4%) but potentially life-​threatening syndrome caused by platelet-​activating antibodies to complexes of platelet factor 4 (PF4) and heparin. Characteristic features are thrombocytopenia, a systemic reaction within 30 min of intravenous unfractionated heparin administration, and a hypercoagulable state with a high risk of thromboembolic complications. Severe thrombo- cytopenia and/​or thrombosis in a patient on unfractionated hep- arin should raise strong suspicions. The presence of antiheparin/​ PF4 antibody is confirmatory in these circumstances, in which case unfractionated heparin and low molecular weight heparin should be avoided. Danaparoid and argatroban are probably the best alternatives. Acute haemolysis This uncommon complication should be suspected if the patient develops backache, chest tightness or breathlessness, and blood in the venous line has a port-​wine appearance or there is pink plasma in the venous chamber. This complication may be due to excessive dialysate temperature, kinking of the venous line, or water contam- ination with chloramines, nitrates, or copper. Air embolism This life-​threatening complication should be prevented by the machine alarms if a disconnection of the arterial line or arterial access occurs. Foam is often seen in the dialysis lines and the com- monest symptoms are chest tightness if the patient is recumbent and impaired conscious level or seizures if the patient is sitting upright. If suspected, the blood pump should be stopped, the venous line clamped immediately, and the patient placed in the recumbent position on their left side and with their head tilted downwards. Dialyser reactions Chemical sterilization of dialysers and tubing with ethylene oxide has been associated with anaphylactoid reactions. This risk is now avoided by the routine use of either steam or gamma radiation-​ sterilized dialysers and blood lines. Dialysis disequilibrium Nausea, vomiting, restlessness, headache, confusion, drowsiness, and, more rarely, seizures may occur during or shortly after dia- lysis when patients with advanced chronic renal failure receive high-​intensity dialysis. As symptoms result from cerebral oedema, presumed due to disequilibrium between cerebral water and blood water solute or hydrogen ion concentrations, this syndrome can be avoided by the use of incremental dialysis dosing when patients start HD, for example, 2 h, 3 h, and then 4 h of treatment for the first three dialysis sessions. Table 21.7.1.10  Comparison of home HD versus PD Advantages of home HD Disadvantages of home HD Higher doses of therapy per unit time Need for a designated treatment room or portacabin at home Ability to prescribe ultrafiltration volume Need for anticoagulation and risk of bleeding No need for peritoneal access Need for vascular access Quality control of the dialyser membrane as well as the dialysis fluid and
no loss of dialysis efficiency with time Training of the patient is more difficult and requires more time Lower daily protein losses Most home HD training centres require that the patient has a helper at home Box 21.7.1.6  Strategies to reduce the risk of dialysis-​related hypotension • Increase postdialysis target weight if the patient is assessed as below ‘dry’ weight • Reduce interdialytic weight gain by patient reducing interdialytic fluid and salt intake • Decrease the rate of fluid removal • Reduce food intake during dialysis • Avoid the administration of blood pressure-​lowering medication be- fore dialysis • A reduction in dialysate temperature during dialysis • Increase dialysate sodium concentration (but this may increase interdialytic weight gain)

21.7.1  Haemodialysis 4873 Hyperkalaemia Performing an urgent electrocardiogram is of proven use in guiding management of patients with serum potassium concentrations greater than 6 mmol/​litre and can be used to determine which pa- tients should receive emergency medical treatment and/​or HD for hyperkalaemia (see Chapter 21.5). Hyperkalaemia is a common indication for emergency dia- lysis among patients already on HD and accounts for 3 to 5% of deaths among dialysis patients in general. Noncompliance with the dialysis prescription and diet are the commonest contribu- tory factors, but medications such as angiotensin-​converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal anti-​inflammatory drugs, β-​blockers, and potassium supplements may be implicated. HD is the most appropriate emergency treatment for hyper­ kalaemia in the dialysis patient. The serum potassium level usually falls by 1 mmol/​litre during the first hour of treatment and by a fur- ther 1 mmol/​litre during the next 2 h. The rate of potassium removal is increased by using a higher dialyser blood flow rate, higher di- alysate bicarbonate concentration, or lower dialysate potassium concentration. Dialysis-​related amyloidosis Dialysis-​related amyloidosis is a disabling, progressive condition caused by the polymerization of β2-​microglobulin within tendons, synovium, and other tissues. β2-​microglobulin is a large molecular weight molecule (molecular weight 11 600 Da) released into the cir- culation as a result of normal cell turnover and not excreted in renal failure. It is not removed by cellulose membranes and exposure to bioincompatible membranes may increase β2-​microglobulin gen- eration. Symptoms are usually first reported 7–​10 years after com- mencing HD, although tissue accumulation of dialysis-​related amyloid in the joints and bone is demonstrable much earlier. The most common clinical presentations of dialysis-​related amyloid are shown in Box 21.7.1.7. Symptoms from dialysis-​related amyloidosis may occur earlier if patients have no significant residual renal function or are eld- erly at the onset of dialysis, and impure dialysis fluid has been implicated in the pathogenesis. High-​flux HD membranes re- move β2-​microglobulin by a combination of diffusive clearance and adsorption, and HDF removes substantially more as a result of additional convective clearance. HDF has been recommended for use in patients who are not suitable for transplantation or are predicted to remain on dialysis for at least 3.7 years. Renal trans- plantation usually results in improvement in amyloid-​related symptoms. Incidence and prevalence of comorbid medical conditions The incidence and prevalence of a wide range of comorbid medical conditions is increased in HD patients. These include ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, falls and fractures, infective endocarditis, and metastatic staphylo- coccal infections. The management of these medical complications is similar to standard clinical practice but needs to take account of a reduction in the dosage of renally excreted drugs and allow for drug removal by dialysis therapy. FURTHER READING Randomized controlled trials in haemodialysis Astor BC, et al. (2005). Type of vascular access and survival among incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study. J Am Soc Nephrol, 16, 1449–​55. Augustine JJ, et al. (2004). A randomized controlled trial comparing intermittent with continuous dialysis in patients with acute renal failure. Am J Kidney Dis, 44, 1000–​7. Cheung AK, et al. (2006). Serum beta-​2-​microglobulin levels predict mortality in dialysis patients: results of the HEMO study. J Am Soc Nephrol, 17, 546–​55. Cooper BA, et al. (2010). A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med, 363, 609–​19. Eknoyan G, et al. (2002). Effect of dialysis dose and flux on mortality and morbidity in maintenance hemodialysis patients: primary re- sults of the HEMO study. N Engl J Med, 347, 2010–​19. Grooteman MPC, et al. (2012). Effect of online hemodiafiltration on all cause mortality and cardiovascular outcomes. J Am Soc Nephrol, 23, 1087–​96. Karamperis N, Sloth E, Jensen JD (2005). Predilution hemofiltration displays no hemodynamic advantage over low-​flux hemodialysis under matched conditions. Kidney Int, 67, 1601–​8. Maduell F, et  al. (2013). High efficiency postdilution online hemodiafiltration reduces all-​cause mortality in hemodialysis pa- tients. J Am Soc Nephrol, 24, 487–​97. Ok E, et  al. (2013). Mortality and cardiovascular events in online haemodiafiltration (OL-​HDF) compared with high-​flux dialysis: re- sults from the Turkish OL-​HDF Study. Nephron Dial Transplant, 28, 192–​202. RENAL Replacement Therapy Study Investigators, et  al. (2009). Intensity of continuous renal replacement therapy in critically ill patients. N Engl J Med, 361, 1627–​38. Rocco MV, et al. (2011). The effects of frequent nocturnal home hemo- dialysis:  the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int, 80, 1080–​91. The FHN Trial Group (2010). In-​center hemodialysis six times per week versus three times per week. N Engl J Med, 363, 2787–​300. VA/​NIH Acute Renal Failure Trial Network, et al. (2008). Intensity of renal support in critically ill patients with acute kidney injury.
N Engl J Med, 359, 7–​20. Meta-​analyses and systematic reviews in haemodialysis Lim W, Cook DJ, Crowther MA (2004). Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-​ stage renal failure: a meta-​analysis of randomised trials. J Am Soc Nephrol, 15, 3192–​206. Box 21.7.1.7  Clinical presentations of dialysis-​related amyloidosis • Carpal tunnel syndrome (usually after 7 or more years of HD) • Joint pains and stiffness especially in hands, arms, and shoulders (usually after 10 or more years of HD) • Tenosynovitis of tendons in the hands • Pathological fractures due to amyloid bone cysts • Destructive spondyloarthropathy

21.7.2 Peritoneal dialysis 4874 Simon Davies

21.7.2 Peritoneal dialysis 4874 Simon Davies

section 21  Disorders of the kidney and urinary tract 4874 Macleod AM, et al. (2005). Cellulose, modified cellulose and synthetic membranes in the haemodialysis of patients with end-​stage renal disease. Cochrane Database Syst Rev, 3, CD003234. Mostovaya IM, et  al. (2014). EUDIAL1—​an official ERA-​EDTA Working Group. Clinical evidence on hemodiafiltration: a system- atic review and a meta-​analysis. Semin Dial, 27, 19–​27. Rabindranath KS, et  al. (2005). Comparison of hemodialysis, hemofiltration, and acetate free biofiltration for ESRD: systematic review. Am J Kidney Dis, 45, 437–​47. Selby NM, McIntyre CW (2006). A systematic review of the clin- ical effects of reducing dialysate fluid temperature. Nephrol Dial Transplant, 21, 1883–​98. Clinical practice guidelines in haemodialysis Ashby D, et al. (2019). Clinical practice guideline:  haemodialysis, https://renal.org/wp-content/uploads/2019/07/FINAL-HD-Guide line.pdf European Best Practice guidelines on haemodialysis (2007). Nephrol Dial Transplant, 22 Suppl 2, S1–​S120. National Institute for Health and Care Excellence (2018). Renal re- placement therapy and conservative management. https://www. nice.org.uk/guidance/ng107/resources/renal-replacement-therapy- and-conservative-management-pdf-66141542991301 National Kidney Foundation (2015). KDOQI clinical practice guide- line for hemodialysis adequacy. Am J Kidney Dis, 66, 884–930. 21.7.2  Peritoneal dialysis Simon Davies ESSENTIALS Peritoneal dialysis is achieved by repeated cycles of instillation and drainage of dialysis fluid within the peritoneal cavity, with the two main functions of dialysis—​solute and fluid removal—​occurring due to the contact between dialysis fluid and the capillary circulation of the parietal and visceral peritoneum across the peritoneal mem- brane. It can be used to provide renal replacement therapy in acute kidney injury or chronic kidney disease. Practical aspects—​choice of peritoneal dialysis as an effective mo- dality for renal replacement in the short to medium term (i.e. sev- eral years) is, for most patients, a lifestyle issue. Typically, a patient on continuous ambulatory peritoneal dialysis will require three or four exchanges of 1.5 to 2.5 litres of dialysate per day. Automated peritoneal dialysis and use of the glucose polymer dialysis solution icodextrin enables flexibility of prescription that can mitigate the ef- fects of membrane function (high solute transport). Peritonitis—​this remains the most common complication of peritoneal dialysis, presenting with cloudy dialysis effluent, with or without abdominal pain and/​or fever, and confirmed by a leucocyte count greater than 100 cells/​µl in the peritoneal fluid. Empirical anti- biotic treatment, either intraperitoneal or systemic, with cover for both Gram-​positive and Gram-​negative organisms, should be com- menced immediately while awaiting specific cultures and sensitivities. Long-​term changes in peritoneal membrane function influ- ence survival on peritoneal dialysis if fluid removal is less efficient
(ultrafiltration failure), especially in the absence of residual kidney function. This is the main limitation of treatment, along with avoiding the risk of encapsulating peritoneal sclerosis—​a life-​ threatening complication of peritoneal dialysis, particularly if of long duration (15–​20% incidence after 10 years), that is charac- terized by severe inflammatory thickening, especially of the mes- enteric peritoneum, resulting in an encapsulation and progressive obstruction of the bowel. Introduction Peritoneal dialysis, along with haemodialysis and renal transplant- ation, is an effective form of renal replacement therapy. Worldwide it is used for both acute kidney injury and chronic renal failure, al- though patterns of use vary considerably. In the treatment of chronic kidney disease, peritoneal dialysis should be considered as a short-​ to medium-​term (several years) treatment option, to be used in the context of an integrated approach to renal replacement therapy. For example, it is of value both before and after transplantation in a life- time of treatment that might require more than one period on each of the renal replacement modalities. The only absolute contraindica- tion is the lack of a peritoneal cavity. Historical perspective In the 1890s, Henry Starling, while conducting experiments from which he made his seminal observations on the forces that govern transcapillary fluid transport, provided evidence that the peritoneal membrane could be used to remove fluid and solutes—​the fundamental requirements of renal replacement therapy. By the 1940s, peritoneal dialysis was established in the treatment of acute kidney injury, and a decade later intermittent treatments, typically twice weekly, were used to maintain pa- tients with chronic kidney disease. Critical to this was the devel- opment in 1968 of the Tenckhoff catheter, a soft silicone-​based tube that could create permanent access to the peritoneal mem- brane. In 1978, Popovitch and Moncreif argued that peritoneal dialysis could be performed continuously in ambulant patients with permanent renal failure, coining the term ‘continuous am- bulatory peritoneal dialysis’ (CAPD), following which peritoneal dialysis became established as a renal replacement modality that could be undertaken in the home environment. Modifications of this approach, using a device that delivers multiple exchanges of dialysis fluid overnight, so reducing the number of exchanges required during the daytime, is termed ‘automated peritoneal dialysis’ (APD). In addition to the reduced daytime burden of the treatment, the advantages of this approach are that it can facilitate delivery of care by a parent, partner, or assistant. Assisted peritoneal dialysis is the treatment of choice for elderly frail patients in some countries, notably France, providing a vi- able alternative to centre-​based haemodialysis for this patient population.

21.7.2  Peritoneal dialysis 4875 The use of peritoneal dialysis in renal replacement Acute kidney injury Peritoneal dialysis is an important component of the International Society of Nephrology’s ‘0by25’ strategy to reduce the global burden of acute kidney injury-​related deaths. There is much greater reliance on peritoneal dialysis to treat acute kidney injury in developing coun- tries, the exception to this being in infants and small children in whom it remains the treatment of choice in the developed world. Advantages of peritoneal dialysis in acute kidney injury include lack of reliance on a clean water supply, relatively stable haemodynamics, no need for vascular access, and the avoidance of anticoagulation and its com- plications. The International Society for Peritoneal Dialysis has pub- lished guidelines for peritoneal dialysis in acute kidney injury, freely available at https://ispd.org/ispd-guidelines/​; key recommendations include the routine use of tunnelled soft Tenckhoff catheters, anti- biotic prophylaxis, and advice on the constitution of dialysis fluids. Chronic kidney disease The EVEREST study (Explaining the Variation in Epidemiology of RRT through Expert opinion, Secondary data sources and Trends over time) found that 70% of the international variability in the use of peritoneal dialysis to treat chronic kidney disease (the proportion of patients on peritoneal dialysis differs from 4 to 80% by country), is explained by healthcare systems, clinical factors, and macroeco- nomic factors. Independent determinants of lower peritoneal dia- lysis use include a high proportion of incident patients with diabetes as primary renal disease, a higher percentage of GDP per capita spent on healthcare, a larger private-​for-​profit share of haemodi- alysis facilities, and the high cost of peritoneal dialysis consumables relative to staffing. Currently, the highest growth rates for peritoneal dialysis are seen in the developing world, especially Indo-​Asia. Predictors of survival As for all types of renal replacement therapy, the most important fac- tors associated with survival are age, inflammation, and comorbidity, the latter being weighted towards cardiovascular disease. As for haemodialysis patients, the continued presence of residual renal function, a benefit that can be demonstrated with creatinine clear- ances as low as 1 to 2 ml/​min, or just 250 ml/​day of urinary volume, also improves survival. In addition, there is strong evidence that peritoneal membrane function has an effect. Membranes associated with less efficient fluid removal, due to high solute transport char- acteristics or low ultrafiltration capacity (see ‘Monitoring treatment quality’), are associated with worse outcomes. Comparison with haemodialysis Current evidence supports the view that when both haemodialysis and peritoneal dialysis are equally available, the choice between the therapies is largely determined by lifestyle issues (Table 21.7.2.1). The failure to date to perform a randomized controlled trial com- paring modalities lies in the fact that most patients (96%) demon- strate a strong modality preference when the choice is made freely available. Modality comparisons have thus relied on observational studies from registry data, with adjustment for baseline factors. Over the last 20 years, survival has improved dramatically (>50% reduc- tion in mortality), such that early survival (1–​3 years) tends to be better on peritoneal dialysis than haemodialysis, with equivalence at 5 years. The early survival advantages, most apparent in nondiabetic patients, are likely to reflect relatively better preservation of residual kidney function, avoidance of central venous catheters, and residual confounding. Technique failure is more likely to occur in peritoneal dialysis than haemodialysis, reflecting the effects of membrane damage associated with infection and long-​term exposure to dialysis fluid, as well as changes in a patient’s circumstances, such that con- tinuing with home treatment becomes untenable. Taken overall, these patient and technique survival differences are not sufficient to override patient preferences associated with lifestyle choices, provided there is an understanding that modality switching may well be required. APD extends choice to the patient or their carer, so accommodating a variety of lifestyles; it is the preferred dialysis treatment for children. Choosing the right dialysis modality is an im- portant component to preparing for renal replacement therapy and can be facilitated by the use of a dialysis decision aid, freely available at https://​www.kidneyresearchuk.org/kidney-health-information/. Principles of therapy Peritoneal dialysis is achieved by repeated cycles of instillation and drainage of dialysis fluid within the peritoneal cavity. The fluid is heat sterilized, a process that requires an acidic pH; ideally a pH of 2 to 3 should be used, but this requires two or more dialysis bag com- partments to enable reconstitution just prior to infusion. This ap- proach enables a physiological pH solution with low concentrations of glucose degradation products and in some cases substitution of bicarbonate for lactate as the buffer. The benefits of biocompatible solutions include reduced infusion pain, better preservation of re- sidual kidney function, and more stable peritoneal solute transport characteristics. Such solutions are not universally available, how- ever, and most conventional peritoneal dialysis solutions have a pH of 5.2, with 35 to 40 mmol/​litre of lactate as the buffer. Typically, a patient on peritoneal dialysis will require three or more exchanges of 1.5 to 2.5 litres of dialysate per day. CAPD re- gimens usually comprise three 4-​ to 6-​h daytime exchanges and an overnight exchange; APD regimens may use up to six exchanges overnight and a long daytime dwell period. The frequency of over- night exchanges can be further increased by using a ‘tidal’ pro- gramme, which exchanges a proportion of the intraperitoneal fluid Table 21.7.2.1  Typical reasons for choosing peritoneal dialysis or haemodialysis as renal replacement modality Reasons favouring peritoneal dialysis Reasons favouring haemodialysis No vascular access No peritoneal access Haemodialysis-​induced hypotension Multiple comorbidities Preference for home treatment Increasing age Independence Living alone Distant from haemodialysis facility Dependent Family and work commitments Close to haemodialysis facility Dependent, when assisted APD performed
by a carer or parent is available Home haemodialysis option preferred and available APD, automated peritoneal dialysis.

section 21  Disorders of the kidney and urinary tract 4876 more rapidly without losing dialysis time due to complete emptying. APD can be further augmented by adding an additional—​typically evening—​exchange, so increasing the dose of dialysis given. These volumes will be very different for children in whom they are ad- justed according to body surface area. The patient or their carer is trained in the sterile procedure of dia- lysis fluid exchange by a specialist peritoneal dialysis nurse, a process that generally takes a few days and can be achieved by most individ- uals, despite physical and educational disabilities. Peritoneal access In order to drain peritoneal dialysis fluid in and out of the peritoneal cavity, a flexible permanent dialysis catheter is required, and this is also to be preferred when peritoneal dialysis is used for acute kidney injury. Correct insertion and subsequent catheter management is critical for success. Insertion should be performed as a planned procedure by an experienced operator and may be achieved using either the Seldinger technique, open surgery, or with the use of a laparoscope. Catheters usually have two Dacron cuffs, one at each end of the subcutaneous tunnel: the deep cuff is placed at the entry to the peritoneum, whereas the superficial cuff should be situated about 1.5 cm deep to the exit site, which should be positioned on the abdominal wall so that it is visible to the patient. Up-​to-​date recommendations for peritoneal dialysis catheter insertion (also for the management of peritonitis, see later) are freely available at the International Society for Peritoneal Dialysis website (https://ispd.org). Peritoneal physiology The two main functions of dialysis, solute and fluid removal, occur due to the contact between dialysis fluid and the capillary circulation of the parietal and visceral peritoneum. In a typical adult, approxi- mately 0.5 m2 of the peritoneum is in contact with fluid, representing about one-​third of the anatomical membrane. Solute clearance Removal of solute is predominantly by diffusion across the mem- brane and is thus governed by the concentration gradient, the number and density of capillaries in contact with dialysate (often termed effective peritoneal surface area), and the size of the solute in question. Equilibration time for urea is typically within 4 to 5 h, hence removal is limited by the drained dialysate volume rather than length of dwell. Equilibration is more time-​limited for larger mol- ecules such as creatinine and glucose, for example, the average di- alysate to plasma ratio of creatinine at 4 h is 0.65, with a range of 0.4 to 0.85 that is normally distributed. This measurement is termed the solute transport rate and is used to measure the diffusive component of membrane function in the ‘peritoneal equilibration test’. There is considerable variability between patients, which appears to be re- lated to local production of the inflammatory cytokine interleukin-​ 6 rather than clinical variables such as body size or comorbidity. Whereas systemic inflammation is an independent predictor of pa- tient survival, the local inflammatory response is not, provided ap- propriate dialysis regimens are prescribed. Ultrafiltration Fluid transport across the membrane is governed mainly by pres- sure gradients, including hydrostatic, osmotic, and oncotic, as well as some fluid reabsorption due to lymphatics. Instillation of fluid within the peritoneal cavity creates a positive pressure that is close to capillary pressure, resulting in little net fluid movement by this mechanism unless excessive intraperitoneal pressures are created. Conventional glucose-​containing dialysis fluids create an osmotic pressure gradient proportional to glucose concentration (1.5–​ 4.25%) that results in a peak net ultrafiltration volume between 2 and 4 h, depending on solute transport characteristics of the membrane (Fig. 21.7.2.1). It is by prescription of exchanges containing different glucose concentrations (‘weak’, ‘medium’, and ‘strong’ bags) that the –300 –200 –100 0 100 200 300 400 500 600 700 0 60 120 180 240 300 360 420 480 540 600 660 720 Time (min) Intraperitoneal ultrafiltration volume (ml) Aquaporins Intercellular pores Lymphatics Net fluid Icodextrin Fig. 21.7.2.1  Pathways of fluid transport across the peritoneal membrane. The net changes in intraperitoneal fluid volume and thus ultrafiltration achieved at each time point when using glucose (3.86%) as the osmotic agent are the result of fluid transport via at least three pathways: aquaporins (water exclusive), small intercellular pores, and lymphatic reabsorption. Fluid is reabsorbed once the intraperitoneal glucose has equilibrated with plasma. By contrast, when using the glucose polymer icodextrin, sustained ultrafiltration occurs for several hours.

21.7.2  Peritoneal dialysis 4877 patient’s fluid status can be controlled to achieve the target weight specified by their physician. There are two pathways of water trans- port by this mechanism, intercellular and transcellular, each con- tributing about half the fluid removal, the latter being via aquaporins and thus water exclusive. Once the osmotic gradient has dissipated, fluid reabsorption occurs due to a combination of transcapillary oncotic (Starling) forces and lymphatics. Removal of ions such as sodium and calcium is predominantly by convection because the diffusion gradient is small (typical dialysate sodium concentration is 132 mmol/​litre). Due to the existence of the aquaporin pathway, there is uncoupling of water and sodium removal, termed sodium sieving, that is most pronounced in the early part of the dwell. As a consequence, peritoneal dialysis is always at risk of removing excess water compared with sodium, and treatment regimens that rely on too many short, hypertonic glucose exchanges are to be avoided. By the same token, lack of sodium sieving is an indicator of poor free-​ water transport and thus membrane failure. Monitoring treatment quality Solute clearance Residual renal and peritoneal solute clearances are not equivalent in their impact on patient survival. To date, in chronic kidney disease, no randomized study has been able to demonstrate an association between survival and peritoneal clearances, and there are no studies published in acute kidney injury. It is important, therefore, that both residual and peritoneal clearances are measured. Both urea (Kt/​ Vurea) and creatinine clearances can be used to monitor treatment, and there is general agreement in international guidelines—​based on at least two large randomized trials—​on minimum treatment targets. For Kt/​Vurea, a combined residual and peritoneal clearance of 1.7 using the Watson formula to calculate V (total body water) should be achieved. Alternatively, a combined creatinine clearance of 50 litres/​week per 1.73 m2 can be used. In either case, however, dialysis dose should be increased in the presence of symptoms at- tributable to uraemia. Ultrafiltration Several observational studies have shown that a reduced peritoneal ultrafiltration and by implication sodium removal is associated with reduced survival, especially in anuric patients. Several reasons for this association have been proposed, but there is little doubt that a failure to remove adequate fluid due to membrane characteristics that result in less good ultrafiltration or excessive fluid reabsorption are important. The simplest way to monitor membrane function is to perform a regular peritoneal equilibration test that measures solute transport rate and net ultrafiltration capacity in a standard- ized 4-​h dwell. A membrane that results in less than 400 ml ultra- filtration using 3.86% or less than 100 ml using 2.27% glucose is unlikely to achieve adequate fluid removal once the patient becomes anuric. If this is associated with a fast rate of solute transport (4-​ h dialysate:plasma creatinine ratio above 0.65), and thus early loss of the glucose gradient and more rapid fluid reabsorption, then a combination of APD delivering shorter exchanges overnight and icodextrin (a polydispersed glucose polymer derived from starch) in the long exchange will result in adequate fluid removal in most cases. Use of APD in this situation is associated with better patient survival, mitigating the observed increased mortality seen in patients with rapid transport membranes when using CAPD. Icodextrin achieves sustained ultrafiltration in the long dwell as it acts rather like a colloidal agent, thus counterbalancing Starling forces. It has been shown to improve fluid status, reduce peritoneal glucose exposure, and enhance diabetic control, and it represents a major advance in peritoneal dialysis therapy. Note, however, that icodextrin metab- olites in blood can interfere with estimation of blood glucose by monitors that use glucose dehydrogenase, such that there is a risk of failing to diagnose hypoglycaemia. Complications and their management Peritonitis Peritonitis is the most common and potentially serious complica- tion of peritoneal dialysis, resulting in up to 50% of technique fail- ures. With enhanced training, patients can be expected to have one episode of peritonitis for every 3 years of treatment. Presentation is with cloudy dialysis effluent, with or without abdominal pain and/​ or fever, and the diagnosis is confirmed if the leucocyte count is above 100/​µl in the peritoneal fluid. Clinical assessment should in- clude examination of the exit site and tunnel for infection, and the abdomen for signs of intraabdominal pathology. At least 20 ml of freshly drained dialysate should be sent for culture by appropriate methods, which are absolutely crucial. The technique recommended by the International Society for Peritoneal Dialysis (freely accessible at https://ispd.org) is for 50 ml of peritoneal effluent to be centri- fuged at 3000 g for 15 min, followed by resuspension of the sediment in 3 to 5 ml of sterile saline and inoculation of material on both solid culture media and into a standard blood culture medium. With this method, fewer than 5% of cases should be culture negative. Empirical antibiotic treatment, either intraperitoneal or systemic, with cover for both Gram-​positive and Gram-​negative organisms should be commenced immediately while awaiting specific cultures and sensitivities. The reader is again directed to the International Society for Peritoneal Dialysis website for detailed up-​to-​date guidelines on management, but most typically Gram-​positive or- ganisms will be covered by vancomycin or a cephalosporin, and Gram-​negative infections by a third-​generation cephalosporin, aminoglycoside, or (if local sensitivities support such use) quin- olone, with the regimen adjusted as and when results of culture and sensitivity of peritoneal fluid are available. A mixed bacterial growth, especially associated with anaerobes, should dictate early surgical assessment, catheter removal, and laparotomy. Catheter removal is also likely to be necessary if there is an associated catheter-​tunnel infection or a failure to respond to antibiotics within a few days. Exit-​site infection A simple scoring system has been devised to assess the exit site (Table 21.7.2.2). Mechanical failure Mechanical failure is common in the early stages of a patient’s career on peritoneal dialysis, and can be due either to catheter displace- ment (outflow affected), wrapping of the catheter by the omentum

section 21  Disorders of the kidney and urinary tract 4878 (in-​ and outflow), or leakage. The latter can occur at the deep cuff or at any hernia site and may present as genital swelling. Diagnosis is either obvious or requires appropriate imaging, usually a CT scan with contrast introduced into the catheter. Ultrafiltration failure Changes can occur in membrane function with time on peritoneal dialysis that result in less good ultrafiltration. Drivers of this change appear to be early loss of residual renal function and use of more hypertonic glucose dialysis solutions. Most frequently, this is due to a progressive increase in solute transport that can be addressed using APD and icodextrin (discussed previously). In some patients, however, more serious membrane damage occurs which results in reduced osmotic conductance (efficiency) of the membrane for a given osmotic gradient due to progressive membrane fibrosis. These patients require transfer to haemodialysis. Encapsulating peritoneal sclerosis Encapsulating peritoneal sclerosis (EPS) is a relatively uncommon but life-​threatening complication of peritoneal dialysis, character- ized by severe inflammatory thickening, especially of the visceral peritoneum, resulting in an encapsulation and progressive obstruc- tion of the bowel. Diagnosis is made from CT scan or laparotomy confirmation of bowel obstruction due to macroscopic appearances of thickened membrane, with cocoon-​like encapsulation of the entire intestine in severe cases. Risk factors identified include prolonged time on treatment (incidence 15–​20% after 10 years), severe and protracted peritonitis, and acquired, severe ultrafiltration failure characterized by loss of membrane efficiency and in particular reduced free water transport. EPS may resolve slowly after stopping peritoneal dialysis, but often continues to progress and presents after modality transfer, including after renal transplantation. Corticosteroids and immuno- suppressants (both anti-​inflammatory) and tamoxifen (antifibrotic) have been used as treatments, but without convincing evidence of benefit. Management includes nutritional support, parenteral feeding in the presence of vomiting, and in severe cases—​ especially with life-​threatening obstruction—​extensive surgical enterolysis. This should be performed in specialized centres which report good primary cure rates when the treatment is planned, although recur- rence can require repeat procedures. Emergency surgery, especially following bowel perforation or infarction, has a very high mortality. EPS is an awful disease: case series report overall mortality of 26 to 58%, although many deaths within such series were not from the EPS itself. Because of the risk of the condition, there has been much discussion in the renal community as to whether patients should be advised against remaining on peritoneal dialysis for more than a particular number of years. However, the risk of developing EPS is extremely low in patients who have been on peritoneal dialysis for less than 5 years, most long-​term peritoneal dialysis patients are not affected, and the risks of EPS must be balanced against those of any alternative renal replacement therapy for the individual patient. Furthermore, there are no prospective data supporting a benefit of pre-​emptively transferring long-​term peritoneal dialysis patients to haemodialysis. FURTHER READING Ballinger AE, et al. (2014). Treatment for peritoneal dialysis-​associated peritonitis. Cochrane Database Syst Rev, 4, CD005284. Brimble KS, et al. (2006). Meta-​analysis: peritoneal membrane trans- port, mortality, and technique failure in peritoneal dialysis. J Am Soc Nephrol, 17, 2591–​8. Brown EA, et al. (2003). Survival of functionally anuric patients on automated peritoneal dialysis: the European APD Outcome Study. J Am Soc Nephrol, 14, 2948–​57. Cho Y (2014). Biocompatible dialysis fluids for peritoneal dialysis. Cochrane Database Syst Rev, 27, CD007554. Crabtree JH, Burchette RJ, Siddiqi NA (2005). Optimal peritoneal dia- lysis catheter type and exit site location: an anthropometric analysis. ASAIO J, 51, 743–​7. Cullis B, et al. (2014). Peritoneal dialysis for acute kidney injury. Perit Dial Int, 34, 494–​517. Davies SJ (2010). Peritoneal dialysis solutions. In:  Himmelfarb J, Sayegh MH (eds) Chronic kidney disease, dialysis and transplantation—​companion to Brenner and Rector’s the kidney, 3rd edition, pp. 417–​31. Elsevier Saunders, Philadelphia. Davies SJ (2013). Peritoneal dialysis—​current status and future chal- lenges. Nat Rev Nephrol, 9, 399–​408. Jager KJ, et  al. (2004). The effect of contraindications and patient preference on dialysis modality selection in ESRD patients in the Netherlands. Am J Kidney Dis, 43, 891–​9. Johnson DW, et al. (2012). Effects of biocompatible versus standard fluid on peritoneal dialysis outcomes. J Am Soc Nephrol, 23, 1097–​107. Lambie M, et al. (2013). Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival. J Am Soc Nephrol, 24, 2071–​80. Li PK, et al. (2016). ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int, 36, 481–508. Mehta R, et al. (2015). International Society of Nephrology’s 0by25 ini- tiative for acute kidney injury: a human rights case for nephrology. Lancet, 385, 2616–​43. Paniagua R, et al. (2002). Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, ran- domized, controlled trial. J Am Soc Nephrol, 13, 1307–​20. Szeto C-C, et al. (2017). ISPD catheter-related infection recommenda- tions: 2017 update. Perit Dial Int, 37, 141–54. Rippe B, et al. (2004). Fluid and electrolyte transport across the peri- toneal membrane during CAPD according to the three-​pore model. Perit Dial Int, 24, 10–​27. Table 21.7.2.2  Classification and treatment of exit-​site infections Symptom Points awarded 0 1 2 Swelling Absent <0.5 cm

0.5 cm or includes tunnel Crust Absent <0.5 cm 0.5 cm Redness Absent <0.5 cm 0.5 cm Pain Absent Slight Severe Drainage Absent Serous Purulent An exit site with a score of 4 or greater, or a purulent discharge, should be treated with empirical antibiotics that cover coagulase-​positive staphylococcus and pseudomonas until sensitivities are available.

21.7.3 Renal transplantation 4879 Nicholas Torpey

21.7.3 Renal transplantation 4879 Nicholas Torpey and John D. Firth

21.7.3  Renal transplantation 4879 van de Luijtgaarden, et al. (2013). Global differences in dialysis mo- dality mix: the role of patient characteristics, macroeconomics and renal service indicators. Nephrol Dial Transplant, 28, 1264–​75. Weinhandl ED, et  al. (2010). Propensity-​matched mortality com- parison of incident hemodialysis and peritoneal dialysis patients. J Am Soc Nephrol, 21, 499–​506. 21.7.3  Renal transplantation Nicholas Torpey and John D. Firth ESSENTIALS Renal transplantation is the preferred option for the treatment of endstage chronic renal failure in patients for whom there are no major medical contraindications. In well-​selected recipients, both life expectancy and quality of life are superior to treatment with long-​ term dialysis. However, as the dialysis population continues to grow, the gap between supply and demand for renal transplantation is widening. Attempts to bridge this gap have included (1) relaxation of the criteria for a suitable deceased donor (expanded/​extended criteria or ‘marginal donors’); (2) increased procurement of kidneys from donors with circulatory death (DCD donors, previously known as non-​heart-​beating donors); and (3)  encouragement of living donation—​including techniques for desensitization of recipients, also paired exchanges, both to circumvent blood group incompatibilities or preformed antibodies that would otherwise bar transplantation. Technical aspects Immunosuppression—​excepting for transplants between HLA-​ identical twins, immunosuppression is required to prevent rejec- tion, but there is no clear consensus on the best immunosuppressive regimen. Most centres use an induction antibody directed against CD25 (the interleukin-​2 receptor) or a T-​lymphocyte-​depleting antibody (thymoglobulin or alemtuzumab), followed by what is now called standard triple therapy—​comprising a calcineurin in- hibitor (CNI) (almost always tacrolimus), combined with either mycophenolate mofetil or azathioprine, and steroids. Steroids are not infrequently tailed off rapidly in the early post-​transplant period. Transplant rejection This can be classified into four main categories: (1) hyperacute—​due to preformed cytotoxic antibodies; always leads to very rapid graft failure; (2) accelerated—​a predominantly T-​cell-​mediated rejection occurring within the first few days, usually requiring powerful T-​cell-​ depleting immunotherapy and often leading to irreversible graft damage; (3)  acute cellular—​due to a primary T-​cell-​mediated re- sponse; occurs in 10 to 20% of recipients; manifests histologically as interstitial and tubular inflammation; first-​line treatment (usually suc- cessful) with intravenous steroids; (4) humoral—​antibody mediated, manifest histologically as microvascular inflammation and some- times evidence of complement activation (defined by deposition of the complement breakdown product C4d in peritubular capillaries); best treatment uncertain. Complications of renal transplantation Specific side effects of immunosuppressive agents—​these are im- portant causes of morbidity and (rarely) mortality. Steroids cause many complications; nephrotoxicity is the main drawback of CNIs. Nonspecific side effects of immunosuppressive agents—​all currently available immunosuppressive regimens are nonspecific in the sense that they suppress not only the immune response to the allograft, but also the immune response to infections and tumours. Infective complications—​transplant recipients are vulnerable to opportunistic infections including (1)  viral infections—​particularly cytomegalovirus (the main infectious complication in solid organ transplantation, with manifestation ranging from asymptomatic viraemia to life-​threatening multiorgan failure), Epstein–​Barr virus (EBV or human herpes virus (HHV)-​4), varicella zoster virus, herpes simplex, human polyomavirus (especially BK, which can lead to nephropathy and graft failure), human papillomavirus (HPV), and HIV; (2)  bacterial infections—​particularly mycobacterial, nocardia, nontyphoid salmonella, and listeria; (3) fungal infections—​including candidiasis, aspergillosis, and pneumocystis (a dreaded complication of transplantation before routine introduction of prophylaxis with co-​trimoxazole or pentamidine); (4) parasitic infections—​including Strongyloides stercoralis, scabies, and toxoplasmosis. Malignant complications—​post-​transplant neoplasia is an im- portant cause of morbidity and mortality. Particular conditions in- clude (1)  post-​transplant lymphoproliferative disorder—​driven by EBV; first-​line treatment by stepwise reduction in immunosuppres- sion; (2) Kaposi’s sarcoma—​caused by HHV8; (3) HPV—​responsible for skin, vulval, and anogenital warts, and some types are associated with carcinoma; (4) squamous cell carcinoma—after 20 yrs will affect most white renal transplant recipients. Other complications—​these include hypertension, accelerated atherosclerosis, and electrolyte, musculoskeletal, haematological, gastrointestinal, and cosmetic disorders. Prognosis First-​year transplant losses from rejection have been dramatically reduced from about 40% in the 1970s to 5%. However, the rate of chronic graft loss remains at about 4% per year. The commonest cause of insidious late graft failure is probably chronic antibody-​ mediated rejection, sometimes associated with poor adherence to immunosuppression. Calcineurin toxicity may also contribute. A major focus of research is to identify non-​nephrotoxic immuno- suppressive agents able to suppress antibody-​mediated rejection. Introduction Renal transplantation is the preferred treatment option for patients with endstage renal disease (ESRD) for whom there are no medical or surgical contraindications to transplantation. With improvements Acknowledgement: the authors and editors gratefully acknowledge the inclusion in this chapter of material contributed to previous editions of the Oxford Textbook of Medicine by Dr Paul Sweny.

section 21  Disorders of the kidney and urinary tract 4880 in immunosuppression and in the equally important general med- ical support of the immunocompromised patient, the age ranges and permissible comorbidities of recipients continue to be extended. In well-​selected recipients, both life expectancy and quality of life are superior to long-​term dialysis. The two principal challenges facing transplantation are the shortage of donor organs and the adverse effects of the still crude immunosuppressive agents. Xenotransplantation may remove the first of these hurdles, but is likely to increase dependence on potent immunosuppressive regimen and remains far from clinical prac- tice. Similarly, strategies to promote immunological tolerance to the graft, with preservation of normal immunity to infections and tu- mours, remain to be achieved. Supply, demand, and kidney donation On 31 March 2017, there were 5197 adult patients actively listed for a kidney transplant in the United Kingdom. In the previous 12 months, 2105 patients had received a kidney from a deceased donor, 937 a kidney from a living donor, and 179 a combined pancreas and kidney transplant. These figures represent substantial success in United Kingdom clinical practice, with the active waiting list falling from a peak of nearly 7000 patients in 2009, and a year-​on-​year increase in deceased organ donation. Strategies to increase deceased donation include public information programmes, the use of organ donor re- gisters, and—​in some countries (including the UK from Spring 2020)—​ legislation to permit organ donation unless the donor has indicated that they do not wish to donate (so-​called opt-​out legislation). In the United Kingdom, United States of America, and many European countries, the result has been a small but steady increase in deceased donation, although in most countries the demand for kidney trans- plantation is such that the waiting list continues to increase. In addition to general measures aimed at promoting deceased organ donation, criteria defining suitable organ donors have been widened. Thus it is now common to transplant organs from older donors (in 2007, 20% of donors in the United Kingdom were aged more than 60 years old, rising to 36% in 2017), donors following circulatory death (DCD donors), donors with acute kidney injury, and donors previously excluded because of a definite but small risk of disease transmission (‘low-​risk’ malignancy or infection). One recent proposal is the use of kidneys retrieved from hepatitis C vir- aemic (HCV) donors transplanted into recipients without HCV, with the recipient receiving post-​transplant treatment with highly efficacious antiviral therapy. Increased transplant activity in recent years has been a con- sequence of increased deceased donation, but growth in activity between 2000 and 2010 (in the United Kingdom, United States of America, and some European countries) was principally in living donation. However, the number of living donor transplants has reached a plateau, or even fallen: in 2010, in both the United Kingdom and United States of America, more than 40% of all adult kidney transplants were from living donors, falling to 30% in recent years, likely because of concern over long-​term donor outcomes. The use of paired living donation is also increasing in many coun- tries, including the United Kingdom. The principles are straightfor- ward: A wishes to give a kidney to B, but is prevented from doing so because they are immunologically incompatible; C wishes to give a kidney to D, but again is prevented from doing so because of im- munological incompatibility; however, A is not incompatible with D, and C is not incompatible with B, hence a paired exchange can be organized such that A gives to D and C to B and blood group incompatibilities or preformed donor-​reactive anti-​HLA anti- bodies that would otherwise bar transplantation are circumvented. Depending on local regulatory arrangements there can be several interlinked pairs or chains. A further possibility is altruistic donation, in which an individual offers a nondirected kidney (i.e. with no specific intended recipient) for transplantation. It would be possible to use this to start a series of paired donations or chains, and this is permitted in some countries. Another proposal (not implemented) is that by donating a kidney to the national pool, a family member might secure the highest possible priority for the next suitable kidney for their relative. Living donors Every care must be taken to protect the interests of the donor. Informed consent is crucial, particularly regarding the increased risk of ESRD in those who have donated a kidney. Potential donors must be aware that giving a kidney carries a risk of death, although with a low perioperative mortality of 0.03%, most fatalities being attributable to acute pulmonary embolus. The other risks that are involved in a general anaesthetic and an abdominal operation must also be fully explained. Increasing use of laparoscopic kidney re- trieval in live donors has done much to improve donor acceptability and speed postoperative recovery. Needless to say, a donor should be in good general physical health and have normal kidney function and surgically acceptable renal anatomy. The assessments required are summarized in Box 21.7.3.1. Apart from exceptional circumstances, donors outside the age limits of 18 to 70 years are not considered. It is usual to wait for a young female potential donor to complete her family. Past studies suggested an increase in life expectancy and re- duced risk of developing ESRD of donors when compared with age-​ matched controls from the general population. However, the general population is not the correct control group and the outcomes for living kidney donors should be compared to a control group con- sidered as suitable donors but who have not undergone a neph- rectomy (‘healthy nondonors’). Several recent reports have clearly demonstrated an increased risk of ESRD in living donors, with a 5-​ to 10-​fold relative risk compared to healthy nondonors. Note that this increased risk is from a very low baseline risk of ESRD, and living donors still have a lower risk of ESRD than the general popula- tion. The estimated lifetime risk of ESRD is less than 0.1% in healthy nondonors, 0.2 to 0.5% in living donors, and about 1% in the general population. Risk factors for ESRD in donors include young age at donation (because there is more time to develop renal disease), black race, and a family history of renal disease. ESRD in donors is predominantly caused by immunologically- mediated kidney disease (vasculitis and glomerulonephritis) in the first 10-15 years after donation, with diabetes, hypertension and vascular disease the main causes later on (>20 years). A few donors will develop hypertension and proteinuria (typically <0.5 g/​24). Particularly important in this regard is a twofold increase risk in pre-​ eclampsia complicating pregnancy in previous living donors. Renal function usually returns to 75 to 80% of the pre-​donation level. Lifelong follow-​up of donors is essential to both monitor for and manage risk factors for ESRD.

21.7.3  Renal transplantation 4881 The use of living kidney donors is driven not only by the shortage of deceased donor organs for transplantation, but also by the fact that these kidneys do better than those from a deceased donor. This is partly due to better matching, with many related donors and recipients sharing one or two extended HLA haplotypes, but an additional benefit—​shared also by kidneys from living unre- lated donors, which similarly outperform those transplanted from deceased donors—​is the physiological state of the organ when re- covered under ideal and planned conditions, and without the ne- cessity for prolonged cold storage. Deceased donors In this situation, the prime responsibility is to the potential recipient. The kidney should be in as good a physiological state as possible, and there should be no obvious risk of transfer of infection or ma- lignancy by the donor organ. The major contraindications to organ procurement are listed in Box 21.7.3.2. Expanded/​extended criteria donors are increasingly being considered, particularly for older re- cipients and for those with a limited life expectancy. In some situ- ations it may be appropriate to consider organs from hepatitis B (HBV)-​positive or HCV-​positive donors for positive recipients. The availability of highly effective antiviral therapy for HCV brings the possibility of transplanting HCV-​positive kidneys into HCV-​ negative recipients, with antiviral therapy given post-​transplant—​an approach already taken in some countries. Most deceased donor kidneys are retrieved from donors following brain death (DBD donors). Retrieval surgery takes place in a venti- lated donor with intact circulation, with the organs cold perfused before circulatory arrest, thus eliminating any warm ischaemia to the kidneys. However, the last 10 years have seen a rapid increase in the use of organs from DCD donors. Retrieval surgery begins only after the donor has reached circulatory arrest and the formal pro- cess for certifying death is complete. Accordingly, the organs are ex- posed to warm ischaemia for 5 to 20 min before cold perfusion can be accomplished. The additional ischaemic insult to DCD kidneys means that there is often a period of delayed graft function following Box 21.7.3.1  Assessment of the potential living donor • Medical history • Psychiatric and psychosocial history—​including at-​risk behaviour • Physical examination • Blood group (ABO) • Tissue typing • Lymphocyte cross-​match (recipient serum against donor lymphocytes) • DNA testing to prove family relationship (where relevant) • Urine:

—​ Stick testing—​blood, protein, glucose, leucocytes, nitrites

— Culture and microscopy

— Quantify protein excretion (albumin:creatinine ratio)

— Creatinine clearance • Blood:

— Glucose, HbA1c

— Electrolytes

— Urea, creatinine, uric acid

— Liver function tests

— Full blood count

— Glucose-​6-​phosphate dehydrogenasea

— Haemoglobin, electrophoresisa

— Sickle testa

— Procoagulant screena • Infection screen:

— HIV

— HTLV 1 and 2

— Cytomegalovirus (HHV5)

— Epstein–​Barr virus (HHV4)

— Hepatitis B virus

— Hepatitis C virus

— Kaposi’s sarcoma virus (HHV8)a

— Syphilis

— Toxoplasmosis

— Schistosomiasisa

— Malariaa

— Trypanosoma cruzia

— Strongyloides stercoralisa • Chest radiograph • ECG • Cardiac stress testinga • GFR estimation by isotopic method • Renal imaging:

— Ultrasonography and DMSA scan

— Donor renal arteriogram (magnetic resonance angiography or CT) • Informed consent, assessment by independent assessor (Human Tissue Act) (legal requirements vary from country to country) a Where clinically indicated, such as specific geographical or other risk. Box 21.7.3.2  Contraindications to cadaver organ procurement • Donor age:

— Younger than 3 years (en bloc dual transplant possible)

— Older than 70 yearsa • Cancer not confined to the central nervous system (CNS), but note:

— Nonmelanoma skin tumours and carcinoma in situ of the uterine cervix are permissible

— Cancer confined to CNS is acceptable, excepting medulloblastoma and glioblastoma • Risk of transmissible infection:

— At-​risk behaviour

— HCVa

— HBVa

— HIV

— HTLV 1, 2

— Deep fungal infections

— Parenchymal renal infection

— Meningoencephalitic syndromes of unknown aetiology

— Inadequately treated bacterial infection

— Infection with resistant organisms (e.g. MRSA, VRE, ESBL) • Diabetes mellitusa • Acute kidney injuryb • Hypertensiona • Chronic kidney disease • Warm ischaemia >90 min • Cold ischaemia >30 ha ESBL, extended-​spectrum β-​lactamase producer; HTLV, human T-​cell lymphocytotropic virus; MRSA, methicillin-​resistant Staphylococcus aureus; VRE, vancomycin-​resistant enterococcus. a Relative contraindication. b Donors with acute tubular necrosis (proven by biopsy of the explanted kidney) will often be used.

section 21  Disorders of the kidney and urinary tract 4882 transplantation, but several large studies have clearly demonstrated equivalent outcomes (patient and graft survival) when compared to kidneys retrieved from equivalent DBD donors. DCD donation now accounts for 40% of all deceased donor transplants in the United Kingdom. A second important development in recent years has been the in- creased use of ‘marginal’ kidneys—​those retrieved from extended criteria donors (ECDs). A  widely accepted definition of ECD is (1) donors aged 60 or older; or (2) donors aged 50 or older with any two of a history of hypertension, cerebrovascular cause of death, or a serum creatinine level at the time of donation of greater than 130 µmol/​litre. Nearly 50% of deceased donors in the United Kingdom meet ECD criteria. Although long-​term graft survival of kidneys transplanted from ECD is compromised, such kidneys are a reason- able option for older recipients in whom many years of graft func- tion may not be necessary. In some countries, the concept of deceased donor organ quality has been refined by using scoring systems based on multiple donor characteristics—​for example, the Kidney Donor Risk Index (KDRI or UKKDRI). An alternative approach is to perform a pretransplant biopsy to determine the extent of any established damage (tubulointerstitial fibrosis, glomerulosclerosis, and vascular dis- ease) in the donated kidney. Kidneys without significant damage are transplanted and those with extensive damage discarded. In some countries, kidneys with moderate established damage are trans- planted as dual kidneys (i.e. both kidneys into one recipient). The use of DCD and ECD kidneys has been central to the ex- pansion of deceased donor transplantation in the United Kingdom and many other countries. It is essential that potential recipients are aware of the broad range of kidneys used for transplantation, and of any donor-​specific risks. For example, kidneys are frequently re- trieved from donors with primary brain tumours or those with a history of intravenous drug abuse (at risk for transmissible viruses). It is neither practical nor reasonable to discuss these issues with a potential recipient at the time they are admitted for a transplant. Instead, it is common practice to provide recipients with informa- tion regarding the broad range of donor kidneys, and to obtain con- sent (or not) for specific donor risks at the time that they go onto the deceased donor waiting list. Recipient assessment Patients may be transplanted before the need for dialysis (pre-​ emptive transplantation) or from an established dialysis programme (haemodialysis or peritoneal dialysis). It is essential that all patients are fully assessed by both a transplant surgeon and transplant phys- ician before being placed on the waiting list or offered a kidney, whether it be from a deceased or living donor. Patients with chronic renal failure develop a multitude of complications that need as- sessment before surgery. Transplantation carries with it the risks of any major surgical procedure, together with the added risks of pro- longed immunosuppression. An additional consideration is that, given the shortage of organs for transplantation, it is important that the best use is made of all or- gans. Although everyone would agree with this in principle, making decisions in individual cases can be difficult. In some situations, the general health and life expectancy of a potential recipient argue strongly against transplantation. Patients with congenitally ab- normal lower urinary tracts can be difficult to transplant and ideally should be managed in centres with urological transplant expertise, with some needing complex bladder augmentation or drainage pro- cedures before transplantation. Since the main cause of death after transplantation is cardiovas- cular, it is important to screen at-​risk patients for occult vascular disease (carotid, aorto-​iliac, peripheral, and cardiac). This is par- ticularly true for coronary artery disease since many patients on dia- lysis exercise little and appear free of symptoms—​both angina and heart failure. Accordingly, in many centres cardiac stress testing or coronary angiography is performed in ‘at-​risk’ patients—​those older than 50, those with diabetes as a cause of ESRD, any patient with clinical evidence of vascular disease, and those with a long dialysis history (>3 years). Although coronary artery disease is frequently identified, it is not clear that intervention (either angioplasty and stenting, or coronary artery surgery) offers a prognostic benefit in asymptomatic patients. With or without intervention, it is important to identify high-​risk recipients in order to plan surgery and anaes- thesia, and to guide informed consent. Recipient age is not of itself a barrier to transplantation, and bio- logically fit patients aged over 70 are now often transplanted. It is uncertain whether older recipients obtain a survival benefit from transplantation when compared to dialysis, but successful trans- plantation likely improves quality of life. High recipient body mass index (BMI) has been considered a contraindication to transplantation, with many centres declining to transplant patients with a BMI greater than 35. Although obese pa- tients are more likely to develop delayed graft function, postoperative infections, and wound complications, it is clear that patients with a BMI up to 40 nevertheless derive survival benefit from transplant- ation when compared to dialysis. Such patients are now considered for transplantation, although clearly interventions to allow weight loss are appropriate, including the possibility of bariatric surgery. Recipient hepatitis (HCV or HBV) complicates transplantation. In the presence of active infection, immunosuppression accelerates liver disease and death may occur within 5 to 10 years of transplant- ation, usually from sepsis or progressive liver disease. However, the outcomes for patients with HBV and HCV have been transformed with the introduction of modern (noninterferon) antiviral therapy. In both cases, viraemia can be cleared and the risk of progressive liver disease largely eliminated. Ideally patients are identified and treated before advanced liver disease or cirrhosis develops, and as- sessment for transplantation must include liver imaging and often a liver biopsy. In the setting of advanced liver disease (cirrhosis and ascites), assessment for a combined liver and renal transplant may be appropriate. Similarly, patients with HIV who are clinically stable on highly active antiretroviral therapy (HAART) can also be trans- planted safely. Kidney allocation and donor–​recipient matching Organ allocation takes place following the identification of a suitable organ donor and the confirmation of consent for donation. Practice varies from country to country, with kidneys allocated locally, re- gionally, or nationally. The aim of allocation policy is twofold; first to maintain equity of access to kidneys for patients on the transplant

21.7.3  Renal transplantation 4883 waiting list, and second to ensure the best use of donated kidneys. In most countries a points system is used with patients accruing points based on waiting time and some measure of how difficult the pa- tient is to match (equity). Additional points are awarded for HLA matching and for donor–​recipient matching (utility). The aim of the latter is to allocate kidneys from younger donors with good renal function to younger recipients for whom many years of graft func- tion are likely needed. In contrast, kidneys from older ECD donors are matched to older recipients, for whom the priority is to receive a transplant quickly (minimizing dialysis-​associated morbidity) with less regard to kidney quality and HLA matching. HLA matching is central to most allocation schemes. Matching the donor and recipient at as many HLA alleles as possible reduces (in principle) the immunogenicity of the transplanted organ, with less risk of rejection and prolonged graft survival. In practice, kidneys are matched at HLA A, B, and DR. A transplant with no mismatches is termed a 0–​0–​0 mismatched transplant, and if all A, B, and DR alleles are different, a 2–​2–​2 mismatch. There is an incremental re- duction in expected graft survival with each HLA mismatch from 0–​0–​0 to 2–​2–​2 mismatched kidneys (see later). However, because of the extreme polymorphism of the HLA system, for most donated kidneys there is unlikely to be a HLA identical (or even 0–​0–​0 mis- matched) recipient—​about 15% of deceased donor transplants in the United Kingdom are 0–​0–​0 mismatches; most transplants are ‘favourable matches’—​for example, *–​0–​1 or *–​1–​0 mismatches (where * can be 0, 1, or 2). One important consequence of HLA matching is to reduce the risk of the recipient generating antibodies against mismatched donor HLA antigens—​donor-​specific antibodies (DSA). Antibody-​ mediated pathology is probably the leading cause of late allograft loss (see ‘Causes of late allograft loss’), in part accounting for the benefi- cial effect of HLA matching. However, in many patients DSA appear only after graft failure (and a reduction in immunosuppression). Patients with anti-​HLA antibodies directed against nonself HLA antigens (whether in response to a previous transplant, pregnancy, or blood products) are termed ‘sensitized’ patients. Transplantation of such patients has been transformed by the introduction of sensitive assays able to detect HLA-​specific antibodies in a serum sample, and regular HLA antibody screening is now routine practice for patients on the transplant waiting list. Those HLA antigens to which a wait-​ listed patient has detectable antibody are often defined as ‘unaccept- able antigens’, preventing allocation of kidneys to which the recipient has preformed DSA and thus eliminating hyperacute and early antibody-​mediated rejection (ABMR). Accordingly, most kidney al- location policies aim to optimize HLA matching and avoid allocation of kidneys with antibody-​defined ‘unacceptable’ HLA types. HLA matching is important for younger recipients, both to pro- long graft survival and to reduce the risk of sensitization: it can be very challenging to find a compatible kidney for sensitized and espe- cially highly sensitized patients. In contrast, older recipients are very unlikely to require a second transplant, or be well enough to receive one, and so HLA matching is less important for them. Surgical technique The new kidney is placed in one or other iliac fossa, usually in an extraperitoneal position that allows ease of repeated biopsy to detect any cause of graft dysfunction. The renal artery is anastomosed end to side to the external iliac artery (Fig. 21.7.3.1) or end to end to the internal iliac artery (Fig. 21.7.3.2). The renal vein is usually anas- tomosed to the external iliac vein. The transplant ureter only has a short distance to run to its site of implantation into the bladder, which is usually done through a submucosal tunnel to reduce the chances of reflux of urine from the bladder into the transplant. Most surgeons routinely place a vesicoureteric stent to reduce the risks of urine leakage and to promote healing. A drain is usually placed near the renal hilum. Lymphatics in the perihilar region are tied off. Fig. 21.7.3.1  End-​to-​side anastomosis between the renal artery and external iliac artery. Reproduced with permission from Barratt J, Harris K, Topham P (eds) (2008). Nephrology (Oxford desk reference). Copyright © 2008 Oxford University Press. Fig. 21.7.3.2  End-​to-​end anastomosis between the renal artery and internal iliac artery. Reproduced with permission from Barratt J, Harris K, Topham P (eds) (2008). Nephrology (Oxford desk reference). Copyright © 2008 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4884 A urethral catheter and/​or suprapubic bladder catheter is inserted and left in situ for about 5 days. The ureteric stent is removed at cyst- oscopy after a few weeks. Most units use prophylactic antibiotics to cover surgical site infection and instrumentation of the urinary tract, and all recipients should receive low molecular weight hep- arin (LMWH) both as general prophylaxis against venous thrombo- embolism and specifically to prevent transplant vein thrombosis. Note that in the standard renal transplant operation described previously, the native kidneys are left in situ. In some patients, one or both may need to be removed (at a separate operation) before the patient can be listed for transplantation: mandatory indications for this include suspicion of renal tumour (usually in those with cystic disease), chronic renal infection, and massive organomegaly in pa- tients with adult polycystic kidney disease, when there is literally no space in which to put a new kidney. Some would also advocate nephrectomy as a prelude to transplantation in those with gross ur- eteric reflux, persistent upper tract infection, renal stone disease, or analgesic nephropathy. Pretransplant nephrectomy may also rarely be indicated in patients with persistent gross nephrotic syndrome in order to correct the procoagulant state, but gross nephrosis usually ameliorates as patients develop advanced chronic kidney disease. A combination of the improved care of comorbidities and a will- ingness to offer transplantation to higher-​risk recipients means that retransplantation is increasingly being undertaken. Second trans- plants are now common, and even third and fourth transplants are considered. Third and fourth transplants are more surgically demanding since at least one failed transplant is likely to require removal in preparation, with the vessels available for anastomosis becoming limited. Aortic and inferior vena cava anastomoses can be performed, often with the kidney placed within the peritoneal cavity, which can make biopsy challenging. Ischaemia times Warm ischaemia is defined as the time between circulatory arrest and renal artery cannulation for ice-​cold perfusion (primary warm ischaemia), together with the time between the removal of the kidney from ice and release of the vascular clamps at implantation (secondary warm ischaemia). With the beating heart donor, the first component is zero. The maximum permissible warm ischaemia time before irreversible damage occurs is 60 to 90 min. Cold ischaemia time is defined as the time between cold perfu- sion of the kidney and removal from ice at the start of the implant- ation operation. Cold ischaemia times of up to 96 h have resulted in functioning grafts, but times in excess of 20 h are associated with a less favourable outcome. The permissible cold ischaemia time of 20 h allows for organ sharing and suitable operating times for the surgical teams. The manifestation of ischaemic injury sustained during retrieval and cold storage, followed by re-​perfusion with recipient blood, is acute tubular injury and a delay in the onset of graft function and diuresis—​called delayed graft function—​which may last several days or occasionally several weeks. In extreme circumstances, the kidney may never function—​primary nonfunction—​which occurs in 1 to 2% of deceased donor transplants. Kidneys retrieved from DCD donors are more susceptible to damage from prolonged cold storage than are DBD kidneys, mani- fest in two ways. First, the rate of delayed graft function is much higher (approximately 50% for DCD and 20% for DBD transplants). Secondly, there is a progressive (although small) reduction in long-term graft survival of DCD kidneys as cold ischaemic time exceeds 12 h. Improving organ preservation Much current research is focused on organ preservation techniques that may prevent ischaemic injury and improve outcomes. Following organ retrieval, most kidneys are cold flushed with preservation so- lution and maintained in ice slurry—​static cold storage. The most widely used alternative is cold pulsatile machine perfusion during which the kidney is placed in a device that perfuses the vasculature with cold preservation solution. Clinical trials have not conclusively demonstrated that this technique is of clinical benefit. A newer technique being trialled is ex vivo normothermic reperfusion. Here a kidney that has been maintained in static cold storage is reperfused for several hours prior to implantation with warmed, oxygenated packed red cells, critically without proinflammatory white blood cells and serum components (e.g. complement). The aim is to restore aerobic metabolism without in- flammation, thus reducing delayed graft function. Perhaps the most promising approach, applicable to DCD organ donors, is normothermic regional perfusion. Following confirm- ation of death a rapid laparotomy is performed, the aorta and inferior vena cava are cannulated, and the donor circulation restored using an extracorporeal membrane oxygenation circuit. This technique effect- ively converts a DCD donor into a DBD donor and allows for con- trolled organ retrieval without prolonged primary warm ischaemia. Postoperative management Excepting for transplants between HLA-​identical twins, immuno- suppression is required to allow transplantation. The first dose of this is often given pre-​ or intraoperatively. Details are discussed in later sections. Following implantation, the function of the new kidney is assidu- ously monitored. The use of dopamine and/​or mannitol in the im- mediate postimplantation period has now virtually ceased as there is no evidence of benefit. Furosemide may be given to provoke a urine output for ease of management, but again there is no convincing evi- dence of benefit as far as improving glomerular filtration rate (GFR) is concerned. Hourly urinary volumes are closely monitored for the first few days. Fluid balance is usually maintained by a prescription that re- quires 100% replacement of urinary volumes and drain losses with crystalloid, plus 25 ml/hr for insensible losses, and central venous pressure is monitored and maintained in the high normal range (+10 cmH2O) with blood or colloid. Serum creatinine is measured at least daily. A failure to fall rap- idly, or a 15% rise once it has fallen to a plateau, is evidence of graft dysfunction and requires prompt investigation. A kidney that fails to function initially, despite good perfusion on the table when the vas- cular clamps were removed, is usually suffering from acute tubular necrosis, which is expected to recover. A sudden cessation of urine flow usually means a surgical problem (e.g. clot obstruction, urinary leak, or vascular catastrophe). A slow tailing-​off of the urinary vol- umes is more suggestive of rejection, hypovolaemia, or developing drug nephrotoxicity. Two of the major immunosuppressive agents,

21.7.3  Renal transplantation 4885 ciclosporin and tacrolimus, are nephrotoxic: doses have to be care- fully adjusted to maintain blood levels within the therapeutic range. Blood pressure should be returned to normal, obstruction excluded, and coagulation checked before any diagnostic biopsy is under- taken. Close and careful monitoring needs to continue for the first 6 months after transplantation as the risk of rejection is at its greatest during this period. One of the ‘holy grails’ of transplant medicine is a method of determining the immunological relationship between the recipient and their transplanted organ, since this would allow tailoring of immunosuppression to immunological need. However, immuno- logical monitoring of transplant recipients is still primitive: lympho- cyte T-​ and B-​cell subsets and activation markers can be of value, particularly when antilymphocyte preparations are being used; serial estimation of post-​transplant anti-​HLA antibodies can help predict patients at risk of humoral rejection. Much work continues to look for better ways of monitoring patients, such as testing for cytokine gene polymorphisms to predict those at highest risk of rejection, and examination of graft biopsies for alterations in gene expression and the expression of adhesion molecules, HLA, cyto- kines, and enzymes (e.g. granzyme, perforin) to better characterize the rejection process. Protocol biopsies may demonstrate subclin- ical rejection, and there is limited data that treatment of these may improve outcome. However, the optimum frequency and timing of protocol biopsies is yet to be determined, their benefits (if any) have to be weighed against their risks (certainly present), and they are not routine practice in most transplant centres. What is abundantly clear is that chronic damage and interstitial scarring with tubular at- rophy is present within the first few months of transplantation, and that after 5 to 10 years, evidence of nephrotoxic damage from the calcineurin inhibitors (CNIs) is almost universal. Complications of renal transplantation Table 21.7.3.1 summarizes the main complications of transplantation. Surgical Table 21.7.3.1 summarizes the main surgical complications of trans- plantation, to which must be added those of any general anaesthetic and laparotomy. Extra risk is added because patients on dialysis are immunosuppressed by uraemia per se, and transplant patients also require immunosuppressive drugs following surgery. Wound healing is significantly delayed in the early post-​transplant period by steroids, and particularly by sirolimus, which for this reason is rarely used in transplantation practice until wounds have healed. Some patients on dialysis will have a marked bleeding tendency related to defective platelet–​endothelial cell interaction. The com- bination of uraemia, surgical stress, a bleeding tendency, and high-​dose steroids produces an increased risk of bleeding peptic ul- ceration, which the routine use of H2 or proton pump blockers has virtually abolished. Many donor organs have small polar arteries that can be lost during or shortly after surgery, in which case the resulting segment of kidney will atrophy. Occasionally, a polar infarct can lead to ne- crosis of a significant segment of renal cortex, causing a calyceal fis- tula and urinary leak. An area of ischaemia around a polar infarct may drive post-​transplant hypertension. The ureteric artery derives from the main renal artery or its lower branch. If this is damaged at harvesting or surgery then an ischaemic necrosis of the ureter may develop, leading to an intra-​abdominal urinary leak or insidious scarring and late obstruction. Diagnosis of a urinary leak is most typically by analysis of fluid emerging from a drain or the transplant wound (urine has a creatinine concentration in mmol/​litre, rather than µmol/​litre as in serum or lymph). Urinary leakage can also be detected by renography (late films). Perirenal collections of fluid (whether from inadequately tied-​off perihilar lymphatics, haemorrhage, or a urinary leak) can become infected: these are best demonstrated by ultrasonography, which can guide aspiration for estimation of creatinine and electrolytes, mi- croscopy and culture, and drainage. On review of a patient’s predialysis and dialysis history, it may be apparent that the patient has a procoagulant state (e.g. systemic lupus erythematosus, numerous thrombotic episodes involving vas- cular access, or a past history of deep venous thrombosis or pul- monary embolus). Such patients should have a full procoagulant work-​up before transplantation, and, if appropriate, be offered post-​ transplant anticoagulation. It is also of note that both the CNIs have a procoagulant effect. Acute graft dysfunction The most common clinical scenario following transplantation is that of acute graft dysfunction, most often characterized by a rise in serum creatinine over a period of days. Delayed graft function is also a form of acute graft dysfunction, but since the kidney is not yet functioning, measurement of serum creatinine is unhelpful. Common causes of acute graft dysfunction are shown in Box 21.7.3.3 and clinical assessment described in Table 21.7.3.2. In the first 1 to 2 post-​transplant weeks, acute graft dysfunction is most commonly surgical (vascular thrombosis, or peri-​renal col- lections compressing the graft vasculature), caused by acute tubular Table 21.7.3.1  Complications of renal transplantation Surgical Medical Wound infection (<1%) Infections transmitted by graft Wound haematoma Opportunistic infections Perirenal (collections → infections):   Lymph (1–​5%)   Haematoma   Urine Specific complications of immunosuppression Complex aetiologies:   Accelerated vascular disease   Hypertension   Electrolyte disturbances   Cosmetic   Thromboembolism   Erythrocytosis   Marrow suppression   Liver dysfunction   Neoplasia   Metabolic bone disease Vascular catastrophe (arterial or venous):   Haemorrhage   Thrombosis (1% arterial/​1–​6% venous) Segmental artery occlusions:   Ischaemia → hypertension (2%)   Infarction → calyceal fistula Devitalization of ureter (stripping):   Sloughing   Ischaemic stricture Urinary leaks:   Cystotomy   Ureteric–​bladder dehiscence Venous thromboembolism/​PE (8%) Pancreatitis Urinary sepsis

section 21  Disorders of the kidney and urinary tract 4886 injury (manifest either immediately as delayed graft function, or in response to hypovolaemia or sepsis), or caused by acute rejec- tion. Occasionally the recipient’s primary renal disease can recur acutely in the transplant kidney, for example, focal segmental glomerulosclerosis (FSGS), IgA nephropathy, atypical haemolytic uraemic syndrome (aHUS), and primary hyperoxaluria. Acute graft dysfunction must be investigated promptly: in many cases the cause of a rise in serum creatinine may not be apparent with the patient having no symptoms, normal vital signs, and a normal transplant ultrasound examination, and an urgent renal bi- opsy is required. For those patients with delayed graft function it is common practice to perform a biopsy 7 to 10 days after trans- plantation (to ensure that acute rejection has not developed on top of acute tubular injury), and to repeat the biopsy every 10 to 14 days until the graft begins to function. Rejection Rejection occurs when the recipient’s adaptive immune system is activated against mismatched donor HLA antigens. Diagnostic cri- teria for both T-​cell-​mediated rejection and ABMR are frequently updated, and in kidney transplantation are referred to as the Banff classification—​the most recent version was published in 2017. A summary of clinically important rejection types is presented in Table 21.7.3.3: these are not mutually exclusive and there is overlap in the pathological processes. Hyperacute rejection Hyperacute rejection occurs if transplantation is performed in the presence of preformed cytotoxic antibodies—​either antibodies dir- ected against ABO blood group antigens (which are expressed on vascular endothelium) or mismatched HLA antigens. In modern transplant practice, hyperacute rejection should never occur. Techniques for determining donor and recipient ABO blood group type are robust, and very rare cases of hyperacute rejection caused by inadvertent ABO blood group incompatible transplants are almost always due to clerical errors. Similarly, careful screening of wait-​ listed patients for preformed HLA antibodies and pretransplant cross-​match testing effectively prevents hyperacute rejection caused by preformed anti-​HLA antibodies. Acute cellular rejection In most centres about 10 to 20% of patients will experience an acute cellular rejection, usually occurring in the first 3 months after trans- plantation. Acute cellular rejection is often clinically silent as the inflammatory component of the rejection is masked by immuno- suppression. Oliguria, fluid retention, increasing hypertension, and a sharp rise in creatinine sometimes occur, particularly in the presence of a robust memory T-​cell response directed against mis- matched donor HLA antigens, which can cause early episodes of ag- gressive T-​cell-​mediated rejection (often in the first post-​transplant week, and sometimes referred to as ‘accelerated cellular rejection’). However, most episodes of cellular rejection present as a rising serum creatinine over days/​weeks in an asymptomatic patient. Clinical assessment is described in Table 21.7.3.2 and diagnosis re- quires a kidney transplant biopsy. Histological diagnosis Obtaining a histological diagnosis is very important to diagnose acute rejection and exclude other causes of acute graft dysfunction (Box 21.7.3.3). Biopsy also allows the histological classification of a rejection episode. The hallmarks of acute cellular rejection are interstitial infiltration by lymphocytes (and other inflammatory cells) and tubulitis, in which the invading lymphocytes have pene- trated the tubular epithelial cell basement membrane and directly engage tubular epithelial cells. In more severe episodes of cellular rejection there is evidence of vascular involvement, with lympho- cytic infiltration beneath the endothelial cells lining arterioles and small arteries (‘endothelialitis’). In the most severe form of cellular rejection, endothelialitis spreads to include transmural arterial in- flammation with vessel wall necrosis. These features form the basis of the Banff classification of kidney transplant rejection. A third im- portant benefit of biopsy is to exclude the presence of an antibody-​ mediated component of rejection, especially in those patients with more severe (vascular) rejection. These histological distinctions are important guides to treatment. Management Most episodes of T-​cell-​mediated rejection can be managed with pulsed high-​dose corticosteroid, a typical regimen being 500–1000 mg methylprednisolone given intravenously on three consecutive days. Such treatment leads to resolution of rejection in 90% of pa- tients with tubulointerstitial or mild vascular rejection, with serum creatinine returning to baseline in most. If serum creatinine does Box 21.7.3.3  Causes of acute graft dysfunction • Acute tubular injury • Acute arterial or venous stenosis or thrombosis • Ureteric obstruction • Acute rejection • Ascending infection with graft pyelonephritis • CNI nephrotoxicity • Recurrent renal disease • BK virus nephropathy Table 21.7.3.2  Investigation of acute graft dysfunction History Primary renal disease Intercurrent illness—​fever, urinary tract infection, diarrhoea/​vomiting Medications—​especially any new drugs interacting with CNI (increased levels are nephrotoxic) and adherence to immunosuppressive therapy (absent or low levels predispose to rejection) Examination Fever Volume status (hypovolaemia or fluid overload) Graft tenderness or vascular bruit Urinalysis and
urine culture Evidence of infection (pyuria, urinary nitrites) Proteinuria (may indicate recurrent disease) Blood tests Serum creatinine, C-​reactive protein, full blood count, and coagulation screen HLA antibody screen BK virus PCR Imaging Ultrasound scanning with Doppler studies (exclude ureteric or bladder outflow obstruction and confirm perfusion) CT imaging if ultrasound suggests anatomic pathology (arterial or venous pathology, perinephric collections) Renal biopsy

21.7.3  Renal transplantation 4887 not return to baseline, a follow-​up biopsy is required to determine if there is ongoing inflammation, defining steroid-​resistant rejection. Treatment of steroid-​resistant rejection is with T-​cell-​depleting anti- body therapy (antithymocyte globulin (ATG)). Treatment with ATG is often given as first-​line therapy for more severe cellular rejection with significant vascular involvement. Maintenance immunosuppression should be optimised in all patients with acute rejection, typically to include the three-​drug regimen of tacrolimus, mycophenolate mofetil, and corticosteroid. Taken as a whole, patients with one or more episodes of acute cel- lular rejection have inferior graft survival when compared to those without rejection. However, early episodes of rejection that are readily reversed, with serum creatinine returning to baseline and without the formation of DSA, likely have a negligible detrimental effect on long-​term outcomes. In contrast, later episodes of rejection (where there is often established scarring on biopsy at the time of diagnosis), those with significant vascular involvement, and those with associated DSA predict poor graft survival. Acute antibody-​mediated (humoral) rejection Acute ABMR is much less common than acute cellular rejection, comprising about 10% of all early rejection episodes. It is almost always caused by antibodies directed against mismatched HLA (DSA), although some pathogenic non-​HLA antibodies have been reported (e.g. anti-​angiotensin II receptor antibodies). Acute ABMR typically occurs in the first 1 to 3 post-​transplant weeks, often with very rapidly rising serum creatinine or even an- uria. It is the manifestation of a memory B-​cell response and usually it is possible to demonstrate previous exposure to the target HLA molecule, for example, through previous pregnancy or organ trans- plantation. DSA may be absent at the time of transplantation, or pre- sent at a low level such that cross-​match testing is negative, but rises rapidly following transplantation. Histological diagnosis The pathological hallmark of ABMR is antibody-​mediated in- jury to the microcirculation. DSA binding to target HLA mol- ecules on the graft endothelial cell surface has several effects. Firstly, the endothelial cells become activated, procoagulant, and secrete proinflammatory mediators. Secondly, bound antibody ac- tivates complement leading to direct endothelial cell damage (and also the deposition of the complement breakdown product C4d, which can be identified histologically). Thirdly, bound DSA re- cruit proinflammatory cells (monocytes, NK cells and neutrophils) through ligation of Fc receptors. On biopsy, ABMR is defined by mononuclear cell and neutro- phil infiltration of glomeruli (‘glomerulitis’) and within peritubular capillaries (‘capillaritis’), with associated endothelial cell swelling and evidence of thrombi within the microcirculation (thrombotic microangiopathy). C4d immunohistochemistry is frequently posi- tive in acute ABMR, although is not required for diagnosis. Most episodes of acute ABMR are accompanied by evidence of associated T-​cell-​mediated rejection, and even in the absence of T-​cell path- ology on biopsy, alloreactive T-​cell help is important in initiating the alloantibody response. Management There is no consensus as to the optimum treatment for ABMR, al- though many centres use protocols combining three strategies. First is treatment for the associated cellular component with pulsed steroid or ATG as described previously. Second is treatment aimed at reducing circulating DSA levels using plasma exchange or other techniques to remove antibody. Third is treatment to try and sup- press new DSA formation, commonly with rituximab and/​or intra- venous immunoglobulin. Between 50 and 80% of acute ABMR episodes can be reversed with such treatment, and in a few cases graft function returns to baseline and DSA disappear. However, in most patients the antibody response becomes established (with the generation of bone marrow-​resident plasma cells producing DSA), leading to chronic active ABMR (see later). Overall, 50% of patients with acute ABMR will lose their graft within 5 years. Late rejection The term ‘chronic rejection’ has been used for many years and is so poorly defined that it is of little value, although it is useful to distin- guish late episodes of rejection (months or years post-​transplant) Table 21.7.3.3  Classification of transplant rejection Hyperacute Acute T-​cell mediated Acute antibody mediated Chronic active antibody mediated Timing Minutes 5 days onwards, with most episodes within 6 months Any time Months to years after transplantation Mediators Preformed anti-​HLA
or ABO antibodies Complement T lymphocytes Anti-​HLA antibodies Complement Anti-​HLA antibodies Complement Recruitment of many other inflammatory cell types Histology Infarction Platelets Fibrinogen Polymorphs Tubulitis Interstitial inflammation Endovasculitis (acute) Microcirculation inflammation (peritubular capillaritis ± glomerulitis) Endovasculitis Transplant glomerulopathy Splitting of peritubular capillary basement membrane Interstitial fibrosis and tubular atrophy Obliterative arteriopathy Treatment Nephrectomy High-​dose intravenous steroids Polyclonal T-​cell-​depleting antibodies (ATG) High-​dose intravenous steroids Antibody removal (e.g. by plasma exchange) Complement inhibition Rituximab and intravenous immunoglobulin Optimize maintenance immunosuppression (tacrolimus + mycophenolate + steroid) Consider plasma exchange, intravenous immunoglobulin, rituximab (but no strong evidence of efficacy) NB: cellular and humoral rejection often coexist.

section 21  Disorders of the kidney and urinary tract 4888 from the early acute rejection episodes described previously. While early episodes of acute rejection reflect an alloimmune response developing despite immunosuppression, late episodes of rejection generally reflect inadequate or even absent immunosuppression. On occasion, immunosuppression is deliberately reduced, for ex- ample, in patients with infection or malignancy, but most often late-​developing rejection is the result of poor adherence to im- munosuppressive treatment by the patient. The typical presentation is with rising creatinine over weeks or months leading to a biopsy demonstrating rejection. Cellular rejection is diagnosed and man- aged as for acute cellular rejection, but there is very often significant established graft damage (interstitial fibrosis and tubular atrophy) and a poor response to treatment. More important is chronic active ABMR, now the leading cause of progressive GFR loss and allograft failure. Patients present with a rising creatinine over weeks or months, often with significant proteinuria. Most have detectable DSA that can develop months or years before GFR loss is evident. DSA are most commonly spe- cific for class II antigens (especially HLA DQ). On biopsy, features of acute microcirculation inflammation are present as for acute ABMR, but at a reduced intensity. C4d staining is often negative. Chronicity is evident by splitting and reduplication of the glom- erular basement membrane (‘transplant glomerulopathy’—​which gives rise to proteinuria) and of the peritubular capillary basement membrane. There is almost always established interstitial fibrosis and tubular atrophy. No currently available therapy is effective in suppressing established chronic active ABMR, with disappointing results from treatments including plasma exchange, intravenous im- munoglobulin, rituximab, proteasome inhibition, and complement blockade. Immunosuppressive regimens Immunosuppressive therapy has evolved considerably since the first successful kidney transplant in 1954. Indeed, that first transplant was performed between monozygotic twins and without immuno- suppression. The first effective agent, azathioprine, was introduced in the 1960s, and ciclosporin in the 1980s. The choice of agents avail- able today is summarized in Table 21.7.3.4. Most contemporary immunosuppressive agents were introduced into clinical practice based on large randomized clinical trials com- paring newer agents with their older equivalents—​for example, tacrolimus compared to ciclosporin, mycophenolate to azathioprine, and induction compared to no induction. All of these trials used short-​term (6-​ or 12-​month) endpoints of acute rejection, and pa- tient and graft survival. It is of note that all these immunosuppres- sive agents target T-​cell activation and that ABMR was a rare event in most studies. Accordingly, contemporary immunosuppression is based on trials demonstrating a reduction in acute cellular rejection, with little evidence to indicate the optimum regimen in terms of pro- moting long-​term graft survival or preventing chronic active ABMR. Induction immunosuppression Almost all present-​day immunosuppressive regimens use an induc- tion agent followed by tacrolimus-​based maintenance immuno- suppression. Induction refers to treatment given at the time of the transplant to provide enhanced immunosuppression covering the first few post-​transplant months, when acute rejection is most likely. There are two approaches: nondepleting and depleting induction. Nondepleting induction This uses the engineered monoclonal antibody basiliximab, which binds to CD25—​the inducible subunit of the interleukin 2 receptor. CD25 is induced upon T-​cell activation and basiliximab blocks IL2 binding, thus preventing interleukin-​2-​induced T-​cell proliferation and survival. Basiliximab induction reduces the incidence of acute rejection by about 33% when added to a ciclosporin-​based mainten- ance regimen, although it is less clear that it reduces acute rejection when added to contemporary tacrolimus/​mycophenolate-​based maintenance therapy. Basiliximab appears free of adverse effects and in particular does not seem to add to the adverse effects of long-​term immunosuppression. Depleting induction The alternative approach to induction is to use a depleting anti-​ T-​lymphocyte antibody—​either a polyclonal antilymphocyte serum (ATG) or the humanized monoclonal anti-​CD52 antibody alemtuzumab. Both induce profound depletion of circulating CD4 and CD8 T lymphocytes, with alemtuzumab additionally depleting B lymphocytes, monocytes, and NK cells. When depleting induction is used in combination with tacrolimus-​ based maintenance immunosuppression, very low 1-​year acute rejec- tion rates of 5 to 10% can be achieved, compared to 15 to 20% with basiliximab induction. Historically, the use of depleting induction was associated with significant adverse effects, including a cytokine-​ release syndrome leading to high fever, myalgia, noncardiogenic pul- monary oedema, and aseptic meningitis, as well as increased risks of infection (especially cytomegalovirus (CMV)) and post-​transplant lymphoproliferative disorder (PTLD). However, modern protocols, including administration of the first dose intraoperatively with steroid premedication and lower cumulative doses, accompanied by less in- tense maintenance therapy, have largely eliminated these risks. Maintenance immunosuppression ‘Triple immunosuppression’ Maintenance immunosuppression is usually started on the day fol- lowing transplantation, with almost all patients receiving CNI-​based Table 21.7.3.4  Immunosuppressive agents used in kidney transplantation Calcineurin inhibitors Ciclosporin Tacrolimus Antimetabolites Azathioprine Mycophenolate mofetil Antibodies Anti-​CD25 (interleukin-​2 receptor): basiliximab Polyclonal anti-​T-​cell antibodies: ATG Anti-​CD20: rituximab Anti-​CD52: alemtuzumab Corticosteroids Prednisolone Costimulation blockade Belatacept mTOR inhibitors Sirolimus Everolimus

21.7.3  Renal transplantation 4889 therapy. Tacrolimus has almost completely replaced ciclosporin as the CNI of choice, with randomized trials demonstrating a sig- nificant reduction in acute rejection by up to 50% in tacrolimus-​ treated patients. Meta-​analysis of trials comparing tacrolimus with ciclosporin suggests both improved patient and graft survival with tacrolimus. Tacrolimus is most commonly given in combination with the antiproliferative agent, mycophenolate mofetil (which has largely replaced azathioprine). Corticosteroids are often added—​‘triple im- munosuppression’—​although the use of induction therapy allows for either steroid-​free immunosuppression (with T-​cell-​depleting induction) or rapid steroid withdrawal (with basiliximab induction). Fig. 21.7.3.3 illustrates common immunosuppressive protocols. There is no question that tacrolimus-​based immunosuppression is effective, with low rates of acute cellular rejection as indicated earlier. For those patients maintained on long-​term tacrolimus (and who adhere to prescribed treatment), there is additionally a low incidence of chronic active ABMR. DSA develop in about 10% of patients at 10 years post-​transplant (de novo DSA), indicating that effective T-​cell immunosuppression can prevent the development of humoral alloimmune responses. However, long-​term tacrolimus (or ciclosporin) exposure leads to one of the principal drawbacks of CNI-​based immunosuppression—​ that of nephrotoxicity. CNI exposure inevitably leads to histological evidence of CNI nephrotoxicity in almost all patients biopsied at 10 years post-​transplant, characterized by interstitial fibrosis (said to be in ‘stripes’) and arteriolar hyalinosis. Despite the accumula- tion of histological damage, GFR loss is slow in many patients and CNI nephrotoxicity is almost certainly not an important cause of graft loss. Nevertheless, there is great interest in finding alternative immunosuppressive strategies that would allow CNI elimination while preserving graft function and preventing DSA formation. Attempts to withdraw tacrolimus from patients maintained on mycophenolate and steroid have been disappointing, with an un- acceptable incidence of acute rejection, DSA formation, and the development of recurrent glomerulonephritis (in up to 50% of patients). Alternatives to calcineurin inhibitors There are several alternatives to CNIs as part of maintenance im- munosuppression. Sirolimus and the newer drug everolimus are mammalian target of rapamycin (mTOR) inhibitors, and both have been used in place of CNI (usually with induction, mycophenolate, and steroid) with mixed results. mTOR inhibitors are powerfully antiproliferative and lead to poor wound healing and lymphocele formation, limiting their use early post-​transplant. Both are associ- ated with adverse effects that many patients find troublesome (skin rashes, mouth ulcers, oedema, and arthralgia) such that between 30 and 50% of patients allocated to mTOR inhibition in randomized trials have to discontinue therapy. They can also cause other signifi- cant side effects including interstitial lung disease and hyperlipid- aemia. However, neither drug is nephrotoxic (in nonproteinuric patients) and, in patients with CNI nephrotoxicity able to tolerate mTOR inhibition, replacement of CNI with either drug can halt or even partly reverse GFR loss. A more promising alternative is belatacept, a recombinant protein that prevents T-​cell activation by blocking costimulation and which is not nephrotoxic. When compared to ciclosporin-​based immuno- suppression, belatacept is associated with an excess of acute cellular rejection, despite which GFR is preserved in belatacept-​treated patients with little evidence of GFR loss over 7 years of follow-​up, and significantly lower de novo DSA formation. Several trials using belatacept and T-​cell-​depleting induction (to eliminate the excess of early cellular rejection) are underway. One feature of belatacept is IV methylprednisolone No induction Basiliximab Thymoglobulin Alemtuzumab 8–10 ng/ml 8–10 ng/ml 8–10 ng/ml 5 ng/ml 5 ng/ml 5 ng/ml 1000 mg BD 1000 mg BD 500 mg BD 500 mg BD Tacrolimus MMF/MPA Prednisolone (20 mg 5 mg) Tacrolimus MMF/MPA Tacrolimus months 0 6 12 MMF/MPA Prednisolone (20 mg 0 mg) 500 mg BD Fig. 21.7.3.3  Commonly used immunosuppressive protocols for renal transplantation. BD, twice daily; MMF, mycophenolate mofetil; MPA, mycophenolic acid. Target trough serum levels for tacrolimus are shown (ng/ml).

section 21  Disorders of the kidney and urinary tract 4890 that it is given as a monthly intravenous infusion that, while incon- venient, ensures adherence to treatment. Specific side effects of particular immunosuppressive agents Steroids Steroids are responsible for many of the complications of transplant- ation, and intensely disliked by patients (Box 21.7.3.4). In recent years, the dose of steroids used has been safely reduced and most contemporary protocols either eliminate steroids completely (with the use of T-​cell-​depleting induction) or aim to withdraw mainten- ance steroid in the first few post-​transplant weeks (with basiliximab induction). Where no induction is used, prednisolone can be rapidly tapered to a maintenance dose of 5 mg, thus minimizing steroid-​ related adverse effects. Other groups of patients in whom long-​term steroids may be indicated are those at risk of steroid-​sensitive recur- rent glomerular disease (FSGS, IgA nephropathy—​although there is little evidence indicating a benefit from steroids), those at very high immunological risk, and those who have developed acute rejection following steroid withdrawal. Calcineurin inhibitors The main drawback of both ciclosporin and tacrolimus is nephro- toxicity (Table 21.7.3.5), which adds another level of complexity to the differential diagnosis and management of both acute and chronic graft dysfunction. Tacrolimus is a more potent immunosuppressive agent than ciclosporin, but perhaps more toxic (diabetes mellitus and neurotoxicity). It does, however, have real cosmetic advantages over ciclosporin, perhaps mediated by lower levels of transforming growth factor-​β (TGFβ). New-​onset diabetes after transplant- ation occurs in about 10% of patients on ciclosporin and 15% of patients on tacrolimus, a risk significantly reduced by eliminating corticosteroids. Azathioprine and mycophenolate mofetil Both agents block purine synthesis. The main side effects of azathioprine are hepatotoxicity and bone marrow suppression (Table 21.7.3.6). Mycophenolate mofetil is more potent and more specific than azathioprine, blocking purine synthesis in lympho- cytes. Its most troublesome side effects are abdominal colic and diarrhoea:  about 10% of patients are so badly affected that they are unable to tolerate the drug, but some can manage with mycophenolate sodium, which is associated with a lower incidence of gastrointestinal problems than the prodrug mycophenolate mofetil. A higher incidence of invasive CMV disease has been asso- ciated with mycophenolate. Biologics Side effects vary with the preparation used. Polyclonal antilymphocyte preparations can cause a marked first-​dose effect in which lympho- cytes are activated and secrete cytokines. High fever, rigors, and joint, muscle, and back pains are common, becoming less marked and less severe with subsequent doses. A widespread capillary leak syndrome with noncardiogenic pulmonary oedema, hypotension, and shock can occur, and for this reason ATG should not be ini- tiated in patients who are fluid overloaded. The practice in many Box 21.7.3.4  Side effects of steroids • Acne • Hypertrichosis • Redistribution of body fat • Obesity • Cushingoid facies • Insulin resistance—​diabetes mellitus • Hypertension • Hyperlipidaemia • Proximal myopathy • Osteoporosis—​avascular necrosis of bone • Tendon ruptures • Poor wound healing • Skin atrophy/​fragility/​easy bruising • Scleromalacia • Growth inhibition: premature fusion of the epiphyses • Erythrocytosis • Cataracts • Benign intracranial hypertension • Psychosis • Peptic ulceration • Colonic perforation • Pancreatitis Table 21.7.3.5  Side effects of calcineurin inhibitors—​relative risk Side effect Ciclosporin Tacrolimus Nephrotoxicity ++ ++ Hypertension/​sympathetic overactivity ++ + Hyperuricaemia ++ ++ Hyperkalaemia (type IV renal tubular acidosis) + + Hypomagnesaemia (urine leak) + + Haemolytic uraemic syndrome + + Platelet hyperaggregability + ?± Insulin resistance → diabetes mellitus + +/​++ Dyslipidaemia + ± Hepatoxicity + + Breast fibroadenosis + –​ Coarsening of facial features + –​ Gum hypertrophy + –​ Hypertrichosis + –​ Distal limb pain/​periostitis + ± Cardiotoxicity –​ + Neurotoxicity: + ++   Fits + +   Ataxia + +   Posterior fossa leukoencephalopathy + +   Paraesthesiae +   Tremor + + Neoplasia ++ + Infection + +

21.7.3  Renal transplantation 4891 centres is to administer a test dose before the first treatment dose, and premedication before the treatment dose with corticosteroids, antihistamines, and antipyretics is routine. Aseptic meningitis and encephalitis are rare side effects. By contrast, the humanized and chimeric anti-​CD25 (anti-​ interleukin-​2 receptor) antibodies do not appear to have any short-​ term side effects. Although rituximab may cause a first-​dose effect from cytokine release it appears remarkably safe. Alemtuzumab can also cause infusion reactions and a range of autoimmune complications have been reported (e.g. haemolytic anaemia and thrombocytopenia). General side effects of immunosuppression It is important to remember that all currently available immuno- suppressive regimens are nonspecific in the sense that they suppress not only the immune response to the allograft, but also the immune response to infections and tumours. All the agents used have sig- nificant side effects and toxicities, and to a very large extent the long-​term complications of renal transplantation are those of the immunosuppressive agents used. Some side effects are more related to the total burden of immunosuppression rather than to any spe- cific single agent (e.g. infections and cancer). Opportunistic infections The CNIs used for immunosuppression act to inhibit the T-​helper cell (CD4) and prevent the elaboration of interleukin-​2 and other cytokines. In some respects this is akin to the effects of HIV infec- tion and it is therefore not surprising that the renal transplant re- cipient may develop the same range of opportunistic infections and tumours as is seen in patients with AIDS (see Chapter 8.5.23). Clinical features are often dramatic and rapidly evolving, hence prompt and precise microbiological diagnosis is essential. This re- quires early recourse to invasive techniques, for example, biopsy, node aspiration, node excision, bronchoalveolar lavage, and even lung bi- opsy. Neurological symptoms and signs may herald CNS infection and require urgent CT scanning or magnetic resonance imaging (MRI) and the examination of cerebrospinal fluid whenever possible. A brain biopsy may be the only route to a specific diagnosis. Any pyrexial episode in a transplant recipient should prompt a search for infection. Blood and urine cultures should be undertaken routinely. Figure 21.7.3.4 summarizes the timetable of infections. In the first month, before immunosuppression is fully established, renal Table 21.7.3.6  Side effects of azathioprine and mycophenolate mofetil Side effect Azathioprine Mycophenolate mofetil Hepatotoxicity ++ + Marrow suppression: ++ ±   Platelets ± ±   Red cells ± –​   Granulocytes ++ ± Megaloblastic anaemia + –​ Gut toxicity ± ++ Pancreatitis + –​ Hypogammaglobulinaemia ± + Lung fibrosis + ± Alopecia + –​ Infection + +/​++ Cancer + ± Conventional HSV Unconventional Viral CMV onset EBV VZV Papova Adenovirus CMV Chorioretinitis Fungal CNS Listeria Aspergillus, Nocardia, Toxoplasma Cryptococcus Onset of non-A, non-B hepatitis UTI:, bacteraemia, pyelitis, relapse UTI:, relatively benign Bacterial Wound pneumonia Line-related Hepatitis Hepatitis B Transplant Months 0 1 2 3 4 5 6 Pneumocystis TB Fig. 21.7.3.4  Timetable of infections. Reproduced by permission from Rubin R.H. and Young L.S. (eds) 1994, Clinical approach to infection in the compromised host, 3rd edn. Plenum Medical Book Co., New York.

section 21  Disorders of the kidney and urinary tract 4892 transplant recipients may develop the same sort of infection as seen after any general anaesthetic, abdominal operation, or urological procedure. From months 1 to 6, immunosuppression is maximal and the risk of opportunistic infections greatest. Thereafter, the risk of infection declines but remains greater than the general popula- tion, particularly in the patient with a poorly functioning graft. Viral infections Not all virus infections prove dangerous to the immunosuppressed renal transplant recipient. Those with particularly important clin- ical sequelae are summarized in Table 21.7.3.7. The most important group are the DNA viruses of the herpes group: infection with these is immunomodulating in its own right and further immunosuppresses the patient, hence they are not infrequently associated with super- imposed infections with other microorganisms (e.g. Pneumocystis jirovecii, listeria, and bacterial sepsis). Several of the viruses have proven oncogenic potential and are considered later in this chapter. There has been a steady and dramatic fall in deaths from infection after transplantation. This is due to many factors including better use of immunosuppressive agents, effective control of CMV, and major advances in the diagnosis and treatment of some infections. Cytomegalovirus CMV is the main infectious complication in solid organ transplant- ation (Box 21.7.3.5), with presentation ranging from asymptomatic, through a minor febrile illness or mild abnormality of liver blood tests (‘transaminitis’), to a life-​threatening condition. Primary infec- tion is more likely to produce serious disease than either reinfection or reactivation. Viral load and the total burden of immunosuppres- sion are the main determinants of disease. Use of potent T-​cell-​ depleting agents, for either induction or rescue, is associated with CMV disease, and—as would be expected—the total number of treated rejection episodes is an important risk factor. Diagnosis is usually by quantitative polymerase chain reaction (PCR) for viral DNA, or by an antigen assay (pp65) on peripheral blood leucocytes. Monitoring the serological response for diag- nostic purposes is obsolete as it is far too insensitive, and routine cultures are too slow. A range of effective prophylactic regimens are available:  oral valaciclovir or oral valganciclovir is effective. When used, these are typically given to patients deemed at risk of CMV infection (cer- tainly CMV-​negative recipients of CMV-​positive grafts, and in many centres any patient in whom recipient and/​or donor are CMV posi- tive) for 90 to 180 days. Another equally valid approach is careful monitoring by quantitative CMV PCR, combined with pre-​emptive treatment of infection if the CMV count rises above a threshold value, and before clinical disease becomes apparent. In this situ- ation, 2 or 3 weeks of oral valganciclovir is usually effective. With this expectant approach only 40 to 50% of patients develop signifi- cant viraemia and need pre-​emptive therapy. Foscarnet is a more toxic (nephrotoxic) alternative that can be used in resistant CMV. CMV may play a role in triggering or augmenting both acute and chronic rejection. More prolonged and universal prophylaxis may be indicated if this is confirmed. Epstein–​Barr virus EBV-​related syndromes (Box 21.7.3.5) are an important cause of morbidity and mortality in renal transplant recipients, the most ser- ious problem being Post-transplant lymphoproliferative disorder (PTLD), which is considered later. Varicella zoster virus Reactivation of latent varicella zoster virus (VZV) produces shingles, which is a common and unpleasant complication of transplantation. Immediate treatment with oral valaciclovir can limit spread and reduce post-​herpetic pain. Much more dangerous is a primary VZV infection in an immunocompromised individual: this can cause a fulminating disease with hepatitis, pneumonitis, and disseminated intravascular coagulation occurring within a few days, and with high mortality. All patients who are to receive immunosuppression should have their VZV antibody status established. Those who are seronegative should be warned about exposure to chickenpox or shingles and should report any contact immediately. Vaccination is available, but being a live attenuated vaccine this can only be given prior to trans- plantation. If exposed, susceptible individuals should be given zoster immune globulin and monitored closely. High-​dose intravenous aciclovir should be given at the first suggestion of disease. Table 21.7.3.7  Opportunistic infections in transplant recipients Viruses Human herpes viruses (HHV): Herpes simplex (HHV1, HHV2) Varicella zoster (HHV3) Epstein–​Barr virus (HHV4) Cytomegalovirus (HHV5) Kaposi’s sarcoma virus (HHV8) Hepatitis viruses:   Hepatitis B virus (HBV)   Hepatitis C virus (HCV) Papovaviruses:   Human papillomavirus (HPV)   Polyomavirus (BK/​JC) Human immunodeficiency virus (HIV) Bacteria Mycobacteria:   Tuberculosis   Atypicals Nocardia Listeria Nontyphoid salmonella Legionella Fungi Hospital acquired, e.g.:   Aspergillosis Community acquired, e.g.:   Candida   Torulopsis   Cryptococcus   Mucormycosis   Pneumocystis jirovecii Reactivation (geographically restricted), e.g.:   Histoplasmosis   Coccidioidomycosis Parasites Toxoplasmosis Cryptosporidium Geographically restricted:   Strongyloides stercoralis   Trypanosoma cruzi   Malaria Leishmaniasis Schistosomiasis

21.7.3  Renal transplantation 4893 Herpes simplex Although the classic herpetic cold sore is common after trans- plantation, herpes simplex virus (HSV), particularly if a primary infection, can produce a variety of serious clinical sequelae in the immunocompromised patient (Box 21.7.3.5). Use of prophylactic valaciclovir or valganciclovir (primarily for CMV prophylaxis) dramatically reduces the risks of HSV infection. Treatment with valaciclovir is very effective. BK virus Most adult recipients are already seropositive for the human BK polyomavirus (BKV), indicating childhood infection that is usually asymptomatic. Primary infection can occur from the allograft, and in many cases this is also asymptomatic, but it can manifest with a progressive rise in serum creatinine over weeks to months, typically occurring about 12 months after transplantation (but with consider- able variation in timing). BKV can also cause ureteric stenosis. Cytological analysis of the urine may reveal infected cells with an enlarged nucleus containing a large basophilic intranuclear inclu- sion (decoy cells, named for their resemblance to cells from renal carcinoma), but these have poor sensitivity and specificity for BKV nephropathy, which occurs in up to 10% of kidney transplant recipi- ents. Diagnosis of BKV nephropathy is typically based on the finding of significant BKV replication by plasma PCR testing of viral DNA load, and the finding on renal biopsy of characteristic cytopathic changes with positive staining for the cross-​reacting SV40 large T antigen (or less commonly staining with antibodies specific for BKV). Histological distinction from acute cellular rejection is not always straightforward, but very important clinically as treatments for the two conditions are very different. There is no effective antiviral agent to treat BKV nephropathy. Most centres monitor plasma BKV by PCR for the first 2 years after transplantation and proceed to renal biopsy if quantitative assay shows levels above a threshold (typically >10 000 copies/​ml). If this shows BKV nephropathy, then the standard response is to reduce im- munosuppression, typically (in a patient on triple immunotherapy) by withdrawal of azathioprine/​mycophenolate, which sometimes leads to a fall in BKV titre and improvement in renal function. Many cases, however, do not respond, when other treatments given in- clude intravenous immunoglobulin, leflunomide, cidofovir, and fluoroquinolones. Evidence that these are effective is not compelling and BKV nephropathy leads to graft loss in 15 to 50% of those af- fected. This is not, however, a contraindication to retransplantation. JC virus The JC human polyomavirus has been reported to cause a progres- sive multifocal leukoencephalopathy in renal transplant recipients, but this is very rare. Human papillomaviruses Human papillomavirus (HPV) can cause an extensive range of viral warts in renal transplant recipients. Some types have been impli- cated in the pathogenesis of anogenital carcinomas and squamous cell carcinomas (SCCs) of the skin (see ‘Skin cancers’). The man- agement of viral warts in the immunocompromised patient is diffi- cult when they are very extensive and consideration should be given Box 21.7.3.5  Clinical features of post-​transplantation viral infections Cytomegalovirus • Asymptomatic • CMV syndrome:

— Fever

— Wasting

— Malaise • Leucopenia • Transaminitis • Hepatitis • Pseudolymphoma • Retinitis • Pneumonitis • Colitis • Gastroduodenitis • Pancreatitis • Myocarditis • Superinfection (e.g. Pneumocystis jirovecii pneumonia) Epstein–​Barr virus • Asymptomatic • Classic glandular fever • Hairy leucoplakia • Hepatitis • Post-transplant lymphoproliferative disorder (PTLD) Herpes simplex virus • Stomatitis • Oesophagitis • Anogenital ulcers • Corneal ulcers • Kaposi’s varicelliform eruption • Haemorrhagic skin blisters • Paronychia • Pneumonitis • Hepatitis • Pancreatitis • Meningoencephalitis Varicella zoster virus • Reactivation:

— Shingles • Primary infection:

— Pneumonitis

— Hepatitis

— Encephalitis

— Pancreatitis • Disseminated intravascular coagulation Human papilloma virus • Cutaneous warts • Condyloma acuminatum • Bowen’s disease • Squamous cell carcinoma • Anogenital carcinoma (e.g. cervical invasive neoplasia, vulvovaginal invasive neoplasia)

section 21  Disorders of the kidney and urinary tract 4894 to reducing immunosuppression. Localized lesions can be treated conventionally with topical agents such as glutaraldehyde or laser therapy, but widespread surgical excision is sometimes required. Local recurrence in scar tissue is common. A combination of oral isotretinoin (50 mg daily) and topical tretinoin cream (0.05%) can control the lesions in severe cases. Topical imiquimod can be useful, and cidofovir ointment is of value in anogenital disease. HIV Before the advent of HAART, infection with HIV was considered an absolute contraindication to transplantation. However, several studies have demonstrated patient and graft outcomes for HIV-​ infected recipients with undetectable viral load, CD4 count greater than 200/​µl and on stable HAART, that are comparable to those obtained in recipients without HIV infection. The combination of HAART with immunosuppressive regimens involves complex drug interactions and toxicities, requiring expert management. Bacterial infections There are a limited number of bacterial infections that are signifi- cantly more common and more severe in the transplant population (Table 21.7.3.7), but bacteraemias are more common in transplant recipients, usually as a result of urinary tract infections, and meta- static abscesses in joints, skin, muscles, and the brain are also more frequent. Mycobacterial infections Reactivation of mycobacterial infection following transplantation is very common in the ‘at-​risk’ population, and most United Kingdom units recommend prophylaxis with isoniazid (with pyridoxine to prevent neuropathy) in these groups. Isoniazid should not be given to patients with underlying liver disease. Experience in the Indian subcontinent suggests that pretransplant bacillus Calmette–​Guérin (BCG) vaccination is not effective. Tuberculosis should be considered in any transplant patient with unexplained night sweats, fever, and weight loss. Mycobacterial infections (both atypical and tuberculous) can present in many different guises, for example, pneumonia, lymphadenopathy, intra- cranial space-​occupying lesions, discharging sinus, and skin ulcers. Tissue biopsy, cultures, and smears using special stains are essen- tial, and PCR-​based techniques can speed diagnosis. Gallium scan- ning may identify nodes that can be aspirated under CT guidance. Skin testing is unreliable in the immunocompromised patient and γ-​interferon release assays cannot distinguish between active and la- tent tuberculosis. Treatment is made challenging by serious drug interactions be- tween rifampicin and both the CNIs, prednisolone and sirolimus. Rifampicin is such a potent inducer of cytochrome P450 that subtherapeutic levels of the CNIs and steroids can develop within weeks. Graft loss from rejection will occur unless doses are in- creased: that of prednisolone is usually doubled, and the calcineurin blockers may have to be increased still further and given three times daily. Monitoring of drug levels is essential. In many units a four-​drug antituberculous regimen is recom- mended, comprising rifampicin, ethambutol, isoniazid, and pyrazinamide. This can be reduced when sensitivities become avail- able. Treatment should be continued for at least a year, particularly in the case of atypical mycobacterial infections. Therapy may be further complicated by hepatotoxicity, for which the differential diagnosis is complex as many other factors can cause deranged liver function tests in renal transplant recipients (e.g. viral infections—​ HBV, HCV, CMV—​and other drugs). Nocardia The lungs are the commonest primary site of nocardial infection, but other primary sites include the CNS, skin and other extrapulmonary locations (e.g. bone, eyes). Dissemination to secondary sites, usually from the lungs, is common. Tissue or fluid samples obtained by bi- opsy or aspiration are required. Examination of these by Gram stain or modified acid-​fast staining may allow a presumptive diagnosis to be made. As cultures may need to be prolonged for up to 3 weeks, 16S ribosomal PCR-​based assays can both speed up diagnosis and are the preferred method for speciation, which is important in predicting antibiotic resistance. For most species, prolonged treatment (at least 6 months) with co-​trimoxazole is usually effective, following which long-​term co-​trimoxazole should continue indefinitely. Untreated or inadequately treated infections have high mortality. Nontyphoid salmonella Nontyphoid salmonella infections are noteworthy because of their tendency to produce metastatic abscesses following bacter- aemia. Continued excretion of the organism may occur in stool or urine after control of the acute illness. Relapse is common, hence treatment needs to be prolonged. Suitable antimicrobials include ciprofloxacin, co-​trimoxazole, and ampicillin. Listeria Listeria has a tendency to localize in the CNS following a bacter- aemic phase. Neurological syndromes vary from meningitis and meningoencephalitis to space-​occupying lesions, and listeria is the commonest cause of post-​transplant meningitis. In the absence of evidence of raised intracranial pressure, all patients will require lumbar puncture and examination of cerebrospinal fluid. Delayed or inadequate treatment may result in permanent neurological deficit. Treatment usually includes high-​dose ampicillin for at least 6 weeks, combined with gentamicin for the first week. The source of listeria is usually contaminated dairy products, chicken, or uncooked veget- ables contaminated by manure. Fungal infections Oral candidiasis is a common post-​transplant infection. Spread to the oropharynx and lungs may occur. All patients should receive prophylaxis (nystatin mouthwashes or amphotericin lozenges) for at least 4 weeks. Intercurrent courses of antibiotics may need to be covered with oral prophylaxis against candida. The spectrum of diseases produced by fungal infections is wide, ranging from mucocutaneous syndromes, severe pneumonias, and CNS syndromes, to skin or muscle abscesses. This variation in clin- ical presentation again highlights the need for aggressive pursuit of investigations, including invasive biopsies. Aspergillosis Outbreaks of aspergillus are usually related to hospital building pro- jects and should prompt a search for the source. Invasive aspergil- losis most commonly affects the lungs, typically manifesting as single or multiple nodules that may cavitate, or as patchy consolidation.

21.7.3  Renal transplantation 4895 Dissemination to many different organs can occur and is associ- ated with very poor prognosis. Aside from tissue biopsy, detection of galactomannan antigen in the serum can be useful in making the diagnosis of invasive aspergillosis in immunocompromised pa- tients. Initial therapy is typically with voriconazole, alone or in com- bination with another agent. Pneumocystis jirovecii Until the widespread introduction of prophylactic low-​dose co-​ trimoxazole, Pneumocystis jirovecii pneumonia (PCP) was a dreaded complication of solid organ transplantation. Oral co-​trimoxazole (480 mg or 960 mg, once daily or three times per week) or inhaled pentamidine (300 mg monthly) is effective prophylaxis and usually given for 6 to 12 months after transplantation and after any episode of augmented immunosuppression for treatment of rejection. PCP is now most commonly seen in the setting of augmented immunosuppression following an episode of rejection, and in pa- tients who already have developed CMV disease. Presentation is with fever, dry cough, and profound shortness of breath, occurring in the context of few added sounds in the chest and a remarkably clear chest radiograph (Fig. 21.7.3.5), although a CT scan will usu- ally show more significant abnormalities (Fig. 21.7.3.6). By the time the chest radiograph has altered, pulmonary fibrosis is occurring. Successful treatment depends on early diagnosis, such that the renal transplant recipient who complains of shortness of breath on exercise and who desaturates on exercise should be admitted and investigated as a medical emergency. Bronchoalveolar lavage is vir- tually mandatory under these circumstances. The diagnosis is made by seeing the organism by classic (Gomori Grocott) or immuno- fluorescence staining (Fig. 21.7.3.7), or by detecting it in lavage fluid by flow cytometry or (increasingly commonly) real-​time PCR (note that nested PCR reactions can detect colonization as well as infec- tion, which can mislead the unwary). High-​dose intravenous co-​trimoxazole is given: 15 to 20 mg of trimethoprim and 75 to 100 mg of sulphamethoxazole per kg body weight per day (reduced in severe renal failure). Treatment should be continued for at least 2 weeks. Overall immunosuppression should be reduced, but (largely based on extrapolation of experience in HIV-​positive patients with PCP) patients with moderate or severe PCP should be given steroids (e.g. prednisolone 40 mg twice daily for 5 days, then tapering off). It is essential to monitor respiratory effort carefully in the renal transplant recipient with an interstitial pneumonitis and intervene with continuous positive airways pressure or full ventilation if the patient tires or cannot protect their airway. Nutrition should be en- sured, using total parenteral nutrition if necessary. Patients who have recovered from PCP should remain on lifelong prophylaxis. Fig. 21.7.3.5  Chest radiograph showing bilateral interstitial infiltrates typical of pneumocystis pneumonia. Fig. 21.7.3.6  CT of thorax showing diffuse bilateral ‘ground-​glass’ shadowing typical of pneumocystis pneumonia. Fig. 21.7.3.7  Section of lung stained with Gomori methenamine silver, showing a cluster of Pneumocystis jirovecii cysts within an alveolus. A nearby alveolus contains characteristic foamy macrophages. Reproduced with permission from Kibbler CC, et al. (eds) (2018). Oxford textbook of medical mycology. Copyright © 2018 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4896 Parasitic infections Some of the parasitic infections listed in Table 21.7.3.7 are geo- graphically restricted and therefore only of specific relevance in those areas. Schistosomiasis, for example, can cause ureteric stric- tures and leaks following transplantation. Strongyloides stercoralis This is usually found in patients from the West Indies or East Asia: in the immunocompromised it can reactivate, complete its life cycle in the patient without need for an intermediate host, and produce a hyperinfestation syndrome. A pretransplant eosinophilia is some- times present. Clinical presentation is with recurrent bouts of Gram-​ negative septicaemia as the worm penetrates the gut mucosa. Other clinical features include pruritus ani, haemorrhagic enteritis, larva currens, cough, wheeze, and a haemorrhaging bronchopneumonia. Meningitis may also occur. Diagnosis usually requires a duodenal aspirate. Treatment is with tiabendazole, which should be given prior to transplantation to patients at risk. Several courses of treat- ment may be needed to eradicate the infestation. Scabies This may occur in transplant recipients and can produce so-​called Norwegian scabies in which there may be many parasitic mites per burrow. In the immunocompromised patient, skin organisms are readily carried into the bloodstream, hence cellulitis and septicaemia are common. Toxoplasma gondii The transplant organ, particularly the heart, can transmit toxo- plasmosis. The organism becomes widely disseminated, including into the CNS. Other clinical features may include low-​grade fever, lymphadenopathy, pneumonia, myocarditis, retinopathy, and myo- sitis, producing a picture that can mimic CMV. Treatment is with pyrimethamine and sulphadiazine for at least 4 weeks. Prophylaxis with co-​trimoxazole has greatly reduced the incidence of toxoplas- mosis following solid organ transplantation. Other specific infections Hepatitis B All transplant recipients who are anti-​HBc (hepatitis B core anti- body) positive are at risk of HBV reactivation, which is highest in those who are HBsAg positive. HBV reactivation is diagnosed by the presence of HBV DNA in the blood (in a patient previously HBV DNA negative) or a significant rise in the titre of HBV DNA (in a patient previously HBV DNA positive). In some patients, reactiva- tion will lead to a flare of HBV hepatitis, typically defined as a rise in serum alanine aminotransferase to three to five times the base- line value. Liver failure can occur as a result of reactivation, but the likelihood of this is very low with the use of prophylactic or pre-​ emptive antiviral treatment (e.g. with entecavir or tenofovir). Aside from antiviral therapy it is standard practice to modify immunosup- pression by minimizing or stopping steroids in patients with HBV reactivation. Use of rituximab is associated with a high incidence (probably around 10%) of HBV reactivation and hence all patients at risk of reactivation who receive this drug should be started on pre- ventive antiviral therapy. Primary HBV infection can occur if a patient who has not previ- ously been exposed to HBV receives a kidney from a donor who is anti-​HBc positive, with the risk highest if the donor is also HBsAg positive. For this reason, kidneys from HBsAg-​positive donors are not accepted for transplantation by most centres, although recipi- ents who have immunity (anti HBs (hepatitis B surface antibody) positive) to HBV as a consequence of vaccination or exposure have a low chance (probably <2%) of becoming HBsAg positive if they receive a transplant from an HBsAg positive donor and are given perioperative anti-​HBV immunoglobulin. Hepatitis C Patients who are infected with HCV and have chronic kidney dis- ease should be treated for HCV in the usual manner. Those who are potential renal transplant candidates should undergo liver biopsy to exclude cirrhosis. Patients with cirrhosis and decompensated liver disease due to HCV should not be offered renal transplantation alone but can be considered for combined liver–​kidney transplant- ation. Those who have well preserved liver function and do not have portal hypertension can be offered renal transplantation alone. Before the availability of effective antiviral treatment the inci- dence of post-​transplant liver disease was 20 to 65% in anti-​HCV-​ positive recipients, with some studies (but not all) reporting rapid progression of HCV-​related liver disease to cirrhosis. Other compli- cations of renal transplantation in HCV-​infected recipients include membranoproliferative glomerulonephritis (recurrent and de novo), an increased risk of new-​onset diabetes after transplantation, and an increased risk of PTLD. This picture has been altered with the availability of very effective direct-​acting antiviral regimens, which require the nephrologist to work in close liaison with specialist hepatological services to manage patients with advanced chronic kidney disease (which limits drug options) and after transplantation (where consideration needs to be given to choice of immunosup- pression and there is the possibility of complex drug interactions). Patient survival and allograft survival are lower in patients with HCV infection before transplantation than those without such in- fection, but HCV-​infected patients who are transplanted have better survival than those who remain on the transplant waiting list. Transplantation of a kidney from an HCV-​infected donor into an uninfected recipient carries a very high chance of transmitting HCV infection and liver disease. Recipients of such kidneys have de- creased survival compared to those receiving kidneys from donors without HCV infection, although better than that of controls who remain on the transplant waiting list. Most centres adopt a policy of only offering kidneys from anti-​HCV-​positive donors to HCV RNA-​ positive recipients, unless there are exceptional other circumstances. Other infective problems Pulmonary disease Recurrent chest infections are common. Many are viral and will be self-​limiting, even in the immunosuppressed transplant recipient. An abrupt clinical onset with fever and a lobar pattern of lung in- filtrates is likely to be due to a bacterial infection. A more insidious onset with scattered or diffuse pulmonary infiltrates is more likely to be due to an opportunistic infection. Blood and sputum should be cultured urgently. Sputum samples need careful microscopy, and cul- tures should be set up for mycobacteria, fungi, and legionella. PCR

21.7.3  Renal transplantation 4897 testing is available for Mycobacterium tuberculosis, Pneumocystis jirovecii, CMV, and most respiratory viruses. For the transplant patient presenting from the community, anti- biotics appropriate for community-​acquired pneumonia may be started pending culture results, noting the effect of clarithromycin to inhibit metabolism of CNIs and making appropriate arrangements for close monitoring of levels and dose adjustment. Atypical presen- tation or failure to respond promptly to therapy is an indication for bronchoscopy and bronchoalveolar lavage, the diagnostic accuracy of which is about 80 to 90%. It is essential to examine the fluid thor- oughly, which will involve viral and bacterial cultures, special stains, and PCR testing. In patients who are seriously ill and without a diagnosis, it may be appropriate to start treatment ‘blindly’ with high-​dose co-​ trimoxazole (to cover PCP) and valganciclovir (to cover CMV) in addition to conventional antibiotics. With the passage of time, and when the results of investigations become available, it may then be possible to reduce the antimicrobial regimen or change to specific antituberculous or antifungal therapy. The greatest mimic of a chest infection is pulmonary oe- dema:  measurement of an elevated pulmonary capillary wedge pressure is diagnostic, and a therapeutic test of a potent diuretic sometimes produces a dramatic clearing of the chest radiograph. Other noninfectious causes of acute pulmonary syndromes that may occur in the renal transplant recipient are shown in Box 21.7.3.6. Urinary tract infection Up to one-​third of renal transplant recipients will develop a urinary tract infection. In most this is related to postoperative bladder cath- eterization and/​or the presence of a ureteric stent, and usually re- solves with removal of the catheter or stent and a short course of antibiotics. Some patients develop numerous recurrent infections, particu- larly in the first couple of years following transplantation. In some this can be related to a focus of infection in the native kidneys, when bilateral native nephroureterectomy may be indicated if sepsis is se- vere. A few patients will develop encrustation or even a stone in the bladder as a result of the surgical implantation of the ureter: a plain abdominal radiograph may reveal such calculi, which should be re- moved cystoscopically. More worrying is infection ascending into the transplant kidney itself during the intermediate period of post-​transplant immunosup- pression when the patient is most immunocompromised. A severe bacterial pyelonephritis can develop in the transplant, presenting with a swollen kidney, low-​grade fever, and deteriorating graft function. Such upper tract infections are frequently complicated by septicaemia, and it is always worth remembering that urinary sepsis is the commonest cause of post-​transplant bacteraemia. It is essential that episodes of graft dysfunction due to upper tract infec- tion are clearly diagnosed and aggressively treated with appropriate high-​dose parental antibiotics. Every effort should be made to es- tablish and maintain sterile urine. Long-​term prophylactic low-​dose antibiotics may be indicated. Neurological conditions The main concerns are those of PTLD or an opportunistic infec- tion producing progressive neurological deterioration due to an increasing space-​occupying lesion. Examples of neurological syn- dromes seen in the renal transplant recipient and their common causes are given in Table 21.7.3.8. The range of infectious microorganisms that can cause CNS le- sions is such that a diagnostic lumbar puncture is usually essential, and cerebrospinal fluid should be examined unless there is any evi- dence of raised intracranial pressure. Tuberculosis is common in at-​risk patients. Investigation should include CT with contrast or MRI, so that abscesses are not missed. As with the processing of bronchoalveolar lavage fluid, close cooperation between clinician and the cytological and microbiological laboratories is essential. Fits may occur in the early post-​transplant period, when the cause is usually multifactorial, including hyponatraemia, hypertension, hypomagnesaemia, hypocalcaemia, and the toxic effects of CNIs. Fits occurring after the first month should prompt a search for an intracranial space-​occupying lesion. Post-​transplant liver dysfunction Abnormal liver function tests following transplantation are common: both drugs and infectious agents may be responsible. Full investigation is required, including imaging of the liver, bile ducts, and gallbladder, as well as (in many cases) a liver biopsy. In some in- stances, transient elevation of liver transaminases may herald CMV disease. In other situations, raised liver enzymes can represent pro- gressive HCV-​ or HBV-​induced liver disease. It is important to re- member that the donor organ can transmit most of the hepatotropic viruses. Treatment clearly depends on the cause. Where possible, Box 21.7.3.6  Noninfective differential diagnoses of acute pulmonary syndromes in transplant recipients • Pneumothorax:

— Central venous lines • Pulmonary embolus • Noncardiogenic pulmonary oedema:

— Cytokine release syndrome • Left ventricular failure:

— Fluid overload

— Tacrolimus cardiotoxicity

— Unrecognized ischaemic heart disease

— Acute arrhythmias—​hypokalaemia, hypomagnesaemia

— Uncontrolled hypertension • Pulmonary fibrosis:

— Mycophenolate mofetil (rare)

— Azathioprine (rare)

— Co-​trimoxazole • Interstitial pneumonitis:

— Sirolimus • Bronchospasm:

— Allergic reactions—​antilymphocyte serum

— X-​ray contrast media • Pulmonary vasculitis:

— Recurrence of original disease • Pulmonary aspiration:

— Diabetic coma

— Fits • Impaired ventilation:

— Neuromuscular blockade • Pulmonary infiltration:

— PTLD

— Kaposi’s sarcoma

section 21  Disorders of the kidney and urinary tract 4898 any offending drug (e.g. azathioprine) should be withdrawn, and highly effective antiviral therapy is available for HBV, HCV, and the emerging problem of hepatitis E viral infection. Neoplasia Post-​transplant neoplasia is an important cause of morbidity and mortality. There is some debate as to whether some of the conditions often regarded as neoplastic can truly be classed as cancers, since several are clearly viral related and will regress with reduction of im- munosuppression. Box 21.7.3.7 summarizes the tumours seen with increased frequency after transplantation. There is a marked geo- graphical variation: for instance in Japan, renal, thyroid, and uterine cancers as well as lymphoma are common; in Saudi Arabia, Kaposi’s sarcoma is the most common; in Australia, SCC of the skin is almost ubiquitous 20 years after transplantation (75%). It is also important to remember that the donor organ can transmit cancer. Post-​transplant lymphoproliferative disorder PTLD is driven by EBV (HHV4) present in a latent form (episomal or circular DNA) in B lymphocytes. In nonimmunosuppressed individuals, a normal T-​cytotoxic lymphocyte response termin- ates infected proliferating B cells. In the presence of effective immunosuppression this does not happen and an unrestricted, in- creasingly monoclonal B-​cell proliferation develops. The more po- tent the immunosuppressive regimen, the earlier PTLD occurs. In most centres, the incidence of this disorder is about 1 to 2%. The clinical features are summarized in Box 21.7.3.7. In common with many other infections following transplantation, a primary infec- tion (i.e. the recipient is naive or seronegative for EBV antibodies, while the donor is seropositive) leads more frequently to disease. The clinical presentation of PTLD is very variable. There may be nonspecific constitutional symptoms (e.g. fever, weight loss), lymphadenopathy, extranodal masses (present in 50% of cases), and dysfunction of involved organs. About 25% of patients will have in- filtration of the renal allograft and a similar proportion will have CNS involvement. Detection by PCR of a high level of EBV viral DNA in the blood is suggestive in an appropriate clinical context of PTLD, but diagnosis relies on biopsy with expert processing of the tissue. Classification into early lesions, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-​like PTLD determine management. The first line of treatment in all cases of PTLD is to reduce im- munosuppression, typically to around 50% of baseline (it remains to be proven, but seems very likely, that carefully monitored stepwise reduction of immunosuppression may also be appro- priate for other virally induced neoplasms in renal transplant re- cipients, e.g. Kaposi’s sarcoma and SCC). Depending on disease category, rituximab is given to patients with CD20-​positive PTLD, with or without combination chemotherapy (typically CHOP—​ cyclophosphamide, doxorubicin, vincristine, prednisolone), the latter being given without rituximab to patients with CD20 nega- tive disease. Radiation therapy is given to patients with Hodgkin lymphoma-​like PTLD in the same manner as for classic Hodgkin lymphoma. Surgery may be required for complications such as bowel obstruction or perforation. Adoptive immunotherapy, by in- fusion of unselected donor lymphocyte or EBV-​specific cytotoxic T cell lines, may be of use in refractory cases, but these treatments are not widely available. Table 21.7.3.8  Causes of neurological syndromes in transplant recipients Syndrome Causes Psychosis Steroids Space-​occupying lesions (focal) Bacteria:   Mycobacteria   Listeria   Nocardia Fungi:   Aspergillosis   Mucormycosis Parasitic:   Toxoplasmosis   Strongyloides Other:   PTLD Meningitis: acute/​subacute Listeria Meningitis: subacute/​chronic Mycobacteria Cryptococcus Coccidioidomycosis Meningoencephalitis Cryptococcus OKT3 Encephalitis/​multifocal Herpes simplex and varicella zoster viruses Toxoplasmosis Progressive dementia Primary measles JC polyomavirus Fits Hypertension Hyponatraemia CNIs Hypomagnesaemia Acute rejection Space-​occupying lesions Tremor/​ataxia CNIs Peripheral neuropathy Diabetes mellitus Pre-​existing uraemic neuropathy Myopathy Steroids Statins or fibrates Box 21.7.3.7  Post-​transplant neoplasia • PTLD (EBV driven)

— Lymphadenopathy (33%)

— Central nervous system (15–​20%)

— Graft infiltration

— Gut (25%)

— Skin masses (1%)

— Scar infiltration (1%)

— Pulmonary nodules/​infiltrates

— Widely disseminated (1–​3%) • Kaposi’s sarcoma (HHV8 driven):

— Local (60%)—​skin-​infiltrating nodules

— Disseminated (40%)—​lymphadenopathy, upper or lower gastro- intestinal tract, lungs or pleura, bladder, oropharynx • Anogenital carcinoma (HPV driven):

— Cervical invasive neoplasia

— Anal carcinoma

— Vulvovaginal invasive neoplasia • Squamous cell carcinoma of the skin (HPV driven) • MALT lymphoma (Helicobacter pylori driven)

21.7.3  Renal transplantation 4899 Overall mortality of PTLD is in the range 65 to 75%, better for those with early and polymorphic disease and worse for those with monomorphic of Hodgkin lymphoma-​like disease. Patients who have been successfully treated for PTLD but lost their grafts can be successfully retransplanted, with a low risk of recurrent PTLD. Kaposi’s sarcoma Kaposi’s sarcoma is a vascular tumour composed of proliferating spindle cells (latently infected lymphatic endothelial cells) and thin-​ walled neovascular formations that is driven by human herpes virus 8 (HHV-​8), also known as Kaposi’s sarcoma-​associated herpes virus. In the context of renal transplantation, cutaneous presentations of angiomatous lesions are commonest on the legs, and visceral in- volvement is relatively common. Kaposi’s sarcoma may regress with reduction and modification of immunosuppression, standard practice being to switch from CNIs to sirolimus, which has been reported to lead to complete regres- sion of the condition, likely due to the effect of sirolimus on vas- cular endothelial growth factor and other signalling pathways. Some cases, however, can follow an aggressive course. Retransplantation of a patient with proven Kaposi’s sarcoma has usually resulted in recurrence. It is not yet known if sirolimus will allow safe retransplantation. Skin cancers Skin cancers (mainly SCC and basal cell carcinoma (BCC)) are the commonest post-​transplant malignancies. The risk of SCC is increased by up to 250 times over that in the general population, and SCCs or BCCs occur in over 50% of white and around 6% of nonwhite renal transplant recipients. Proposed mechanisms are re- duced immune surveillance due to therapeutic immunosuppression, carcinogenic effects of immunosuppressive agents, and proliferation of oncogenic viruses in the context of immunosuppression. Risk fac- tors include fair skin, high lifetime and ongoing sun exposure, older age, a history of SCC or BCC or actinic keratoses prior to trans- plantation, and greater intensity of immunosuppression, with use of azathioprine seeming to be a particular risk. The risk of melanoma is about two to three times that in the general population. Prevention of SCC is achieved by patient education (sun pro- tection and self-​examination of the skin), choice and modulation of immunosuppressive regimen, chemoprevention, and assiduous post-​transplant surveillance. Incorporation of sirolimus in the im- munosuppressive regimen is associated with about a 40% reduction in the risk of malignancy, but at the expense of an increased mor- tality, hence this and other mTOR inhibitors are not a general so- lution to the problem of immunosuppression-​induced malignancy. Individual skin cancers are treated with local measures, usually by cryosurgery or surgical excision or (very occasionally) radiotherapy. The first-​line approach to the patient with multiple, recurrent, aggressive, or metastatic SCC is to reduce immunosuppression, with the first manoeuvre (if the patient is on it) being to reduce the dose of azathioprine or stop it. The obvious hazard of reducing im- munosuppression is precipitation of rejection, but patients who are developing frequent or aggressive SCCs are ‘physiologically over-​ immunosuppressed’ and the risk of closely-​monitored reasonable reduction in immunosuppression is low. Systemic retinoids (e.g. acitretin) are used in patients where SCCs continue to be problematic despite a reduction in immunosuppression, but a dose adequate to have a significant ef- fect on skin malignancy is commonly associated with side effects that cannot be tolerated, including dryness, soreness and desquam- ation of eyes, lips, mouth, and skin, abnormalities of liver function tests, and hyperlipidaemia. Other agents that have been used include nicotinamide, capecitabine, and photodynamic therapy, but without strong evidence of benefit. The prognosis for patients with metastatic SCC is poor. Platinum-​ based chemotherapies are sometimes used and use of the checkpoint inhibitor pembrolizumab has been described. HPV-​related warts and carcinoma HPV is responsible for vulval and anogenital warts, and some types are clearly associated with carcinoma. Female renal transplant re- cipients with HPV are at a 20 to 100 times increased risk of cervical intraepithelial neoplasia, and male and female recipients at greatly increased risk for other anogenital cancers. It is therefore routine practice to offer HPV vaccination to all patients on a transplant waiting list or with a transplant who have a standard indication for it, and it may be that in the future the criteria will be widened to include others on transplant waiting lists or with transplants who do not otherwise meet current standard indications. Women with transplants should be encouraged to have gynaecological examin- ations at regular intervals. Management involves cautious dose-​reduction of immunosup- pressive agents, which can lead to regression of in situ carcinomas. Anogenital warts can be treated with topical imiquimod. Invasive tumours require wide local excision, with or without removal of local lymph nodes and adjuvant therapy. Other post-​transplant complications Hypertension The aetiology of post-​transplant hypertension is complex. Over 75% of renal transplant recipients will need drug therapy for hyper- tension in addition to lifestyle modification, and hypertension plays a significant role in accelerating vascular disease and chronic allo- graft damage. Patients with renal transplants have been excluded from the big trials of blood pressure control and there has been debate as to whether it is appropriate to extrapolate their findings into the trans- plant population. However, carefully collected data in transplant recipients confirms that the risk of cardiovascular events increases by about 40% for each 20 mmHg increase in systolic BP, but also that cardiovascular event rate increases by about 30% for every 10 mmHg that the diastolic blood pressure falls below 70 mmHg. Most units aim for a BP target of less than 140/​90 mmHg. A tighter target (<130/​80 mmHg) is often recommended for patients with sig- nificant proteinuria, but without good data in the transplant popu- lation to support this. CNIs induce hypertension and it is sensible practice to ensure that blood levels are not above the therapeutic target range and to reduce their dose if possible. Most transplant physicians use a dihydropyridine calcium channel blocker (e.g. amlodipine) as the first-​line antihypertensive agent, which both reduces blood pressure and CNI-​induced renal vasoconstriction (note that nondihydropyridine calcium channel blockers, e.g. diltiazem,

section 21  Disorders of the kidney and urinary tract 4900 inhibit cytochrome P450 3A/​4 and therefore lead to elevated blood levels of CNIs, requiring substantial adjustment of their dosage). Angiotensin-​converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are second-​line agents, but particular care needs to be taken to ensure that they do not precipitate acute deteri- oration in transplant function (see ‘Transplant renal artery stenosis’) and/​or significant hyperkalaemia (exacerbating the effect of CNIs). Diuretics can be helpful, particularly in patients with fluid retention secondary to allograft dysfunction. It is important to consider the possibility of transplant renal artery stenosis in cases of refractory hypertension. Transplant renal artery stenosis Transplant renal artery stenosis is most likely to develop between 3 and 12 months after transplantation. Risk factors include tech- nical surgical difficulties with harvesting of the donor kidney or vascular anastomosis at implantation, atherosclerotic disease, CMV infection, and delayed graft function. Stenosis may sometimes (but not always) be associated with a bruit over the kidney. A substantial rise in serum creatinine after the introduction of an ACE inhibitor or ARB may be the most obvious clue. Although some centres have described the use of ultrasonography to screen for transplant renal artery stenosis, most do not find this to be sufficiently reliable. Spiral CT angiography or renal arteriography is the investigation of choice if there is a high index of suspicion. The preferred treatment is by angioplasty, with or without stenting. Surgery may be considered if the anatomy precludes a radiological approach but is difficult because of the extensive fibrosis and scar- ring that occurs around a transplanted kidney and is only to be undertaken as a last resort. Accelerated atherosclerosis In common with patients on dialysis, the major cause of death fol- lowing renal transplantation is cardiovascular disease. Indeed, death with a functioning graft is now commoner than late graft failure. Much of the cardiovascular disease that shortens life expectancy in renal transplant recipients will have developed and be established pretransplantation. Table 21.7.3.9 summarizes the pre-​ and post-​ transplant aetiological factors. Prevention and treatment of established vascular disease is essential. About one-​third of renal transplant recipients will have hypercholesterolaemia and many will also be hypertensive. Lifestyle modification is important. All renal transplant recipients should be strongly advised not to smoke. Some transplant recipi- ents will become obese following transplantation. It is important to remember that the cardiovascular risk factors multiply rather than summate, hence the long-​term management of renal transplant re- cipients has to address all cardiovascular risk factors. Treatment recommendations are by extrapolation from studies in the general population as there is little in the transplant literature to guide the physician. Lipid abnormalities Hypercholesterolaemia is found in about 30% of patients after transplantation and is related to drugs (particularly steroids and CNIs—​with ciclosporin worse than tacrolimus), protein- uria, and diet. Sirolimus and other mTOR inhibitors mainly cause hypertriglyceridaemia. Along with standard dietary advice, statins are the first-​line treatment for hypercholesterolaemia, but the best choice and dose of statin is not established in transplant patients. Several statins are metabolized by the cytochrome P450 3A4 hepatic enzyme system, which is also responsible for the metabolism of CNIs and mTOR inhibitors. Ciclosporin has the biggest effect and in- creases the blood levels of all statins, irrespective of the pathway of their metabolism; hence, particular care needs to be taken with the combination of ciclosporin and statin. It is standard practice to start with a low dose of the chosen statin and increase this to the target dose (e.g. atorvastatin 20 mg daily, pravastatin 40 mg daily) if the patient does not report side effects. Ezetimibe can be added to statin treatment, or used alone if statins are not tol- erated, and—​after lifestyle changes—​is the first-​line drug treat- ment for significant hypertriglyceridaemia. The use of fibrates is not recommended. Table 21.7.3.9  Aetiological factors for accelerated atherosclerosis in transplant recipients Factor Cause Hypertension Insulin resistance (sympathetic overactivity) Drugs:   CNIs   Steroids Native kidneys Transplant kidneys (ischaemia, rejection) Hyperlipidaemia Dialysis and chronic renal failure Proteinuria Insulin resistance CNIs Steroids β-​Blockers Thiazides Proteinuria Glomerular disease in native/​transplant kidneys Endothelial cell activation Oxidized low-​density lipoproteins CNIs Hypertension Smoking Oxidized lipids CNIs Proteinuria Hyperhomocysteinaemia Renal failure per se Vitamin B12 and folate deficiency Platelet hyperaggregability Nephrotic syndrome CNIs Hyperfibrinogenaemia Nephrotic syndrome Acute-​phase response Insulin resistance Steroids, obesity CNIs Chronic renal failure per se Diabetes mellitus Primary renal disease Acquired after transplantation (e.g. steroids and CNIs) Lifestyle Smoking Excessive alcohol Diet Obesity Inflammation Original nephritis Haemodialysis per se Infection and rejection

21.7.3  Renal transplantation 4901 Electrolyte disorders Hypophosphataemia and hypercalcaemia Many patients receiving a renal transplant will have secondary or (sometimes) tertiary hyperparathyroidism. With good transplant function, over many months secondary hyperparathyroidism may resolve, but it does not always do so and many transplant recipients have long-​term modest elevation of serum parathy- roid hormone (two to three times the upper limit of normal). This should be treated in the usual manner with active vitamin D metabolites as long as the serum calcium remains within the normal range. In the presence of secondary or tertiary hyperparathyroidism a well-​functioning transplant will waste phosphate, which may be exacerbated by steroid-​related malabsorption of phosphate. In the first few months after renal transplantation, phosphate wasting can be severe and oral supplements are sometimes required. Untreated chronic hypophosphataemia can lead to bone fractures (hypophosphataemic rickets). Hypercalcaemia can develop after grafting if renal osteodystrophy has been poorly controlled and severe secondary or tertiary hyperparathyroidism is present at the time of trans- plantation. The transplant kidney produces adequate amounts of 1,25-​dihydroxycholecalciferol, which in the presence of high levels of parathyroid hormone will result in hypercalcaemia. Widespread metastatic deposition of calcium can occur if hypercalcaemia is severe. Simple controlling measures include adequate fluids, sodium supplements, and the use of loop diuretics rather than thiazides. Occasional patients will require regular infusions of pamidronate, which can be combined with intermittent doses of oral α-​calcidol (or other active vitamin D sterol) to suppress parathyroid hyper- plasia. Cinacalcet can be effective, but hyperparathyroidism tends to recur quickly once treatment has stopped. Parathyroidectomy is occasionally required. Hyperkalaemia The CNIs cause hyperkalaemia, particularly when levels are above the therapeutic range. This is thought to be due to decreased activity of the renin–​angiotensin–​aldosterone system and impairment of the tubular action of aldosterone. The addition of ACE inhibitors, ARBs, nonsteroidal anti-​inflammatory drugs (NSAIDs), or potassium-​ conserving diuretics can produce a brisk rise in serum potassium in renal transplant recipients. Management consists of ensuring that blood CNI levels are towards the lower end of the target range, avoid- ance of other drugs exacerbating hyperkalaemia, dietary advice, and (sometimes) the addition of a loop diuretic. Use of fludrocortisone (100–​200 µg daily) has been described. Hypomagnesaemia Renal tubular magnesium wasting is a component of the nephrotox- icity of the CNIs and can be exacerbated by diuretics and diarrhoea. Hypomagnesaemia may predispose to fits and cardiac arrhythmias in susceptible individuals. Levels should be monitored and oral supplements of magnesium glycerophosphate given if the level of magnesium is severely reduced or there are symptoms indicating clinically significant hypomagnesaemia. Metabolic acidosis Tubular effects of CNIs can impair acid excretion, which may be exacerbated by hyperkalaemia-​induced suppression of ammonium excretion. A  chronic metabolic acidosis will contribute to post-​ transplant osteoporosis and should be treated with bicarbonate supplements. Rheumatological and musculoskeletal Tendon rupture Steroids impair collagen synthesis. Tendons and tendon insertions are weakened and avulsions may occur, most commonly in the fin- gers or Achilles’ tendon. Myopathy An important complication of steroid therapy is proximal myop- athy, which can be incapacitating in some patients and is an indi- cation for rapid steroid withdrawal or use of a steroid-​free regimen. Hypophosphataemia should be corrected. Acute rhabdomyolysis may develop if fibrates or statins are used with the CNIs. Care should be taken with colchicine and CNIs. Avascular necrosis of bone Avascular necrosis of bone, particularly of the weight-​bearing ends of the long bones, causes an extremely painful joint. MRI is diag- nostic. When the hips are involved, walking can become impos- sible and total hip replacement is the only treatment. Risk factors include renal mineral bone disorder before transplantation and use of glucocorticoids, particularly in high dose, in an immuno- suppressive regimen. The condition is now much less common (0.5%) with better management of renal mineral bone disorder be- fore transplantation and reduction in the use and dosage of steroids after transplantation. Osteoporosis Osteoporosis is a common and progressive complication of long-​ term steroid therapy, such that regular bone-​density assessment should be part of long-​term renal transplant follow-​up. Transplant patients with normal bone density or osteopenia should be advised to perform regular weight-​bearing exercise and their steroid dose should be reduced as much as possible. Many centres would routinely recommend calcium supplements with cholecal- ciferol for those with a normal serum calcium concentration, and all would treat persistent hyperparathyroidism in a conventional manner. Transplant patients with osteoporosis who do not have evi- dence of low-​turnover bone disease (usually detected by the pres- ence of low levels of serum parathyroid hormone and bone-​specific alkaline phosphatase) are typically treated with bisphosphonates or (if bisphosphonates are contraindicated) denosumab. Those with osteoporosis and low bone turnover may be given teriparatide, but experience is limited in the transplant population. Renal mineral bone disorder As described previously, many patients with a functioning renal transplant have persistent hyperparathyroidism. This should be treated in the usual manner, as described in Chapter  21.6. Uncontrolled post-​transplant hypercalcaemia has the potential to

section 21  Disorders of the kidney and urinary tract 4902 significantly damage graft function, should be avoided if possible, and treated promptly if it occurs. Gout Hyperuricaemia is present in 30 to 80% of renal transplant recipi- ents, and gout is common after renal transplantation, affecting 7.6% of patients within 3 years in one large cohort study. It is most common in those receiving CNIs, particularly ciclosporin. This impairs urate secretion in the proximal tubule, and urate retention is exacerbated by the concomitant use of diuretics, particularly in patients with poorly functioning grafts. Uric acid levels may rise dramatically and be associated with attacks of clinical gout as well as tophi. Acute attacks affecting only one or two joints are best managed by joint fluid aspiration and intra-​articular injection of steroid. If such treatment is not available in a timely manner, or if many joints are affected, then first-​line treatment is with oral steroid (e.g. pred- nisolone 30 mg daily, continued until the acute attack has eased and then returned to baseline dosage) or low-​dose colchicine (0.5 mg twice daily). NSAIDs are generally avoided but can be used in the short term in transplant recipients with good renal function. There is a small risk of rhabdomyolysis with a combination of colchicine and CNIs and patients should be advised to stop the colchicine and seek urgent help from their transplant physician if they develop unusual muscular aches or pains. As regards prophylaxis, the xanthine oxidase inhibitor allopur- inol is generally the first-​line urate-​lowering treatment, starting at a dose of 100 mg daily, titrated up to get the serum urate level below target (typically 350 µmol/​litre). However, allopurinol sig- nificantly inhibits the metabolism of azathioprine and is relatively contraindicated in those taking this drug, although it can be used if the dose of azathioprine is reduced to about 25% of normal, and with very careful monitoring for leucopenia. In some patients re- ceiving azathioprine, the best strategy is to stop it and substi- tute mycophenolate mofetil so that allopurinol can be used more safely. Similar considerations apply to use of the xanthine oxidase inhibitor febuxostat. Most uricosuric agents (e.g. probenecid and benzbromarone) work poorly in the presence of renal impairment. Losartan has a modest uricosuric effect and it is reasonable to use this drug in patients who have both hypertension and gout. Haematological Venous thromboembolism Deep venous thrombosis/​pulmonary embolus occur in 5 to 8% of patients following renal transplantation. The local effects of sur- gery on the pelvic veins together with immediate postoperative bed rest contribute to the risk. The CNIs have an activating and procoagulant effect on endothelial cells and platelets. Nephrotic patients have a profound disturbance of many coagulation fac- tors and represent an extremely high-​risk group for periopera- tive venous thromboembolism. Prophylactic subcutaneous LMWH (e.g. enoxaparin at 20 mg daily) is standard practice during admission for renal transplantation, with higher doses (e.g. enoxaparin at 40 mg daily) in those at highest risk. LMWH is relatively contraindicated in severe renal failure but used in many units with the precaution of monitoring anti-​Xa levels to guard against excessive dosing. Haemolytic uraemic syndrome A patient with renal failure due to infection-related haemolytic ur- aemic syndrome (HUS) is most unlikely to suffer a recurrence in a transplant kidney, but this is very probable in those with atypical HUS (aHUS). Many cases of aHUS are genetically determined and all patients with renal failure due to HUS should be screened for causal genetic mutations before they are listed for renal transplant- ation. These mutations affect complement components and regu- lators of the alternative complement pathway, leading to pathogenic complement activation at endothelial cell surfaces. The renal manifestation of aHUS is a thrombotic microangiopathy, and since transplanting the kidney does not usually correct the gen- etic disease, aHUS frequently recurs. Understanding the pathogen- esis of aHUS has led to an effective treatment using eculizumab—​a monoclonal antibody that depletes the complement component C5, thus preventing complement-​mediated damage. Patients with aHUS and a complement regulatory mutation can be safely transplanted provided they receive lifelong eculizumab, starting intraoperatively before reperfusion of the transplant. Recurrent HUS is typically managed by stopping drugs that may exacerbate it (CNIs, mTOR inhibitors), giving eculizumab (if not already administered), and plasma exchange. Biopsy-​proven de novo HUS occurs in about 3% of renal trans- plants, typically presenting as a rise in serum creatinine often in association with a microangiopathic haemolytic anaemia and thrombocytopenia. It usually occurs within days to weeks of transplantation. Associations include medications (CNIs, mTOR inhibitors), infections (including CMV), and ABMR. Management is by stopping CNIs/​mTOR inhibitors and (if mat- ters do not resolve promptly) plasma exchange. In refractory cases, it is appropriate to test for pathogenic mutations predisposing to complement mediated HUS and to initiate eculizumab if these are present. It is important to note that eculizumab is associated with life-​ threatening and fatal meningococcal infections:  patients re- ceiving it should receive appropriate vaccination and antimicrobial prophylaxis. Leucopenia Leucopenia occurs in up to 50% of renal transplant recipients, usually within the first few months after transplantation. It may be caused by drugs including ATG and lymphocyte-​depleting biologics (e.g. alemtuzumab), antimetabolite immunosuppres- sants (azathioprine, mycophenolate), agents used to treat CMV (ganciclovir, valganciclovir), and co-​trimoxazole (used as prophy- laxis against pneumocystis). It can also be caused by viral infections, notably CMV. Management is by reducing the dose of or stopping relevant medications and testing for active CMV infection by quan- titative blood PCR assay (and treating if present). As described previously, profound bone marrow suppression may occur when allopurinol is used with azathioprine if the dose of the latter is not appropriately reduced. Anaemia Most patients undergoing renal transplantation are anaemic due to chronic kidney disease or have a normal haemoglobin concentra- tion supported by use of erythropoiesis stimulating agents (ESAs).

21.7.3  Renal transplantation 4903 Immediately after transplantation, most patients will be anaemic as a consequence of surgical blood loss, compounded by the effects of an acute postsurgical inflammatory reaction that renders the bone marrow less responsive to ESAs, and bone marrow suppression caused by antimetabolite immunosuppressants. With good trans- plant function and in the absence of other issues, anaemia normally resolves within 6 months or so. Persistent anaemia requires diagnosis in the same manner as for a nontransplant patient, beginning with enquiry for evidence and causes of blood loss and check of haematinics. There is a low threshold for use of intravenous iron therapy, and ESAs are given in the context of poor graft function (eGFR <30 ml/​min per 1.73 m2). Other considerations of particular note include the possibility of HUS (see ‘Haemolytic uraemic syndrome’) and drug toxicity. In addition to antimetabolite immunosuppressants, sirolimus can cause bone marrow suppression, and ganciclovir/​valganciclovir, co-​ trimoxazole, ACE inhibitors, and ARBs can cause post-​transplant anaemia. Parvovirus B19 infection may occur after transplantation and cause severe anaemia, which should be suspected in cases of rapidly developing anaemia with a low reticulocyte count. Diagnosis is con- firmed by detection of viral DNA in the blood by PCR-​based testing. Treatment is by reduction in immunosuppression and intravenous immunoglobulin, usually with a good result. Erythrocytosis Up to 15% of renal transplant recipients develop erythrocytosis. The mechanism is not well understood but erythropoietin (increased in most studies), other haemopoietic growth factors (increased plasma concentration of insulin-​like growth factor-​1 has been described), activation of the renal angiotensin system, and endogenous andro- gens (post-​transplant erythrocytosis is much commoner in men than women) have all been incriminated. The threshold for intervention is not well defined, but most trans- plant clinicians would intervene if haemoglobin rises to greater than 170 g/​litre. First-​line treatment is with an ACE inhibitor or ARB, which is effective in most patients. Phlebotomy is used if haemo- globin rises to greater than 185 g/​litre or in those who cannot be given or tolerate ACE inhibitors or ARBs. Gastrointestinal About 20% of patients have gastrointestinal complications, which are severe in 10%. Gastrointestinal bleeding due to peptic ulceration was a much feared and often fatal complication in the early days of renal transplantation, but with modern treatments (Helicobacter pylori eradication and use of H2 blockers and proton pump inhibi- tors) this is now rare. Some immunosuppressive drugs have gastrointestinal side ef- fects. Mycophenolate mofetil causes abdominal colic and diar- rhoea that can be severe enough to interrupt therapy in 10% of cases. Dose reduction and/​or splitting, or a switch to enteric-​coated mycophenolate sodium can sometimes be helpful. Up to 25% of pa- tients on sirolimus develop oral ulceration, which usually responds to dose reduction. CMV (e.g. colitis), Kaposi’s sarcoma, and PTLD (intestinal ob- struction) can present with gastrointestinal symptoms and signs. Diarrhoea in a transplant patient is often caused by an infectious agent and requires appropriate investigations. Cosmetic The psychological importance of the cosmetic disfigurement that can be produced by some of the treatment regimens used in trans- plantation should not be underestimated. It is an important contrib- uting factor to noncompliance, particularly in adolescents, and can even lead to agoraphobia and suicide. Steroids and ciclosporin are the main culprits. Currently avail- able choices of immunosuppressive agents mean that it should be possible to minimize cosmetic complications when these cause great distress, for example, steroid withdrawal, substitution of tacrolimus for ciclosporin, and use of mycophenolate mofetil to reduce reliance on steroids and CNIs. The better cosmetic profile of tacrolimus is thought to be due to lower TGFβ production. Outcome of renal transplantation Graft and patient survival Figures 21.7.3.8 and 21.7.3.9 summarize the graft survival rates for first cadaver and living related transplants. The highest rate of graft loss is within the first few months. Graft losses due to technical fac- tors should be less than 5%. The commonest cause of early graft loss continues to be acute rejection, but it is a matter of concern that the attrition of grafts following the first year has altered little, even with the introduction of newer, more potent immunosuppressive agents. Currently some 4% of grafts fail annually for a variety of causes loosely grouped together as chronic allograft nephropathy (see pre- vious discussion). As stated before death with a functioning graft is now the most common cause of late graft failure. Factors affecting graft survival are summarized in Table 21.7.3.10. Even with potent immunosuppressive regimens, HLA matching remains extremely important, forming the rationale for local and national organ sharing schemes to ensure that the best possible matches can be obtained. Fig. 21.7.3.8 shows that beneficially matched cadaver kidneys (1–​0–​0 or 0–​1–​0 mismatch) fare signifi- cantly better than nonbeneficially matched, and well-​matched living related transplants do best of all (Fig. 21.7.3.9). Survival (%) 60 50 40 Number of years since transplant 0 100 90 80 70 30 20 10 HLA matching (number at risk at day 0) 0 1 2 3 4 5 Beneficial (2027) Non-beneficial (8777) Fig. 21.7.3.8  Graft survival: first cadaver graft. Courtesy of UK transplant.

section 21  Disorders of the kidney and urinary tract 4904 Early studies indicated that an acute rejection episode had a major impact on long-​term graft survival, reducing it by almost one-​half, but if an acute rejection episode is completely reversed, the effect on long-​term graft survival is markedly reduced. Long-​ term graft survival can be clearly related to the creatinine level at 1 year, which has led to great emphasis on efforts to reduce the rate of early acute rejection episodes. One crucial observation that pre- dicts those at increased risk is the presence of widely reactive anti-​ HLA antibodies to potential donors. Newer techniques allow the detection of individual specificities of anti-​HLA antibodies at very low titres both before and after transplantation. The development of donor-​specific anti-​HLA antibodies after transplantation predicts a poor outcome. Patients who have already rejected a kidney within 6 months of transplantation also do poorly on subsequent transplantation un- less immunosuppression is augmented. Increasingly potent induc- tion regimens and combinations of drugs have been introduced, but in the absence of accurate predictors of the risk of rejection, this has the effect that many patients will be over-​immunosuppressed, while others remain under-​immunosuppressed. Poor long-​term graft survival is also related to hypertension, proteinuria, hyperlip- idaemia, and a high BMI (Table 21.7.3.10). Causes of late allograft loss First-​year transplant losses from rejection have been dramatically reduced from about 40% in the 1970s to 5%. Similarly, early rejec- tion rates can be reduced from around 50% to (using some immuno- suppressive regimens) less than 10%. However, as already stated, the rate of chronic graft loss remains at about 4% per year. About half of these graft losses are due to death with a functioning graft, but many patients present with an insidiously rising creatinine, increasing proteinuria, and worsening hypertension. Chronic antibody-​mediated rejection The causes of late graft dysfunction are multifactorial, but in re- cent years it has become clear that antibody-​mediated pathology is likely the leading cause of late graft loss, often associated with under-​immunosuppression as a consequence of poor adherence to immunosuppressive therapy by the patient. Histologically, many of these kidneys will show evidence of established ABMR with associated tubular atrophy, interstitial scarring, and an ob- literative vasculopathy. Much current research is directed at identifying an effective intervention to halt antibody-​mediated pathology. Every effort should be made to produce an accurate diagnosis in patients with late graft function, with investigations as for acute graft dysfunction (Table 21.7.3.2). Obstruction due to ureteric is- chaemia must be excluded by ultrasound scanning. A review of past urine cultures and a technetium-​99 m labelled dimercaptosuccinic acid (DMSA) single-​positron emission computed tomography (SPECT) scan may reveal pyelonephritic scarring. Late graft dys- function due to renal artery stenosis can be demonstrated by angi- ography. The presence of DSA should prompt a renal biopsy, which is required to make a diagnosis of CNI nephrotoxicity or of re- current glomerular disease, although confirming the diagnosis of chronic ABMR may not alter management given the lack of an ef- fective intervention. Recurrence of original disease After ABMR, the next commonest cause of late allograft loss is probably recurrent primary renal disease, with most of the Table 21.7.3.10  Factors affecting graft outcome Adverse factors Other clinical factors Recipient factors: Organ matching policy Obesity Choice of immunosuppression Poor compliance Surgical and medical expertise Recurrence of original disease Nephrotoxicity of CNIs Hypertension Adequacy of control of hypertension De novo glomerulonephritis Control of CMV Diabetes mellitus/​insulin resistance Repeated acute rejection episodes High immune responsiveness
(highly sensitized) Poorly reversed acute rejections Race: black individuals Late acute rejections Infections: CMV Inadequate long-​term immunosuppression High serum creatinine at 1 year Proteinuria/​hyperlipidaemia Smoking Donor factors: Extremes of age (reduced nephron mass) Delayed graft function Size mismatch Long ischaemia times Poor donor organ quality Source: cadaver less good than living donor Agonal cytokine storm Survival (%) 60 50 40 Number of years since transplant 0 1 2 3 100 90 80 70 30 20 10 Haplotype match (number at risk at day 0) 0 1 Haplotype match (187) Identical match (71) 0 Haplotype matches (36) Fig. 21.7.3.9  Graft survival: living related grafts. Courtesy of UK transplant.

21.7.3  Renal transplantation 4905 primary glomerular diseases able to recur in the transplant. Overall, histologically demonstrable recurrence occurs in about 50% of patients, with 10 to 15% losing their graft as a result. Accurate re- currence rates are difficult to determine but estimates for different glomerular disease are shown in Table 21.7.3.11. Primary focal and segmental glomerulosclerosis The most important glomerular disease with regard to recurrence in a renal transplant is primary FSGS. The pathogenesis of this con- dition remains uncertain, but it is clearly associated with an as yet unidentified circulating factor. Following transplantation, FSGS recurs in about 30% of patients, and this happens very quickly in about half of these—​even in the operating room following release of the vascular clamps. Younger patients, those with steroid-​resistant nephrotic syndrome in their native kidneys, and those progressing quickly (with 2 years of diagnosis) to dialysis dependency are par- ticularly at risk of recurrent disease. Recurrent FSGS presents as nephrotic proteinuria, often with profound acute tubular injury and graft dysfunction. Recurrence can be diagnosed by transplant biopsy, although initially light mi- croscopy features of FSGS are absent and electron microscopy is required. Treatment of recurrent FSGS is not particularly effective but has usually involved intensive plasma exchange and an increase in immunosuppression, often with high-​dose steroids. Rituximab may have a role to play. Overall, treatment leads to complete or partial disease remission in about 50% of patients with recurrent disease. Similar treatment has been given to patients with recurrent IgA disease or mesangiocapillary glomerulonephritis, with limited success. Other conditions Oxalosis will recur rapidly in the kidney unless a liver transplant is also performed to correct the underlying enzyme defect in primary hyperoxaluria. Recurrence of aHUS and its prevention/​treatment have been discussed earlier in this chapter. Other aspects of medical management of transplant recipients Diet Patients may eat voraciously after renal transplantation due to a combination of enhanced appetite with improvement in renal function, release from the restrictions of dialysis, and (in many cases) the effects of steroids. Some gain in excess of 20 kg in the first year and about 5% become grossly obese. Overweight patients significantly increase their risk of developing new-​onset diabetes mellitus after transplantation, which reduces both graft and patient survival. Diet and exercise should be the measures advised to con- trol weight and also in the management of lipid abnormalities. Transplant recipients also need education about the risks of contaminated food, for example, with listeria, campylobacter, and cryptosporidium. The help of a renal-​trained dietitian is essential. Table 21.7.3.11  Risk or recurrent renal disease following transplantation Primary disease Recurrencea Clinical courseb IgA nephropathy 20–​50% (>80%)a Graft loss in 2–​10%, usually >5 years post-​transplant Aggressive disease with early graft loss is unusual FSGS 30–​40% (>80%)a Graft loss in approximately 20% by 10 years post-​transplant. Early recurrence in approximately 10% Membranous GN 5–​20% Graft loss in 10–​15% by 10 years post-​transplant MCGN type 1 10–​20% (>80%)a Recurrence invariably leads to graft loss by 10 years post-​transplant MCGN type 2

90% Usually indolent course, but graft loss in 20% by 5 years post-​transplant Anti-​GBM disease Unusual Recurrent disease unusual if antiglomerular basement membrane (anti-​GBM) Ab absent for >6 months prior to transplantation Anti-​neutrophil cytoplasmic antibodies
(ANCA) + vasculitis 5–​20% Renal involvement in 20% of those with recurrent disease, often responds to increased immunosuppression SLE 2–​10% Graft loss due to recurrent SLE is uncommon (1–​3% at 10 years) HUS (D+) 0% Recurrence unusual HUS (D–​) 50% Graft loss inevitable HUS (factor H or I mutation) 80% Graft loss inevitable within 2 years Diabetes ×100% Diabetic nephropathy may recur eventually in all grafts, but is rarely the cause of graft failure. Avoided by simultaneous pancreas and kidney transplant Deposition diseases (AL amyloid, light chain deposition disease (LCDD), fibrillary GN) Insufficient data GN, glomerulonephritis; MCGN, mesangiocapillary glomerulonephritis; SLE, systemic lupus erythematosus. a Recurrence rate in second transplants, the first being lost to recurrent disease, is shown in parenthesis. b Graft loss is expressed as a percentage of those with recurrent disease. Reproduced from Torpey N, Moghal NE, Watson W, Talbot D (eds) (2010). Renal transplantation (Oxford specialist handbooks). By permission of Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4906 Polypharmacy The medical complications of renal transplantation are so nu- merous that many recipients will require many different drugs. The regimen may become intolerable and noncompliance can be a major problem. In the early post-​transplant period, it is neces- sary to give prophylaxis with co-​trimoxazole, an H2-​antagonist or a proton pump inhibitor, and possibly an appropriate anti-​CMV regimen. Patients who are at risk of tuberculosis require isoniazid for the duration of immunosuppression, and those with or at risk of osteoporosis require calcium and cholecalciferol supplements. Hypertension needs aggressive control. Uric acid levels may be high and clinical gout may develop, requiring allopurinol. Long-​ term management needs to include regular vaccinations (influenza and pneumococcus). To reduce the risks of accelerated vascular disease, aspirins and statins may also be indicated. In patients with poorly functioning transplants, medical manage- ment must also include the same measures as would be undertaken in a low-​clearance clinic for patients expected to start dialysis. Under these circumstances, treatment may include iron and vitamin sup- plementation, ESAs, active vitamin D sterols, and oral phosphate binders, as discussed in Chapter 21.6. Drug interactions Great care has to be taken when prescribing drugs for renal trans- plant recipients. Renal function must be considered, as well as the potential for drug interactions between immunosuppressive agents and other pharmaceuticals. Table 21.7.3.12 summarizes the more common interactions. ACE inhibitors, ARBs, and NSAIDs can com- promise the perfusion of a transplanted kidney, particularly if there is a degree of renal artery stenosis. Great care must be taken with potent enzyme inducers such as rifampicin as subtherapeutic levels of steroids and CNIs can result. Routine follow-​up Patients typically remain in hospital for about 7 days following an uncomplicated renal transplant operation. After discharge, patients are usually seen two or three times a week for the first month, once or twice a week for the second month, and then weekly for the third month. At each visit, blood pressure and graft function are checked. Many units undertake weekly CMV surveillance for at least the first 3 months after transplantation. After 3 months, outpatient visits are gradually reduced with patients eventually being reviewed only every 3 to 4 months. Particular attention has to be paid to cardiovascular risk factors, infections, and neoplasia. Ideally, all patients should have an annual dermatological examination, and women should have an annual cervical smear and colposcopy if indicated. Bone density should be monitored regularly. Patients at risk of tuberculosis will require a regular chest radiograph. Vaccinations should be kept up to date. Many centres offer an anniversary clinic when these medical com- plications can be more fully assessed. Pregnancy A successful renal transplant restores fertility, and pregnancy with normal vaginal delivery (unless there are obstetric indications for caesarean section) is possible. Most recommend that pregnancy is not embarked upon in the first year or if the serum creatinine is above 150 µmol/​litre or proteinuria greater than 2 g/​day. Many successful pregnancies have been undertaken with renal function worse than this, but the risks are greater. Overall, 20% of patients show a deterioration in graft function during pregnancy and up to 10% in some series lose their grafts. A meta-​analysis of 4706 pregnancies in renal transplant recipients found the incidence of pre-​eclampsia to be 27% (vs 4% in the general population), of ges- tational diabetes to be 8% (vs 4%), and of preterm delivery to be 46% (vs 13%). There is little evidence that immunosuppression with prednis- olone, azathioprine, and a CNI has a significant adverse effect on the fetus, although prednisolone may produce neonatal adrenal suppression. To maintain therapeutic levels of the CNI, dosage may have to be increased considerably, which requires careful explan- ation to women who may be worried about toxic effects of drugs during pregnancy. Mycophenolate mofetil and sirolimus are not safe in pregnancy and patients should be advised not to become preg- nant while taking them. Hypertension in the pregnant renal transplant recipient is treated conventionally: amlodipine is commonly used, and labetalol and methyldopa have withstood the test of time. During delivery, intravenous fluid should be given and great care taken to avoid episodes of hypovolaemia and hypotension. For transplant recipients whose immunosuppressive regimen includes steroids, it is usual to give an extra dose of steroid during the de- livery, for example, 100 mg of intravenous hydrocortisone, and to increase oral prednisolone for a few days afterwards. Regular mid- stream urine specimens should be sent in the postpartum period. Table 21.7.3.12  Common drug interactions in transplantation Drugs Interaction Cytochrome P450 induction, e.g. Subtherapeutic levels of:   CNIs   Steroids   Oral contraceptives   Sirolimus   Rifampicin   Barbiturates   Carbamazepine   Phenytoin Cytochrome P450 inhibition, e.g. Toxic levels of:   CNIs   Sirolimus   Macrolides, e.g. erythromycin   Triazoles, e.g. fluconazole   Calcium channel blockers Statins (or fibrates) plus CNIs Rhabdomyolysis Colchicine plus CNIs Rhabdomyolysis Allopurinol plus azathioprine Toxic accumulation of 6-​mercaptopurine Marrow suppression ACE inhibitors (or angiotensin-​I receptor antagonists) Risk of hyperkalaemia with combinations CNIs NSAIDs Potassium-​conserving diuretics Diuretics and CNIs Hyperuricaemia, gout, tophi Nephrotoxins NSAIDs Nephrotoxins summate—​risk of acute kidney injury CNIs Aminoglycosides

21.7.3  Renal transplantation 4907 FURTHER READING General Knechtle SJ, Marson LP, Morris PJ (2019). Kidney transplantation: prin- ciples and practice, 8th edition, Elsevier, Saunders, Philadelphia. Ponticelli C (2007). Medical complications of kidney transplantation. Informa Health Care, London. Infections Green M, Avery RK, Preiksaitis J (eds) (2004). Guidelines for the pre- vention and management of infectious complications of solid organ transplantation. Am J Transplant, 4 Suppl 6, 1–​166. Kotton CN, et al. (2018). The Third International Consensus Guidelines on the Management of Cytomegalovirus in solid organ transplant- ation. Transplantation, 102, 900–​31. Locke JE, et  al. (2015). A national study of outcomes among
HIV-​infected kidney transplant recipients. J Am Soc Nephrol, 26, 2222–​9. Randhawa P, Ramos E (2007). BK viral nephropathy:  an overview. Transplant Rev, 21, 77–​85. Razonable RR, Humar A (2013). AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant, 13 Suppl 4, 93–​106. Malignancy Au E, Wong G, Chapman JR (2018). Cancer in kidney transplant re- cipients. Nat Rev Nephrol, 14, 508–​20. Engels EA, et al. (2011). Spectrum of cancer risk among US solid organ transplant recipients. JAMA, 306, 1891–​901. Kim C, Cheng J, Colegio OR (2016). Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strat- egies for surveillance, staging, and treatment. Semin Oncol, 43, 390–​4. Knoll GA, et al. (2014). Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-​analysis of individual patient data. BMJ, 349, g6679. Mittal A, Colegio OR (2017). Skin cancers in organ transplant recipi- ents. Am J Transplant, 17, 2509–​30. Moosa MR (2005). Kaposi’s sarcoma in kidney transplant recipients: a 23-​year experience. QJM, 98, 205–​14. Parker A, et al. (2010). Diagnosis of post-​transplant lymphoprolifera­ tive disorder in solid organ transplant recipients—​BCSH and BTS guidelines. Br J Haematol, 149, 675–​92. Parker A, et  al. (2010). Management of post-​transplant lympho­ proliferative disorder in adult solid organ transplant recipients—​ BCSH and BTS guidelines. Br J Haematol, 149, 693–​705. Particular complications Aroldi A, et al. (2005). Natural history of hepatitis B and C in renal allograft recipients. Transplantation, 79, 1332–​6. Baid-​Agrawal S, et  al. (2014). Hepatitis C virus infection and kidney transplantation in 2014: what’s new? Am J Transplant, 14, 2206–​20. Bouquegneau A, et al. (2016). Bone disease after kidney transplant- ation. Clin J Am Soc Nephrol, 11, 1282–​96. Kaisiske BL, et  al. (1996). Cardiovascular disease after renal trans- plantation. J Am Soc Nephrol, 7, 158–​65. Kasiske B, et  al. (2004). Clinical practice guidelines for managing dyslipidaemias in kidney transplant patients. Am J Transplant, 4 Suppl, 1–​53. Kujovick JL (2004). Thrombophilia and thrombotic problems in renal transplant patients. Transplantation, 79, 959–​64. Mangray M, Vella JP (2011). Hypertension after kidney transplant. Am J Kidney Dis, 57, 331–​41. Pontielli C, Passerini P (2005). Gastrointestinal complications in renal transplantation. Transplant Int, 18, 643–​50. Sharif A, et al. (2014). Proceedings from an international consensus meeting on posttransplantation diabetes mellitus:  recommenda- tions and future directions. Am J Transplant, 14, 1992–​2000. Wheeler DC, Steiger J (2000). Evolution and etiology of cardiovascular diseases in renal transplant recipients. Transplantation, 70, 41–​5. Yabu JM, Winkelmayer WC (2011). Posttransplantation anaemia: mechanisms and management. Clin J Am Soc Nephrol, 6, 1794–​801. Immunosuppression Cianco G, Miller J, Gonwa T (2005). Review of major clinical trials with mycophenolate mofetil in renal transplantation. Transplantation, 80 Suppl 2, S191–​200. Danovitch GM (2000). Immunosuppressant-​induced metabolic toxicities. Transplant Rev, 14, 65–​81. Grgic I, Chandraker A (2018). Significance of biologics in renal trans- plantation: past, present, and future. Curr Opin Organ Transplant, 23, 51–​62. Haller M, Oberbauer R. (2009). Calcineurin inhibitor minimization, withdrawal and avoidance protocols after kidney transplantation. Transplant Int, 22, 69–​77. Kumar NSA, Heifets M, Moritz MJ (2006). Safety and efficacy of steroid withdrawal two days after kidney transplantation: analysis of results at three years. Transplantation, 81, 832–​9. Lim MA, Kohli J, Bloom RD (2017). Immunosuppression for renal transplantation: where are we now and where are we going? Transplant Rev, 31, 10–​17. Matas AJ (2009). Minimization of steroids in kidney transplantation Transpl Int, 22, 38–​48. Samaniego M, Becker B, Djamali A (2006). Drug insight: maintenance immunosuppression in kidney transplant recipients. Nature Clin Pract Nephrol, 2, 688–​99. Webster AC, et al. (2017). Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Cochrane Database Syst Rev, 7, CD004756. Rejection and causes of allograft loss Cai J, Terasaki PI (2005). Humoral theory of transplantation:
mechanism, prevention and treatment. Human Immunol, 66, 334–​42. Dudley C, et  al. (2005). Mycophenolate mofetil substitution for ciclosporine A  in renal transplant, recipients with chronic pro- gressive allograft dysfunction:  the ‘Creeping Creatinine’ study. Transplantation, 79, 466–​75. Joosten SA, et al. (2005). Chronic renal allograft rejection: pathological considerations. Kidney Int, 68, 1–​13. Montgomery RA, Loupy A, Segev DL (2018). Antibody-​mediated rejection:  new approaches in prevention and management. Am J Transplant, 18 Suppl 3, 3–​17. Nankivelli BK, Chapman JR (2006). Chronic allograft nephropathy: current concepts and future directives. Transplantation, 81, 643–​54. Outcomes and other topics Choy BY, Chan TM, Lai KN (2006). Recurrent glomerulonephritis after transplantation. Am J Transplant, 6, 2535–​42.

section 21  Disorders of the kidney and urinary tract 4908 Deshpande NA, et al. (2011). Pregnancy outcomes in kidney trans- plant recipients:  a systematic review and meta-​analysis. Am J Transplant, 11, 2388–​404. Hariharan S, et al. (2002). Post transplant renal function in the first year predicts long-​term kidney transplant survival. Kidney Int, 62, 311–​18. Opelz G, Dohler B (2005). Improved long-​term outcomes after renal transplantation associated with blood pressure control. Am J Transplant, 5, 2725–​31. Wolfe RA, Ashby VB, Milford EL (1999). Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med, 341, 1725–​30.

21.8 Glomerular diseases 4909 21.8.1 Immunoglobuli

21.8 Glomerular diseases 4909 21.8.1 Immunoglobulin A nephropathy and IgA vasculitis (HSP) 4909

CONTENTS 21.8.1 Immunoglobulin A nephropathy and
IgA vasculitis (HSP)   4909 Jonathan Barratt and John Feehally 21.8.2 Thin membrane nephropathy  4918 Peter Topham and John Feehally 21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919 Moin Saleem and Lisa Willcocks 21.8.4 Membranous nephropathy  4928 An S. De Vriese and Fernando C. Fervenza 21.8.5 Proliferative glomerulonephritis  4933 Alan D. Salama and Mark A. Little 21.8.6 Membranoproliferative glomerulonephritis  4937 Tabitha Turner-​Stokes and Mark A. Little 21.8.7 Antiglomerular basement membrane disease  4943 Mårten Segelmark and Thomas Hellmark 21.8.1  Immunoglobulin A nephropathy and
IgA vasculitis (HSP) Jonathan Barratt and John Feehally ESSENTIALS Immunoglobulin A nephropathy (IgAN) is the commonest pattern of glomerulonephritis identified in areas of the world where renal biopsy is widely practised. It is defined pathologically by IgA depos- ition in the glomerular mesangium accompanied by a mesangial proliferative glomerulonephritis which may vary greatly in severity. Aetiology is uncertain, but abnormalities of IgA1 hinge-​region O-​glycosylation are consistently found. Clinical features—​IgAN can present with (1)  visible haematuria, typically in children and young adults, developing within a day or two of upper respiratory tract infection (‘synpharyngitic’); (2) asymptom- atic nonvisible haematuria/​proteinuria; (3) nephrotic syndrome (<5% of cases); (4) acute kidney injury (uncommon); and (5) chronic renal failure with up to 25% of patients reaching endstage renal failure within 20 years of diagnosis. IgA vasculitis (HSP) is a small vessel systemic vasculitis characterized by small blood vessel deposition of IgA that predominantly affects the skin, joints, gut, and kidney, with nephritis that may be histologically indistinguishable from IgA nephropathy. Management—​there is no treatment known to modify mesangial deposition of IgA. Treatment options are mostly directed at con- trolling blood pressure and limiting proteinuria through blockade of the renin–​angiotensin–​aldosterone axis. In the rare patient pre- senting with acute kidney injury in whom biopsy shows crescentic IgA nephropathy, a regimen such as those used for renal vascu- litis and other forms of crescentic glomerulonephritis should be considered, for example, oral prednisolone in combination with cyclophosphamide. Introduction Immunoglobulin A  nephropathy (IgAN) was first described by Berger in 1968 and at one time was known as Berger’s disease. It is defined by IgA deposition in the glomerular mesangium accom- panied by a mesangial proliferative glomerulonephritis which may vary greatly in severity. Although recurrent visible haematuria is the hallmark of the disease, the old term ‘benign recurrent haematuria’ is a discredited misnomer since it is now clear that IgAN is associ- ated with a significant risk of progression to endstage renal failure. IgA vasculitis (HSP) is a somewhat misleading historical term: the purpuric rash is in fact a cutaneous vasculitis, and the renal lesion (HSP nephritis) is a mesangial proliferative glomerulonephritis usu- ally indistinguishable from IgAN. Aetiology In most cases the aetiology of IgAN remains unclear. The provo- cation of visible haematuria by mucosal infection in IgAN and the 21.8 Glomerular diseases

section 21  Disorders of the kidney and urinary tract 4910 presumption that the mesangial IgA represented deposited immune complexes led to the view that IgAN was a complication of infection. Cytomegalovirus and Haemophilus parainfluenzae have been most studied, but neither these nor any other viral or bacterial antigens have been consistently associated with development of the disease or identified in IgA immune complexes or mesangial deposits. Alternatively, it has been suggested that IgAN results from hyper- sensitivity to food antigens, in view of its association with gluten-​ sensitive enteropathy. There is some evidence that withdrawal of gluten from the diet of these specific patients may improve the renal disease, but there is little evidence for widespread hypersensitivity to food antigens in IgAN. Genetics Despite many studies of potential immunogenetic associations, the genetic basis for susceptibility to IgAN has not yet been identified. IgAN is familial in less than 10% of cases, but the true frequency of familial IgAN remains uncertain because there are no reliable serological markers for the disease. Four kindreds have been de- scribed in which IgAN appears to show Mendelian inheritance, in each case autosomal dominance with incomplete penetrance. The genetic linkage differs in each of the four kindreds, arguing strongly against any generalizability of these findings to spor- adic IgAN. Furthermore, study of the three novel loci (designated IGAN1, IGAN2, IGAN3) has identified no likely candidate genes. Only the 2q36 locus identified in the Canadian pedigree is poten- tially informative since it contains COL4A3 and COL4A4 genes coding for basement membrane collagen, mutations of which are associated with thin membrane nephropathy (see Chapter 21.8.2). Three independent genome-​wide association studies in different populations with IgAN have also been reported, and a fourth meta-​analysis incorporating the populations from all three pre- vious genome-​wide association studies and including additional populations from both Europe and Asia. All have shown an en- richment of single nucleotide polymorphisms implicated in auto- immune or inflammatory traits (multiple alleles within the HLA region at chromosome 6p21 and chromosome 1q32 suggesting a role for complement regulatory proteins), and furthermore most loci associated with IgAN encode proteins implicated in mainten- ance of the intestinal barrier and regulation of mucosal immune response to pathogens. Pathogenesis Mechanism of mesangial IgA deposition Mesangial proliferative glomerulonephritis such as is seen in IgAN and HSP nephritis may be the consequence of immune complex deposition, either due to trapping of circulating IgA immune com- plexes or the formation of complexes in situ by reaction of IgA with antigen which has already been deposited. No exogenous antigen has been consistently identified in the mesangial deposits in IgAN, which may indicate that the IgA complexes are a common re- sponse to different antigens, or that the initiating antigen has dis- appeared by the time of the renal biopsy. Alternatively, the IgA may be deposited by some mechanism independent of classic antigen–​ antibody interactions, such as a physicochemical abnormality of the IgA. The frequent recurrence of both IgAN and HSP nephritis after renal transplantation strongly suggests that the abnormality resides in the host IgA immune system. The mesangial IgA deposits are polymeric IgA1 (pIgA1). Most pIgA is synthesized in the mucosa and the clinical association of visible haematuria with mucosal in- fection originally led to the assumption that an exaggerated mucosal IgA response resulted in mesangial IgA deposition. But IgA produc- tion is in fact down-​regulated in the mucosal immune system and up-​regulated in the bone marrow, and exaggerated IgA1 responses to immunization in these patients are marrow rather than mucosally derived. There is increasing evidence of under-​galactosylation of both serum and mesangial IgA1 in patients with IgAN and HSP neph- ritis. Changes in the O-​glycan composition of circulating IgA1 may favour the development of immune complexes or may directly pro- voke mesangial deposition. Data suggest that poorly galactosylated IgA1 O-​glycoforms might in fact act either as autoantigens driving the formation of glycan-​specific autoantibodies, or antigens for cross-​reactive antimicrobial antibodies. The resultant formation of IgA:IgG immune complexes appears pivotal to the pathogenesis of IgAN and there is strong in vitro data to support their role in activa- tion of mesangial cells, induction of podocyte injury, and activation of proximal tubular epithelial cells. Progression of IgA nephropathy IgA deposition may occur in many patients with mild disease with little mesangial injury. What decides the prognosis in any individual is the extent to which the IgA deposition is followed by mesangial proliferation, inflammation, and scarring. There is nothing to suggest that these subsequent mechanisms of damage and scar- ring are unique to IgAN, rather they are generic to many forms of glomerulonephritis. Relationship of IgAN and HSP There is much indirect evidence to suggest a close relationship be- tween IgAN and HSP. Monozygotic twins have been described, one who developed IgAN and the other HSP at the same time. HSP developing on a background of proven IgAN has been described in both adults and children. Many abnormalities of the IgA im- mune system, including abnormal IgA1 glycosylation, have been described in both IgAN and HSP. IgAN is increasingly thought of as ‘HSP without the rash’. Why some individuals get a renal-​limited disease (IgAN) and others a systemic disease (HSP) is not known. Pathology Immune deposits IgAN and HSP nephritis are defined by the presence of mesangial IgA detected by immunofluorescence or immunoperoxidase (Fig. 21.8.1.1). Complement C3 frequently accompanies IgA in the same mesangial distribution; IgG and IgM are less common. Electron microscopy identifies mesangial electron-​dense deposits corresponding to the mesangial IgA (Fig. 21.8.1.2).

21.8.1  Immunoglobulin A nephropathy and IgA vasculitis (HSP) 4911 Light microscopy Mesangial proliferative glomerulonephritis is the characteristic ap- pearance, although when haematuria is the only clinical finding abnormalities on light microscopy may be minimal despite florid IgA deposition. Mesangial hypercellularity and matrix expansion are usually global (Fig. 21.8.1.3a) but may be focal and segmental (Figs. 21.8.1.3b and 21.8.1.3c). The hypercellularity is followed by increasing mesangial matrix deposition and eventual sclerosis (Fig. 21.8.1.3b). In acute kidney injury there may be severe glom- erular inflammation with crescent formation. In advanced cases there is glomerulosclerosis and corresponding tubular atrophy and interstitial fibrosis; these are entirely nonspecific changes of ‘endstage kidney’. A number of histological scoring systems have been devised to evaluate the renal biopsy appearances of IgAN. Of these the most extensively evaluated is the Oxford Classification of IgAN. In the recently updated classification, five variables—​(1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3)  endocapillary hyper­cellularity, (4)  tubular atrophy/​interstitial fibrosis, and (5) presence of crescents—​were shown to have inde- pendent value in predicting renal outcome. Epidemiology IgAN is the commonest glomerulonephritis in countries where renal biopsy is widely used. It is typically found in 30% of biopsies Fig. 21.8.1.1  Immunofluorescence of a glomerulus in IgAN. Bright fluorescent staining is seen within the mesangium with labelled antibodies to IgA. In some cases similar staining is also seen along capillary walls. A similar distribution of staining for C3 is commonly present. Antihuman IgA, magnification ×375. Fig. 21.8.1.2  Electron micrograph of glomerular capillary loop in IgAN. Numerous electron-​dense deposits representing deposits of IgA (large arrows) are seen within the expanded mesangium. BM, basement membrane; BS, Bowman’s space; C, capillary lumen; En, fenestrated endothelium; Ep, visceral epithelium; MC, mesangial cell nucleus. Magnification ×5200. (a) (b) (c) Fig. 21.8.1.3  Light microscopic appearances of IgA nephropathy. (a) Glomerulus showing global increase in mesangial matrix and cellularity. Alcian blue/​PAS stain, magnification ×375. (b) Glomerulus showing segmental increase in mesangial matrix and hypercellularity with fibrinoid necrosis (solid arrow) and synechia formation (open arrow) between the segmental lesion and parietal epithelium of Bowman’s capsule. Alcian blue/​PAS stain, magnification ×375. (c) Glomerulus showing segmental increase in mesangial matrix and segmental sclerosis with synechia formation (open arrows) overlying Bowman’s capsule. Masson’s trichrome stain, magnification ×375.

section 21  Disorders of the kidney and urinary tract 4912 with primary glomerular disease, but the apparent prevalence varies markedly around the world. It is commoner in the Pacific rim and Mediterranean countries, and less so in North America and northern Europe. At least part of this apparent difference is ex- plained by the varying use of urine testing in health screening and varying attitudes to the value of renal biopsy in individuals with isolated haematuria or other minor clinical evidence of renal dis- ease. For example, in Japan there is routine urine testing of school- children and employed adults, the threshold for renal biopsy is low, and the reported prevalence of IgAN is high. There are also important racial differences in susceptibility. IgAN is uncommon in Afro-​Caribbean people and also less common in Polynesian people than white people in Australasia, a particularly striking finding given the exaggerated susceptibility of Polynesian people to most forms of renal disease. Clinical features IgAN IgAN can occur at any age, but the peak age of onset is in the second and third decades of life (Fig. 21.8.1.4). In western Europe, IgAN is three times more common in males than females, but this sex differ- ence disappears in the Pacific Rim. Visible haematuria The characteristic clinical picture of recurrent visible haema- turia occurs in about 40 to 50% of cases. A child or young adult develops episodes of painless visible haematuria occurring within a day or so of the onset of an upper respiratory tract infection, or occasionally infections of other mucosal or IgA-​se- creting surfaces such as gastrointestinal tract, bladder, or breast. The urine may be frankly bloody, but more often is brown (like Coca-​ Cola or tea without milk), there are no clots passed, and it is usually painless although there may be dull loin ache. The episodes settle spontaneously after 1 to 5 days and may be recurrent, but rarely for more than a year or two. Serum IgA is moderately elevated in 30% of cases, but serum complement C3 and C4 are normal. Between episodes there will be persistent nonvisible haematuria. This pres- entation does not occur beyond the age of 40 years (Fig. 21.8.1.4). Asymptomatic haematuria/​proteinuria About 30 to 40% of cases of IgAN are identified by urine testing, when nonvisible haematuria may be combined with proteinuria (usually <2 g/​24 h). Since this is glomerular haematuria, dysmorphic red cells may be seen on phase contrast microscopy, but red cell casts are frequently absent in mild disease. Nephrotic syndrome Nephrotic syndrome is the presentation in only 5% of IgAN. Very occasionally in children or young adults this appears to be the con- sequence of coincidental minimal-​change nephrotic disease; the proteinuria resolves completely with corticosteroid therapy, but haematuria and IgA deposits persist. More commonly nephrotic syndrome may develop in IgAN with overt mesangial proliferative glomerulonephritis, or may be a consequence of glomerular scar- ring in advanced IgAN. Acute kidney injury Acute kidney injury occurs for two reasons in IgAN. Episodes of macroscopic haematuria may produce acute tubular occlusion by red cells in the face of minor glomerular injury. Alternatively, there can be acute severe necrotizing glomerulonephritis with crescent formation, ‘crescentic IgA nephropathy’, which may be the presenting feature or occur on a background of known milder disease. Chronic kidney disease IgAN may also present with hypertension and established renal impairment, often in older patients (Fig. 21.8.1.4). Too little is yet known about the pathogenesis of IgAN to understand whether this is a distinct disease entity or the same disease presenting much later because there was never an episode of visible haematuria or a urine test to bring it to medical attention earlier. Clinical associations with IgAN The commonest secondary cause of IgAN is chronic liver disease, typically alcoholic liver disease, in which it is probable that IgA deposition is a consequence of impaired IgA clearance from the circulation via the liver. Most hepatic IgAN is asymptomatic, and progression to endstage renal failure is unusual. The other best established associations are with coeliac disease and dermatitis 10 20 30 Age (years) Number of cases 40 50 60 70 80 IgA vasculitis (HSP) Asymptomatic urine abnormality Nephrotic syndrome Chronic kidney disease Visible haematuria Fig. 21.8.1.4  Clinical presentations of IgAN and HSP in relation to age at diagnosis. HSP is most common in childhood but may occur at any age. Visible haematuria is very rare over the age of 40 years. The importance of asymptomatic urine abnormality as the presentation of IgAN will depend on attitudes to routine urine testing and renal biopsy. It is uncertain whether those presenting with chronic kidney disease have a disease distinct from that of those presenting younger with visible haematuria.

21.8.1  Immunoglobulin A nephropathy and IgA vasculitis (HSP) 4913 herpetiformis; with rheumatoid arthritis, ankylosing spondylitis, and Reiter’s disease; and with HIV infection. Many other condi- tions have been reported occasionally with IgAN, but since IgAN is so common it is difficult to know if these are more than chance associations. HSP nephritis HSP can occur at any age but is commonest in the first decade of life (Fig. 21.8.1.4). There is a slight male preponderance. A palp- able purpuric rash caused by cutaneous vasculitis is the presenting feature. It has a characteristic extensor surface distribution with sparing of the trunk and face (Fig. 21.8.1.5). Crops of rash, often provoked by intercurrent infection, may continue for some time, but rarely beyond a year from first presentation. Polyarthralgia is common. Abdominal pain, due to gut vasculitis, is usually mild and transient, but severe pain and bloody diarrhoea may develop due to intussusception. Apart from intussusception, the major sequelae of HSP come from renal involvement. Much of the renal disease in HSP is tran- sient, with asymptomatic haematuria or proteinuria disappearing in a few weeks. Of those with persistent evidence of renal disease, asymptomatic haematuria/​proteinuria is the commonest clinical state, but 20% will have nephrotic syndrome. Serum IgA is raised in 50%, but complement C3 and C4 are normal. Acute kidney in- jury due to crescentic HSP nephritis usually occurs early and is com- moner than crescentic IgAN. Differential diagnosis Visible haematuria Nonglomerular causes of haematuria, including renal stones and neoplasia, must always be considered and excluded where appro- priate by urological investigation. While episodic visible haema- turia coinciding with upper respiratory tract infection in children and young adults is the hallmark of IgAN, it is not pathognomonic. Similar episodes can occur with other glomerular diseases, most commonly hereditary nephropathies such as Alport’s syndrome and thin membrane nephropathy. The distinction of IgAN from postinfectious (usually poststreptococcal) glomerulonephritis is also important. In poststreptococcal glomerulonephritis there is a 10-​ to 14-​day latency from the onset of infection and the devel- opment of symptomatic renal disease, contrasting with the imme- diacy of haematuria in IgAN, for which the term ‘synpharyngitic haematuria’ has been coined. The haematuria is usually less heavy in poststreptococcal glomerulonephritis so that the urine is typ- ically smoky rather than frankly bloody; hypertension, oedema, and other features of the acute nephritic syndrome are usually present. Serological evidence of recent streptococcal infection (such as antibodies to endostreptosin) and low C3 are not found in IgAN. Nephrotic syndrome The differential diagnosis when IgAN presents with nephrotic syn- drome includes the usual range of glomerular disease known to cause nephrotic syndrome given the age of the patient. Chronic kidney disease Advanced IgAN presenting with hypertension, proteinuria, and renal impairment is clinically indistinguishable from many other causes of chronic progressive renal disease. Renal biopsy can estab- lish the diagnosis since mesangial IgA can often still be identified even when light microscopy shows ‘endstage kidney’, but should only be performed if there is a reasonable expectation that the result might benefit the particular patient. HSP In children, HSP is the commonest form of vasculitis, and a clinical diagnosis is often made from the characteristic rash and abdom- inal pain. In adults, the differential diagnosis is wider, including many other forms of small vessel vasculitis which must be distin- guished on the basis of clinical, serological, and histopathological findings. Clinical investigation No accumulation of clinical and laboratory evidence has suffi- cient specificity and sensitivity to avoid the need for diagnostic biopsy in IgAN or HSP. IgA deposits are seen in blood vessels in affected skin, but this is not a universal feature. Raised serum IgA1 levels are found in 30 to 50% of all patients, but are less common in children and do not correlate with disease activity or severity. A high proportion of λ light chain, rather than the normal predominance of the κ isotype, is also a distinctive fea- ture of serum IgA in IgAN, although the significance of this is unknown. Complement components C3 and C4, and CH50 in the serum, are usually normal, but there is some evidence of systemic complement activation with more specific testing. Circulating autoantibodies to the IgA1 hinge region glycans, IgA rheumatoid factors, and IgA-​containing circulating immune complexes have been reported by many different assay methods, but they are not currently diagnostically useful, nor can they be reliably correlated with disease activity. Fig. 21.8.1.5  Characteristic purpuric rash affecting the lower
limbs in HSP.

section 21  Disorders of the kidney and urinary tract 4914 Secondary causes of IgAN must be identified. A thorough history and physical examination, along with laboratory checks for liver function and hepatitis B status are sufficient to exclude the common secondary associations with IgAN. Criteria for diagnosis IgAN By definition, the diagnosis of IgAN requires a renal biopsy; no sero- logical or other laboratory indices provide diagnostic information reliable enough to avoid the need for biopsy. HSP While the distribution of the vasculitic rash may be highly suggestive in HSP, ultimate confirmation requires identification of tissue IgA deposition which can be found in the vessels of affected skin as well as the kidney. Treatment IgAN The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) treatment guidelines for IgAN are summarized in Table 21.8.1.1. Only in very few patients with IgAN is there any evidence that drug therapy alters the natural history of the disease. Despite being so common among renal diseases, there is still a dearth of well-​ conducted prospective randomized controlled trials in IgAN on which to base therapeutic decisions. Specific treatment for IgAN would either restrict the forma- tion of relevant pathogenic IgA molecules or prevent their depos- ition in the mesangium. However, so little is understood about the pathogenesis of the disease that the prospect for such treatment is still remote. Haematuria There is no specific treatment for the great majority of patients with IgAN who have isolated haematuria with or without low-​grade proteinuria (<1 g/​24 h). Nonvisible haematuria should merely be observed. Recurrent visible haematuria settles without treatment; there is no role for prophylactic antibiotics as most precipitating in- fections are viral. Tonsillectomy will reduce the number of episodes of visible haematuria, but there is no evidence that it reduces the risk of progressive renal failure. Proteinuria Those with proteinuria above 1 g/​24 h as well as haematuria have a worse prognosis. Immunosuppressive therapies have been tried, although the frequent recurrence of IgAN in transplanted kidneys when patients are receiving immunosuppressive therapy argues against their value. Short-​term randomized controlled trials of cor- ticosteroids have shown no benefit. A controlled trial of 6 months of treatment with corticosteroids (prednisolone 0.5 mg/​kg per day) showed a significant reduction in proteinuria and reduced risk of developing renal impairment at 10 years’ follow-​up. This requires further confirmation, and corticosteroid treatment is not presently recommended except in the rare circumstance where the biopsy suggests coincidental minimal-​change nephrotic syndrome which may be fully steroid responsive. Other immune modulating drugs have been tried in IgAN, including cyclophosphamide, mycophenolate mofetil, azathioprine, ciclosporin, and pooled human intravenous im- munoglobulin, but there are few properly controlled studies and for none is there consistent evidence of benefit or an acceptable risk–​benefit ratio in most patients who have indolent slowly pro- gressive disease. There are a number of well-​designed, placebo-​controlled, double-​ blinded randomized controlled trials examining the efficacy of a variety of novel therapies in IgAN underway or nearing formal re- porting (Table 21.8.1.2). Table 21.8.1.1  Current recommendations for the treatment of IgAN Clinical feature Recommendation Visible haematuria No treatment Nonvisible haematuria No treatment—​no indication for prophylactic antibiotics or tonsillectomy Acute kidney injury Biopsy Tubular occlusion Supportive treatment only Crescentic IgAN Prednisolone 0.5 mg/​kg per day, reducing to 5–​10 mg daily by 3 months Cyclophosphamide 2–​3 mg/​kg per day for 3 months, followed by azathioprine 2–​3 mg/​kg per day Proteinuria <1 g/​24 h No treatment Nephrotic syndrome with minimal change on biopsy Prednisolone 0.5 mg/​kg per day for 8–​12 weeks All other proteinuria >1 g/​24 h ACE inhibitor and ARB Hypertension Target BP 125/​75 mmHg if proteinuria >1 g/​24 h, otherwise target BP 130/​80 mmHg, using regimen including ACE inhibitor and ARB Proteinuria >1 g/​24h and GFR >50 ml/​min per 1.73 m2 despite maximal ACE inhibitor/​ARB and BP control Consider immunosuppression or enrolment in a randomized controlled trial (see Table 21.8.1.2) ACE, angiotensin-​converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; GFR, glomerular filtration rate.

21.8.1  Immunoglobulin A nephropathy and IgA vasculitis (HSP) 4915 Acute kidney injury Renal biopsy is mandatory when acute kidney injury develops in IgAN. If this shows mild glomerular disease but tubular occlusion with erythrocytes and accompanying acute tubular necrosis, sup- portive treatment only is required while recovery is awaited. If there is crescentic IgAN, a regimen such as those used for renal vascu- litis and other forms of crescentic glomerulonephritis should be considered unless the histological appearances are thought to be advanced and irreversible, for example, oral prednisolone 0.5 mg/​ kg per day (reducing to a maintenance dose of 5–​10 mg daily by Table 21.8.1.2  Clinical trials of novel/repurposed drugs in IgAN underway or nearing formal reporting Trial Intervention Inclusion criteria Exclusion criteria Trial design Primary end point Follow-up duration Atacicept NCT02808429 Atacicept at varying doses vs placebo Proteinuria 1–6 g/day Stabilized on RASi for 8 weeks Prior cyclophosphamide treatment Use of other immuno- suppressants within 4 months Randomized, double-blind, placebo-controlled Phase II trial Incidence of adverse events 180 weeks BRIGHT-SC NCT02062684 Blisibimod vs placebo Proteinuria 1–6 g/day Stabilized on RASi for 8 weeks Immunosuppressant use over last 6 months or corticosteroid use over last 3 months. Malignancy over last 5 years Randomized, double-blind, placebo-controlled Phase II/III trial Reduction of proteinuria at 24 weeks 104 weeks SIGN NCT02112838 Fostamatinib at varying doses vs placebo Stabilized on RASi for 90 days. BP < 130/80 Proteinuria > 1 g/day at diagnosis and > 0.5 g/day at second screening visit Recent use of corticosteroids, cyclophosphamide, mycophenolate mofetil, azathioprine or rituximab Randomized, multicentre, double-blind, placebo- controlled, Phase II trial Reduction of proteinuria at 24 weeks 24 weeks VELCADE NCT01103778 Bortezomib Proteinuria > 1 g/day Stabilized on RASi for 4 weeks Peripheral neuropathy, history of cardiac problems, malignancy within last 3 years Open-label, Phase IV trial Reduction of proteinuria at 1 year 1 year ACTHAR NCT02282930 Acthar gel Proteinuria > 1 g/day Stabilized on RASi for 3 months BP > 130/80 HSP patients included Crohn’s disease or celiac sprue Glucocorticoid treat- ment in last 3 months Immunosuppressive therapy in last 6 months Previous ACTH treatment History of malignancy History of cardiac or pulmonary disease Open-label, Phase III trial Reduction in proteinuria at 1 year, stabilization of eGFR at 1 year 1 year OMS721 NCT02682407 OMS721 vs placebo Patients on immuno- suppressive patients in- cluded, if on stable dose for 2 months Optimized RASi, BP < 150/90, Urine ACR > 600 mg/g Renal transplant History of malignancy Use of belimumab, rituximab, or eculizumab within last 6 months HSP within 2 years Randomized, double-blind, placebo- controlled, Phase II trial Incidence of adverse events 18 weeks LNP023 NCT03373461 LNP023 vs placebo Stabilized on RASi for 90 days eGFR ≥ 30, pro- teinuria ≥ 0.75 g/ day Recent use of immunosuppression, history of drug/alcohol abuse, malignancy Randomized, double-blind, placebo-controlled Phase IIa/IIb trial Reduction of proteinuria at 90 days 180 Days Cemdisiran NCT03841448 Cemdisiran vs placebo Stabilized on RASi for 90 days eGFR ≥ 30, proteinuria ≥ 1 g/day Recent use of immunosuppression, history of drug/alcohol abuse, malignancy Randomized, double-blind, placebo-controlled Phase IIa/IIb trial Reduction of proteinuria at week 32 952 Days Sparsentan NCT03762850 Sparsentan vs Irebsartan Stabilized on RASi for 12 weeks eGFR ≥ 30, proteinuria ≥ 1 g/day Recent use of immunosuppression, history of drug/alcohol abuse, malignancy Randomized, double-blind, controlled Phase III trial Reduction of proteinuria at week 36 798 Days Nefecon NCT03643965 Nefecon vs placebo Stabilized on RASi for 90 days eGFR ≥ 45, proteinuria ≥ 1 g/day Recent use of immunosuppression, history of drug/alcohol abuse, malignancy Randomized, double-blind, placebo-controlled Phase III trial Reduction of proteinuria at 9 months 2190 Days

section 21  Disorders of the kidney and urinary tract 4916 3 months) in combination with oral cyclophosphamide 2 to 3 mg/​kg per day (replaced by azathioprine 2–​3 mg/​kg per day after 3 months). Plasma exchange has also been used. There are no randomized con- trolled trials of these treatments in crescentic IgAN. Although the initial response to treatment is excellent, the medium-​term outlook is much less good; 50% will be on long-​term dialysis after 12 months. Progressive renal impairment Slowly progressive renal impairment due to IgAN requires a management approach common to any form of chronic renal failure. Rigorous control of blood pressure is the one established method of delaying progressive renal failure. Angiotensin-​ converting enzyme inhibitors and angiotensin II receptor blockers are widely used as first-​line therapy for their special role in lessening proteinuria for the same degree of blood pres- sure control. Fish oil therapy (which provides a supplement of ω-​3 fatty acids) has effects likely to impact favourably on mech- anisms of progressive renal damage and has been used in ran- domized controlled trials in IgAN, but there is no reason to expect its effects are specific for IgAN rather than other pro- gressive diseases. One randomized controlled trial has shown a substantial reduction in the risk of progression to endstage renal failure, but other studies have not shown comparable benefit and at present the use of fish oil is not recommended until confirma- tory studies are available. HSP nephritis There is very little information to guide treatment of HSP neph- ritis. There are no published randomized controlled trials and most therapeutic studies in IgAN exclude those with HSP, hence it is un- clear whether their conclusions can be extrapolated to HSP. Transient early nephritis requires no specific treatment. There is no evidence that corticosteroids or other immunosuppressive re- gimens alter the natural history of nephrotic syndrome or slowly progressive glomerular damage in HSP. Crescentic HSP nephritis is more common than crescentic IgAN. Regimens used for renal vas- culitis have also been applied to crescentic HSP nephritis with ap- parent benefit, although there are no controlled trials. Prognosis Thirty per cent of children will have a spontaneous clinical remis- sion with complete disappearance of haematuria within 10 years of diagnosis. But IgAN, despite the apparently benign presentation in many cases, is an important cause of endstage renal failure, with up to 25% of patients reaching this within 20 years of diagnosis. Where a lower risk of endstage renal failure is reported, the series will con- tain larger numbers of patients with mild disease, such as those with isolated nonvisible haematuria. Perhaps unexpectedly, a history of episodic visible haematuria is a favourable prognostic feature. The prognosis for patients who present with microscopic haematuria and minimal proteinuria (<1 g/​24 h) is very good, but not perfect; even in this group up to 5% of patients will develop worsening proteinuria and hypertension during follow-​ up and are at eventual risk of endstage renal failure. Consequently, the long-​term follow-​up of any patient with biopsy-​proven IgAN is mandatory. The risk of progressive renal failure can be predicted by clinical and pathological features at diagnosis (Table 21.8.1.3). Both IgAN and HSP nephritis recur after renal transplantation. Mesangial IgA deposits appear within a few months in 60% of pa- tients with IgAN. Initially this is benign, accompanied by little mesangial injury, but in the long term, recurrent disease will con- tribute to progressive graft loss in a number of patients. However, overall transplant success and graft longevity do not differ in IgAN or HSP from other primary renal diseases. The changes in im- munosuppressive regimens used to prevent rejection over the last two decades have not altered the recurrence rate or its prognosis. FURTHER READING Clinical Barbour SJ, et al. (2019). Evaluating a New International Risk- Prediction Tool in IgA Nephropathy. JAMA Intern Med, doi: 10.1001/jamainternmed.2019.0600. D’Amico G (2004). Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol, 24, 179–​96. Davin JC, Ten Berge IJ, Weening JJ (2001). What is the difference be- tween IgA nephropathy and Henoch–Schönlein purpura nephritis? Kidney Int, 59, 823–​34. Floege J (2004). Recurrent IgA nephropathy after renal transplant- ation. Semin Nephrol, 24, 287–​91. Pouria S, Feehally J (1999). Glomerular IgA deposition in liver disease. Nephrol Dial Transplant, 14, 2279–​82. Table 21.8.1.3  Variables included in the IgA nephropathy risk prediction score eGFR at biopsy MAP at biopsy Proteinuria at biopsy Histology: ● M1 ● E1 ● S1 ● T1 ● T2 ● Crescents Age Race: ● Chinese ● Japanese ● Caucasian RASB at biopsy (Immunosuppression use after biopsy) Source data from Barbour SJ, Coppo R, Zhang H, et al. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy, JAMA Intern Med. 2019 Apr 13. doi: 10.1001/ jamainternmed.2019.0600. [Epub ahead of print] PMID: 30980653.

21.8.1  Immunoglobulin A nephropathy and IgA vasculitis (HSP) 4917 Trimarchi H, et al. (2017). Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int, 91(5), 1014–21. doi: 10.1016/j.kint.2017.02.003. Wyatt RJ, Julian BA (2013). IgA nephropathy. N Engl J Med, 368, 2402–​14. Yeo SC, Goh SM, Barratt J (2019). Is IgA Nephropathy Different in Different Ethnic Populations? Nephrology (Carlton). doi: 10.1111/ nep.13592. Pathogenesis and genetics Barratt J, Feehally J (2011). Primary IgA nephropathy: new insights into pathogenesis. Semin Nephrol, 31, 349–​60. Coppo R, Amore A (2004). Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int, 65, 1544–​7. Gale DP, et al. (2017). Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1. J Am Soc Nephrol, 28(7), 2158–66. doi: 10.1681/ASN.2016091043. Gharavi AG, et  al. (2000). IgA nephropathy, the most common
cause of glomerulonephritis, is linked to 6q22–​23. Nat Genet, 26, 354–​7. Gharavi AG, et al. (2008). Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol, 19, 1008–​14. Hastings MC, et  al. (2010). Galactose-​deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol, 5, 2069–​74. Hsu SI, et  al. (2000). Evidence for genetic factors in the devel- opment and progression of IgA nephropathy. Kidney Int, 57, 1818–​35. Li M, Yu XQ (2018). Genetic Determinants of IgA Nephropathy: Eastern Perspective. Semin Nephrol, 38(5), 455–60. doi: 10.1016/j. semnephrol.2018.05.015. Lin X, et al. (2009). Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant, 24, 3372–​55. López-Mejías R, et al. (2018). Genetics of immunoglobulin-A vascu- litis (Henoch-Schönlein purpura): An updated review. Autoimmun Rev, 17(3), 301–15. doi: 10.1016/j.autrev.2017.11.024. Neugut YD, Kiryluk K (2018). Genetic Determinants of IgA Nephropathy: Western Perspective. Semin Nephrol, 38(5), 443–54. doi: 10.1016/j.semnephrol.2018.05.014. Novak J, Barratt J, Julian BA, Renfrow MB (2018). Aberrant Glycosylation of the IgA1 Molecule in IgA Nephropathy. Semin Nephrol, 38(5), 461–76. doi: 10.1016/j.semnephrol.2018.05.016. Suzuki H, et al. (2009). Aberrantly glycosylated IgA1 in IgA nephrop- athy patients is recognized by IgG antibodies with restricted hetero- geneity. J Clin Invest, 119, 1668–​77. Yeo SC, Cheung CK, Barratt J (2018). New insights into the patho- genesis of IgA nephropathy. Pediatr Nephrol, 33(5), 763–77. doi: 10.1007/s00467-017-3699-z. Treatment Appel GB, Waldman M (2006). The IgA nephropathy treatment di- lemma. Kidney Int, 69, 1939–​44. Audemard-Verger A, et al. (2017). Characteristics and Management of IgA Vasculitis (Henoch-Schönlein) in Adults: Data From 260 Patients Included in a French Multicenter Retrospective Survey. Arthritis Rheumatol, 69(9), 1862–70. doi: 10.1002/art.40178. Audemard-Verger A, Pillebout E, Guillevin L, Thervet E, Terrier B (2015). IgA vasculitis (Henoch-Shönlein purpura) in adults: Diagnostic and therapeutic aspects. Autoimmun Rev, 14(7), 579–85. doi: 10.1016/j.autrev.2015.02.003. Barratt J, Feehally J (2006). Treatment of IgA nephropathy. Kidney Int, 69, 1934–​8. Cattran DC, et al. (2009). The Oxford classification of IgA nephrop- athy: rationale, clinicopathological correlations, and classification. Kidney Int, 76, 534–​45. Donadio JV Jr, et al. (1999). The long-​term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol, 10, 1772–​7. Floege J (2006). Is mycophenolate mofetil an effective treatment for persistent proteinuria in patients with IgA nephropathy? Nat Clin Pract Nephrol, 2, 16–​17. Floege J, et al. (2019). Management and treatment of glomerular dis- eases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 95(2), 268–80. doi: 10.1016/j.kint.2018.10.018. Gharavi AG, et al. (2008). Aberrant IgA1 glycosylation is inherited in fa- milial and sporadic IgA nephropathy. J Am Soc Nephrol, 19, 1008–​14. Hastings MC, et  al. (2010). Galactose-​deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol, 5, 2069–​74. Hou JH, et al. (2017). Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial. Am J Kidney Dis, 69(6), 788–95. doi: 10.1053/j.ajkd.2016.11.027. Lin X, et al. (2009). Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant, 24, 3372–​5. Lv J, et al. (2017). Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA, 318(5), 432–42. doi: 10.1001/ jama.2017.9362. Pozzi C, et al. (2004). Corticosteroid effectiveness in IgA nephrop- athy: long-​term results of a randomized, controlled trial. J Am Soc Nephrol, 15, 157–​63. Rauen T, et al. (2015). Intensive Supportive Care plus Immuno­ suppression in IgA Nephropathy. N Engl J Med, 373(23), 2225–36. doi: 10.1056/NEJMoa1415463. Rauen T, et al. (2018). Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy. J Am Soc Nephrol, 29(1), 317–25. doi: 10.1681/ASN.2017060713. Samuels JA, et al. (2004). Immunosuppressive treatments for immuno- globulin A nephropathy: a meta-​analysis of randomized controlled trials. Nephrology, 9, 177–​85. Suzuki H, et al. (2009). Aberrantly glycosylated IgA1 in IgA nephrop- athy patients is recognized by IgG antibodies with restricted hetero- geneity. J Clin Invest, 119, 1668–​77. Tumlin JA, Hennigar RA (2004). Clinical presentation, natural history, and treatment of crescentic proliferative IgA nephropathy. Semin Nephrol, 24, 256–​68. Yeo SC, Liew A, Barratt J (2015). Emerging therapies in IgA nephrop- athy. Nephrology (Carlton), 20, 788–​800.

21.8.3 Minimal- change nephropathy and focal segme

21.8.3 Minimal- change nephropathy and focal segmental glomerulosclerosis 4919 Moin Saleem and Lisa Willcocks

21.8.3  Minimal-change nephropathy and focal segmental glomerulosclerosis 4919 also be sporadic. Persistent nonvisible haematuria is usually lifelong, and episodic visible haematuria may also occur in up to one-​fifth of patients, sometimes in association with upper respiratory tract infection. Flank pain occurs in up to 30% of patients and a small number of cases with loin-​pain haematuria syndrome have been de- scribed. Hypertension may be more common than in the general population, although this is not confirmed in all studies. Proteinuria is uncommon and patients with nephrotic-​range proteinuria usually have a second, additional renal diagnosis. Progressive renal impair- ment is rare but has been described in several families. Heterozygous G1334E and G187C mutations of COL4A3 protein have been iden- tified in families with TMN that progresses to proteinuria after age 30 years and renal insufficiency after age 50 years. This is associ- ated with the development of focal segmental glomerulosclerosis on renal biopsy. Deafness and other extrarenal manifestations seen in Alport’s syndrome are absent. There is no specific treatment. Differential diagnosis TMN can only be distinguished from IgA nephropathy (IgAN) by renal biopsy. The coexistence of TMN and IgAN is well recorded and it is a matter of debate whether this merely represents the coinci- dence of two common glomerular diseases or is more than a chance occurrence. TMN must be distinguished from Alport’s syndrome (hereditary nephritis with deafness), of which the commonest form is X-​linked. If there is a clear autosomal dominant pattern of haematuria without renal impairment or extrarenal problems, then a clinical diagnosis of TMN may be established with reasonable con- fidence, but a renal biopsy in at least one family member is still pref- erable. Once the diagnosis is established in a kindred, biopsy is not required unless there are unexpected clinical changes. Differentiation from the less common autosomal forms of Alport’s syndrome is less straightforward. Subclinical deafness must be excluded by audiography, and the renal biopsy must be carefully assessed. In TMN there is uniform thinning, whereas early in the course of Alport’s syndrome marked variability in GBM width is typical, even if the characteristic structural disruption of the GBM has not yet developed. Staining of GBM for the α-​chains of type IV collagen is highly informative since in Alport’s syndrome α3, α4, and α5 are absent, whereas normal α-​chain distribution is preserved in TMN. Genetic testing for COL4A3 or COL4A4 mutations to diag- nose TMN is clinically not practical because of the huge size of these genes, their frequent polymorphisms, and the likelihood of the ex- istence of further gene loci. Familial C3 glomerulonephritis caused by mutation of comple- ment factor H-​related protein 5 (CFHR5) has recently been described in kindreds of Cypriot descent. Affected individuals invariably have nonvisible haematuria, and recurrent (often synpharyngitic) vis- ible haematuria is present in about 50% of patients. Impaired renal function ensues in most affected males but is much less common in females. Prognosis The prognosis is excellent in the great majority of families with TMN, but there is a small but real risk of developing progressive renal insufficiency, heralded by the onset of proteinuria and hyper- tension. Long-​term follow-​up of those with TMN is therefore man- datory; urinalysis and measurement of blood pressure and renal function are recommended every 1 to 2 years. FURTHER READING Dische FE, et  al. (1990). Incidence of thin membrane nephrop- athy:  morphometric investigation of a population sample. J Clin Pathol, 43, 457–​60. Gale DP, et  al. (2010). Identification of a mutation in complement factor H-​related protein 5 in patients of Cypriot origin with glomer- ulonephritis. Lancet, 376, 794–​801. Nieuwhof CM, et al. (1997). Thin GBM nephropathy. Premature glom- erular obsolescence is associated with hypertension and late onset renal failure. Kidney Int, 51, 1596–​601. Pierides A, et al. (2009). Clinico-​pathological correlations in 127 pa- tients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/​COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis. Nephrol Dial Transplant, 24, 2721–​9. Tiebosch AT, et al. (1989). Thin-​basement-​membrane nephropathy in adults with persistent hematuria. N Engl J Med, 320, 14–​18. Tryggvason K, Patrakka J (2006). Thin basement membrane nephrop- athy. J Am Soc Nephrol, 17, 813–​22. 21.8.3  Minimal-​change nephropathy and focal segmental glomerulosclerosis Moin Saleem and Lisa Willcocks ESSENTIALS Minimal-​change nephrotic syndrome Minimal-​change nephrotic syndrome (MCNS) is an immune-​medi- ated condition, usually of unknown cause. On light microscopy the glomeruli appear normal, and on electron microscopy there is ef- facement of epithelial cell foot processes over the outer surface of the glomerular basement membrane. MCNS is the cause of about 75% of cases of nephrotic syndrome in children and 17% in adults. Management and prognosis—​treatment in adults is with pred- nisolone at an initial dose of 80 mg/​day, then tapering. This leads to complete remission in 90 to 95% of patients, but 50 to 75% of glucocorticoid-​responsive adults will have a relapse. Occasional re- lapses are treated in the same manner as initial presentations, but fre- quent relapses (more than three per year) occur in 10 to 25%, and in a further 25 to 30% the prednisolone dose cannot be reduced below 0.2 to 0.3 mg/​kg per day without relapse (steroid dependence). Treatment options then include cyclophosphamide, calcineurin in- hibitors, mycophenolate mofetil, and rituximab. Progression to renal

section 21  Disorders of the kidney and urinary tract 4920 failure is not expected and would call the diagnosis of MCNS into question. Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a histological lesion, often of unknown aetiology, which is characterized by segmental areas of glomerular sclerosis. It may be (1) primary—​either due to genetic mutation, or associated with an unknown circulating plasma factor that causes an increase in glomerular permeability; or (2) secondary—​the end product of a var- iety of pathological processes including glomerular hyperfiltration, healed glomerulonephritis, viral (including HIV) infection, or para- sitic infection. Based on the site of the lesions and other histological features, the primary condition can be divided into five variants: (1) perihilar; (2) glomerular tip; (3) collapsing variant; (4) cellular variant; and (5) ‘not otherwise specified’, when the other variants have been excluded. Most patients with FSGS present with nephrotic syndrome (FSGS is the diagnosis in 20% of adults with nephrotic syndrome), some with persistent proteinuria, and a few have haematuria as well as proteinuria. Management and prognosis—​corticosteroid and immunosup- pressive therapy should be considered only in patients with primary FSGS and nephrotic syndrome. The steroid regimen is as used for MCNS, but with lesser success: response rates for complete remis- sion range from 28 to 74%, and partial remission rates from 0 to 50%. Steroid-​resistant cases are treated with ciclosporin (for which there is most published evidence), mycophenolate mofetil, or cyclophos- phamide. Prognosis depends on histology and response to treatment. Glomerular tip lesions have the best prognosis and collapsing FSGS the worst. Patients who achieve a complete remission have a 5-​year survival off dialysis of 94%, as compared with 53% in those who do not achieve remission. The nephrotic syndrome recurs—​often within days—​after renal transplantation in about 30% of patients with pri- mary FSGS, leading to early graft failure in approximately 50% of cases. Introduction Nephrotic syndrome is defined by the triad of urinary protein ex- cretion greater than 3.5 g/​24 h (>200 mg/​mmol creatinine in chil- dren), hypoalbuminaemia (<25 g/​litre), and tissue oedema. General aspects and clinical features of this condition are discussed in Chapter 21.3, as is the fact that it can be caused by a range of glom- erular pathologies. In adults, minimal-​change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) are together respon- sible for a third of cases of nephrotic syndrome, while in children these two conditions cause over 80% of cases, the vast majority of which will be steroid sensitive. This has led to muddled termin- ology in paediatric practice, with MCNS patients frequently called steroid-​sensitive nephrotic syndrome, with steroid-​resistant neph- rotic syndrome used interchangeably with FSGS, indicating the lack of response to steroids in most of these patients. In this chapter, the terms MCNS and FSGS will be used, and although this is a text- book of adult medicine it will include some discussion of paediatric presentations and management because some will continue to be af- fected in adolescence and adulthood. MCNS and FSGS may be primary or secondary. There continues to be debate as to whether primary MCNS and FSGS are variants of the same disease, or whether they represent separate pathogenetic entities. Both disorders are characterized by diffuse foot process ef- facement on electron microscopy, the absence of immune deposits, and a severe functional defect in glomerular permselectivity. Minimal-​change nephrotic syndrome Aetiology and pathogenesis The cause of MCNS is unknown, although it is thought to be caused by circulating factor(s) released by activated immune cells, particularly at the time of intercurrent infections. In a landmark hypothesis paper in 1974, Shalhoub proposed T-​cell release of cir- culating mediators that affect the glomerulus. It is a relapsing and remitting condition, with relapse triggers including viral infec- tions, pollen and other allergens, meningococcal C vaccination, and an association with active Hodgkin’s disease and other T-​ cell malignancies. Between 30 and 60% of nephrotic children are atopic, and a genetic association with HLA-DRB and DQA/B loci has been reported across different populations. Measles infections have been observed to induce remission in some cases. The suc- cess of B-​cell depletion therapies in a subset of patients suggests that B cells are also involved in pathogenesis. In adults, a number of drugs can induce MCNS, including nonsteroidal anti-​inflammatory drugs, some antimicrobial drugs (ampicillin, rifampicin, cephalosporins), lithium, d-​penicillamine and tiopronin, bisphosphonates, and sulfasalazine. Pathology MCNS describes the observation that on light microscopy there is no evident change: the glomerulus looks normal (Fig. 21.8.3.1). The pathology can only be seen by electron microscopy, where there is effacement of the podocyte cell foot processes (Fig. 21.8.3.2). Epidemiology In children, estimates of incidence of nephrotic syndrome are rela- tively consistent, at around two to seven new paediatric cases (under 16 years) per 100 000 total population per year, with 76% of cases being due to MCNS. The peak incidence of MCNS is in preschool-​ age children, with a male-​to-​female childhood ratio of 2:1. In adults, MCNS accounts for 17% of cases of the nephrotic syndrome, and Fig. 21.8.3.1  Minimal-​change nephropathy. The glomerulus looks normal on light microscopy. Periodic acid–​methenamine silver staining, magnification ×64. By courtesy of Professor A.J. Howie

21.8.3  Minimal-change nephropathy and focal segmental glomerulosclerosis 4921 data from an adult Caucasian population in Northern Europe re- vealed that MCNS accounted for 10% of primary glomeruloneph- ritis, with—​as expected—​the incidence falling with increasing patient age. Genetics Familial MCNS is rare, but has been reported. One pedigree to date has been found to have a monogenic mutation responsible for the disease, affecting the epithelial membrane protein-​2 (EMP2) gene, and other gene mutations have been reported, although most can cause SRNS as well as SSNS. Clinical features See Chapter 21.3. Treatment The clinical trial evidence base is relatively sparse, but stronger in children. It has been comprehensively reviewed in the most recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on glomerulonephritis (in 2012). General approach Adults with MCNS are typically oedematous and often hyperten- sive. Sodium restriction and diuretics are often required to manage the oedema, and angiotensin-​converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are advocated for blood pressure control, with the additional advantage of a reduction in proteinuria. Close monitoring is required if initiating ACE in- hibitors in hypovolaemic patients undergoing diuresis, because of the risk of acute kidney injury. Statin therapy for hyperlipid- aemia and anticoagulation for severe hypoalbuminaemia should be considered for the long-​term management of patients whose nephrosis is refractory to treatment. See Chapter 21.3 for further discussion. MCNS is a condition with a propensity to remissions and relapses. Standard definitions of treatment response are shown in Table 21.8.3.1. Immunosuppression—​initial strategy Immunosuppression with corticosteroids is recommended for ini- tial treatment of nephrotic syndrome, based on evidence from large, prospective randomized controlled trials (RCTs) in children, smaller RCTs in adults, and observational data from adults and children. Adults According to the KDIGO recommendations, prednisone or pred- nisolone should be given at a daily single dose of 1 mg/​kg (maximum 80 mg) or an alternate-​day single dose of 2 mg/​kg (maximum 120 mg). The initial high dose of corticosteroids, if tolerated, should be maintained for a minimum period of 4 weeks if complete remission 100 90 1 2 3 4 5 6 80 70 60 50 40 30 20 10 00 2 4 8 16 Weeks from starting corticosteroid therapy Cumulative % of patients with complete remission 28 Fig. 21.8.3.2  Time of response to corticosteroid treatment in children (1) and five studies in adults (2–​6). Reprinted from Nakayama M, et al. (2002). Steroid responsiveness and frequency of relapse in adult-​onset minimal change nephrotic syndrome. American Journal of Kidney Diseases, 39(3), 503–​512. Copyright © 2002 National Kidney Foundation, Inc., with permission from Elsevier. Table 21.8.3.1  Definitions of nephrotic syndrome by treatment response Classification Definition Nephrotic syndrome Oedema, uPCR ≥2000 mg/​g (≥200 mg/​mmol), or ≥300 mg/​dl or 3+ protein on urine dipstick, hypoalbuminemia ≤2.5 mg/​litre (≤25 g/​litre) Complete remission uPCR <200 mg/​g (<20 mg/​mmol) or <1+ of protein on urine dipstick for 3 consecutive days Partial remission Proteinuria reduction of 50% or greater from the presenting value and absolute uPCR between 200 and 2000 mg/​g (20–​200 mg/​mmol) No remission Failure to reduce urine protein excretion by 50% from baseline or persistent excretion uPCR >2000 mg/​g (>200 mg/​ mmol) Initial responder Attainment of complete remission within initial 4 weeks of corticosteroid therapy Initial nonresponder/​steroid resistance Failure to achieve complete remission after 8 weeks of corticosteroid therapy Relapse uPCR ≥2000 mg/​g (≥200 mg/​mmol), or ≥300 mg/​dl or 3+ protein on urine dipstick for 3 consecutive days Infrequent relapse One relapse within 6 months of initial response, or one to three relapses in any 12-​month period Frequent relapse (FR) Two or more relapses within 6 months of initial response, or four or more relapses in any 12-​month period Steroid dependence (SD) Two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy Late nonresponder Persistent proteinuria during 4 or more weeks of corticosteroids following one or more remission uPCR, urine protein:creatinine ratio. Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int., Suppl. 2012, 2, 139–​274. Copyright © 2012 International Society of Nephrology, with permission from Elsevier.

section 21  Disorders of the kidney and urinary tract 4922 is achieved, and for a maximum period of 16 weeks if complete remission is not achieved. In patients who remit, corticosteroids should be tapered slowly over a total period of up to 6 months after achieving remission. This prolonged course of high-​dose prednisolone is often asso- ciated with significant toxicity. As a result, prophylactic measures are recommended, comprising an H2-​receptor antagonist or proton pump inhibitor to prevent peptic ulceration, and bisphosphonate to prevent osteoporosis. Blood sugar level monitoring is required to identify corticosteroid-​induced diabetes mellitus. For patients with relative contraindications or intolerance to high-​dose corticosteroids (e.g. pre-​existing uncontrolled diabetes mellitus, psychiatric conditions, severe osteoporosis, or morbid obesity), alternative therapy for which there is some evidence in- clude daily oral cyclophosphamide or calcineurin inhibitors as dis- cussed in frequently relapsing MCNS (see ‘Frequently relapsing and steroid-​dependent disease’). Glucocorticoid therapy leads to complete remission in 90 to 95% of cases. The time course to a complete remission is generally longer in adults than in children, with 50% responding by 4 weeks and 10 to 25% requiring more than 3 to 4 months of therapy (Fig. 21.8.3.2). In most cases, response to therapy of nephrotic MCNS is of an ‘all or nothing’ type. Partial responses are not characteristic of MCNS and, when seen, one should suspect a possible misdiag- nosis, most often FSGS that was missed by biopsy sampling error. Deciding how long to pursue treatment with high-​dose steroid in the grossly nephrotic patient who is not responding and yet ac- quiring significant side effects is one of the most difficult judge- ments in nephrology. Children Corticosteroid therapy (prednisone or prednisolone) is given ini- tially for at least 8 weeks. Oral prednisone is administered as a single daily dose starting at 60 mg/​m2 per day or 2 mg/​kg per day to a max- imum of 60 mg/​day. The regimen is daily oral prednisone for 4 to 6 weeks followed by alternate-​day medication as a single daily dose starting at 40 mg/​m2 or 1.5 mg/​kg (maximum 40 mg) on alternate days and continued for 4–8 weeks. Children tend to remit rapidly, with 50% responding within 2 weeks and almost all within 8 weeks. Treatment of relapses Approximately 50 to 75% of glucocorticoid-​responsive adults will have a relapse. The same initial dose and duration of corticosteroids as previously described is generally used for infrequent relapses. However, in certain circumstances, such as if there is a viral or al- lergic trigger for the relapse, a shorter course of prednisolone may be sufficient, for example, oral prednisone at a daily dose of 1 mg/​ kg (maximum dose of 80 mg per day) for 4 weeks; if remission is attained, the dose may then be tapered in 5 mg decrements every 3 to 5 days to discontinuation within 1 to 2 months. Frequently relapsing and steroid-​dependent disease In adults, frequent relapses (more than three per year) occur in 10 to 25% of patients with MCNS, and in a further 25 to 30% of patients the prednisolone dose cannot be reduced below 0.2 to 0.3 mg/​kg per day without relapse (steroid dependence). Due to the high morbidity of prolonged courses of glucocorticoids, steroid-​sparing therapy needs to be considered in these groups of patients. There is evidence for and considerable experience with the use of oral cyclophosphamide 2 to 2.5 mg/​kg per day for 8 weeks, which is effective in approximately 75% adults with frequently relapsing or steroid-​dependent disease. However, side effects are potentially serious, including infertility and malignancy, and consideration of alternative agents as first line is reasonable. A calcineurin in- hibitor may be used (ciclosporin 3–​5 mg/​kg per day or tacrolimus 0.05–​0.1 mg/​kg per day in divided doses) for 1 to 2 years for fre- quently relapsing or steroid-​dependent MCNS patients who have relapsed despite cyclophosphamide, or for people who wish to preserve their fertility. Although there is limited evidence to sup- port it, mycophenolate mofetil 500 to 1000 mg twice daily for 1 to 2 years may be effective for patients who are intolerant of cor- ticosteroids, cyclophosphamide, and calcineurin inhibitors, and is suggested in this situation by KDIGO. However, there is no RCT evidence for which a steroid-​sparing agent should be used first in frequently relapsing or steroid-​dependent disease, although mycophenolate mofetil is generally well tolerated, with its main potential side effect being gastrointestinal disturbance. All these agents are also used in paediatric practice, where only one course of cyclophosphamide is given, with a maximum cumulative dose of 168 mg/​kg. Rituximab is an anti-​CD20 monoclonal antibody that has been used for the treatment of various glomerulopathies, including MCNS in adults. It depletes circulating B lymphocytes and thus has a more specific mode of action than glucocorticoids and cyclophosphamide. There are no RCTs assessing the efficacy of rituximab in adult MCNS, but in retrospective series it appears to achieve remission without the need for ongoing immunosuppres- sive therapy with other agents in about half of patients treated. It is generally regarded as a safe and well-​tolerated therapy, but is not completely without complications, with a reported mortality rate across a range of autoimmune disease of about 3% in the 3 years following initiation. Rituximab is also considered in children with steroid-​dependent disease who have continuing frequent relapses despite optimal com- binations of prednisone and corticosteroid-​sparing agents, and/​ or who have serious adverse effects of therapy. A  recent trial of rituximab in frequently relapsing or steroid-​dependent disease (in patients who had tried other second-​line treatments) suggests a me- dian relapse time of 267 days in the rituximab group versus 101 days in a placebo group. There is evidence that recovery of B-​cell counts (monitored by CD19/​20 levels in peripheral blood) coincides with relapse risk, so repeated doses of rituximab may be needed to main- tain adequate protection. Another agent used in paediatric practice is levamisole, an immunostimulant, which can be given as a corticosteroid-​sparing agent to prevent frequency of relapses. It is used at a dose of 2.5 mg/​kg on alternate days, given for at least 12 months as most chil- dren will relapse when levamisole is stopped. There is very limited published experience of levamisole in adults; hence, this treatment should be reserved to paediatric nephrology units with expertise in its use. The long-​term benefits and risks of treatment with this agent are largely unknown.

21.8.3  Minimal-change nephropathy and focal segmental glomerulosclerosis 4923 Steroid refractory MCNS Steroid refractory MCNS is defined as no reduction in proteinuria despite more than 16 weeks of high-​dose glucocorticoid therapy and occurs in 5 to 10% of adults with MCNS. It may be due to initial inadequate glucocorticoid therapy (e.g. for <16 weeks), the use of prescribed or over-​the-​counter aluminium-​containing antacids that can decrease the bioavailability of the glucocorticoid, or an incorrect diagnosis, most often FSGS. This may result from sampling error, particularly if the kidney biopsy comprises few glomeruli and only superficial cortical tufts. Reassessment of the original biopsy, or a repeat biopsy, may be helpful from a prognostic perspective. The re- commended treatment based on one small study in these patients is ciclosporin (5 mg/​kg per day in two divided doses) with prednisone (10–​15 mg/​day). This approach could be used even if a repeat biopsy showed FSGS, hence such a biopsy is not mandatory. Prognosis Historically, morbidity and mortality from untreated MCNS was high due to complications such as infection and thromboembolic disease. However, patients did spontaneously remit, possibly as many as 70% by 3  years. With glucocorticoids, remission rates rise to 90 to 95%, although as many as three-​quarters may relapse. Most relapses occur within 1 year after glucocorticoid therapy has been tapered or discontinued, although occasional patients have a glucocorticoid-​responsive relapse after as long as 25 years in remis- sion. Renal function remains well preserved. Although the glom- erular filtration rate (GFR) may fall during a relapse, it will generally return to within normal limits once remission is achieved. A pro- gressive fall in GFR would be regarded by most nephrologists as an indication that the diagnosis of MCNS is incorrect and that some other glomerular pathology, most likely FSGS, is present. Up to 80% of children presenting with nephrotic syndrome will re- spond initially to steroids, and approximately a third of those will have no further relapses. Of the rest, 10 to 20% will have only a few relapses, but the rest will have frequently relapsing or steroid-​dependent disease. Data regarding how many children will continue to relapse into adult- hood are sparse, with some studies suggesting up to 42% will do so. Focal segmental glomerulosclerosis Aetiology and pathogenesis FSGS can be split into primary (idiopathic) and secondary forms. The primary forms are divided into those caused by a Mendelian monogenic gene disorder (Table 21.8.3.2), and idiopathic cases, some of which are likely to be due to as yet undiscovered genetic mutations, and most if not all of the rest due to unidentified circu- lating factor(s), so-​called circulating factor disease. The definitive clinical evidence of a circulating factor in some (if not all) patients with primary FSGS is the phenomenon of post-​ transplant recurrence of nephrotic syndrome, which affects 30 to 40% of patients with this condition, often within minutes or hours of transplant. Other evidence comes from fascinating cases of mother-​ to-​child transfer of proteinuric disease, also a case report of recur- rence in a graft in an FSGS recipient, where the transplanted kidney was then removed and donated to a non-​FSGS recipient, and fully recovered function without proteinuria. One potential candidate for this circulating factor is the soluble urokinase-type plasminogen activator receptor (suPAR). This re- ceptor acts via activation of podocyte αVβ3 integrin, which plays an important role both in the dynamic regulation of mature foot processes and their controlled adhesion to the glomerular base- ment membrane. Certain forms of suPAR can induce FSGS lesions in mice. In some patients with recurrent FSGS, plasmapheresis in- duced clinical remission and decreased both serum suPAR levels and β3 integrin activity. In another study, suPAR was significantly elevated in sera from patients with FSGS compared both with normal controls and with patients with other proteinuric glom- erular disease, and the highest serum suPAR levels were detected in pretransplant sera of patients who developed recurrent FSGS after transplantation. However, suPAR levels rise with falling GFR and are high in patients with stage 5 chronic kidney disease, which may explain why some studies using suPAR have failed to show an association with FSGS. Three large cohorts with a combined total of 1151 patients found that suPAR levels did not discrim- inate between primary FSGS and other causes of renal disease, the major predictor of suPAR in these studies being the level of kidney function. By contrast, a study that only included patients with es- timated GFR (eGFR) greater than 40 mL/​min per 1.73 m2 found that suPAR levels were significantly higher in patients with FSGS than in patients with membranous nephropathy and minimal-​ change disease, and eGFR was not correlated with levels of suPAR. Measurement of circulating suPAR using the commercially avail- able enzyme-​linked immunosorbent assay should not be used in clinical practice to distinguish primary FSGS from other renal diseases. Secondary FSGS may be caused by a number of systemic disorders in which segmental scarring of glomeruli is the end product of a var- iety of pathological processes (Table 21.8.3.2). Secondary FSGS may also result from an adaptive response to glomerular hyperfiltration (e.g. reduced renal mass such as unilateral renal agenesis), or in- creased renal vasodilatation (e.g. in diabetic nephropathy and sickle cell anaemia). Secondary FSGS is often associated with lower levels of proteinuria, which may not be in the nephrotic range, as well as reduced GFR. Table 21.8.3.2  Aetiology of FSGS Cause Comment Primary Idiopathic ‘Circulating factor disease’ Genetic Mutations in one of at least 60 different genes,
e.g. α-​actinin 4, podocin, nephrin, ion-​receptor protein transient receptor potential cation channel 6 (TRPC6) Secondary Healed glomerulonephritis IgA nephropathy, vasculitis, systemic lupus erythematosus Viral infection HIV, parvovirus B19 Drugs Heroin, pamidronate, lithium Glomerular hyperfiltration (with or without reduced renal mass) Reduced renal mass, reflux nephropathy, renal agenesis, sickle cell anaemia, obesity, diabetes mellitus Parasitic infection Schistosoma mansoni

section 21  Disorders of the kidney and urinary tract 4924 Pathology FSGS is so named because there is focal (i.e. in some areas of the kidney cortex) and segmental (segments of the glomerulus are affected) fibrosis and occlusion of the glomerular capillaries. Different histological features denote different prognoses and steroid responsiveness: the Columbia FSGS classification is shown in Table 21.8.3.3, with an indication of how management may be affected. Several variants are described, based on the site of the seg- mental sclerosing lesion (perihilar variant and glomerular tip le- sion), the presence of glomerular collapse (collapsing variant), and endocapillary cellularity with visceral epithelial cell hyperplasia (cellular variant), leaving ‘FSGS (not otherwise specified)’ when these have been excluded. This latter lesion is equivalent to classic nephrotic-​associated FSGS, when the areas of segmental sclerosis are typically randomly distributed within the glomerular tuft, with a predilection for the hilar regions (Figs. 21.8.3.3 and 21.8.3.4). Focal areas of tubular atrophy and interstitial nephritis are prom- inent. On immunofluorescence microscopy, deposits of IgM and complement C3 may be seen in the sclerotic areas. Electron micros- copy shows diffuse foot process effacement in apparently unaffected glomeruli. Epidemiology In children, FSGS incidence peaks in the 1 to 3 years age range, with a smaller peak in the early teenage years. However, if patients with a genetic cause are studied separately (c.24% of the total), the peak incidence of age at presentation of these is in the first year of life, reflecting the prevalence of severe phenotypes due to genetic mutations. In adult registries in the United Kingdom and the United States of America, FSGS accounts for 10% of the patients in renal failure requiring transplantation. In some parts of the world, including the United States of America, Brazil, and India, the incidence of FSGS is increasing, with a particularly high incidence (up to 80% of biopsies performed for primary glomerulonephritis) in black and Hispanic patients. By contrast, data from a Caucasian population in Northern Europe revealed a relatively low proportion of FSGS, accounting for 6% of all primary glomerulonephritis, with the population in- cidence of FSGS remaining unchanged over the past two decades at 0.18 per 100 000 population/​year. FSGS incidence peaks in middle age, with 30% of cases occurring between the ages of 46 and 55 years. Genetics In paediatric nephrology, genetic analysis is becoming integral to diagnosis and management of FSGS. The discovery of single gene mutations responsible for hereditary FSGS has continued apace since the discovery of mutations in NPHS1, the gene coding for nephrin, in 1998 (Table 21.8.3.4). This transmembrane protein, a putative member of the immunoglobulin super family, appears to be at the heart of the working slit diaphragm and integral to podocyte functioning. Since then over 50 different genes have been identi- fied as causing FSGS when affected by mutations. Many of the pro- teins encoded by these genes function as key components of the slit diaphragm or actin patterning complex (Fig. 21.8.3.5). Some of the mutations affect only the glomerulus, others have broader ef- fects and the nephrotic syndrome appears as part of a wider clinical syndrome. In paediatric practice, next-​generation sequencing has trans- formed the ability to make the diagnosis of genetic disorders in this patient group, and clinical sequencing services are now available (e.g. http://​www.nbt.nhs.uk/​severn-​pathology/​pathology-​services/​ bristol-​genetics-​laboratory-​bgl). A genetic diagnosis is clearly im- portant for counselling and prognostic implications, but also for im- mediate management decisions. Results are available within a few weeks, and the rate of mutations in childhood (0–​18 years) is >30%, meaning that there is a significant chance of picking up a positive result and therefore modifying therapy because the vast majority of patients with a genetic cause of nephrotic syndrome do not respond to any kind of immunosuppression. In contrast to children with FSGS, adults with nonfamilial FSGS are far less likely to have an identifiable monogenic cause of disease, Table 21.8.3.3  Idiopathic FSGS, classification and treatment Variant, based on site of segmental sclerosing lesion Treatment FSGS, not otherwise specified Steroids if nephrotic, ACE inhibitors Perihilar variant ACE inhibitors Cellular variant Steroids if nephrotic, ACE inhibitors Glomerular tip lesion Steroids if nephrotic, ACE inhibitors Collapsing variant ACE inhibitors Fig. 21.8.3.3  Classic segmental sclerosing glomerulonephritis at an early stage. The glomerulus shows an erratic increase in mesangium with a segmental area of foamy cells and sclerosis opposite the vascular pole, next to the tubular origin (between 12 and 1 o’clock). Haematoxylin and eosin staining, magnification ×50. By courtesy of Professor A.J. Howie. Fig. 21.8.3.4  Classic segmental sclerosing glomerulonephritis at a late stage. Four glomeruli show an erratic increase in mesangium and segmental lesions at various sites. Periodic acid–​methenamine silver staining, magnification ×64. By courtesy of Professor A.J. Howie.

21.8.3  Minimal-change nephropathy and focal segmental glomerulosclerosis 4925 Table 21.8.3.4  List of genes associated with the nephrotic syndrome Gene Inheritance Accession # Disease ACTN4 AD NM_​004924 Familial and sporadic SRNS (usually adult) ADCK4 AR NM_​024876 SRNS ALG1 AR NM_​019109 Congenital disorder of glycosylation ANLN AD NM_​018685 FSGS (mainly adult) ARHGAP24 AD NM_​001025616 FSGS ARHGDIA AR NM_​001185078 Congenital nephrotic syndrome CD151 AR NM_​004357 NS, pretibial bullous skin lesions, neurosensory deafness, bilateral lacrimal duct stenosis, nail dystrophy, and thalassemia minor CD2AP ADAR NM_​012120 FSGS/​SRNS COL4A3 AR NM_​000091 Alport’s disease COL4A4 AR NM_​000092 Alport’s disease COL4A5 X-​linked AR NM_​000495 Alport’s disease COQ2 AR NM_​015697 Mitochondrial disease/​isolated nephropathy COQ6 AR NM_​182476 NS ± sensorineural deafness; DMS CRB2 AR NM_​173689 SRNS CUBN AR NM_​001081 Intermittent nephrotic range proteinuria ± epilepsia DGKE AR NM_​003647 Haemolytic uraemic syndrome + SRNS E2F3 AD NM_​001949 FSGS + intellectual disability (whole gene deletion) EMP2 AR NM_​001424 Childhood-​onset SRNS and SSNS INF2 AD NM_​022489 Familial and sporadic SRNS, FSGS-​associated Charcot–​Marie–​Tooth neuropathy ITGA3 AR NM_​005501 Congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa ITGB4 AR NM_​000213 Epidermolysis bullosa and pyloric atresia + FSGS KANK1 AR NM_​015158 SSNS KANK2 AR NM_​015393 SSNS/​SDNS ± haematuria KANK4 AR NM_​0181712 SRNS + haematuria LAMB2 AR NM_​002292 Pierson syndrome LMNA AD NM_​170707 Familial partial lipodystrophy + FSGS LMX1B AD NM_​002316 Nail patella syndrome; also FSGS without extrarenal involvement MYO1E AR NM_​004998 Familial SRNS NPHS1 AR NM_​004646 Congenital nephrotic syndrome/​SRNS NPHS2 AR NM_​014625 CNS, SRNS NXF5 X-​linked recessive NM_​032946 FSGS with cosegregating heart block disorder OCRL X-​linked recessive NM_​000276 Dent’s disease 2, Lowe’s syndrome, ± FSGS, ± nephrotic range proteinuria PAX2 AD NM_​003987 Adult-​onset FSGS without extrarenal manifestations PDSS2 AR NM_​020381 Leigh syndrome PLCe1 AR NM_​016341 Congenital nephrotic syndrome/​SRNS PMM2 AR NM_​000303 Congenital disorder of glycosylation PODXL AD NM_​005397 FSGS PTPRO AR NM_​030667 NS SCARB2 AR NM_​005506 Action myoclonus renal failure syndrome ± hearing loss SMARCAL1 AR NM_​014140 Schimke’s immuno-​osseous dysplasia SYNPO AD NM_​007286 Sporadic FSGS (promoter mutations) TRPC6 AD NM_​004621 Familial and sporadic SRNS (mainly adult) TTC21B AR NM_​024753 FSGS with tubulointerstitial involvement WDR73 AR NM_​032856 Galloway–​Mowat syndrome (microcephaly and SRNS) WT1 AD NM_​024426 Sporadic SRNS (children—​may be associated with abnormal genitalia); Denys–​Drash and Frasier’s syndromes

section 21  Disorders of the kidney and urinary tract 4926 although it is estimated that 6 to 10% of adults with primary FSGS have a currently discoverable genetic mutation, rising to at least 17% in those with a positive family history. Currently, genetic screening is not considered cost-​effective in adults, but this may change as the cost of sequencing continues to fall. In adults, the genetic contribution to FSGS susceptibility, both pri- mary and secondary, may be polygenic, with the incidence of FSGS increased in family members of patients with FSGS without mono- genic inheritance patterns. Much of the increased (four-​ to fivefold) risk of FSGS seen in African American compared with Caucasian patients has been attributed to a risk allele in the gene encoding apolipoprotein L1 (APOL1), which also contributes to the increased risk of developing HIVAN, diabetic nephropathy, and hypertension-​ associated arterionephrosclerosis. Clinical features See Chapter 21.3. Treatment General approach FSGS patients without the nephrotic syndrome who have normal kidney function typically have indolent disease that either spontan- eously remits or remains stable for years. Patients without nephrotic syndrome who have decreased GFR may have secondary FSGS or else previously severe primary FSGS that went undiagnosed; such patients respond poorly to immunosuppressive therapies. ACE in- hibitors/​ARBs to reduce proteinuria and reduce the rate of decline of renal function are indicated, as well as close attention to blood pres- sure control. In nephrotic FSGS patients, supportive treatment with salt restriction and diuretics is required as for MCNS. Immunosuppression—​initial strategy Corticosteroid and immunosuppressive therapy should be con- sidered only in idiopathic FSGS associated with clinical features of the nephrotic syndrome. Studies have reported spontaneous remis- sion in 5 to 25% of patients, particularly in patients with tip lesions, well-​preserved renal function, and lower grades of proteinuria. In such patients, immunosuppression could be delayed in case spon- taneous remission occurs. Given the lack of an evidence base, there is debate about the optimal glucocorticoid regimen in FSGS: KDIGO recommends that, when appropriate, glucocorticoid treatment is initiated and tapered as in MCNS (see earlier discussion). Data from retrospective studies show response rates for complete remis- sion ranging from 28 to 74%, and partial remission rates from 0 to 50%. The average time to complete remission is 3 to 4 months, with a range up to 8 months. As in MCNS, calcineurin inhibitors should be considered as first-​line therapy for patients with relative contraindi- cations or intolerance to high-​dose glucocorticoids. Steroid-​dependent or steroid-​resistant disease For steroid-​resistant FSGS (defined as per steroid-​refractory MCNS described previously), RCT evidence supports initial treatment with ciclosporin at 3 to 5 mg/​kg per day in divided doses for at least 4 to 6 months. If there is a partial or complete remission, this is con- tinued for at least 12 months, followed by a slow taper. Response rates are 60 to 70%, but relapse rates also high at approximately 60%. Tacrolimus may be an acceptable alternative in patients who do not tolerate ciclosporin, but there are no RCTs. Calcineurin inhibitors Gene Inheritance Accession # Disease ZMPSTE24 AR NM_​005857 Mandibuloacral dysplasia with FSGS MYH9 AD/​assoc. NM_​002473 MYH9-​related disease; Epstein’s and Fechtner’s syndromes APOL1 Risk factor variants NM_​003661 Increased susceptibility to FSGS and ESRD seen mostly in African Americans, Hispanic Americans, and in individuals of African descent NUP107 AR NM_​020401 Early-​onset SRNS AD, autosomal dominant; AR, autosomal recessive; ESRD, endstage renal disease; MYH, myosin heavy chain 9; NS, nephrotic syndrome; SRNS, steroid-​resistant nephrotic syndrome; SSNS, steroid-​sensitive nephrotic syndrome. Fig. 21.8.3.5  A schematic of the locations in the podocyte that proteins encoded by nephrotic syndrome genes are expressed. GBM, glomerular basement membrane; SD, slit diaphragm. Reproduced with permission from Malaga-​Dieguez and Susztak. J Clin Invest. 2013 Dec 2; 123(12):4996–​9. Copyright © 2013 American Society for Clinical Investigation. Table 21.8.3.4  Continued

21.8.3  Minimal-change nephropathy and focal segmental glomerulosclerosis 4927 carry a risk of nephrotoxicity, particularly in patients with a reduced GFR, hence many clinicians would not use a calcineurin inhibitor in patients with an eGFR less than 30 to 40 ml/​min per 1.73 m2. Patients with steroid-​resistant FSGS who do not tolerate ciclosporin can be treated with a combination of mycophenolate mofetil and glucocorticoids. In addition, cyclophosphamide may be considered in patients who have shown a partial response to prednisone and have an eGFR less than 30 to 40 ml/​min per 1.73 m2. If used, cyclophosphamide is added before the prednisone has been discontinued and is administered for 8 to 12 weeks. More prolonged therapy (>12 weeks) is not beneficial. Several case re- ports have described successful use of rituximab in adult patients with steroid-​dependent but not steroid-​resistant FSGS; the efficacy of this therapy appears limited to patients with steroid-​dependent disease. Patients with FSGS and persistent proteinuria are at increased risk of progressive CKD and its accompanying cardiovascular morbidity and mortality. Risks are dependent on the level of proteinuria and kidney function. The potential benefit of therapy includes disease cure, control, and/​or slowing the progression to endstage renal disease. However, the toxicity of the therapies previously outlined is significant, par- ticularly given the prolonged nature of the treatment and the risk of relapse. In addition, some patients, possibly as many as 50%, will not respond to immunosuppression, but can accrue a significant mor- bidity as a result of prolonged attempts with various treatments. It is questionable whether the benefits of immunosuppression outweigh the risks in those patients who have significantly impaired renal function (eGFR <30 ml/​min per 1.73 m2) and histological evidence of extensive glomerulosclerosis and interstitial fibrosis. In addition, for those patients in whom the disease has proved refractory to multiple prolonged courses of immunosuppression, the persistent nephrosis together with treatment side effects can result in multiple hospital admissions for complications including infection, excessive oedema, and thromboembolic disease. Occasionally, the patient and clinician together may take the decision to allow or even encourage renal failure as the disease burden of the resultant renal replacement therapy may be less than that of ongoing nephrosis. In exceptional cases, nephrectomy may be performed. Paediatric perspective In children with FSGS without a genetic cause, or where results are awaited, a calcineurin inhibitor is used as initial therapy as per adult therapy. As in adult practice, concurrent treatment with ACE inhibi- tors or ARBs should be instituted for children with FSGS. In children who fail to achieve complete or partial remission with calcineurin inhibitor therapy, mycophenolate mofetil, high-​dose corticoster- oids, or a combination of these agents is considered. There is evidence that cyclophosphamide is not beneficial in chil- dren with FSGS, although it should be remembered that those trials were done before any genetic testing was available, so stratification of patients into those who have a disease that mechanistically bene- fits may still be possible. A RCT found that rituximab was not bene- ficial in childhood FSGS but the same caveats apply. Prognosis In most cases of idiopathic FSGS, the progress of the disease is pro- longed and characterized by a relapsing–​remitting pattern, with even complete remitters having a relapse rate of up to 40%. Those with partial remissions have a risk of slowly progressive loss of kidney function. Prognosis in patients with idiopathic FSGS is predicted by the se- verity and persistence of proteinuria. Patients with non-​nephrotic proteinuria have a good prognosis, with kidney survival rates of more than 95% after a mean follow-​up of 6.5 to 9.3 years, even in older studies when few patients, if any, were treated with ACE in- hibitors. A recent study concluded that even partial remission (re- duction to non-​nephrotic range proteinuria) was associated with significant improvement in kidney survival (80 vs 40%) compared to no remission. Prognosis of nephrotic FSGS is far worse: in a retrospective ana- lysis of 197 patients with biopsy-​proven nephrotic FSGS, at a median follow-​up of 1.8 years, 23% were on dialysis. Prognosis and treat- ment response were predicted by histological subtype. The 17% with the tip lesion had the least tubulointerstitial injury and best renal function, and almost 50% achieved complete remission with gluco- corticoid therapy. The 11% of patients with the collapsing variant had the worst outcomes, with lower rates of renal survival at both 1 year (74% vs 86% for the remaining patients) and 3 years (33% vs 67%). Treatment response also predicts survival: patients who achieve a complete remission have a 5-​year survival off dialysis of 94%, as compared with 53% of those who do not achieve remission. In children with FSGS, up to 50% will reach established renal failure within 5 years. Following progression to endstage kidney disease, patients are assessed for renal transplantation, although this carries a risk of re- current disease. As already described, a remarkable phenomenon in FSGS is that of recurrence of massive proteinuria after transplant- ation, sometimes within minutes or hours of the graft being placed. The reported recurrence rate in adults is 30%, and this leads to graft failure in approximately 50% of cases. After recurrence in a first trans- plant, the rate of recurrence in a subsequent transplant approaches 75%. Plasma exchange and protein immunoadsorption have re- sulted in a reduction of proteinuria or a remission of the nephrotic syndrome in some patients. In children, recurrence occurs in 50% who test negative for currently known genetic mutations. Children at highest risk are those with steroid sensitivity early in the course of disease, followed by resistance to steroids with eventual renal failure, where there is a 90% risk of post-​transplantation recurrence. Future developments The podocyte is the target cell of nephrotic syndrome and is dam- aged by either inherent insults (genetic mutations) or external in- sults, most prominently by circulating factor(s) in this disease. Much has been learnt about important cellular pathways in the podocyte that are disrupted in disease states, most involving slit diaphragm-​ based signalling. As our understanding increases, this will allow much better stratification of disease according to mechanism-​ based understanding of the pathogenesis. For example, Mendelian monogenic disease can already be identified and treated differently, and the prospect of gene therapy based on constructs that utilize podocyte-​specific promoters for targeting is realistic. As our know- ledge of podocyte (or immune-​related) biomarkers advances, we will be able to stratify nongenetic nephrotic syndrome into groups that will respond to targeted biological therapies that specifically af- fect those pathways.

21.8.4 Membranous nephropathy 4928 An S. De Vriese

21.8.4 Membranous nephropathy 4928 An S. De Vriese and Fernando C. Fervenza

section 21  Disorders of the kidney and urinary tract 4928 FURTHER READING Braun N, et al. (2008). Immunosuppressive treatment for focal seg- mental glomerulosclerosis in adults. Cochrane Database Syst Rev, 3, CD003233. Brown EJ, Pollak MR, Barua M (2014). Genetic testing for nephrotic syndrome and FSGS in the era of next-​generation sequencing. Kidney Int, 85, 1030–​8. Iijima K, et al. (2014). Rituximab for childhood-​onset, complicated, frequently relapsing nephrotic syndrome or steroid-​dependent nephrotic syndrome:  a multicentre, double-​blind, randomised, placebo-​controlled trial. Lancet, 384, 1273–​81. Jalanko H (2009). Congenital nephrotic syndrome. Pediatr Nephrol, 24, 2121–​8. Kidney Disease:  Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group (2012). KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int, 2 Suppl 2, 139–​274. Korbet SM (2012). Treatment of primary FSGS in adults. J Am Soc Nephrol, 23, 1769–​76. Maas RJ, Deegens JK, Wetzels JF (2014). Permeability factors in idio- pathic nephrotic syndrome: historical perspectives and lessons for the future. Nephrol Dial Transplant, 29, 2207–​16. McCarthy HJ, Saleem MA (2011). Genetics in clinical practice: neph- rotic and proteinuric syndromes. Nephron Exp Nephrol, 118, e1–​8. Shaloub (1974). Pathogenesis of lipid nephrosis: a disorder of T-​cell function. Lancet, 2, 556–​60. Siligato R, et al. (2018). Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis. Expert Opin Investig Drugs, 27, 839–79. Stokes MB, et al. (2004). Glomerular tip lesion: a distinct entity within the minimal change disease/​focal segmental glomerulosclerosis spectrum. Kidney Int, 65, 1690–​702. Zheng Q, et al. (2019). Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with neph- rotic syndrome: a systematic review and network meta-analysis. BMJ Open, 9(9), e030919. doi: 10.1136/bmjopen-2019-030919. 21.8.4  Membranous nephropathy An S. De Vriese and Fernando C. Fervenza ESSENTIALS Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasians adults. It may also present with asymptomatic proteinuria. Its defining feature is the presence of subepithelial immune deposits, localized between the podocyte and the glomerular basement membrane. Aetiology—​primary MN (80% of cases) is caused in most cases by antibodies against the M-​type phospholipase A2 receptor (PLA2R). Secondary MN occurs in relation with drugs, malignancy, or auto- immune disease. Prognosis—​the clinical course of primary MN is variable: spontan- eous complete remission of proteinuria occurs in 20 to 30% and progressive kidney failure develops in 20 to 40% over 5 to 15 years. Patients with gross proteinuria (>8 g/​day) are at high risk of progres- sion, as are those with a high and rising anti-​PLA2R antibody level. Management—​patients at low risk of progression have an excellent long-​term prognosis and should be treated conservatively without immunosuppression. Patients at medium and high risk for progres- sion benefit from immunosuppression in addition to conservative treatment. Standard treatment regimens include corticosteroids with cyclophosphamide, calcineurin inhibitors (ciclosporin, tacrolimus) and rituximab. Introduction Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasians adults. The defining feature is the presence of subepithelial immune deposits, localized between the podocyte and the glomerular basement membrane (GBM). These deposits and the subsequent formation of basement membrane ma- terial between and around them result in the thickened appearance of the GBM, hence the term ‘membranous’. Due to their localization on the subepithelial side of the GBM, the deposits do not result in in- filtration by inflammatory cells and subsequent glomerular inflam- mation. Thus, the term ‘nephropathy’ or ‘glomerulopathy’, rather than ‘glomerulonephritis’, is preferred. Primary MN, responsible for approximately 80% of cases, is an organ-specific autoimmune disease, in which circulating auto- antibodies bind to an autoantigen on the surface of the podocytes. Three major target antigens are now recognized: the M-type phospholipase A2 receptor 1 (PLA2R), the thrombospondin type 1 domain-containing 7A (THSD7A) and exostosin 1 (EXT1)/exostosin 2 (EXT2). Future research may reveal other—​as yet unknown—​ autoantibodies against components of the GBM in patients with MN. In approximately 20% of cases, MN occurs in relation with drugs, malignancy, or autoimmune disease, and the disease is categorized as secondary. Aetiology Primary membranous nephropathy The understanding of the autoimmune processes involved in primary MN has advanced substantially over the past few years. First was the discovery of antibodies against neutral endopeptidase (NEP) in rare cases of neonatal MN. Mothers with truncating mutations of the metallomembrane endopeptidase gene do not express NEP on cell membranes. NEP-​deficient mothers, who were immunized during pregnancy, transplacentally transfer nephritogenic antibodies against NEP to their children, causing MN in the newborns. Subsequently, antibodies to the PLA2R were found in 70 to 80% of patients with MN. The PLA2R is a member of the mannose receptor family. It was cloned based on its ability to bind secreted phospholipase A2 mol- ecules, but its exact cellular function is not fully understood. With the exception of Japanese patients who have a lower prevalence of PLA2R-​associated MN, the prevalence of these antibodies is con- sistent among ethnic patient populations around the world. More recently, 10% of the patients who are seronegative for anti-​PLA2R were found to have antibodies directed to the thrombospondin type-​1 domain-​containing 7A (THSD7A) protein. THSD7A is a transmem- brane protein expressed in many organs, including the kidney. Most recently, EXT1 and EXT2 were identified as target antigens in MN.

21.8.4  Membranous nephropathy 4929 Exostosins are glycosyltransferases responsible for the synthesis of the heparin sulfate backbone that add glycosaminoglycan residues to the core protein resulting in the generation of complex polysaccharides. The remaining 20% of cases may have disease caused by antibodies not yet identified or have secondary MN. Secondary membranous nephropathy The most frequent causes of secondary MN are listed in Table 21.8.4.1. A few cases of MN secondary to high levels of cir- culating antibovine serum albumin antibodies have been reported in children. In some geographic areas, infection is an important cause of secondary MN: malaria in Africa or hepatitis B in Asia. In older patients, solid tumours are the most common cause of sec- ondary MN. In some reports, there is a lag of months and some- times years from the time of the diagnosis of MN and detection of a tumour. Differentiating between primary MN and MN secondary to underlying malignancy is crucial because treatment approaches differ. Positive anti-​PLA2R antibodies have been reported in a few patients with MN associated with solid tumours, but resection of the tumour was not accompanied by remission of proteinuria, sug- gesting that the association of malignancy and MN was coincidental rather than causative. A  negative test for anti-​PLA2R antibodies emerged as the most important predictor of malignancy. Pathology In early MN, the glomeruli appear normal by light micros- copy. Increasing size and number of immune complexes in the subepithelial space produce thickening of the capillary walls. With time, new basement membrane is formed around the immune complexes. This produces the spikes and pinholes along the epithe- lial side of the GBM visible on the silver methenamine and peri- odic acid–​Schiff stains, as the deposits themselves do not stain (Fig. 21.8.4.1). In primary MN, proliferative features, including mesangial proliferation and endocapillary proliferation, are typically absent. Immunofluorescence microscopy shows diffuse and global bright granular (beaded) capillary wall staining for IgG, C3, kappa light chains, and lambda light chains, with negative staining for IgM, IgA, and C1q (Fig. 21.8.4.1). In some cases, the granular staining can be so dense that it may resemble a linear pattern. Staining for IgG sub- classes reveals predominance of IgG1 and IgG4. Electron microscopy shows numerous subepithelial deposits typically separated from each other by GBM material (Fig. 21.8.4.1). In primary MN, subendothelial deposits and mesangial deposits are not present, and the mesangium is usually unremarkable. Most cases of MN with active disease show extensive foot processes effacement. Some pathological features are strongly suggestive of a secondary cause of MN (Table 21.8.4.2). In MN caused by anti-​PLA2R antibodies, glomeruli may stain for PLA2R, in tight correlation with the presence of serum anti-​ PLA2R antibodies (Fig. 21.8.4.2). Some patients who are seronega- tive for anti-​PLA2R antibodies at the time of kidney biopsy show glomerular PLA2R positivity. Many of these cases may represent PLA2R-​associated disease that has already gone into immunological remission, leaving a historical clue to the immunological activity. A few seronegative, tissue-​positive cases may reflect very early dis- ease, with rapid clearance of the antibodies from the circulation and deposition in glomeruli due to the very high affinity between the anti-​PLA2R autoantibody and the abundant podocyte antigen. Clinical features Most patients with MN present with nephrotic syndrome, the re- mainder with asymptomatic proteinuria (usually <3.5 g/​24 h), com- monly found on a routine medical examination. At presentation, most are normotensive and have normal kidney function. The urine sedi- ment is generally bland, but microscopic haematuria is present in 30 to 40% of cases. The clinical features associated with nephrotic syndrome in MN can be severe, and ascites, pleural effusions, and pericardial ef- fusions may be present. Hyperlipidaemia, characterized by both an in- crease in total and low-​density lipoprotein cholesterol and a decrease in high-​density lipoprotein cholesterol, is common. Thromboembolic events frequently complicate the nephrotic syndrome in MN. The pre- cise mechanism of the hypercoagulable state in MN is unknown, but likely includes a combination of risk factors, such as a local decrease in perfusion pressure in the renal vein due to the low oncotic pressure, loss of anticlotting factors in the urine, increased hepatic production of clotting factors, as well as a genetic predisposition. Diagnosis The diagnosis of MN is made by kidney biopsy. Further diagnostic steps should be undertaken to differentiate primary from secondary MN. Careful medical history, physical exam, laboratory evaluation, and re- view of histological features are essential to identify potential secondary causes. Evaluation should include a complement profile, assays for antinuclear antibodies, rheumatoid factor, hepatitis B surface antigen and hepatitis C antibody, thyroid antibodies, and cryoglobulins. Testing for anti-​PLA2R and anti-THSD7A antibodies further aids the diag- nostic work-up. Initially, an indirect immunofluorescence test was used that provided semiquantitative titres. Currently, a higher-​throughput enzyme-​linked immunosorbent assay (ELISA) is commercially avail- able for these antibodies and offers a quantitative titre based on reference standards. Anti-EXT1/EXT2 antibodies have not yet been identified. Patients aged older than 60 years should undergo appropriate screening for underlying malignancy. There should be a low threshold for a CT scan of the thorax in patients with risk factors for lung cancer, upper and lower gastrointestinal endoscopy in anyone with abdominal or bowel symptoms of any sort, and mammography in women, particularly in Table 21.8.4.1  Secondary causes of MN Aetiology Examples Neoplasm Carcinomas (especially solid organ tumours of the lung, colon, breast, kidney, stomach, and prostate), Infections Malaria, hepatitis B and C, secondary or congenital syphilis, leprosy, filariasis Drugs Penicillamine, gold, captopril, mercury, nonsteroidal anti-​inflammatory drugs Immunological Systemic lupus erythematosus, mixed connective tissue disease, thyroiditis, dermatitis herpetiformis, rheumatoid arthritis Miscellaneous Sickle cell anaemia; graft-​versus-​host disease, sarcoidosis Bovine serum albumin In children

section 21  Disorders of the kidney and urinary tract 4930 (a) (b) (c) (d) Fig. 21.8.4.1  (a, b) Light microscopy showing thickened glomerular basement with pin holes and spikes ((a) periodic acid Schiff stain, (b) silver methenamine stain; both magnification ×40). (c) Immunofluorescence microscopy showing granular IgG along the capillary walls (magnification ×40). (d) Electron microscopy showing numerous subepithelial deposits (black arrows). Note basement membrane material between the deposits (white arrows) forming the spikes (magnification ×6800). Courtesy of Dr. Sanjeev Sethi, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN. Table 21.8.4.2  Pathological clues to a secondary cause of MN Light microscopy Mesangial or endocapillary proliferation Immunofluorescence microscopy Full-​house pattern of Ig staining (IgG/​ IgA/​IgM) and C1q staining IgG subclass staining IgG1, IgG2, IgG3 → class V lupus nephritis Absence of IgG4 → MN secondary to malignancy. Electron microscopy Electron-​dense deposits located in the subendothelium and/​or mesangium or along the tubular basement membrane and vessel walls, presence of endothelial tubuloreticular inclusions Only few superficially scattered subepithelial deposits → malignancy-​ or drug-​associated MN Fig. 21.8.4.2  Membranous nephropathy showing positive granular staining for PLA2R along the glomerular basement membranes (magnification ×40). Courtesy of Dr. Mariam P. Alexander, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

21.8.4  Membranous nephropathy 4931 patients who test negative for anti-​PLA2R antibodies. In patients with preserved kidney function and no evidence of secondary causes, a posi- tive PLA2R test highly predicts a tissue diagnosis of PLA2R-associated MN. In this subgroup of patients, a renal biopsy may not be necessary to make treatment decisions, especially for patients at high risk of compli- cations or in whom a renal biopsy is contraindicated. Natural history The clinical course of MN is variable. Spontaneous complete remis- sion of proteinuria occurs in 20 to 30% of patients with primary MN. Progressive kidney failure develops in 20 to 40% of cases over 5 to 15 years of observation. In the remaining patients, mild to moderate pro- teinuria persists. A complete remission and a lower relapse rate are more common in patients with persistent low-​grade (subnephrotic) protein- uria and in females. In contrast, male sex, age greater than 50 years, high levels of proteinuria (>10 g/​day), abnormal kidney function at presenta- tion, and tubulointerstitial disease, including focal and segmental lesions on biopsy, have all been associated with a lower renal survival. In a few cases, a rapid change in either the degree of proteinuria or the rate of loss of renal function may occur. This event should raise the suspicion of a superimposed condition, for example, acute renal vein thrombosis, superimposed acute interstitial nephritis, or cres- centic glomerulonephritis (antineutrophil cytoplasmic antibody-​ associated vasculitis or anti-​GBM disease). Anti-​PLA2R levels and disease activity Levels of circulating anti-​PLA2R antibodies correlate with clinical status, that is, the disappearance of the antibody is associated with remission of proteinuria, while reappearance of the antibody may herald a relapse of the nephrotic syndrome. Spontaneous remission is more likely in patients with low or moderate anti-​PLA2R antibody titres, but is rare in patients with high antibody levels. High levels of anti-​PLA2R antibodies are associated with progression of protein- uria and declining kidney function over time. Further, changes in antibody levels precede changes in proteinuria, independent of the type of immunosuppressive treatment. Serial measurement of anti-​ PLA2R antibodies levels may help in monitoring disease activity and response to immunosuppression. Preliminary data show that cyto- toxic agents, calcineurin inhibitors, mycophenolate mofetil (MMF), adrenocorticotropic hormone (ACTH), and rituximab all can induce depletion of circulating anti-​PLA2R antibodies. Finally, patients with high anti-​PLA2R antibody levels are more prone to relapse. Risk prediction and timing of therapy The principal challenge in the treatment of MN is to identify those patients at risk for progression. Until recently, the best prediction of renal outcome was a semiquantitative model using proteinuria and level of kidney func- tion. Patients who present with proteinuria up to 4 g/​24 h and stable kidney function over a 6-​month observation period are classified as being at low risk of progression. Patients with normal kidney function and stable creatinine clearance during a 6-​month observation period, but persistent proteinuria of between 4 and 8 g/​24 h, have a 55% prob- ability of developing chronic kidney injury, and are classified as being at medium risk of progression. Patients with persistent proteinuria greater than 8 g/​24 h, independent of the degree of kidney function, have a 66 to 80% probability of progression to chronic renal failure within 10 years, and are classified as being at high risk of progression. Patients at low risk of progression have an excellent long-​term prog- nosis and should be treated conservatively without immunosuppres- sion. Patients at medium risk and at high risk for progression benefit from immunosuppression in addition to conservative treatment. The commercial availability of an ELISA that quantifies anti-​ PLA2R antibody titres profoundly affects risk prediction in pa- tients with anti-​PLA2R antibody-​positive MN. As discussed earlier, emerging data demonstrate that the titres are commensurate with dis- ease activity, hence the prediction of the renal outcome model based on proteinuria will need to be reconciled with the new information obtained by monitoring of anti-​PL2R antibody titres. For example, a patient with very high anti-​PLA2R antibody levels is unlikely to go into spontaneous remission and should be considered for early im- munosuppressive therapy, even if proteinuria is less than 10 g/​24 h. Treatment Conservative therapy Conservative treatment involves dietary sodium restriction to less than 4 g/​day, moderation of dietary protein intake (0.8 to 1 g/​kg per day), and control of blood pressure, hyperlipidaemia, and oedema, and applies to all patients. Drugs that block the angiotensin II system are preferred because of their antiproteinuric effect beyond that ex- pected by their antihypertensive action. However, the evidence that angiotensin II inhibition is beneficial in MN is weak and largely in- ferential. The degree of renal protection is related to the degree of proteinuria reduction: if proteinuria does not decrease substantially, the beneficial influence is attenuated. In patients with MN, the antiproteinuric effect is modest (<30% decrease) and is more signifi- cant in patients with lower levels of proteinuria. Whereas patients with diabetic nephropathy are generally severely hypertensive and require multiple antihypertensive drugs, patients with MN are usu- ally normotensive, precluding the use of high doses of angiotensin-​ converting enzyme inhibitors/​angiotensin II receptor blockers. Thus, these drugs may not offer the same degree of renal protection in patients with MN as in diabetic nephropathy. In fact, a multi- variate analysis on the use of angiotensin-​converting enzyme in- hibitors/​angiotensin II receptor blockers in MN did not show an independent protective effect. If a significant antiproteinuric re- sponse will occur, it is usually seen within 2 months of initiation of angiotensin II blockade. The aim is to reduce proteinuria as close as possible to less than 0.3 g/​24 h. This goal is unrealistic in patients with proteinuria greater than 5 g/​24 h, even at high drug doses. Hyperlipidaemia increases the risk for cardiovascular disease in patients with nephrotic syndrome and we advocate the use of statins in patients with MN and persistent proteinuria. There is no consensus on when to start prophylactic anticoagulation in patients with MN. A recent study showed that in patients with MN, a serum albumin level less than 28 g/​litre was the most significant independent pre- dictor of venous thromboembolism. A positive familial or personal history of a thrombotic event, prolonged serum albumin levels less

section 21  Disorders of the kidney and urinary tract 4932 than 20 g/​litre, immobilization, and obesity should prompt consid- eration of prophylactic anticoagulation. Immunosuppressive therapy Corticosteroids Corticosteroid monotherapy is ineffective in preventing disease pro- gression and monotherapy with these drugs should not be used in primary MN. Corticosteroids with alkylating agents An initial study by Ponticelli and colleagues evaluated whether a regimen consisting of 1 g of intravenous methylprednisolone on the first 3 days of months 1, 3, and 5, followed by 27 days of oral prednisone at 0.5 mg/​kg, and alternating in months 2, 4, and 6 with chlorambucil at 0.2 mg/​kg per day for 30 days, was beneficial in patients with MN at moderate risk of progression. The prob- ability of achieving complete or partial remission was significantly higher in the group treated with immunosuppression versus con- servative therapy (83 vs 38% respectively). About 40% of conserva- tively treated patients reached endstage renal disease after 10 years, compared with only 8% of patients treated with steroids/​cytotoxic agents. The original regimen appeared remarkably safe and all ad- verse events were reversed after withdrawal of the drugs. In a sub- sequent study, the same regimen but containing cyclophosphamide (2.5 mg/​kg per day) rather than chlorambucil was found to be equally effective, better tolerated, and safer. Cyclophosphamide has become the preferred cytotoxic drug since. The beneficial effects of the studies by Ponticelli and colleagues have been confirmed by an Indian randomized controlled trial on 93 patients. The most frequent side effects of cyclophosphamide are leuko- penia and infection. We recommend that blood cell count should be checked weekly and the dose of cyclophosphamide be stopped if the total white cell count falls below 3000/​mm3. The target is to obtain lymphocyte counts below 700/mm3. Since cyclophosphamide can cause azoospermia and ovarian failure, patients at reproductive age are encouraged to undergo fertility consultation prior to starting therapy (sperm cryopreservation and ovarian protection therapy, e.g. leuprolide acetate). Cyclophosphamide accumulates with age and decreased kidney function and we recommend dose adjustments for age (>60 years, reduce dose by 25%) and serum creatinine (>220 μmol/​L (2.5 mg/​dl) reduce dose by 25%). A main concern with cyto- toxic drugs is the long-​term risk of neoplasia in patients receiving cyclophosphamide when the cumulative dose exceeds 36 g. Corticosteroids with mycophenolate mofetil MMF (2 g/​day for 12  months) combined with intravenous methylprednisolone (1 g the first 3  days of months 1, 3, and 5, followed by alternate-​day prednisone at 0.5 mg/​kg per 48 h for 6 months) may result in response rates similar to steroid therapy for 6 months combined with cyclophosphamide (1.5 mg/​kg per day) for 12 months. However, 75% of the patients treated with MMF relapsed within 2 years of treatment cessation. Monotherapy with MMF ap- pears ineffective in primary MN. Calcineurin inhibitors Therapy with a calcineurin inhibitor, that is, ciclosporin (3.5 to 5 mg/​ kg per day) or tacrolimus (0.05 to 0.1 mg/​kg per day), results in similar rates of remission as combined steroid/​cytotoxic therapy in patients at medium risk of progression. Relapses are common following dis- continuation and treatment should be maintained for at least 1 year. These drugs require monitoring for nephrotoxicity, hypertension, and development of diabetes. A recent multicentre randomized clin- ical trial found that ciclosporin did not prevent decline of kidney function in patients with primary MN and was associated with an excess of side effects as compared to placebo. However, a number of concerns have been raised and the study may have underestimated the efficacy of ciclosporin, one of the criticisms being the surrogate renal endpoint used (i.e. a mere 20% drop in estimated glomerular fil- tration rate). Too many variables, such as lowering of blood pressure, use of diuretics, and change in kidney creatinine handling during nephrotic syndrome, may contribute to slight changes in serum cre- atinine values, as well as the high ciclosporin starting dose of 5 mg/​ kg, which may have induced a sudden drop of estimated glomerular filtration rate and result in treatment failure as per protocol. Adrenocorticotropic hormone The use of ACTH, either under synthetic form (Synacthen, 1 mg subcutaneously twice weekly) or as a natural, highly purified gel for- mulation (H.P. Acthar gel, 80U subcutaneously twice weekly) has demonstrated promising results in primary MN. Rituximab Experimental data suggest that B cells are involved in the pathogen- esis of MN. Rituximab is a chimeric monoclonal antibody that acts through ligation with the membrane receptor CD20 of B cells, and inhibits their activation, proliferation, differentiation, and immuno- globulin secretion. In contrast to cyclophosphamide, which has striking but nonselective effects on B-​cell function, rituximab offers a more targeted approach to B-​cell depletion. In patients with MN and persistent nephrotic syndrome, rituximab given as once-​weekly infusions for 4 weeks of 375 mg/​m2 (the ‘lymphoma’ regimen) significantly decreases proteinuria. The response in proteinuria is gradual and sustained and may extend over a period of 2 years. Total B-​cell counts start to recover at 3 months, which is faster than in patients with other autoimmune nonproteinuric conditions, but there is no correl- ation between rituximab levels, degree of proteinuria, or response to the drug. The ‘rheumatology’ regimen, consisting of 1 g intravenously, given twice 2 weeks apart, was found to be as effective as the regimen with four weekly infusions. Finally, a B-​cell titrated protocol using a single dose of 1 g rituximab was shown to be equally successful as the four-​dose protocol but at a lower cost. Rituximab may also allow withdrawal of calcineurin inhibitors in dependent patients. A recent multicentre randomized con- trolled trial of rituximab versus ciclosporin in patients with severe MN (MENTOR) revealed that rituximab is not inferior to ciclosporin in inducing complete or partial remission of proteinuria and is superior in maintaining long-term remission of proteinuria. In summary, rituximab appears effective in inducing remission of proteinuria in many patients with MN, not only as initial treatment but also in those refractory to other treatments. The few short-​term side effects and assurance of compliance are advantages over more conventional immunosuppressive regimens, although some concerns about the long-​term risks of rare and fatal com- plications such as progressive multifocal leukoencephalopathy remain. Prophylaxis Corticosteroids/​cytotoxic agents and rituximab increase the risk of Pneumocystis jirovecii pneumonia and prophylaxis (usually with

21.8.5 Proliferative glomerulonephritis 4933 Alan

21.8.5 Proliferative glomerulonephritis 4933 Alan D. Salama and Mark A. Little

21.8.5  Proliferative glomerulonephritis 4933 co-​trimoxazole) should be considered in these patients. Routine prophylaxis against gastrointestinal bleeding in patients taking cor- ticosteroids without nonsteroidal anti-​inflammatory drugs is no longer recommended. Adequate measures to prevent corticosteroid-​ induced osteoporosis are advocated. Treatment of secondary membranous nephropathy The therapy of secondary MN consists of removing the offending agent or treating the underlying disease. If this can be done success- fully the clinical manifestations are likely to resolve. Areas of uncertainty, controversy, and future developments The timing of initiation of immunosuppressive therapy in patients with nephrotic syndrome remains a matter of debate. Some advocate a conservative approach, based on the observation that up to 30% of MN patients achieve spontaneous remission of proteinuria, enjoy long-​term renal survival, and, as a consequence, should be spared the risks of immunosuppression. In patients with higher grades of proteinuria at presentation (>10 g/​24 h), however, the chance of spontaneous remission is much lower. One approach has been to start immunosuppression only when progressive loss of kidney func- tion occurs, and studies in this group of patients have been deemed successful because proteinuria and azotaemia decreased. However, careful review of the data shows that reversal of azotaemia is almost always incomplete and often transient, suggesting that the decline in GFR is merely attenuated. In addition, persistence of nephrotic syn- drome may lead to long-​term cardiovascular complications because lipid abnormalities remain uncorrected. Conversely, an early start of treatment has been demonstrated to reduce the risk of loss of renal function, but may expose a number of patients to unnecessary and potentially hazardous treatment. The prognostic value of the anti-​ PLA2R antibody titres may provide a compromise between these diverging approaches. Early treatment should be given to patients with severe nephrotic syndrome (e.g. proteinuria >10 g/​24 h) and high or increasing anti-​PLA2R antibody titres, while conservative therapy is continued in asymptomatic patients, who maintain pro- teinuria at less than 4 g/​24 h and have low or decreasing anti-​PLA2R antibody titres. Patients with severe kidney failure (serum creatinine

265 μmol/​L (3 mg/​dl)) are unlikely to benefit from immunosup- pression therapy, and as such treatment carries a high risk of serious adverse events, they should be managed conservatively. FURTHER READING Beck LH Jr, et al. (2009). M-​type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med, 361, 11–​21. Beck LH Jr, et al. (2011). Rituximab-​induced depletion of anti-​PLA2R autoantibodies predicts response in membranous nephropathy.
J Am Soc Nephrol, 22, 1543–​50. Bobart SA, et al. (2019). Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies. Kidney Int, 95(2), 429–38. Cattran DC, et al. (1997). Validation of a predictive model of idio- pathic membranous nephropathy: its clinical and research implica- tions. Kidney Int, 51, 901–​7. Cattran DC, et al. (2001). Cyclosporine in patients with steroid re- sistant membranous nephropathy: a randomized trial. Kidney Int, 59, 1484–​90. De Vriese AS, et al. (2017). A Proposal for a Serology-Based Approach to Membranous Nephropathy. J Am Soc Nephrol, 28(2), 421–30. Fervenza FC, et al. (2019). Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New Engl J Med, 381, 36–46. Hladunewich MA, et  al. (2009). The natural history of the non-​ nephrotic membranous nephropathy patient. Clin J Am Soc Nephrol, 4, 1417–​22. Howman A, et al. (2013). Immunosuppression for progressive mem- branous nephropathy:  a UK randomised controlled trial. Lancet, 381, 744–​51. Ponticelli C, et al. (1995). A 10-​year follow-​up of a randomized study with methylprednisolone and chlorambucil in membranous neph- ropathy. Kidney Int, 48, 1600–​4. Ruggenenti P, et  al. (2012). Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol, 23, 1416–​25. Sethi S, et al. (2019). Exostosin 1/Exostosin 2-associated Membranous Nephropathy. J Am Soc Nephrol (in press). Tomas NM, et al. (2014). Thrombospondin type-​1 domain-​containing 7A in idiopathic membranous nephropathy. N Engl J Med, 371, 2277–​87. 21.8.5  Proliferative glomerulonephritis Alan D. Salama and Mark A. Little ESSENTIALS Proliferative glomerulonephritis describes the finding of increased cellularity of the glomerulus, which may be due to proliferation of intrinsic glomerular cells, infiltration of leucocytes, or both. This principally occurs in the context of glomerular deposition of im- munoglobulins, immune complexes, or complement components. Different subtypes are described based on histological features: pro- liferation of mesangial cells, endocapillary proliferation, diffuse proliferation, or extracapillary proliferation (also termed crescentic glomerulonephritis). Patients will typically have haematuria, and this may be associated with proteinuria and/​or impairment of excretory renal function and/​or hypertension. The best characterized proliferative glomerulonephritis is post­ streptococcal glomerulonephritis. This most commonly affects children, who present with nephritis about 2 weeks after pharyn- gitis or skin infection caused by streptococci of Lancefield group A. Treatment is directed at eradicating the infection with an appro- priate antimicrobial and providing symptomatic relief. Recovery is the rule, although haematuria and proteinuria may persist. Acknowledgement: the chapter on proliferative glomerulonephritis in the fifth edition of this textbook was written by Professor Peter W. Mathieson. Much of his chapter is retained here.

section 21  Disorders of the kidney and urinary tract 4934 Introduction The term proliferative glomerulonephritis covers a wide variety of conditions (Box 21.8.5.1) where there is increased cellularity within the glomerulus, either due to the proliferation of resident glomerular cells, or infiltration of leucocytes, or both. The proliferative changes may be focal (only affecting some glomeruli) and/​or segmental (only affecting parts of each glomerulus). Many of these entities are considered in other chapters, and only those not covered elsewhere (Box 21.8.5.1) will be described here. Different forms of prolifera- tive glomerulonephritis may coexist, for example, in IgA nephrop- athy with mesangial, endocapillary, and extracapillary proliferation. Mesangial proliferative glomerulonephritis Patients will typically have haematuria and this may be associated with proteinuria and/​or impairment of excretory renal function and/​or hypertension. Most patients whose renal biopsies show only mesangial prolif- eration will have IgA nephropathy (see Chapter 21.8.1), but a few will have no IgA deposits and their classification is not straightfor- ward; possibilities include IgM nephropathy, ‘idiopathic’ mesangial proliferative glomerulonephritis, and C3 glomerulonephritides (see Chapter 21.8.6). IgM nephropathy There is continuing controversy about this diagnostic entity. In pa- tients with nephrotic syndrome, if the only abnormalities on the renal biopsy are in the mesangial region, with proliferation of mesangial cells and deposition of IgM, many authorities would assign a diag- nosis of minimal-​change nephropathy (see Chapter  21.8.3) and advocate treatment with corticosteroids. Some would consider that these morphological features are markers for a poorer prognosis and a reduced likelihood of a response to corticosteroids, but others would consider the patient to have a completely different disease entity and give a diagnosis of IgM nephropathy. Some of this confusion may be explained by methodological fac- tors: assessment of the degree of mesangial hypercellularity is sub- jective, and reagents to detect IgM are notoriously unreliable since they may give high background staining. Mesangial IgM has been found in up to 60% of ‘normal’ kidneys donated for transplantation, and the diagnostic significance of IgM is also cast into doubt by its presence in over 75% of controls as well as in patients with various other forms of glomerulonephritis. However, the presence of signifi- cant electron-​dense deposits on electron microscopy in some cases suggests that the IgM may not be nonspecifically deposited and may be part of a specific pathological process. The best support for the existence of IgM nephropathy as an entity distinct from minimal-​change nephropathy comes from the occur- rence of a familial form; from the identification of this pattern of glomerular injury in patients who, after lengthy follow-​up, have an appreciable risk of developing impaired excretory kidney function; and from a case report in which there was recurrence of IgM neph- ropathy after renal transplantation. Idiopathic mesangial proliferative glomerulonephritis This term may be applied if there is isolated mesangial proliferation without deposition of IgA or IgG, with no evidence of a systemic disorder such as systemic lupus erythematosus. With this patho- logical appearance it is important to exclude the rare entity of fibril- lary glomerulonephritis with electron microscopy. Again there is overlap with minimal-​change nephropathy; if the patient presents with nephrotic syndrome, most nephrologists would not allow the presence of mesangial proliferation to deflect them from treating the patient with corticosteroids, although there is evidence that the presence of this histological finding is associated with a poorer re- sponse rate. If, however, the patient has haematuria and/​or hyper- tension and/​or impaired kidney function, none of which are typical features of minimal-​change nephropathy, it is difficult to resist the need for another separate diagnostic category. Unfortunately, there are no informative studies to guide treatment or give information on prognosis. Glomerulonephritis with C3 deposition Proliferative glomerulonephritis associated with immune deposits restricted to C3, a key component of the complement cascade, is now termed C3 glomerulonephritis and is described in detail in the chapter on membranoproliferative glomerulonephritis (see Chapter 21.8.6). This lesion is associated with mutations in com- plement regulatory genes factor H and/​or factor I, and so almost certainly shares aetiological similarities with other forms of glom- erulonephritis seen in association with such genetic variants, such as haemolytic uraemic syndrome (see Chapter 21.10.6) and mesangiocapillary glomerulonephritis (see Chapter 21.8.6). Familial C3 glomerulonephritis caused by mutation of the comple- ment factor H-​related protein 5 gene (CFHR5) has been described in kindreds usually of Cypriot descent. Mutations in CFHR1–​4 causing C3 glomerulonephritis have recently been described. Affected indi- viduals invariably have nonvisible haematuria, and recurrent (often Box 21.8.5.1  Proliferative glomerulonephritis 1.  Proliferation of mesangial cells

— IgA nephropathy ± IgA vasculitis (HSP) disease

— IgM nephropathya

— Systemic lupus erythematosus

— Idiopathica 2.  Endocapillary proliferation

— Postinfectious glomerulonephritisa

— Infective endocarditis

— Other infections, including leprosy 3.  Extracapillary proliferation (crescent formation)

— Small vessel vasculitides (granulomatosis with polyangiitis/​micro- scopic polyangiitis)

— Antiglomerular basement membrane disease

— IgA vasculitis (HSP) disease

— Systemic lupus erythematosus

— HIV nephropathy (proliferation of podocytes)

— Idiopathic (rare) 4.  Diffuse proliferative glomerulonephritis (may include elements of 1–​3)

— Systemic lupus erythematosus

— Idiopathica a Conditions discussed in this chapter.

21.8.5  Proliferative glomerulonephritis 4935 synpharyngitic) visible haematuria is present in about 50% of pa- tients. Impaired renal function ensues in most affected males, but is much less common in females. Endocapillary proliferative glomerulonephritis Patients will often have impaired excretory function, haematuria, proteinuria, and hypertension, sometimes presenting acutely as a ‘nephritic syndrome’. On renal biopsy, the glomerular hypercellularity is confined within the glomerular capillary tuft, which is probably due to the combination of a proliferation of intrinsic (endothe- lial and mesangial) cells together with an infiltration of inflam- matory cells. This can occur in systemic lupus erythematosus (see Chapter 21.10.3), IgA disease, and as a complication of a variety of infections (see Chapter  21.10.8). Only postinfectious glomerulo- nephritis (PIGN) will be considered here, with the main focus on poststreptococcal glomerulonephritis. Poststreptococcal glomerulonephritis Most infection-​related glomerulonephritis occurs concurrently with the infection. By contrast, PIGN—​of which poststreptococcal glom- erulonephritis is the most frequent and best characterized—​occurs, as the name implies, after the infection. In poststreptococcal glom- erulonephritis the delay between the inciting infection and the onset of the renal complication may be long enough for the infection to have resolved, and this may contribute to diagnostic confusion. The typical case follows infection with streptococci of Lancefield group A (β-​haemolytic streptococci, Streptococcus pyogenes), either causing pharyngitis or skin infection such as cellulitis or impetigo. Children are most commonly affected, although the disease can occur in all age groups, and males more often than females. Poststreptococcal glomerulonephritis is less common in the developed than in the developing world, possibly influenced by socioeconomic factors. Approximately 2 weeks following the infection, sometimes longer after skin infections, the patient develops nephritis which may be suf- ficiently acute and severe to cause a nephritic syndrome with oliguria, hypertension, and oedema. If a renal biopsy is performed, it will show diffuse proliferative glomerulonephritis, with infiltration by neutro- phil polymorphs often particularly prominent (Figs. 21.8.5.1 and 21.8.5.2). Immunohistochemistry shows deposition of IgG, IgM, and complement in the mesangial and subepithelial areas, and electron microscopy shows large subepithelial deposits (‘humps’). Serological tests There are typical serological features which give clues to the patho- genesis, including IgG antibodies to streptococcal antigens and evidence of activation of the complement cascade. Reactivity with numerous streptococcal antigens has been reported, including streptolysin O, deoxyribonuclease B, hyaluronidase, and strepto- kinase. Antistreptolysin O (the ASO test) is the most useful diag- nostic test after pharyngitis; anti-​DNase B is best after skin infections. Hypocomplementaemia (low C3 in most cases, also low C4 in some) reflects activation of both the alternative and the classic pathways (the complement system is discussed in more detail in Chapter 21.8.6). In poststreptococcal glomerulonephritis, the alter- native complement pathway may be activated by bacterial antigens and/​or by IgG autoantibodies called nephritic factors, which re- semble those seen in mesangiocapillary glomerulonephritis; the classic pathway may be activated by circulating immune complexes. Pathogenesis It is believed that the pathogenesis of poststreptococcal glomerulo- nephritis can be explained as follows: streptococcal antigens are de- posited in glomeruli by virtue of some aspect of their charge, size, or other physicochemical characteristics, during the early phase of the infection. After the 10 to 14 days necessary for the host to mount an immune response to the bacterial infection, circulating antibody ap- pears and binds to the ‘planted’ glomerular antigens. Complement is activated, leucocytes are attracted (by complement-​activation prod- ucts C3a and C5a among other chemoattractants), and an inflam- matory reaction is provoked, injuring the glomeruli. The precise nature of the streptococcal antigens that act in this nephritogenic manner remains controversial; only certain sero- logical types of streptococci (referred to as M types and serotyped according to cell wall protein antigens) are capable of inciting Fig. 21.8.5.1  Poststreptococcal glomerulonephritis. The glomerulus shows significant hypercellularity with many neutrophils. Fig. 21.8.5.2  Poststreptococcal glomerulonephritis. The electron micrograph shows three large subepithelial ‘humps’, and a single small subendothelial deposit (arrow). Reproduced with permission from Rodríguez-​Iturbe B, and Haas M. Post-​ streptococcal glomerulonephritis. In: Turner N, Lameire N, Goldsmith DJ, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4936 glomerulonephritis, but the M proteins themselves are not believed to be nephritogenic. In addition to the planted antigen mechanism, streptococci may lead to glomerulonephritis by their other complex effects on the immune response. These include the direct activation of T cells by a superantigen effect, whereby M proteins can bind to particular Vβ regions of the T-​cell receptor and activate families of T cells sharing receptors of this ‘family’. Antigenic cross-​reactivity (‘molecular mimicry’) similar to that thought to be responsible for rheumatic fever may also occur, so that antistreptococcal antibodies cross-​react with, and therefore bind to, renal autoantigens such as laminin and collagen. The immunopathological mechanisms previously outlined may be instructive in understanding other forms of glomerulonephritis where the inciting stimulus is not so evident. Management Treatment of patients with poststreptococcal glomerulonephritis should be directed at eradicating the infection (a 10-​day course of penicillin or erythromycin is advised even if the original infection appears to have resolved) and providing symptomatic relief of the consequences of the acute nephritis, including aggressive treatment of hypertension, which is common but generally transient; salt and water restriction, with or without diuretics, for oedema; and dialysis if necessary (which is uncommon). The prognosis in children is good, but historical series describe early mortality in adults of 25%, mainly due to cardiovascular com- plications. Haematuria, proteinuria, and hypertension may persist. Some authors believe that in the long term there is a risk of chronic renal failure, but this is uncertain: adult communities with a high incidence of poststreptococcal glomerulonephritis (e.g. aboriginal populations) have a high prevalence of other conditions that cause chronic renal failure (e.g. diabetes). Nonstreptococcal postinfectious/​infection-​related proliferative glomerulonephritis It is apparent in modern series of patients with infection-​related glomerulonephritis that similar clinical and histopathological fea- tures occur without evidence of prior streptococcal infections. In one series from France describing 76 adult patients from suburban Paris, including a high proportion of alcoholics and intravenous drug abusers, staphylococci and Gram-​negative organisms were more commonly isolated than streptococci, and a poor renal prog- nosis was reported. The importance of knowledge of local variations in prevalent in- fections or other environmental factors is further emphasized by the description of a novel form of eosinophilic glomerulonephritis in a large series of children from rural Uganda (Fig. 21.8.5.3). The cause of this is not known, but it does not seem to be attributable to streptococcal infection, or to HIV or malaria that are also locally prevalent. Symptomatic treatment allows most children to recover. Various infectious agents have been described in association with PIGN, including viral (rotavirus, parvovirus, influenza), parasitic (plasmodium), and bacterial (borrelia, pneumococcus, klebsiella) agents, with many case reports or cohorts describing additional mi- crobes that have rarely been associated with PIGN. However, there is some dispute whether these should be termed postinfectious or infection related, the former being reserved for glomerulonephritis that arises following a resolved infection. A form of IgA-​rich PIGN has been described recently. This was originally reported in diabetics and older patients, often following a coagulase-​positive staphylococcal infection, frequently a methi- cillin resistant form (MRSA). It may be difficult to differentiate this condition from classical IgA nephropathy, with deposited IgA dominant or codominant with IgG, and in association with C3 deposition. There may be associated crescent formation. Again, this may not be a true postinfectious entity, but rather may relate to ongoing immune complex deposition in the presence of active infection. The basic principles of management of infection-​related glomer- ulonephritis apply, including eradication of the infection if possible, supportive care during the acute phase, and moves towards pre- vention whenever possible by detailed investigation of underlying causes. Idiopathic diffuse proliferative glomerulonephritis A few cases will have no preceding history of infection, no evidence of lupus, and/​or atypical features on the renal biopsy. These may be assigned the unsatisfactory ‘idiopathic’ descriptor, with the implica- tion that the prognosis and the appropriate treatment are uncertain. FURTHER READING Gale DP, et  al. (2010). Identification of a mutation in complement factor H-​related protein 5 in patients of Cypriot origin with glomer- ulonephritis. Lancet, 376, 748–​50. Glassock RJ, et al. (2015). Staphylococcus-​related glomerulonephritis and poststreptococcal glomerulonephritis: why defining ‘post’ is im- portant in understanding and treating infection-​related glomerulo- nephritis. Am J Kidney Dis, 65, 826–​32. Ji-​Yun Y, et  al. (1984). No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome. Kidney Int, 25, 100–​6. Myllymäki J, et al. (2003). IgM nephropathy: clinical picture and long-​ term prognosis. Am J Kidney Dis, 41, 343–​50. Fig. 21.8.5.3  Eosinophilic proliferative glomerulonephritis. Numerous eosinophils (some arrowed) expand the glomerulus.

21.8.6 Membranoproliferative glomerulonephritis 49

21.8.6 Membranoproliferative glomerulonephritis 4937 Tabitha Turner- Stokes and Mark A. Little

21.8.6  Membranoproliferative glomerulonephritis 4937 Oliveira DB (1997). Poststreptococcal glomerulonephritis: getting to know an old enemy. Clin Exp Immunol, 107, 8–​10. Salmon AH, et al. (2004). Recurrence of IgM nephropathy in a renal allograft. Nephrol Dial Transplant, 19, 2650–​2. Scolari F, et al. (1990). Familial IgM nephropathy: a morphologic and immunogenetic study of three pedigrees. Am J Nephrol, 10, 261–​8. Servais A, et al. (2007). Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uremic syndrome. J Med Genet, 44, 193–​9. Walker A, et al. (2007). Eosinophilic glomerulonephritis in children in south western Uganda. Kidney Int, 71, 569–​73. Watanabe-​Ohnishi R, et al. (1994). Characterization of unique human TCR V beta specificities for a family of streptococcal superantigens represented by rheumatogenic serotypes of M protein. J Immunol, 152, 2066–​73. 21.8.6  Membranoproliferative glomerulonephritis Tabitha Turner-​Stokes and Mark A. Little ESSENTIALS The key histological features of membranoproliferative glomer- ulonephritis (MPGN) are mesangial hypercellularity, endocapillary proliferation, and capillary wall remodelling. There are two main types: (1) immune complex-​mediated disease—​caused by chronic infection causing persistent antigenaemia (notably hepatitis C), autoimmune disease, or monoclonal immunoglobulin produc- tion by plasma cell dyscrasia, and a few ‘idiopathic’ cases; and (2)  complement-​mediated disease—​caused by dysregulation of the alternative pathway of complement, including by C3 neph- ritic factor (C3Nef), an autoantibody that stabilizes the alternative pathway C3 convertase. Clinical presentation is varied, including nephrotic syndrome, episodic visible haematuria, hypertension/​rapidly progressive glom- erulonephritis, asymptomatic nonvisible haematuria, and chronic kidney disease. Treatment depends on the underlying disease. All patients should receive appropriate conservative measures (blood pressure control, angiotensin-​converting enzyme inhibitor/​angiotensin II receptor blocker). Underlying infection or monoclonal gammopathy should be treated, when possible, in those with immune complex-​mediated MPGN. Eculizumab may have a role in treatment of some patients with complement-​mediated MPGN. Steroids and cyclophospha- mide or mycophenolate mofetil are used in patients with severe idiopathic MPGN. Introduction Membranoproliferative glomerulonephritis (MPGN) (synonymous with mesangiocapillary glomerulonephritis) describes a particular histopathological appearance of glomerular inflammation on light microscopy that is common to a heterogeneous group of diseases. The key features are: • mesangial hypercellularity • endocapillary proliferation • capillary wall remodelling through duplication of the basement membrane, which traps immune complexes and cellular elements forming double contours Traditionally, MPGN was classified according to the position of glomerular immune deposits relative to the basement membrane, demonstrated on electron microscopy: • MPGN I: subendothelial deposits • MPGN II:  intramembranous electron-​dense transformation of the glomerular basement membrane, pathognomonic for dense deposit disease (DDD) • MPGN III: subendothelial and subepithelial deposits However, this classification did not provide much insight into the pathophysiology of the underlying disease causing glomerular in- flammation. A newer classification system divides MPGN into two main types, based on immunofluorescence microscopy: • Immune complex-​mediated MPGN—​with capillary wall and mesangial deposition of immunoglobulin and C3 on immuno- fluorescence microscopy • Complement-​mediated MPGN, termed C3 glomerulonephritis—​ with capillary wall and mesangial deposition of C3 without immuno­globulin This classification is more practical in the clinical setting as it describes the pathogenetic mechanisms of glomerular inflamma- tion as either immune complex mediated or complement mediated and hence helps guide appropriate further investigations to estab- lish the underlying disease causing MPGN in the individual patient (Fig. 21.8.6.1). Epidemiology MPGN accounts for 7 to 10% of all cases of biopsy-​confirmed glom- erulonephritis and is an important cause of endstage renal failure among the primary glomerulonephritides. MPGN occurs in chil- dren and young adults, although patients of any age may be affected, and there is an equal sex distribution. Pathogenesis Immune complex-​mediated MPGN Immune complex-​mediated MPGN results from circulating im- mune complexes, which are deposited along the glomerular capillary wall, resulting in activation of the classical pathway of complement. This triggers injury in the glomerular capillaries and mesangium, and subsequent recruitment of leucocytes giving rise to the prolif- erative inflammatory glomerular changes seen on light microscopy. Immunoglobulin and complement deposition along the capillary walls can be detected by immunofluorescence microscopy. Circulating immune complexes may be associated with sys- temic autoimmune disease, B-​cell dyscrasias (with monoclonal

section 21  Disorders of the kidney and urinary tract 4938 immunoglobulin production), or chronic antigenaemia associated with persistent viral, bacterial, or parasitic infection (Table 21.8.6.1). Many of these diseases may be associated with cryoglobulinaemia, which is an important cause of MPGN. Although systemic lupus erythematosus is arguably the archetypal autoimmune disease associated with immune complex-​mediated MPGN, rheumatoid arthritis and Sjögren’s syndrome are also common causes. Hepatitis B and C are the most common infectious causes. There is a high incidence of immune complex-​mediated glomerulonephritis, particularly MPGN with cryoglobulinaemia, among patients with chronic hepatitis C viral (HCV) infection. Monoclonal gammopathy is an important cause of MPGN in patients who have no evidence of autoimmune disease or chronic infection. Lymphoproliferative malig- nancies may be the source of monoclonal immunoglobulin in some patients, but the most common cause is monoclonal gammopathy of undetermined significance (MGUS), although, in many cases, no circulating monoclonal immunoglobulin can be found. As MPGN-​ associated MGUS is a significant disease, the term monoclonal gammopathy-​associated MPGN or ‘monoclonal gammopathy of renal significance (MGRS)’ rather than MGUS may be used in these patients. Immunofluorescence studies may point to a specific cause: auto- immune diseases are often associated with deposition of multiple im- munoglobulins along the glomerular capillary wall, including IgG, IgM, IgA, and C1q, along with C3 and kappa and lambda light chains. HCV infection is typically associated with deposition of IgM, IgG, C3, and kappa and lambda light chains. MPGN associated with mono- clonal gammopathy shows kappa or lambda light chain restriction. Complement-​mediated MPGN Complement-​mediated MPGN results from dysregulation of the alternative pathway (AP) of complement. Complement is an im- portant component of the innate immune system and activation within the glomerular vasculature induces inflammation through chemotaxis of leucocytes and cell lysis, resulting from formation of anaphylatoxins and the membrane attack complex respectively. Immunofluorescence microscopy Immune complex-mediated MPGN C3 glomerulonephritis (C3GN) Chronic infection TMA Complement-mediated MPGN MPGN pattern of glomerular inflammation on light microscopy Capillary wall +/– mesangial deposition of lg and C3 Activation of classical complement pathway by circulatiog immune complexes Mesangial, subendothelial +/– subepithelial and intramembranous deposits Mesangial, subendothelial +/– subepithelial and intramembranous deposits Intramembranous electron- dense transformation of GBM Dysregulation of alternative complement pathway Capillary wall +/– mesangial deposition of C3 without lg No glomerular deposition of lg or C3 Monoclonal gammopathy Systemic autoimmune disease Dense Deposit Disease (DDD) Underlying disease Electron microscopy Pathophysiology of glomerular inflammation Classification of MPGN Fig. 21.8.6.1  New classification system for MPGN based on immunofluorescence microscopy. C3, complement factor 3; Ig, immunoglobulin; MPGN, membranoproliferative glomerulonephritis; TMA, thrombotic microangiopathy. Adapted with permission from Sethi et al. (2012). Kidney International, 81, 434–​441. Table 21.8.6.1  Causes of immune complex-​mediated MPGN Mechanism of immune complex formation Disease Chronic infection
causing persistent antigenaemia Viral: Hepatitis C (HCV)a Hepatitis B (HBV) with or without cryoglobulinaemia Bacterial: Endocarditis Shunt infection Abscesses Parasitic: Malaria Schistosomiasis Autoimmune disease Systemic lupus erythematosus Rheumatoid arthritis Sjögren’s syndrome Mixed cryoglobulinaemia Monoclonal immunoglobulin production by plasma
cell dyscrasia Monoclonal gammopathy of undetermined significance (MGUS) Myeloma Lymphoma Chronic lymphocytic leukaemia Type I cryoglobulinaemia Unidentified Primary (idiopathic) MPGNb a The most common cause of immune complex-​mediated MPGN in patient populations where there is high prevalence of chronic HCV infection e.g. Japan. b An uncommon cause of MPGN, and made only after the listed secondary causes have been excluded.

21.8.6  Membranoproliferative glomerulonephritis 4939 Activation of the complement system occurs via three path- ways: the classical, lectin, and alternative pathways, which converge at C3 to generate an enzyme complex (C3 convertase). The AP is continuously active at low levels in the circulation through spon- taneous hydrolysis of soluble C3, generating C3b, which binds to complement factor B to generate the AP C3 convertase (C3bBb) (Fig. 21.8.6.2). This amplifies activation of the AP, generating chemo- tactic anaphylatoxins (C3a and C5a) and the membrane attack com- plex (C5b–​9). In steady state, activation of this pathway is tightly regulated by multiple complement regulatory proteins, which act at different levels of the AP, to avoid overactivation, inappropriate inflammation, and tissue damage. Important regulatory proteins include factor H (CFH), factor I (CFI), factor H-​related proteins 1 to 5 (CFHR1–​5), and cell-​bound membrane cofactor protein, MCP (CD46). Their sites of action are illustrated in Fig. 21.8.6.2. Dysregulation of the AP of complement can occur through autoanti- bodies or genetic mutations that affect the function of these regulatory proteins. This results in glomerular capillary and mesangial deposition of complement components, triggering glomerular inflammation leading to MPGN. Immunofluorescence in this context demonstrates complement deposition without immunoglobulin, distinguishing complement-​mediated from immune complex-​mediated MPGN. Our understanding of the mechanisms by which dysregulation of the AP occurs in complement-​mediated MPGN has advanced greatly over the past few years. Genetic studies in animal models and a few human families with familial nephropathy have demonstrated common underlying genetic defects (Table 21.8.6.2). Many of these mutations affect proteins that regulate the activity of C3 convertase (e.g. CFH, CFI, and CFHR5), leading to overactivity of the AP. Heterozygous mutations in C3 occur in some patients, generating an abnormal C3 convertase, which is resistant to inactivation by CFH. Finally, autoantibodies to these complement regulatory proteins, and to C3 convertase, can re- sult in AP overactivity. In most cases of complement-​mediated MPGN there is no family history. As this disease can develop later in life, it is likely that environmental factors, in addition to underlying defects in complement regulatory proteins, are required to initiate renal injury. The two main types of complement-​mediated MPGN are DDD and C3 glomerulonephritis (C3GN). Electron microscopy enables Anaphylatoxins: CFH mutation CFHR5 mutation FHAA C3Nef FBAA CFI, CFH, MCP mutations & autoantibodies CFH CFB CFD C3 C3b C3b C5 C3d CFI (+ CFH & MCP) C3c iC3b C3bBb (C3 convertase) C3bBbC3b (C5 convertase) C5b-9 (MAC) C5b C6-9 Cell lysis C5a C3a Amplification loop + Spontaneous hydrolysis continuous ‘tick-over’ Recruitment and activation of circulating leukocytes to glomerulus Fig. 21.8.6.2  Regulation of the alternative pathway of complement and mechanisms of dysregulation in C3 glomerulonephritis. C3 undergoes continuous hydrolysis in the circulation to form C3b, which interacts with CFB and is cleaved by CFD to form C3bBb (the AP C3 convertase). C3bBb cleaves C3 into C3b, which either combines with CFB to create additional C3bBb in an amplification loop or combines with C3bBb itself, generating the C5 convertase enzyme complex, C3bBbC3b. C5 convertase cleaves C5 into C5a and C5b, the latter of which triggers formation of the MAC through activation of complement factors 6 to 9 (C6–​9), resulting in cell lysis. C3a and C5a generated by the C3 convertase and C5 convertase enzymes respectively are anaphylatoxins which mediate recruitment and activation of circulating leucocytes to the glomerulus, augmenting glomerular inflammation. As the AP is constitutively active in the circulation, a number of complement regulatory proteins (purple boxes) exist to maintain tight control over activation of this pathway. Autoantibodies to, or genetic mutations affecting the function of these regulatory proteins (green boxes), lead to overactivation of the alternative pathway of complement and glomerular inflammation, resulting in C3 glomerulonephritis. AP, alternative pathway; CFB, complement factor B; CFD, complement factor D; CFH, complement factor H; CFHR5, complement factor H-​related protein 5; CFI, complement factor I; C3Nef, C3 nephritic factor; FBAA, factor B autoantibodies; FHAA, factor H autoantibodies; iC3b, inactivated C3b; MAC, membrane attack complex; MCP, membrane cofactor protein.

section 21  Disorders of the kidney and urinary tract 4940 differentiation between these two diseases: DDD results in a char- acteristic intramembranous electron-​dense transformation of the glomerular basement membrane, whereas C3GN is associated with deposits in the mesangial, subendothelial, subepithelial, and/​ or intramembranous locations (Fig. 21.8.6.3). Most patients with DDD are positive for C3 nephritic factor (C3Nef), an autoantibody that stabilizes the AP C3 convertase (C3bBb), rendering it resistant to degradation by factor H. However, C3Nef has also been found in a significant proportion of patients with C3GN and so is not a specific marker for DDD. All patients with a detectable C3Nef have marked C3 hypocomplementemia. The differences in the AP dysregulation that lead to divergent patterns of glomerular injury in DDD and C3GN are not understood. A rare variant associated with depos- ition of C4 rather than C3 due to over-activity of the lectin binding pathway (C4 glomerulonephritis) has recently been described. Both DDD and C3GN are encompassed by the term C3 glom- erulonephritis, which describes glomerular inflammation associated with dysregulation of the AP of complement. This term also applies to non-​MPGN glomerular pathologies including mesangioproliferative, endocapillary proliferative, and crescentic glomerulonephritis. C3 glomerulonephritis therefore encompasses a spectrum of disease that is dependent on the level and degree of dysregulation of the AP. Patients with DDD may have associated partial lipodystrophy and/​or retinal deposits within Bruch’s membrane that have a histo- pathological appearance very similar to the glomerular basement membrane deposits. Partial lipodystrophy is thought to result from the deposition of activated complement components in adi- pose tissues, leading to the destruction of adipocytes and loss of subcutaneous fat. MPGN without immune complexes or complement When an MPGN pattern of glomerular inflammation occurs in the absence of immunoglobulin and complement deposition along the Table 21.8.6.2  Genetic and acquired abnormalities associated with dysregulation of the alternative pathway in complement-​mediated MPGN Category Target molecule Relative frequency Mutations in complement regulatory proteins Factor H Factor I CFHR5 (CFHR5 nephropathy) MCP (CD46) Most common genetic abnormality Less common than CFH mutation Endemic in Cyprus Uncommon Mutations in complement proteins C3 Reported in familial DDD Autoantibodies to complement regulatory proteins Factor H Factor I Factor B Isolated cases Autoantibodies to complement proteins Alternative pathway C3 convertase—​C3bBb (C3Nef) Most common acquired abnormality More common in DDD but also found in C3GN May be associated with CFH and CFI mutations DDD, dense deposit disease; C3Nef, C3 nephritic factor; CFH, complement factor H; CFHR5, complement factor H-​related protein 5; CFI, complement factor I; C3GN, C3 glomerulonephritis; MCP, membrane cofactor protein. (a) (b) (c) Fig. 21.8.6.3  Appearance of MPGN on electron microscopy. (a) A case of dense deposit disease illustrating a glomerular capillary loop with electron-​dense transformation of the basement membrane (arrows). (b) A case of immune complex-​mediated MPGN illustrating a capillary loop with subendothelial () and subepithelial (^) electron dense deposits. A new layer of subendothelial basement membrane is formed (arrows), which traps immune deposits and cellular elements between the two layers of basement membrane, forming double contours. (c) A case of thrombotic microangiopathy illustrating a capillary loop with flocculent material () trapped between two layers of basement membrane (arrows), containing cellular debris but no electron-​dense deposits. Images kindly provided by Professor Terry Cook, Imperial College Renal and Transplant Centre, Hammersmith Hospital, London.

21.8.6  Membranoproliferative glomerulonephritis 4941 capillary wall or mesangium, thrombotic microangiopathy is the most likely diagnosis (Fig. 21.8.6.3). There are multiple possible aetiologies of thrombotic microangiopathy, but all share in common endothelial injury, which triggers acute inflammation in glomerular capillaries. Clinical features The clinical presentation of MPGN is varied, reflecting the hetero- geneity in the underlying diseases causing this pattern of glomerular inflammation. The proliferative pattern of glomerular inflammation and re- modelling of the glomerular basement membrane gives rise to an active urinary sediment with nonvisible haematuria and significant proteinuria, which is often in the nephrotic range. Indeed, a mixed ‘nephrotic–​nephritic’ picture is highly suggestive of MPGN. The de- gree of renal impairment varies depending on the underlying dis- ease and severity of glomerular inflammation and scarring. Patients may present with: • overt nephrotic syndrome • episodic visible haematuria, often associated with upper respira- tory tract infections, similar to IgA nephropathy • severe hypertension and rapidly progressive renal impairment with oliguria (‘rapidly progressive glomerulonephritis’) • asymptomatic nonvisible haematuria and proteinuria detected on routine screening • advanced renal impairment with or without symptomatic uraemia Patients with DDD may have associated partial lipodystrophy affecting the face, upper limbs, and torso (Fig. 21.8.6.4). Additionally, fundoscopy may reveal drusen (yellow or white de- posits) between the basement membrane of the retinal pigment epithelium and Bruch’s membrane. This may be associated with macular degeneration and the long-​term risk of visual loss is approximately 10%. Most patients develop progressive renal impairment, although the time to progression to endstage renal failure is variable. Those that have severe renal impairment at diagnosis, heavy pro- teinuria, or extensive scarring on renal biopsy tend to progress more rapidly. DDD carries the greatest overall risk of developing endstage renal failure. Recurrence after renal transplantation is common. Clinical investigations The diagnosis of MPGN is made following renal biopsy showing the characteristic features on light microscopy described earlier. The presence of immunoglobulin and complement on immunofluorescence microscopy should prompt investiga- tion for underly­ing systemic autoimmune disease, monoclonal gammopathy, cryoglobulinaemia, and chronic infections, par- ticularly HCV. The presence of complement without immunoglobulin on im- munofluorescence microscopy should prompt further investigation of the AP. Serological complement assays are useful in investigating uncontrolled activation of the AP, which is suggested by low serum C3, normal C4, and often reduced factor B levels. Increased C3 turnover can be demonstrated by increased serum levels of C3 breakdown products (e.g. C3c and C3d), in association with low C3. Similarly, low serum C5 with increased soluble C5a and C5b–​ 9 (soluble membrane attack complex) levels suggest increased C5 turnover. Haemolytic assays of complement activity for the clas- sical (CH50) and alternative (AH50) pathways should also be used to identify dysregulation of AP activity. Other recommended com- plement investigations assess for autoantibodies to, or genetic mu- tations affecting, complement-​regulating proteins that lead to AP dysregulation (Table 21.8.6.3). Many of these tests require referral to specialist centres. Treatment Treatment of MPGN varies by underlying disease. Most studies of MPGN treatment were conducted before the role of dysregulation of the AP of complement was appreciated, hence this evidence base is of limited use in modern clinical practice. All patients should receive appropriate conservative therapy with antiproteinuric agents (angiotensin-​converting enzyme in- hibitor therapy or angiotensin II receptor blockade) to minimize proteinuria, and antihypertensives to achieve strict blood pressure control, aiming for target blood pressures established for patients with CKD. Immune complex-​mediated MPGN Patients with underlying systemic autoimmune connective tissue disease should be treated with appropriate immunosuppression Fig. 21.8.6.4  Facial appearance in partial lipodystrophy. This patient has had silicone pads inserted into her cheeks, accounting for the bulges in the regions where adipose tissue has been completely lost.

section 21  Disorders of the kidney and urinary tract 4942 according to the underlying disease, preferably in an appropriate specialist setting. MPGN associated with chronic infection requires appropriate treatment of the underlying infection. Patients with chronic HCV infection associated with cryoglobulinaemia that develop rap- idly progressive renal failure or systemic vasculitis may require treatment with immunosuppressive agents (including cortico- steroids, rituximab, or cyclophosphamide) and plasma exchange, in addition to antiviral therapy. However, antiviral therapy is the mainstay of treatment and the 2018 KDIGO Clinical Practice Guidelines recommend treatment with directly acting anti-viral agents (such as Grazopevir or elbasavir). Ribavarin should be avoided if GFR < 30ml/min per 1.73m2. Appropriate antiviral therapy in patients with HCV-​associated MPGN is changing sig- nificantly and will continue to do so—​it should be guided by a hepatologist. Evidence of an associated monoclonal gammopathy should prompt referral to a haematologist to establish the nature of the underlying plasma cell dyscrasia and initiate appropriate chemo- therapy. There is limited evidence to guide treatment for MGUS-​ associated MPGN but, as these patients are likely to have an unidentified plasma cell dyscrasia, they may benefit from myeloma-​ targeted treatment regimens and/​or rituximab. Complement-​mediated MPGN Treatment of complement-​mediated MPGN would logically depend on the mechanism of complement dysregulation, although no cur- rent treatments are of proven benefit. Patients with CFH deficiency may benefit from periodic plasma infusion, and purified or recom- binant factor H preparations are likely to be available in the future. Those with autoantibodies against complement factors or regulatory proteins may benefit from plasma exchange and immunosuppres- sive therapy. The development of eculizumab, and the evidence for its efficacy in atypical haemolytic syndrome associated with AP dysregulation, provides a possible new treatment option for complement-​mediated MPGN. A monoclonal antibody against C5, it inhibits its cleavage by C5 convertase, preventing generation of the terminal complement complex C5b–​9. The role for eculizumab in treating complement-​ mediated MPGN associated with different mechanisms of AP dysregulation requires further study. However, it may be a new and effective treatment in some forms, particularly in those patients who have evidence of C5 activation in the plasma (e.g. increased levels of soluble C5b–​9) or kidney (e.g. increased glomerular C5b–​9 depos- ition on immunofluorescence microscopy). Idiopathic MPGN Following recent advances in understanding the pathogen- esis of MPGN, idiopathic MPGN is now considered uncommon and should be a diagnosis of exclusion, made only following thorough investigation for all possible secondary causes listed in Table 21.8.6.2. The KDIGO Clinical Practice Guidelines on the management of idiopathic MPGN (2012) recommend cyclophos- phamide or mycophenolate mofetil plus corticosteroid therapy only for patients with rapidly progressive renal impairment, se- vere nephrotic syndrome, or crescent formation on renal biopsy. Conservative therapy alone is recommended for patients with mild disease. However, the overall evidence for the efficacy and safety of this treatment regimen is weak. Recurrence after renal transplantation Recurrence of MPGN occurs in 27 to 65% of cases following renal transplantation. Low complement levels may be an early marker for recurrence. Early recurrence, and a more aggressive disease course, is commonly associated with an underlying monoclonal gammopathy. DDD almost universally recurs in renal transplants, with a 5-​year allograft failure rate of 50%. FURTHER READING Bomback AS, Appel GB (2012). Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol, 8, 634–​42. Bomback AS, et al. (2012). Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol, 7, 748–​56. Table 21.8.6.3  Recommended investigations to determine aetiology of MPGN Immune complex-​mediated MPGN Autoimmune disease Clinical evaluation for evidence of systemic connective tissue disease Autoantibodies associated with systemic lupus erythematosus, Sjögren’s syndrome, and rheumatoid arthritis Chronic infection Serology and polymerase chain reaction for HCV and HBV infection Blood cultures Cardiac echocardiogram (bacterial endocarditis) Cryoglobulins in patients with chronic HCV infection Monoclonal gammopathy Serum and urine protein electrophoresis Immunofixation studies Serum free light chains ± Bone marrow investigations Complement-​mediated MPGN Screening tests recommended in all patients Serum C3 and C4 levels Serum factor H level C3 nephritic factor (autoantibody against C3 convertase, C3bBb) Screening for CFHR5 mutation Specialist tests considered on case-​by-​case basis Serum factor B level Serum C5 level Measurement of markers of C3 activation (e.g. C3d, C3c) Measurement of markers of C5 activation (e.g. soluble C5b–​9) Anti-​factor H autoantibodies Anti-​factor B autoantibodies Mutation screening of complement regulatory proteins (CFH, CFI, CD46), activation protein genes (C3, CFB), and assessment of copy number variation across the CFH–​CFHR locus. Recommended complement investigations from Pickering et al. (2013). C3 glomerulopathy: a consensus report. Kidney Int, 84, 1079–​89.

21.8.7 Antiglomerular basement membrane disease 49

21.8.7 Antiglomerular basement membrane disease 4943 Mårten Segelmark and Thomas Hellmark

21.8.7  Antiglomerular basement membrane disease 4943 KDIGO Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease (2018). Kidney Int, 8(3). KDIGO Clinical Practice Guideline for Glomerulonephritis (2012). Summary of recommendation statements. Kidney Int Suppl, 2, 143–​53. Pickering MC, et  al. (2013). C3 glomerulopathy:  consensus report. Kidney Int, 84, 1079–​89. Sethi S, Fervenza FC (2011). Membranoproliferative glomeruloneph- ritis: pathogenetic heterogeneity and proposal for a new classifica- tion. Semin Nephrol, 31, 341–​8. Sethi S, Nester CM, Smith RJ (2012). Membranoproliferative glom- erulonephritis and C3 glomerulopathy:  resolving the confusion. Kidney Int, 81, 434–​41. Sethi S, Fervenza FC (2012). Membranoproliferative glomerulo­nephritis—​a new look at an old entity. N Engl J Med, 366, 1119–​31. 21.8.7  Antiglomerular basement membrane disease Mårten Segelmark and Thomas Hellmark ESSENTIALS Aetiology—​antiglomerular basement membrane (anti-​GBM) disease, also known as Goodpasture’s disease, is a rare autoimmune kidney and/​or lung disease caused by autoantibodies directed against the noncollagenous, C-​terminal domain of the α3 chain of type IV col- lagen (α3(IV)NC1). Epidemiology—​bimodal age distribution with peaks in the third and sixth/​seventh decades; incidence 0.5 to 2/​million population/​ year. Clinical features—​typically presents as a renopulmonary syn- drome with the combination of rapidly progressive glomerulo- nephritis and lung haemorrhage, but can present with isolated glomerulonephritis. Pathology—​light microscopy typically reveals crescent formation, often in more than 80% of glomeruli, with linear staining of IgG along the GBM. Management—​aside from supportive care, this typically consists of (1) stopping the inflammatory process with high doses of cor- ticosteroid, (2)  removal of the pathogenic antibodies by plasma exchange, and (3)  stopping production of new antibodies with cyclophosphamide. It is controversial whether patients presenting with dialysis dependency and no pulmonary disease benefit from immunosuppression. Prognosis—​recent series report mortality at 6 to 12 months of 7 to 36%, with patients’ survival mainly dependent on age and renal func- tion at diagnosis. The most important factor in renal prognosis is the glomerular filtration rate at diagnosis, which is strongly correlated to the proportion of crescents seen in the renal biopsy. Very few pa- tients with dialysis dependency at diagnosis regain enough function to become dialysis independent (0–​7% most series). Patients do not need long-​term immunosuppression, and the disease rarely recurs. Renal transplantation is safe if performed after autoantibodies have been suppressed or naturally disappeared. History The term ‘Goodpasture’s syndrome’ has been used to describe pa- tients presenting with acute or subacute renopulmonary syndromes of unknown aetiology in recognition of a case report in 1919 by E.W. Goodpasture. When the technique for direct immunofluorescence was introduced, it was shown that such patients often had a con- tinuous linear deposit of immunoglobulins along their glomerular basement membrane (GBM). The term Goodpasture’s syndrome was thereafter used for the triad of lung haemorrhage, renal failure, and anti-​GBM antibodies. More recently anti-​GBM disease has be- come the preferred name for any renal and/​or lung disease in com- bination with anti-​α3(IV)NC1 antibodies, and in the latest version of the Chapel Hill nomenclature of vasculitis, the disease is included in the immune complex group of small vessel vasculitides. Pathogenesis Autoantibody specificity In 1984, it was shown that the anti-​GBM antibodies reacted with peptides around 25 and 50 kDa, and these were later shown to be derived from the noncollagenous domain (NC1) of type IV collagen. The peptides were identified as a new chain of type IV collagen, the α3 chain. It was also shown that the epitopes were cryptic and hidden in the NC1 hexamer. Patients have a polyclonal immune response and develop autoantibodies to different parts of the antigen. Two major epitopes have been identified. The major epitope is situated near the triple helical junction (Fig. 21.8.7.1) and is a cryptotope. Accessibility for the anti-​GBM antibodies is normally limited due to cross-​linking of the NC1 hexamer of type IV collagen. Oxidants can open up the structure, as can certain subpopulations of anti-​GBM antibodies. Mediators of disease There is emerging evidence for substantial T-​cell involvement in anti-​GBM disease. The autoantibody IgG subclass distribution is compatible with a T-​cell-​mediated reaction towards a protein antigen. A  mononuclear interstitial cell infiltrate is invariably seen, consisting mainly of CD4+ cells. Animal models indicate a role of autoreactive T cells. Transfer of anti-​GBM antibodies alone can induce disease, but always with a mild glomerulonephritis. Furthermore, immunization with a short peptide, such as a T-​cell epitope, or recombinant α3(IV)NC1 in a DRB1*1501 transgenic mouse, can induce florid glomerulonephritis without measurable levels of anti-​GBM antibodies. A role for the FCGR2B receptor has also been suggested.

section 21  Disorders of the kidney and urinary tract 4944 Genetic susceptibility Genetic studies have revealed a strong link between anti-​GBM dis- ease and HLA DRB11501, also DRB11502. Most reports are from Caucasian populations where the DRB1-​15 antigen is found in 70 to 80% of patients, compared to 20 to 30% of the controls. A negative link is found to HLA DR7 and DR1 in some studies, suggesting that they are protective. Animal models Numerous animal models have been described showing the patho- genic role of anti-​GBM antibodies. In a classic experiment, primates developed glomerulonephritis after injection of autoantibodies eluted from the kidneys of a nephrectomized patient suffering from anti-​ GBM disease. Animal models have shown the importance of autoanti- bodies against the pathogenic epitope as well as genetic background and T-​cell involvement. Due to the clear autoimmune character of the disease, models of anti-​GBM disease are among the most widespread models used to study inflammatory processes in general. Serological findings Anti-​GBM antibodies are by definition present in all patients with anti-​GBM disease, but different detection methods may yield 7S domain (a) (c) (d) (b) α4 α4 α5 α5 α3 α3 NC1 domain Fig. 21.8.7.1  (a) The type IV collagen network is building up the scaffold of basement membranes. (b) Each collagen molecule is comprised of three of α(IV) chains and in human GBM only molecules with one α3(IV), one α4(IV), and one α5(IV) chain is found. Four collagen IV molecules are connected in the N-​terminal end. (c) Two collagen IV molecules are connected via their C-​terminal ends, in which each α(IV) chain is folded into a globular domain, the NC1 domain. (d) This diagram shows a model of the NC1 hexamer of type IV collagen found in the GBM. Each type IV collagen molecule is composed of one α3, one α4, and one α5 chain. The two α4 NC1 domains bind to each other whereas the α3 binds an α5 NC1 domain. The amino acids identified as the epitope of the pathogenic antibodies is indicated on one of the α3 molecules in white and the large arrow. The proposed positions of the six α(IV) NC1 domains found in the human GBM are indicated. Note that the two α4(IV) domains are positioned on the back of the molecule. This picture of the NC1 hexamer is modelled from the NCBI MMDB entry #29412.

21.8.7  Antiglomerular basement membrane disease 4945 discrepant results. Circulating anti-​GBM antibodies can be detected with indirect immunofluorescence, western blotting, or an enzyme-​ linked immunosorbent assay (ELISA). In indirect immunofluor- escence, serum from the patient is overlaid on a section of normal kidney. A good substrate and a good pathologist are needed because nonspecific staining can be difficult to distinguish from the true linear staining pattern. The technique often fails to detect low levels of circulating autoantibodies. Many laboratories have their own in-​ house anti-​GBM assay or western blotting methodology, and there are several commercially available ELISA kits on the market. The performances of these assays depend on the purity of the antigen preparation, but are generally good. In patients presenting with renopulmonary syndrome, anti-​GBM antibodies can be found in around one-​third of the cases, whereas these are present in less than 5% of patients with rapidly progressive glomerulonephritis without pulmonary symptoms. Many patients (20–​35%) with anti-​GBM antibodies also have antineutrophil cytoplasmic antibodies (ANCA), mostly with spe- cificity for myeloperoxidase (MPO-​ANCA). Some double-​positive patients have features typical for granulomatosis with polyangiitis or microscopic polyangiitis, but virtually all published cases have severe renal disease. It is therefore recommend that ANCA and anti-​GBM should be analysed in parallel in patients with renal disease. Pathological findings Light microscopy typically reveals widespread crescent formation. The percentage of glomeruli exhibiting crescents often exceeds 80%, and the percentage usually correlates to renal function as well as out- come after treatment. Tissue-​bound anti-​GBM antibodies can be visualized by direct immunofluorescence of renal biopsy specimens (Fig. 21.8.7.2), a method that can give false-​positive results in cases of diabetes and in biopsies from renal transplants. The typical finding is linear staining of IgG along the GBM (Fig. 21.8.7.2), often accompanied by C3 de- position. Other staining patterns are sometimes seen, especially in mild cases with preserved renal function, as well as in severely dam- aged glomeruli. In electron micrographs, the findings in anti-​GBM disease and pauci-​immune glomerulonephritis are very similar, with ruptures of GBM and Bowman’s capsule, focal effacement of podocyte foot processes, fibrin in the urinary space and tuft, and fibrinoid necrosis. Electron-​dense deposits, which would indicate immune complex disease, are not present. Epidemiology The index case reported by E.W. Goodpasture was a young man. Most studies from the 20th century showed a male preponderance, while most published after the year 2000 show a more equal sex dis- tribution. There seems to be a bimodal age distribution with one peak in the third decade of life and a second peak in the sixth to seventh decades. Using sources such as serology, pathology, or clin- ical registries, estimates of the incidence of the disease report figures between 0.5 to 2 cases per million population per year. Another way to compare the incidence of anti-​GBM disease between countries and regions is by counting the proportion of renal biopsies showing linear staining on direct immunofluorescence. This amounts to 1 to 2% of all biopsies from native kidneys and 10 to 20% of all cases with diffuse crescentic glomerulonephritis. Symptoms and signs The most common presentation of anti-​GBM disease is as a renopulmonary syndrome with the combination of rapidly pro- gressive glomerulonephritis and lung haemorrhage, but in some case series patients with isolated glomerulonephritis exceed those with renopulmonary syndromes. A few patients have isolated lung haemorrhage (see ‘Isolated lung haemorrhage’). Many patients have a prodromal history of malaise, mild nausea, and weight loss, usually lasting a few weeks. This is accompanied by elevations in C-​reactive protein and erythrocyte sedimentation rate. (a) (b) Fig. 21.8.7.2  Renal biopsy from a patient with Goodpasture’s disease. (a) Light microscopy showing a single glomerulus with cellular crescent and focal necrosis. Silver stain. (b) Immunofluorescence of a single glomerulus with linear deposition of IgG along the GBM. This picture is identical to staining using anti-​α3(IV) monoclonal antibodies Panel (a) by courtesy of Associate Professor Martin Johansson, Lund University. Panel (b) by courtesy of Professor H.T. Cook.

section 21  Disorders of the kidney and urinary tract 4946 Renal symptoms and signs All patients with renal involvement have haematuria, and a substan- tial fraction have visible haematuria or a history of ‘dark urine’. Early in the course some patients experience polyuria, but those diag- nosed at later stages may present with oliguria or anuria. Proteinuria is also prevalent, but intensity varies from very mild to nephrotic range. Blood pressure is usually not elevated, excepting for those presenting with oliguria and water overload. Microscopy of the urine reveals dysmorphic red cells, red cell casts, granular casts, and leucocytes. Very few cases are detected with a serum creatinine within the normal range. Instead, it is common that a patient pre- sents with acute kidney injury of unknown origin, with symptoms of uraemia and/​or water overload, although more recent studies from centres with a high prevalence of serological testing report a higher proportion of patients detected with better preserved glomerular filtration rate. Pulmonary symptoms and signs The most common pulmonary symptom is cough, followed by dyspnoea and haemoptysis. Chest pain is less common. Hypoxia may develop, and in severe cases assisted ventilation or even extra- corporeal oxygenation may become necessary (Fig. 21.8.7.3). Pulmonary symptoms may precede, be concomitant with, or first develop after dialysis-​dependent renal failure is established. The concomitant presentation is most common, but there are several cases described where intermittent pulmonary haemorrhage pre- ceded onset of renal dysfunction by months or even years. There are also reports of patients presenting with lung fibrosis, presumably due to longstanding alveolitis. When overt lung bleeding begins after the start of renal replace- ment therapy, it is often precipitated by fluid overload, which em- phasizes that some cases with lung involvement do not have overt haemoptysis. Lung involvement in anti-​GBM disease may be evi- dent only if chest radiography or other investigations have been per- formed. High-​resolution CT and estimation of carbon monoxide diffusing/​transfer capacity have been shown to be more sensitive, the latter because the presence of haemoglobin in the alveolar spaces increases the binding of inhaled carbon monoxide. Bronchoalveolar lavage has been suggested as a gold standard. An indirect sign of lung bleedings is anaemia that is out of pro- portion to renal insufficiency and inflammation. A  haemoglobin concentration of less than 90 g/​litre is rarely seen because of rapidly progressive glomerulonephritis alone. There is an association be- tween lung involvement and cigarette smoking, and the increasing proportion of renal limited cases in recent years might be due to a falling prevalence of smoking. Variants and overlap syndromes Membranous nephropathy Some patients with light microscopy and electron microscopy find- ings of membranous nephropathy have circulating anti-​GBM anti- bodies. Such cases may progress, and later biopsies can show a more typical crescentic glomerulonephritis. It has been suggested that idiopathic membranous nephropathy might precipitate anti-​GBM disease or actually predispose for the development of anti-​GBM antibodies. However, the detection of specific autoantibodies (anti-​ PLRA2) in membranous nephropathy, along with detailed studies of the specificity of anti-​GBM, have shown that patients with mem- branous histology and circulating anti-​GBM have autoantibodies with the same antigen specificity as ordinary cases of anti-​GBM dis- ease, but there might be subtle differences in epitope specificity and IgG subclass distribution. Patients with membranous findings have as a group more proteinuria, better preserved glomerular filtration rate, and better prognosis than those with anti-​GBM disease with more typical histological findings. ANCA positivity and vasculitis overlap ANCA positivity is common in anti-​GBM disease; rates between 20 and 40% have been reported. MPO-​ANCA is more common than proteinase 3 (PR3)-​ANCA. Double-​positive patients are older and more often female. Some double-​positive patients have distinct fea- tures of ANCA-​positive vasculitis such as upper respiratory granu- lomas or pulmonary nodules. More common, however, is that double-​positive patients have general prodromal symptoms. There are divergent reports regarding their renal prognosis. A greater like- lihood of recovery from dialysis dependency has been reported. There might be a correlation between ANCA positivity and low levels of circulating anti-​GBM antibodies, which in itself is associ- ated with better prognosis. Double-​positive patients also have been reported to have more chronic lesions on renal biopsies, as well as a higher relapse rate. The greater relapse risk should be taken into account when deciding on maintenance therapy and follow-​up. Isolated lung haemorrhage A small subgroup of patients with anti-​GBM disease present with severe pulmonary disease and normal renal function. Many of these have mild urinary findings, and all biopsied cases show linear de- posits of IgG. Isolated lung haemorrhage may only represent cases detected at an early stage, but some may belong to a distinct nosoco- mial subgroup. Such cases are preferentially young smoking females. Many have no detectable or low levels of circulating anti-​GBM Fig. 21.8.7.3  Chest radiograph from a patient with Goodpasture’s disease showing florid pulmonary haemorrhage.

21.8.7  Antiglomerular basement membrane disease 4947 detected by standard ELISA. Atypical IgG subclass distribution (high IgG4) and atypical epitope specificity have also been reported. Post-​transplant anti-​GBM in Alport’s syndrome Patients with Alport’s syndrome have mutations in genes coding for type IV collagen. As the α3, α4, and α5 chains are coexpressed in the basement membrane-​producing cells (i.e. podocytes), mutations that do not directly affect the α3 chain can lead to a greatly dimin- ished expression of autoantigen-​binding epitopes on the α3NC1 do- main. After renal transplantation, type IV collagen may function as an alloantigen. However, in most instances this does not lead to overt anti-​GBM disease. Weak linear staining along the GBM is common in transplanted patients with Alport’s syndrome, but only a few per cent develop rapidly progressive glomerulonephritis with circulating autoantibodies. There are divergent reports regarding the specificity of such autoantibodies, but as the alloantigen is not present in the lungs, lung haemorrhage does not occur. If the transplanted kidney is lost there is substantial risk of reoccurrence after retransplantation. Diagnosis, clinical investigation, and differential diagnosis Table 21.8.7.1 shows the differential diagnosis of the patient pre- senting with renal and pulmonary failure. A diagnosis of anti-​GBM disease relies on the detection of anti-​ GBM antibodies in conjunction with renal and/​or pulmonary dys- function. In most cases, kidney-​bound antibodies can be detected by direct immunofluorescence (Fig. 21.8.7.2) and circulating antibodies by solid phase methods (i.e. ELISA). When autoanti- bodies are only found in one of these locations, the situation is less clear: there can be false-​positive and false-​negative cases with all techniques. Negative tests for circulating anti-​GBM can be due to atypical antigen/​epitope specificity and atypical IgG subclass dis- tribution, as well as a longer half-​life of kidney-​bound antibodies (several months) as compared to circulating antibodies (weeks). Reasons for false-​negative tests for kidney-​bound antibodies in- clude factors such as severely sclerotic or injured specimens, other concomitant pathology such immune-​complex disease, or levels of pathogenic antibodies lower than the detection level possible with direct immunofluorescence. Table 21.8.7.2 shows the diagnostic workup appropriate for pa- tients with a positive test for anti-​GBM antibodies. Besides renal biopsy and routine monitoring of renal function and electrolytes, diagnostic work up should include a chest radiograph for the de- tection of lung involvement and—​at least when negative—​also a more sensitive technique to detect lung haemorrhage such as high-​ resolution CT or carbon monoxide trapping scintigraphy. ANCA should be analysed to detect overlap syndromes and determine relapse risk. The haemoglobin level should be monitored to diag- nose and follow the course of lung bleeding. Routine haematology and liver enzyme tests are necessary before prescribing cyclophos- phamide. It is also prudent to exclude the presence of chronic in- fections such as HIV, hepatitis, and tuberculosis before starting immunosuppression. Treatment The aim of the treatment is to stop the inflammatory process, reduce the levels of toxic autoantibodies, and halt their production. The first aim is addressed mainly by high doses of corticosteroid therapy, usu- ally given as pulse doses of methylprednisolone for three consecu- tive days, followed by oral prednisolone at a dose of 1 mg/​kg per day. Removal of autoantibodies is achieved by daily plasma exchanges, exchanging 1.5 plasma volumes each time. Due to the risk of lung Table 21.8.7.1  Differential diagnosis for patients with renal and pulmonary failure Renal and pulmonary failure without alveolar haemorrhage More common •  Kidney failure (acute or chronic) of any cause with pulmonary oedema •  Severe pneumonia with acute kidney injury •  Cardiac failure with pulmonary oedema and acute kidney injury attributable to poor renal perfusion Less common •  Renal failure with pulmonary embolism (nephrotic syndrome) •  Infective endocarditis complicated by pulmonary oedema and glomerulonephritis •  Paraquat poisoning Acute nephritic syndrome with alveolar haemorrhage More common •  Anti-​GBM disease •  ANCA-​associated vasculitis •  Systemic lupus erythematosus Less common •  Eosinophilic granulomatosis with polyangiitis •  IgA vasculitis (IgA vasculitis (HSP) Henoch–​ Schönlein purpura) •  Cryoglobulinaemic vasculitis •  Lung cancer with paramalignant glomerulonephritis •  Acute postinfectious glomerulonephritis with severe fluid overload •  Haemolytic uraemic syndrome with severe fluid overload •  Drug-​induced vasculitis/​lupus-​like syndrome •  HIV-​associated nephritis •  Hantavirus and other haemorrhagic fevers Table 21.8.7.2  Diagnostic workup in patients with a positive test for anti-​GBM antibodies Clinical parameters Vital signs: temperature, pulse rate, blood pressure, respiratory rate, pulse oximetry; body weight; urinary output Urinalysis Dipstick, with urinary microscopy if positive for blood and urinary albumin:creatinine ratio if positive for protein Clinical chemistry Serum creatinine and electrolytes; liver function tests, bone profile, full blood count, clotting screen, C-​reactive protein Clinical immunology MPO-​ANCA, PR3-​ANCA, complement factor C3 and C4, ANA, serum immunoglobulins, plasma and urine electrophoresis Viral serology Hepatitis B and C, HIV Radiology Chest radiography, renal ultrasound, (consider) high-​resolution CT of the lungs Pathology Renal biopsy

section 21  Disorders of the kidney and urinary tract 4948 Table 21.8.7.3  Outcome of anti-​GBM disease in patient cohorts published after 1990 Authors (year) Country Period N Mean age
(n >60 
years; %) ANCA+ n (%) Plasma exchange n (%) No treatment n (%) Dead at
6–​12 months
n (%) Native kidney function at 6–​12 months Total If creatinine <500–​ 600 µmol/​litre at diagnosis If dialysis/​oliguria/​ creatinine >500–​600 µmol/​litre at diagnosis Herody et al. (1993) France 1984–​1992 29 35 (5; 17%) 1 (3%) 24 (82%) 0 2 (7%) 12 (41%) 12/​13 (92%) 0/​16 (0%) Merkel et al. (1994) Germany 1982–​1992 35 35 (NA) NA 25 (71%) 3 (9%) 4 (11%) 10 (29%) 9/​14 (64%) 1/​21 (5%) Daly et al. (1996) Ireland 1976–​1991 40 45 (22; 55%) NA 23 (68%) 7 (21%) 3/​34 (8%) 8/​34 (24%) 8/​14 (57%) 0/​20 (0%) Levy et al. (2001) UK 1975–​1999 71 40 (8; 11%) NA/​Excl 71 (100%) 0 15 (21%) 29 (41%) 18/​19 (95%) 11/​52 (21%) Li et al. (2003) Hong Kong 1992–​2003 10 59 (8; 80%) 2 (20%) 8 (80%) 2 (20%) 2 (20%) 2 (20%) 2/​6 (33%) 0/​4 (0%) Segelmark et al. (2003) Sweden 1987–​1995 75 59 (45; 60%) 29 (39%) 44 (59%) 5 (7%) 27 (36%) 16 (21%) 11/​21 (53%) 4/​54 (7%) Cui et al. (2005) China 1997–​2002 97 38 (19; 20%) 25 (26%) 31 (32%) 28 (29%) NA 15 (15%) 14/​28 (50%) 1/​66 (2%) Taylor et al. (2012) New Zealand 1998–​2008 23 45 (NA) Excl 17 (74%) 1 (4%) 1 (11%) 11 (48%) NA NA Dammacco et al. (2013) Italy 2003–​2012 10 NA 3/​9 (33%) 10 (100%) 0 2 (20%) 6 (60%) NA NA Zhang et al. (2014) China 2003–​2013 28 NA 3 (11%) 28 (100%) 0 4 (14%) 8 (29%) NA NA Alchi et al. (2015) UK 1991–​2011 43 53 (NA) 9 (21%) 32 (74%) 11 (26%) 5 (12%) 10 (23%) 6/​8 (75%) 2/​35 (6%) NA, not available.

21.8.7  Antiglomerular basement membrane disease 4949 haemorrhage, regional anticoagulation should be used, also in cases without overt ongoing bleeding. It is also prudent to replace part of the exchanged volume with fresh plasma to resupplement coagula- tion factors. Plasma exchange should be continued until anti-​GBM antibodies have reached a nontoxic level. Immunoadsorption using protein A columns enables a more rapid removal of antibodies, but this has not been shown to improve prognosis. To stop production of new antibodies, cyclophosphamide is given, either as intermittent intravenous pulses or as daily oral tablets. After plasma exchange is halted, there is a risk of rebound of anti-​GBM necessitating reinsti- tution of therapy. Cyclophosphamide is usually given for 3 months and until anti-​GBM antibodies are no longer detectable. Rituximab, a B-​cell-​depleting monoclonal antibody that has shown efficacy in many other autoantibody-​mediated diseases, has recently been shown to be effective in halting the production of autoantibodies in anti-​GBM disease, but its place in management is uncertain at present. It is controversial whether patients presenting with dialysis de- pendency and no pulmonary disease benefit from immunosup- pression. The small chance of recovery and the risk of late-​onset lung haemorrhage must be weighed against the risk of severe side effects. The renal biopsy appearance can provide valuable informa- tion about the extent of the histological damage, which reflects the chance of renal recovery, in such cases. Another unresolved ques- tion is the benefit from azathioprine and/​or corticosteroids as main- tenance therapy after cyclophosphamide. Prognosis Table 21.8.7.3 shows patient and renal prognosis in patient cohorts published after 1990. As in most renal disease, patients’ survival is mainly dependent on age and renal function at diagnosis. Historical data reveal high mortality from lung bleeding in untreated patients, but if treatment as indicated previously is instituted there are few deaths due to intractable lung disease. Fatalities are mainly seen in severely ill, elderly patients, and mortality at 6 to 12 months was 7 to 36% in the series shown in Table 21.8.7.3. The renal prognosis in anti-​GBM disease is much worse than that in other forms of immune-​mediated rapidly progressive glom- erulonephritis. The most important prognostic factor is the glom- erular filtration rate at diagnosis, which is strongly correlated to the proportion of crescents seen in the renal biopsy. Very few pa- tients with dialysis dependency at diagnosis regain enough func- tion to become dialysis independent (0–​7% in the series shown in Table 21.8.7.3, excepting a single outlier series reporting 21%). The level of circulating anti-​GBM has been shown to correlate with disease severity at diagnosis and with prognosis, but it is not clear if they are independent prognostic risk factors. The role of ANCA for prognosis was discussed earlier (see ‘ANCA positivity and vas- culitis overlap’). Once antibody production has stopped and no circulating anti- bodies can be detected, relapses are rare. Two exceptions to this rule are double-​positive patients (ANCA/​anti-​GBM) and those with isolated lung haemorrhage. As long as anti-​GBM can be de- tected in the circulation there is a considerable risk of flares and renal transplantation should be postponed until antibody produc- tion has ceased. FURTHER READING Bolton WK, et al. (2005). Epitope spreading and autoimmune glom- erulonephritis in rats induced by a T cell epitope of Goodpasture’s antigen. J Am Soc Nephrol, 16, 2657–​66. Borza DB, et al. (2005). Goodpasture autoantibodies unmask cryptic epitopes by selectively dissociating autoantigen complexes lacking structural reinforcement: novel mechanisms for immune privilege and autoimmune pathogenesis. J Biol Chem, 280, 27147–​54. Chen M, Cui Z, Zhao MH (2010). ANCA-​associated vasculitis and anti-​GBM disease: the experience in China. Nephrol Dial Transplant, 25, 2062–​5. Cui Z, et al. (2005). Characteristics and prognosis of Chinese patients with anti-​glomerular basement membrane disease. Nephron Clin Pract, 99, c49–​55. Hellmark T, Johansson C, Wieslander J (1994). Characterization of anti-​GBM antibodies involved in Goodpasture’s syndrome. Kidney Int, 46, 823–​9. Hellmark T, Segelmark M (2014). Diagnosis and classification of Goodpasture’s disease (anti-​GBM). J Autoimmun, 48–​49, 108–​12. Hellmark T, et al. (1997). Comparison of anti-​GBM antibodies in sera with or without ANCA. J Am Soc Nephrol, 8, 376–​85. Hellmark T, et  al. (1999). Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease. Kidney Int, 55, 936–​44. Hellmark T, et al. (2003). Point mutations of single amino acids abolish ability of alpha3 NC1 domain to elicit experimental autoimmune glomerulonephritis in rats. J Biol Chem, 278, 46516–​22. Henderson SR, Salama AD (2018). Diagnostic and management chal- lenges in Goodpasture’s (anti-glomerular basement membrane) dis- ease. Nephrol Dial Transplant, 33, 196–202. Hudson BG, et  al. (2003). Alport’s syndrome, Goodpasture’s syn- drome, and type IV collagen. N Engl J Med, 348, 2543–​56. Jennette JC, et  al. (2013). 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum, 65, 1–​11. Lazor R, et al. (2007). Alveolar hemorrhage in anti-​basement membrane antibody disease: a series of 28 cases. Medicine (Baltimore), 86, 181–​93. Lerner RA, Glassock RJ, Dixon FJ (1967). The role of anti-​glomerular basement membrane antibody in the pathogenesis of human glom- erulonephritis. J Exp Med, 126, 989–​1004. Levy JB, et al. (2001). Long-​term outcome of anti-​glomerular base- ment membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med, 134, 1033–​42. Lou YH (2004). Anti-​GBM glomerulonephritis:  a T cell-​mediated autoimmune disease? Arch Immunol Ther Exp (Warsz), 52, 96–​103. Luo H, et al. (2011). The association of HLA-​DQB1, -​DQA1 and -​ DPB1 alleles with anti-​glomerular basement membrane (GBM) dis- ease in Chinese patients. BMC Nephrol, 12, 21. Ooi JD, et al. (2013). The HLA-​DRB1*15:01-​restricted Goodpasture’s T cell epitope induces GN. J Am Soc Nephrol, 24, 419–​31. Salama AD, et al. (2001). Goodpasture’s disease. Lancet, 358, 917–​20. Savage CO, et al. (1986). Antiglomerular basement membrane anti- body mediated disease in the British Isles 1980–​4. Br Med J (Clin Res Ed), 292, 301–​4. Segelmark M, Hellmark T, Wieslander J (2003). The prognostic signifi- cance in Goodpasture’s disease of specificity, titre and affinity of anti-​ glomerular-​basement-​membrane antibodies. Nephron Clin Pract, 94, c59–​68. Sharp PE, et al. (2012). Increased incidence of anti-​GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional

section 21  Disorders of the kidney and urinary tract 4950 deletion of Fcgr2b on either B cells or myeloid cells alone. Mol Immunol, 50, 49–​56. Sinico RA, et al. (2006). Anti-​glomerular basement membrane anti- bodies in the diagnosis of Goodpasture syndrome: a comparison of different assays. Nephrol Dial Transplant, 21, 397–​401. Stanton MC, Tange JD (1958). Goodpasture’s syndrome (pulmonary haem- orrhage associated with glomerulonephritis). Aust Ann Med, 7, 132–​44. Wieslander J, et al. (1985). Physical and immunochemical studies of the globular domain of type IV collagen. Cryptic properties of the Goodpasture antigen. J Biol Chem, 260, 8564–​70.

21.9 Tubulointerstitial diseases 4951 21.9.1 Acute

21.9 Tubulointerstitial diseases 4951 21.9.1 Acute interstitial nephritis 4951 Simon D. Roger

CONTENTS 21.9.1 Acute interstitial nephritis  4951 Simon D. Roger 21.9.2 Chronic tubulointerstitial nephritis  4956 Marc E. De Broe, Channa Yamasumana, Patrick C. D’Haese,
Monique M. Elseviers, and Benjamin Vervaet 21.9.1  Acute interstitial nephritis Simon D. Roger ESSENTIALS Acute interstitial nephritis (AIN) is an inflammation of the tubules and interstitium within the kidney, associated with a relatively sudden onset and rapid decline in renal function. It is usually secondary to drugs (antibiotics, nonsteroidal anti-​inflammatory drugs, and proton pump inhibitors being most commonly incriminated), with other causes being infections (classically streptococcal, but this is now less common) and immune disorders (systemic lupus erythematosus, sarcoidosis, and tubulointerstitial nephritis with uveitis). Clinical features—​the diagnosis of AIN should be considered in any patient with unexplained acute kidney injury. Drug-​induced AIN may present with a classic allergic response, including arthralgias, fever, rash, loin pain, and eosinophilia/​eosinophiluria, but these are not in- variable and their absence does not exclude the diagnosis. The urine typically shows low-​grade proteinuria (<1 g/​day). Renal biopsy is the only way to confirm or exclude the diagnosis. Management and prognosis—​treatment is by ceasing the offending agent, treating the concurrent infectious cause, or managing the
immune aetiology with steroids (typically prednisolone 1 mg/​kg per day, tapered to zero over 6–​8 weeks). Most patients with drug-​ induced AIN recover renal function, but some are left with chronic renal impairment and a small proportion progress to endstage chronic kidney disease. Introduction Acute interstitial nephritis (AIN) is characterized by an interstitial infiltrate of inflammatory cells with relative sparing of the glomeruli and vessels, and presents as acute impairment of renal function. The term ‘tubulointerstitial’ nephritis is also applied, reflecting the damage that occurs to the tubular cells in addition to the interstitial changes. Historical perspective In 1898, Councilman described the first accounts of acute tubulointerstitial nephritis involving patients with scarlet fever or diphtheria, whose kidneys were sterile but had inflammatory infiltrates. Since then, drug-​induced AIN has surpassed infec- tion as a more common cause of the condition in adults, espe- cially with the widespread use of antibiotics and proton pump inhibitors. Aetiology, pathogenesis, and pathology The aetiology is divided into groups such as drugs, infections, and immune-​based causes. See Box 21.9.1.1. Drugs Medications are now responsible for 70 to 90% of cases of AIN. It is important to remember that any drug can cause this condition, es- pecially with the flood of new agents entering the formulary. The commonly recognized drugs implicated in causing AIN in- clude proton pump inhibitors, nonsteroidal anti-​inflammatory drugs (NSAIDs), penicillins, cephalosporins, sulfa-​based agents, and frusemide (furosemide). Unexpected culprits include cocaine and Chinese herbal agents. The proton pump inhibitors have been recognized as causing AIN since 1992. They have been shown to induce AIN on rechallenge, behave as a class effect rather than due to specific drugs within the group, and are now the most common cause of drug-​induced AIN. 21.9 Tubulointerstitial diseases

section 21  Disorders of the kidney and urinary tract 4952 Infections Many pathogenic organisms (bacterial, viral, protozoal, and fungal) have been implicated as causing AIN, and in children, infection re- mains the most common cause of this condition: • Streptococcal—​what was a very common aetiology has now waned with the advent of and widespread use of antibiotics. • Legionella—​although a relatively rare cause of AIN, the organism can be detected in renal tissue by immunofluorescence and electron microscopy. Coexistent rhabdomyolysis may be present. • HIV—​AIN is present in up to 40% of autopsy series. HIV can also cause a glomerulonephritis in addition to a mononuclear cell in- filtrate of predominantly CD8+-​positive lymphocytes. • Epstein–​Barr virus—​renal involvement is not uncommon. CD8+ T lymphocytes may predominate. • Cytomegalovirus—​more common in immunosuppressed patients (HIV positive or transplant recipients). Irreversible renal failure may ensue. • Polyomavirus (BK)—​the renal transplant population are more spe- cifically at risk of BK virus inducing AIN and acute cellular rejec- tion. This polyomavirus is present in the urothelium of 60 to 80% of people, with immunosuppression allowing it to become a significant pathogen in the renal transplant, resulting in BK virus-​associated nephropathy. Management generally involves reduction in immuno- suppression, with the use of ciprofloxacin, cidofovir, and leflunomide also advocated (but without convincing evidence of efficacy). • Toxoplasmosis—​AIN is uncommon but can occur as part of sys- temic infection. • Leishmaniasis—​disseminated leishmaniasis (kal-​azar) can pre- sent with acute kidney injury from AIN. It tends to resolve. • Mycobacterium—​these have been recognized as inducing AIN and, along with toxoplasmosis and leishmaniasis, are a commoner cause of AIN than drug-​induced cases in developing countries. In septicaemia, bacteria such as Escherichia coli and staphylococci and fungal elements such as Candida albicans can directly invade the renal parenchyma and lead to the development of microabscesses, which are found on diagnostic renal biopsy. Immune • Systemic lupus erythematosus—​lupus is associated with de- position of immunoglobulins and complement. Deposits may be extensive and widespread. Cellular infiltrates include mono- nuclear cells, but also on occasion neutrophils. Although the tubulointerstitial infiltrate usually coexists with significant glom- erulonephritis, it has been found in isolation. • Sjögren’s syndrome—​may be associated with renal tubular acid- osis. IgG and C3 may be detected on immunofluorescent staining on the tubular basement membrane. • Sarcoidosis—​can be coupled with the formation of typical granu- lomas in the interstitium. Associated hypercalcaemia and cellular infiltrate may lead to dialysis-​dependent renal failure. • IgG4 related kidney disease—​lymphoplasmacytic cell-​rich tubulointerstitial nephritis occurs with increased IgG4-​positive plasma cells and storiform fibrosis. It can be associated with type 1 autoimmune pancreatitis, but is now considered to encompass various multiorgan inflammatory conditions. • Tubulointerstitial nephritis with uveitis (TINU) syndrome—​ described by Dobrin in 1975, uveitis may precede or follow the renal dysfunction. Autoimmune pathogenesis is suspected, with a strong association with specific HLAs (DQA101/​DQB105/​ DRB1*01). This commonly affects pubertal females, responds to oral steroids, but is prone to relapse. • Antitubular basement membrane antibodies have been reported in rare idiopathic forms. • A variety of primary glomerulonephritides may cause a secondary tubulointerstitial inflammation and nephritis, for example, in the context of antiglomerular basement membrane antibodies and coexistent antitubular basement membrane antibodies (occurring in 50%), or membranous glomerulonephritis. Box 21.9.1.1  Main causes of acute interstitial nephritis Drugs • Proton pump inhibitors: —​  Esomeprazole —​ Omeprazole —​ Lansoprazole —​ Pantoprazole —​ Rabeprazole • Antibiotics: —​ Cephalosporin —​ Ciprofloxacin —​ Co-​trimoxazole and other sulphonamides —​ Erythromycin —​ Methicillin —​ Other penicillin derivatives —​ Rifampicin —​ Vancomycin • Nonsteroidal anti-​inflammatory drugs • Diuretics: —​ Furosemide (frusemide) —​ Thiazides —​ Triamterene • Chemotherapy agents: —​ Bacille Calmette–​Guérin (BCG) —​ Ifosfamide —​ Tyrosine kinase inhibitors • Others: —​ Aciclovir —​ Allopurinol —​ Captopril —​ Clofibrate —​ Clozapine —​ Diphenylhydantoin —​ Etanercept —​ Fenofibrate —​ H2-​receptor blockers —​ Indinavir —​ Interferon-​α —​ Paracetamol —​ Phenindione —​ Phenobarbital —​ Phenothiazine —​ Salicylate derivatives —​ Streptokinase —​ Valproate —​ Warfarin Infectious • Bacterial: —​ Brucellosis —​ Legionella —​ Leptospirosis —​ Mycoplasma —​ Rickettsia —​ Streptococci, including pneumococci —​ Syphilis —​ Tuberculosis —​ Typhoid fever • Viral: —​ Polyomavirus (BK) —​ Coxsackie virus —​ Cytomegalovirus —​ Echovirus —​ Epstein–​Barr virus —​ Hantavirus —​ HIV —​ Measles —​ Parvovirus B19 • Parasitic: —​ Leishmania —​ Toxoplasma Systemic diseases • Lupus erythematosus • Sarcoidosis • Sjögren’s syndrome Idiopathic • Associated with uni-​ or bilat- eral uveitis (TINU syndrome) • Isolated Adapted with permission from Droz D, Chauveau D (2003). Acute intersti- tial nephritis. In: Warrell DA, et al. (eds). Oxford Textbook of Medicine, p 35. Copyright © 2003 Oxford University Press.

21.9.1  Acute interstitial nephritis 4953 Pathogenesis AIN is characterized by tubulitis with a heavy cellular infiltrate. Renal dendritic cells commence a process that results in intersti- tial fibroblastic cells expressing a variety of growth factors and cytokines such as transforming growth factor-​β (TGF-​β) and platelet-​derived growth factor, which leads to inflammatory cas- cades and subsequent production of extracellular matrix proteins (collagens, fibronectin, laminin) and fibrotic change. This results in tubular destruction and the development of glomerular scler- osis. There are conflicting views on the role of fibroblasts derived from epithelial-​to-​mesenchymal transition having a vital im- portance in tubulointerstitial fibrosis development. This process progresses to the classic pathological changes of chronic intersti- tial nephritis. There are two possible mechanisms by which AIN develops: • Antigen-​driven immunogenicity—​AIN is classically associated with an infiltrate of T lymphocytes (both helper-​inducer and suppressor-​cytotoxic). This leads to T-​cell-​mediated hypersensi- tivity and cytotoxic T-​cell injury. The presence of CD4 helper T cells at the site of injury indicates immune activation. Th1 helper cells (releasing TNFβ and γ-​interferon) favour delayed-​type hypersensitivity responses and the production of CD8 cytotoxic lymphocytes, and Th2 cells (releasing IL-​5 and IL-​4) attract eo- sinophils and help B cells form plasma cells that secrete antibodies. The presence of TGFβ1 acts as a proinflammatory molecule and is the most important profibrotic factor. In proton pump inhibitor-​ induced AIN, CD4+ lymphocytic aggregates combined with costaining of CD4/​IL-​17A/​F suggest a Th17-​mediated inflamma- tory process. The presence of T-​bet+ cell infiltrates point to add- itional Th1 involvement. • Humoral immunogenicity—​although T cells are the main vil- lain implicated in pathogenesis, there is also evidence in ex- perimental animal models to implicate a role for the humoral immune system. This involves tubular basement membrane antibodies and complement. This process is active in the TINU syndrome, when there is an increase in IgG reactive against a 125-​kDa kidney protein. The exact pathogenesis of drug-​induced AIN is yet to be elu- cidated. It is thought that the drug or its metabolites act as either haptens (mimicking renal antigens) or deposit as circulating im- mune complexes. This is believed to stimulate a T-​cell hypersensi- tivity reaction. Evidence for this theory is derived, in part, because of the extrarenal manifestation of hypersensitivity (rash, arthralgias, and eosinophilia). Pathology On light microscopy, the renal biopsy typically shows an infiltrate within the interstitium of T lymphocytes (especially CD4+ and CD8+ cells), monocytes, macrophages (expressing CD14+ and CD68+ in addition to cell activation markers), and possibly poly- clonal plasma cells and eosinophils (Fig. 21.9.1.1). The infiltrate may vary in intensity. There may be extensive interstitial oedema. If granulomas have formed, then the differential includes a drug reaction, sarcoidosis, tuberculosis, or acute bacterial infections (Fig. 21.9.1.2). Fibrosis within the interstitium has been detected within 2 weeks, as a component of the reparative process. The tubules themselves may show necrosis or signs of regeneration. In primary AIN, when the sample is examined by light mi- croscopy or immunofluorescent techniques, the glomeruli and vessels are either unremarkable or show only minor change. Immunofluorescence of the tubules and interstitium may stain positive for antitubular basement membrane antibodies, IgG and IgM in addition to fibrinogen. Linear IgG and C3 deposition is rarely found, although has been associated with antibiotic-​ induced disease (β-​lactams and ciprofloxacin). Electron mi- croscopy reveals altered continuity of the tubular basement membrane. Fibrosis within the interstitium has been detected within 2 weeks as a component of the reparative process. Fig. 21.9.1.1  Renal biopsy (haematoxylin and eosin stain), demonstrating AIN with cellular infiltrate and sloughing of tubular epithelial cells. Fig. 21.9.1.2  Granuloma in AIN. Adapted with permission from Baker R. Acute tubulointerstitial nephritis: overview. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4954 Epidemiology AIN is not a common entity, being found in 1 to 3% of unselected renal biopsy series. Its exact incidence is difficult to gauge as renal physicians apply different criteria for performing diagnostic renal bi- opsies. However, most series suggest 15 to 27% of kidney biopsies per- formed for investigation of acute kidney injury demonstrate AIN, the higher percentage being reported where the cause of AKI is unknown and in the presence of inactive urinary sediment (i.e. lack of heavy proteinuria, lack of significant haematuria, or lack of presence of dys- morphic red blood cells). The prevalence of AIN may be increasing, especially in the elderly, possibly reflecting more diagnostic kidney biopsies or an increased incidence of drug-​induced AIN. Clinical features The clinician should always consider AIN in any patient with unex- plained acute kidney injury, with or without specific tubular dysfunction. It is also important to consider AIN in a patient with chronic kidney dis- ease whose renal function suddenly deteriorates at a rapid rate. A thor- ough drug history is essential, including over-​the-​counter medications, herbal compounds, and other nonprescription agents, and the dates/​ duration of exposure. Given that drug-​induced AIN is an idiosyncratic reaction, it must be presumed that all drugs might be causative. Drug-​induced AIN may present with a classic allergic response, including fever, rash, arthralgias, and eosinophilia/​eosinophiluria. The recognized clinical pattern of drug-​induced AIN has changed since the disappearance of the classic methicillin-​induced damage. These systemic features may present early (days to weeks after drug exposure), or up to a mean of 3 months following drugs such as the proton pump inhibitors. With drugs such as the NSAIDs, it can occur up to years later. In patients who are surreptitiously rechallenged with an offending drug, the onset of AIN is rapid. The development of AIN is not dose related (Table 21.9.1.1). Proton pump inhibitors Proton pump inhibitors are one of the most widely prescribed classes of drugs in the Western world. All five drugs in the class have been reported as causative agents. The triad of fever, rash, and eo- sinophilia associated with classical methicillin-​induced AIN is less prominent or even absent in proton pump inhibitor-​induced AIN. The presenting complaints are nonspecific in nature, including tiredness, nausea, and weight loss. The most common abnormalities on investigation, apart from raised serum creatinine, are low-​level proteinuria, pyuria, and eosinophiluria. Due to the widespread availability of these drugs, both over the counter in some countries and on prescription, there is a high risk of inadvertent rechallenge unless patients are clearly counselled. This iatrogenic complication may be devastating, hence education of all prescribing doctors (including general practitioners, gastroenterol- ogists, and surgeons) in addition to pharmacists is warranted. NSAIDs This class of drugs (including selective COX-​2 inhibitors) rarely causes extrarenal manifestation, but concurrent nephrotic syn- drome with heavy proteinuria and oedema is common, being present in up to 70% of cases. Macroscopic haematuria is rare. In Europe, fenoprofen accounts for up to 50% of cases. Precise history taking is imperative because these medications are readily available over the counter, are usually taken on an ‘as-​needed’ basis, and many patients may not regard them as ‘drugs’ unless specifically asked about them by the clinician. β-​Lactam antibiotics These agents cause the ‘classic’ allergic drug-​induced AIN. Occurring within a few days or up to 2 months after starting treatment, fever, skin rash, arthralgias, eosinophilia, and renal impairment are evident. Other drugs of note The use of herbal medicines has increased in developed coun- tries:  these are often incorrectly believed by patients to be in- nocuous, but they can cause AIN. Cocaine abuse can result in AIN, also in acute kidney injury from rhabdomyolysis and arterial hyper- tension induced by intense vasoconstriction. Deferasirox (oral iron chelator), pamidronate, amlodipine, and tyrosine kinase inhibitors (which more commonly produce nephrotic-​range proteinuria and hypertension) can cause acute kidney injury due to AIN. Differential diagnosis The differential diagnosis includes other causes of renal impairment. The differentiation of acute tubular necrosis from AIN may be dif- ficult. In this situation, renal biopsy is required to conclusively con- firm or dismiss a provisional diagnosis. In contrast, glomerulonephritis generally presents with signifi- cant proteinuria (>1 g/​day; urinary albumin:creatinine ratio (ACR)

60 mg/​mmol; urinary protein:creatinine ratio (PCR) >100 mg/​ mmol), in addition to dysmorphic red cells and granular/​cellular casts on freshly spun urine microscopy. When assessing kidney biopsy specimens, the infiltrate of mono- nuclear cells needs to be differentiated from a monoclonal infiltrate, which would be found be in renal lymphoma or leukaemia. Table 21.9.1.1  Clinical features of AIN (data pooled from several studies). Acute kidney injury 100% Acute kidney injury requiring renal replacement therapy 40% Arthralgia 45% Rash 18% Fever 32% ‘Allergic triad’ (fever, rash, and arthralgia) 10% Eosinophilia 31% Nonvisible haematuria 67% Visible haematuria 5% Leucocyturia 82% Non-​nephrotic-​range proteinuria 93% Nephrotic-​range proteinuria 2.5% Nephrotic syndrome 0.8% Proton pump inhibitors, NSAIDs, and β-​lactam antibiotics are the most commonly found causes of iatrogenic AIN. Reproduced with permission from Baker R. Acute tubulointerstitial nephritis: overview. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, et al. Oxford Textbook of Clinical Nephrology. 4th ed. Oxford: Oxford University Press (2015). Copyright © 2015 Oxford University Press.

21.9.1  Acute interstitial nephritis 4955 Clinical investigation Laboratory testing demonstrates an elevated urea and creatinine. There may be associated biochemical changes reflecting tubular dysfunction such as hypo-​ or hyperkalaemia, aminoaciduria, glyco- suria, uricosuria, or alterations in serum bicarbonate. Either type I (distal) or type II (proximal) renal tubular acidosis patterns may predominate. The full blood count may reveal a high eosinophil count (up to 80% in drug-​induced AIN caused by β-​lactam antibiotics, but less commonly in other drug-​induced causes). Microscopic examination of the urine may demonstrate eosino- phils when stained with Wright’s or Hansel’s stain. These stains are pH dependent. Other causes of eosinophils in the urine include prostatitis, bladder carcinoma, eosinophilic cystitis, and cholesterol emboli. Eosinophils in the urine have a sensitivity of 25 to 40%, a specificity of 72%, and a positive predictive value of 3 to 30%. The use of urine eosinophils as a screening test with such poor sensitivity and low positive predictive value is not recommended: it may not provide solid evidence and may delay renal biopsy and treatment. There may be nonspecific increases in inflammatory markers including erythrocyte sedimentation rate, C-​reactive protein, and globulin concentrations. The urine typically has low-​range proteinuria (<1 g/​day; urinary ACR <60 mg/​mmol; urinary PCR <100 mg/​mmol). Urinary biomarkers of acute kidney injury such as monocyte chemoattractant protein-​1 and neutrophil gelatinase-​associated lipocalin have been compared against renal biopsy findings in AIN, but remain only an experimental tool. Gallium scans have been assessed as another diagnostic tool in helping to differentiate AIN from acute tubular necrosis. They are positive in AIN but negative in the latter. Kidneys with AIN en- hance as a result of the binding of gallium-​67 to lactoferrin, which is produced, released, and found on the surface of lymphocytes within the interstitium. Although not giving a definitive diagnosis, it may be of assistance when renal biopsy is contraindicated or re- fused. Fluoro-​2-​deoxy-​d-​glucose positron emission tomography accumulates not only in cancer cells but also in the lymphocytes, macrophages, and neutrophils of inflammatory reactions, but fur- ther assessment is required to judge the utility of this imaging mo- dality in AIN. Renal biopsy is the gold standard when making the diagnosis of AIN. Its primary usefulness is to confirm or exclude a diagnosis. The clinician is often faced with a patient who presents with an elevated creatinine/​reduced estimated glomerular filtration rate, inactive urine sediment, and a long list of possible offender medications that may cause AIN. This means that a strong argument can be made for performing a renal biopsy in all cases of suspected AIN, with the exception being where the clinician is reasonably confident of the diagnosis and judges that biopsy in the particular patient would con- stitute a greater risk than that of stopping any likely offending drug and giving steroids. Treatment The diagnosis of drug-​induced AIN is vital as prompt identification and discontinuation of the causative agent facilitates recovery of renal function. Steroid treatment is problematic. Immediate verses delayed or no treatment with steroids may result in a lower subsequent creatinine level, with a correlation between the delay in steroid treatment and the final serum creatinine, but there are no randomized controlled trials, only retrospective observational data. If steroids are prescribed, then a standard regimen would be oral prednisone at 1 mg/​kg per day, tapered to zero over a 6-​ to 8-​ week period. Steroid resistance may require the addition of other immunosuppressants such as cyclophosphamide, ciclosporin, and mycophenolate. Plasma exchange has been utilized in patients testing positive for tubular basement membrane antibodies. Supportive treatment may be required if the degree of uraemia warrants, including renal replacement therapy with dialysis. Prognosis Significant recovery of renal function, with return of serum cre- atinine to baseline or near baseline, can be anticipated in most cases of AIN, but this does not happen in all cases, and some even pro- gress to endstage chronic kidney disease. The prognosis depends on the severity and degree of interstitial fibrosis. Other parameters that predict a less good outcome are high initial creatinine, renal impair- ment that has been present for more than 3 weeks, and granulomata or more pronounced interstitial cellular infiltrates on renal biopsy. The phenotype of inflammatory cells or the degree of tubulitis has not been shown to be prognostic. The pattern of recovery often follows two stages: a rapid improve- ment over 6 to 8 weeks and then a slower phase of improvement that may occur over the following 12 months. Likely developments in the near future Treatment of this condition has not been subject to the rigors of a randomized controlled trial, particularly looking at the benefits of corticosteroids. Due to the low incidence of this entity, a multicentre study would be required. This is unlikely to occur without a con- certed effort from a national clinical trials network. Future studies will be required to ascertain whether there are any epidemiological factors in patients that can predispose them to AIN. FURTHER READING Bagnis CI (2004). Herbs and the kidney. Kidney Int, 44, 1–​11. Clarkson MR, et al. (2004). Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dialysis Transplant, 19, 2778–​83. Clive DM, Vanguri VK (2018). The syndrome of tubulointerstitial nephritis with uveitis (TINU). Am J Kidney Dis, 72, 118–28. Councilman WT (1893). Acute interstitial nephritis. J Exp Med, 3, 393–​420. Dobrin RS, Vernier RL, Fish AL (1975). Acute eosinophilic inter- stitial nephritis and renal failure with bone marrow lymph node granulomas and anterior uveitis: a new syndrome. Am J Med, 59, 325–​33. Geevasinga N, et al (2006). Proton pump inhibitors and acute intersti- tial nephritis. Clin Gastroenterol Hepatol, 4, 597–​604.

21.9.2 Chronic tubulointerstitial nephritis 4956 M

21.9.2 Chronic tubulointerstitial nephritis 4956 Marc E. De Broe, Channa Yamasumana, Patrick C. D’Haese, Monique M. Elseviers, and Benjamin Vervaet

section 21  Disorders of the kidney and urinary tract 4956 González E, et  al. (2008). Early steroid treatment improves the re- covery of renal function in patients with drug-​induced acute inter- stitial nephritis. Kidney Int, 73, 940–​6. Quinto LR, Sukkar L, Gallagher M (2019). Effectiveness of cortico- steroid compared with non-corticosteroid therapy for the treatment of drug-induced acute interstitial nephritis: a systematic review. Intern Med J, 49, 562–9. Raghavan R, Eknoyan G (2014). Acute interstitial nephritis—​a re- appraisal and update. Clin Nephrol, 82, 149–​62. Randhawa P, Brennan DC (2006). BK virus infection in transplant re- cipients: an overview and update. Am J Transplant, 6, 2000–​5. Rossert J (2001). Drug-​induced acute interstitial nephritis. Kidney Int, 60, 804–​17. Ruffing KA, et al. (1994). Eosinophils in urine revisited. Clin Nephrol, 41, 163–​6. 21.9.2  Chronic tubulointerstitial nephritis Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers,
and Benjamin Vervaet ESSENTIALS Chronic tubulointerstitial nephritis is usually asymptomatic, presenting with slowly progressive renal impairment. Urinalysis may be normal or show low-​grade proteinuria (<1.5 g/​day) and/​or pyuria. Diagnosis depends on renal biopsy, which reveals variable cellular infiltration of the interstitium, tubular atrophy, and fibrosis. There are many causes including sarcoidosis, drugs (prescribed and nonprescribed), irradi- ation, toxins, and metabolic disorders. Analgesic nephropathy—​this is characterized by renal papillary necrosis and chronic interstitial nephritis and is caused by the pro- longed and excessive consumption of combinations of analgesics, mostly including phenacetin. In the 1960s and 1970s, this was the cause of endstage renal failure in up to 20% of patients on dialysis in some countries (including Australia and Belgium), but it is now a rare condition following withdrawal of phenacetin and limitations in the over-​the-​counter availability of compound analgesic mixtures in most countries. It is associated with a high incidence of urothelial malignancy. Nonsteroidal anti-​inflammatory drugs—​the most frequent cause of permanent renal insufficiency after acute interstitial nephritis, risk factors for irreversible failure being pre-​existing renal damage, long-​ standing intake of the causative drug, slow oligosymptomatic disease development, and histological signs of chronicity. Aristolochic acid nephropathy—​Chinese herb nephropathy—​first recognized in women presenting with renal failure, often near endstage, following exposure to a slimming regimen containing Chinese herbs. Renal biopsy reveals extensive interstitial fibrosis with atrophy and loss of the tubules, but with little cellular infiltration. It is caused in most cases by aristolochic acid, and is associated with a high incidence of urothelial malignancy. Aristolochic acid nephropathy—​Balkan endemic nephropathy—​a chronic, familial, noninflammatory tubulointerstitial disease of the kidneys that is associated with a high frequency of urothelial atypia, occasionally culminating in tumours of the renal pelvis and ur- ethra. Prevalence is very high in farmers living along the valley of the Danube and its tributaries. It has clear clinical and pathological simi- larities with Chinese herb nephropathy, and is likely to be caused in genetically predisposed people by exposure to aristolochic acid. 5-​Aminosalicylic acid—​used in the treatment of chronic inflam- matory bowel disease and causes clinical nephrotoxicity in approxi- mately 1 in 4000 patients/​year. Inflammation can persist in the renal interstitium for months or years after stopping the drug, and renal impairment can continue to worsen even after the drug is stopped. Chronic interstitial nephritis in agricultural communities (CINAC)—​ nonproteinuric chronic kidney disease that presents in young, agri- cultural workers in Central America, Sri Lanka, India, Egypt, Tunisia, Senegal and Peru in the absence of any clear aetiology. The major risk factors are the combination of exposure to herbicides used in high quantities without any protection by agricultural workers in a hot climate. Presentation is with nonspecific symptoms. Urinalysis gen- erally shows low-​level proteinuria but no haematuria. Histological features include tubular atrophy and fibrosis coupled with chronic glomerular changes. IgG4-​related kidney disease—​this refers to any form of renal involve- ment by IgG4-​related disease, most commonly tubulointerstitial nephritis, which presents as acute or chronic renal insufficiency, renal mass lesions, or both, detectable by renal imaging. Lithium—​the most common renal side effect is to cause nephrogenic diabetes insipidus. Long-​term treatment does not af- fect the glomerular filtration rate in most patients, but 20% develop chronic renal insufficiency. It is likely that the serum concentration of lithium is important, and that renal damage is more probable if the serum concentration is consistently high, or if there are repeated episodes of lithium toxicity. Radiation nephropathy—​preventive shielding of the kidneys in patients receiving radiation therapy generally prevents radiation nephropathy, but total body irradiation preceding bone marrow trans- plantation leads 20% to develop chronic renal failure in the long term. Nephropathies induced by toxins. (1) Lead—​a diagnosis of lead neph- ropathy should be considered in any patient with progressive renal failure, mild to moderate proteinuria, significant hypertension, a his- tory of gout, and an appropriate history of exposure. (2) Cadmium—​ exposure to high levels of cadmium is clearly toxic to the kidneys, but in the environmentally exposed population, its renal effects appear to be mild and not associated with progressive renal impairment. Nephropathies induced by metabolic disorders. (1)  Chronic hypokalaemia—​can induce interstitial fibrosis, tubular atrophy, and cyst formation that is most prominent in the renal medulla. (2) Chronic urate nephropathy—​persistent hyperuricaemia can lead to the depos- ition of microtophi of amorphous urate crystals in the interstitium, with a surrounding giant cell reaction (‘gouty nephropathy’). However, clinical evidence linking chronic renal failure to gout is weak; renal dysfunction can be documented only when the serum urate concen- tration is higher than 10 mg/​dl (600 µmol/​litre) in women and higher than 13 mg/​dl (780 µmol/​litre) in men for prolonged periods.

21.9.2  Chronic tubulointerstitial nephritis 4957 Drug-​induced nephropathies Three well-​described forms of drug-​induced chronic interstitial nephritis—​analgesic nephropathy, 5-​aminosalicylic acid (5-​ASA) nephropathy, and Chinese herb nephropathy—​are compared and contrasted in Table 21.9.2.1, along with a fourth condition, Balkan endemic nephropathy (BEN). Analgesic nephropathy Analgesic nephropathy is a specific form of renal disease charac- terized by renal papillary necrosis and chronic interstitial nephritis caused by the prolonged and excessive consumption of analgesics. It is invariably caused by compound analgesic mixtures containing aspirin or other antipyretic agent in combination with phenacetin, paracetamol, or salicylamide, and caffeine or codeine in popular over-​the-​counter proprietary medicines. In the recent past, analgesic nephropathy was one of the com- moner causes of chronic renal failure, particularly in Australia and parts of Europe. Estimates made before phenacetin was removed from over-​the-​counter analgesics and before the enactment of le- gislation making combined analgesic preparations only available by prescription (in Sweden, Canada, and Australia) suggested that analgesic nephropathy was responsible for 13 to 20% of cases of endstage renal failure in Australia and some countries in Europe (such as Belgium and Switzerland). In the United States of America as a whole, a prevalence of 1 to 3% was found, and in areas of North Carolina, up to 10%. During the 1990s, there was a clear decrease in the prevalence and incidence of the condition among patients under- going dialysis in several European countries and Australia. Most au- thors have associated this decrease with the removal of phenacetin from analgesic mixtures, but it is impossible to draw definitive con- clusions from the epidemiological observations since other factors, such as eligibility criteria for dialysis treatment and the availability of remaining analgesic mixtures, may also have had an influence. The presence of analgesic nephropathy further decreased in recent years with incidence rates in patients starting chronic renal replacement therapy of 2.2% in Belgium (2008), 1.6% in Australia (2010), and 0.2% in the United States (2011). In developing countries, however, first data in dialysis patients were recently reported with prevalences of 3.5% in Sudan, 5% in Saudi Arabia, and 5% in Egypt. Pathogenesis and pathology The aetiology of analgesic nephropathy remains controversial, and the question of which kinds of analgesic are nephrotoxic is still a matter of debate. Experimental studies, mainly using rats fed with large amounts of drugs, sometimes aggravating the renal effects by dehydration or by introducing sepsis, have produced results that have been difficult to interpret, but it could be concluded that renal papillary necrosis was most frequently observed after the adminis- tration of aspirin in combination with phenacetin or paracetamol. In humans, the long-​standing excessive use of analgesics observed in patients with analgesic nephropathy is preferentially that of anal- gesic mixtures rather than single agents, with abusers taking these products for their mood-​altering effects rather than for the relief of physical complaints, hence all these mixtures contain caffeine and/​ or codeine, substances that can create psychological dependence. In most of the early reports of analgesic nephropathy, nearly all pa- tients had taken large amounts of analgesic mixtures containing phenacetin. In a variety of case–​control studies, patients with renal failure ranging from newly diagnosed chronic kidney disease (CKD, stages 1–​3) to endstage renal disease, and the specific diagnosis of renal papillary necrosis, have been compared with a variety of controls. The definition of ‘minimal analgesic abuse’ has varied consider- ably, from a frequency of twice a week to daily, and from a period of 1 month to 1 year. However, overall the findings show that analgesic abuse is associated with an exceptionally high relative risk of 17.2 with regard to papillary necrosis, a risk of between 2.2 and 2.9 with regard to CKD or endstage renal failure in four studies, and with nonconclusive results in other studies. The mechanisms responsible for renal injury are incompletely understood. The final injury is most probably due to both the Table 21.9.2.1  Differential diagnosis of some forms of chronic interstitial nephritis Analgesic nephropathy 5-​Aminosalicylic acid nephritis Chinese herb nephropathy Balkan endemic nephropathy Course

10–​15 years 6 months 6 months–​2 years 20 years Kidney imaging Shrunken, irregular contours, papillary calcifications Slightly shrunken, smooth, no calcifications Shrunken, irregular con- tours, no calcifications Shrunken, smooth surface, no calcifications Histology: •  Cellular infiltration ++ +++

•  Fibrosis ++ ++ ++ ++ •  Atrophy ++ + ++ +++ Capillary sclerosis + ?–​ ?/​+ + Apoptosis ? ? ? + Urothelial malignancies +a –​ + + Familial occurrence –​ –​ –​ + Aetiology Analgesics + addictive substances 5-​ASA + additional factors Aristolochic acid + vaso- active substances Aristolochic acid + genetic predisposition a As long as phenacetin was part of the analgesic mixture.

section 21  Disorders of the kidney and urinary tract 4958 haemodynamic and cytotoxic effects of phenacetin metabolized to acetaminophen and aspirin converted to salicylate, resulting in pap- illary necrosis and interstitial fibrosis (Fig. 21.9.2.1). The renal damage induced by analgesics is most prominent in the medulla. The earliest changes consist of thickening of the vasa recta capillaries (capillary sclerosis) and patchy areas of tubular necrosis; similar vascular lesions can be found in the renal pelvis and ureter, suggesting that the primary effect is damage to the vascular endothe- lial cells. Later changes include areas of papillary necrosis and sec- ondary cortical injury, with focal and segmental glomerulosclerosis and interstitial infiltration and fibrosis. Clinical features The renal manifestations of analgesic nephropathy are usually nonspecific; renal function is normal or there is slowly progressive chronic renal failure, and urinalysis may be normal or may reveal sterile pyuria and mild proteinuria (<1.5 g/​day). Hypertension and anaemia are commonly seen with moderate to advanced disease. Most patients have no symptoms referable to the urinary tract, al- though flank pain or macroscopic/​microscopic haematuria from a sloughed or obstructing papilla may occur. Urinary tract infection is also somewhat more common in women with this disorder. Despite the nonspecific nature of the renal presentation, there are frequently other findings that point towards the presence of analgesic nephropathy. Most patients are female and between the ages of 30 and 70 years. Careful questioning often reveals a history of chronic headaches or low back pain that leads to the analgesic use. Also common are other somatic complaints (such as malaise and weakness), and ulcer-​like symptoms or a history of peptic ulcer disease due in part to chronic aspirin ingestion. The decline in renal function can be expected to progress if an- algesics are continued, whereas renal function stabilizes or slightly improves in most patients if analgesic consumption is discontinued. However, if the renal disease is already advanced, then progres- sion may occur in the absence of drug intake, presumably due to secondary haemodynamic and metabolic changes associated with nephron loss. The late course of analgesic nephropathy may also be complicated by urinary tract malignancy, which will develop in as many as 8 to 10% of patients with analgesic nephropathy. The tumours generally become apparent after 15 to 25 years of analgesic abuse, usually but not always in patients with clinically evident analgesic nephropathy. Most patients are still taking the drug at the time of diagnosis, but clinically evident disease can first become apparent several years after cessation of analgesic intake and even after renal transplant- ation. The main presenting symptom of urinary tract malignancy in patients with analgesic nephropathy is microscopic or gross haema- turia, hence continued monitoring is essential, and new haematuria should be evaluated by urinary cytology and, if indicated, cystoscopy with retrograde pyelography. The incidence of urothelial carcinoma after renal transplantation in patients with analgesic nephropathy is comparable to the incidence (up to 10%) of urothelial carcinomas in patients with endstage renal failure due to analgesic nephrop- athy. Removal of the native kidneys before renal transplantation has been suggested, but the efficacy of this regimen has not been proven. Moreover and regardless of an established diagnosis of analgesic nephropathy, analgesic abuse as such forms an increased risk for the development of cancers of the kidney and urinary tract in patients on dialysis and after transplantation. Diagnosis and treatment The lack of reliable criteria for diagnosis and yet the apparent high prevalence of analgesic nephropathy during the 1980s in Belgium (17.9% in 1984) led us to perform a series of prospective multicentre controlled studies to define and validate the diagnostic criteria for this disease. We provided strong evidence that specific anatomical changes, best seen by noncontrast CT scan, have much greater sen- sitivity and specificity than other clinical signs and symptoms in the diagnosis of endstage renal disease due to analgesic nephrop- athy. These changes are (1) a decrease in renal volume, (2) bumpy renal contours, and (3) papillary calcifications (Fig. 21.9.2.2). These observations were validated in a representative sample of patients with analgesic abuse with endstage renal disease and extended to patients with moderate renal failure. Papillary calcifications had the highest sensitivity and specificity. A decrease in volume com- bined with bumpy contours and/​or papillary calcifications showed a sensitivity of 90% and a specificity of 90% in patients with endstage renal failure, and a sensitivity of 77% and a specificity of 100% in those with moderate renal failure. In clinical practice, however, it is important to remember that the predictive value of this test, like any other diagnostic test, is very much dependent on the prevalence of the disease in the population under study. It should therefore be Synergistic toxicity of analgesics in the renal inner medulla Aspirin MFO Cyt p450 Paracetamol Renal papillary concentration Prostaglandin synthase Salicylate Glutathione depletion N-acetyl-p-benzoquinoneimin Arylation of renal papillary protein

21.9.2  Chronic tubulointerstitial nephritis 4959 utilized in patients with a reasonable risk for analgesic nephropathy and not as a general screening test. As indicated previously, patients with normal or only mildly/​ moderately impaired renal function should be strongly encouraged to stop taking analgesics in the hope that further deterioration in renal function can be avoided. Those with severe or endstage renal failure will not recover renal function, although there may be other valid medical reasons for recommending that they stop ingesting large quantities of analgesics. The medical management of chronic renal failure is along conventional lines, as is provision of renal re- placement therapy. Nonsteroidal anti-​inflammatory drugs Nonsteroidal anti-​inflammatory drugs (NSAIDs) are popular for treating a wide range of clinical conditions and are available both over the counter and on prescription. Despite their usefulness, there is substantial evidence from experimental and clinical studies that they have a variety of effects on the kidney. The most common renal disorder associated with NSAIDs is acute, largely reversible, insuffi- ciency due to the inhibition of renal vasodilatory prostaglandins in the clinical setting of a stimulated renin–​angiotensin system. Older age, hypertension, concomitant use of diuretics or aspirin, pre-​ existing renal failure, diabetes, and plasma-​volume contraction are known risk factors for renal failure after the ingestion of NSAIDs. Less commonly, NSAIDs may cause acute interstitial nephritis with proteinuria. NSAIDs may worsen the underlying hyperten- sion. Electrolyte and fluid abnormalities including hyperkalaemia, hyponatraemia, and oedema may occur. In contrast to the well-​characterized acute effects of NSAIDs on the kidney, the chronic effects are less well documented. However, NSAIDs are the most frequent cause of permanent renal insufficiency after acute interstitial nephritis. Risk factors for irreversible failure are pre-​existing renal damage, long-​standing intake of the causative drug, slow oligosymptomatic disease development, and histological signs of chronicity with those of acute interstitial nephritis. Although renal papillary necrosis and chronic renal failure can occur after the prolonged use of NSAIDs, the actual risk of these serious compli- cations is unknown. The frequency of renal papillary necrosis in the context of NSAID intake as a primary or contributing cause of endstage renal disease is also unknown, but most likely very low. Aristolochic acid nephropathies Until recently, two types of chronic interstitial nephritis were con- sidered as two separate entities named respectively Chinese herb nephropathy and BEN. The cause of Chinese herb nephropathy was from the time of its clinical detection attributed to the consumption of a plant, Aristolochia fangchi, which contained the nephrotoxin aristolochic acid. By contrast, the aetiology of BEN was for decades the subject of many hypotheses. However, clinical, histopathological, epidemiological, and toxicological data convincingly suggest that long-​term exposure to aristolochic acid-​contaminated food is the aetiological factor in BEN, such that aristolochic acid nephropathy has been proposed as a more correct term for this condition. Aristolochic acid nephropathy—​Chinese herb nephropathy In 1992, physicians in Belgium noted an increasing number of women presenting with renal failure, often near endstage, following their exposure to a slimming regimen containing Chinese herbs. An initial survey of seven nephrology centres in Brussels identi- fied 14 women under the age of 50 who had presented over a 3-​year period with advanced renal failure due to biopsy-​proven chronic tubulointerstitial nephritis, nine of whom had been exposed to the same slimming regimen. As of early 2000, a total of more than (a) Diagnostic criteria used (b) CT scans RA Right kidney B Decreased: A + B <103 mm (males) <96 mm (females) Bumpy contours 0 1–2 3–5

5 B A SP A RA Left kidney Moderate renal failure Endstage renal failure RV Renal size Indentations Papillary calcifications Fig. 21.9.2.2  Diagnostic criteria of analgesic nephropathy.

section 21  Disorders of the kidney and urinary tract 4960 (b) (a) Fig. 21.9.2.3  Renal biopsy from a patient with Chinese herb nephropathy showing tubular atrophy, widening of the interstitium, cellular infiltration, and fibrosis, with glomeruli surrounded by a fibrotic ring. Masson staining (a), haematoxylin and eosin staining (b). 120 cases had been identified. The epidemiology is unknown, as is the risk for the development of severe renal damage, but the recent publication of case reports from several countries in Europe and Asia would seem to indicate that the incidence of herbal medicine-​ induced nephrotoxicity is more common than previously thought. Pathogenesis and pathology The aetiology of Chinese herb nephropathy is aristolochic acid found in the Aristolochia plant. However, in addition to aristolochic acid, patients with ‘Chinese herb nephropathy’ detected in the Brussels area also received the appetite suppressants fenfluramine and diethylpropion, which have vasoconstrictive properties, and acetazolamide, which alkalinizes the urine, thereby potentially enhancing the nephrotoxic effect of aristolochic acid, although a re- cent experimental study did not support this hypothesis. Another uncertain factor is why only some patients exposed to the same herbal preparations develop renal disease. Women ap- pear to be at greater risk than men, and other factors that might be important include toxin dose, batch-​to-​batch variability in toxin content, individual differences in toxin metabolism, and a genet- ically determined predisposition towards nephrotoxicity and/​or carcinogenesis. The main histological lesion, which is located principally in the cortex, is extensive interstitial fibrosis with atrophy and loss of the tubules (Fig. 21.9.2.3). Cellular infiltration of the interstitium is scarce. Thickening of the walls of the interlobular and afferent ar- terioles results from endothelial cell swelling. The glomeruli are rela- tively spared and immune deposits are not observed. These findings suggest that the primary lesions may be centred in the vessel walls, thereby leading to ischaemia and interstitial fibrosis. At one centre in Belgium, 19 native kidneys and ureters were removed in a series of 10 patients during and/​or after renal trans- plantation. Multifocal, high-​grade, flat, transitional cell carcinoma (carcinoma in situ) was observed in four (40%), while all had multi- focal moderate atypia. Tissue samples revealed aristolochic acid-​ related DNA adducts, indicating a possible mechanism underlying the development of malignancy. In another study of 39 patients with Chinese herb nephropathy and endstage renal disease who underwent prophylactic removal of the native kidneys and ureters, urothelial carcinoma was discovered in 18 and mild to moderate urothelial dysplasia in 19. All atypical cells were found to overexpress a p53 protein, suggesting the presence of a mutation in the gene. Clinical features Patients present with renal insufficiency and other features indicating a tubulointerstitial disease. Blood pressure is either normal or only mildly elevated, and the urinary sediment reveals only a few red and white cells. The urine contains protein (<1.5 g/​ day), consisting of both albumin and low molecular weight pro- teins that are normally reabsorbed by the proximal tubules, hence tubular dysfunction—​also marked by glycosuria—​contributes to the proteinuria. The plasma creatinine concentration at presen- tation has ranged from 1.4 to 12.7 mg/​dl (123–​1122 µmol/​litre). Follow-​up studies have revealed relatively stable renal function in most patients with an initial plasma creatinine concentra- tion below 2 mg/​dl (176 µmol/​litre) once the intake of the drug has been stopped. However, progressive renal failure resulting in eventual dialysis or transplantation may ensue in patients with more severe disease, even if further exposure to Chinese herbs is prevented. A similar clinical and pathological process has been reported in a group of patients from Taiwan who had ingested a selec- tion of uncontrolled traditional Chinese herbs that differed from those of the slimming regimen. Despite discontinuation of these remedies, progressive renal failure was common. In recent years, this disease has been diagnosed in many countries throughout the world, particularly in mainland China. Diagnosis and treatment There are no specific criteria for the diagnosis of this type of renal disease. The condition should be suspected in any patient with un- explained relatively rapidly progressive renal disease who is using/​ abusing herbal remedies. The presence of tubular proteinuria may be a clue to the diagnosis, particularly in the early stages. The histo- logical appearances are not specific, but renal biopsy is necessary to exclude other conditions in this clinical context.

21.9.2  Chronic tubulointerstitial nephritis 4961 There is no proven effective therapy for this disorder, which typ- ically presents with marked interstitial fibrosis without prominent inflammation, although an uncontrolled study suggested that cor- ticosteroids may slow the rate of loss of renal function. The high incidence of cellular atypia of the genitourinary tract suggests that, as a minimum, these patients should undergo regular surveillance for abnormal urinary cytology. Whether more aggressive manage- ment strategies, such as bilateral native nephroureterectomies (par- ticularly in those undergoing renal transplantation), are required is unclear. Findings from a recent report support the more aggressive option. Renal transplantation is an effective modality for those who progress to endstage renal disease; one report noted no recurrence in five patients. Aristolochic acid nephropathy—​Balkan endemic nephropathy BEN is a chronic, familial, noninflammatory tubulointerstitial disease of the kidneys that is associated with a high frequency of urothelial atypia, occasionally culminating in tumours of the renal pelvis and urethra. Epidemiology As the name suggests, BEN is most commonly seen in south-​eastern Europe, including the areas traditionally considered to comprise the Balkans, that is, Serbia, Bosnia and Herzegovina, Croatia, Romania, and Bulgaria. It is most likely to occur among those living in the valley of the Danube river and its tributaries, a region in which the plains and low hills generally have a high humidity and rainfall (Fig. 21.9.2.4). There is a very high prevalence in endemic areas, with rates ranging between approximately 0.5 and 4.4%, increasing to as high as 20% if the disorder is suspected and carefully screened for among an at-​risk population. The prevalence of BEN has remained stable over the last 40 to 50 years in two of the sites where the con- dition was first recognized. A striking observation is that nearly all affected patients are farmers. Pathogenesis Environmental factors Given that the condition is endemic to a specific geographic area, toxins and/​or environmental exposures that are unique to the Balkans have been investigated for many years. In 1969, Ivić proposed that ingestion of flour contaminated with seeds from Aristolochia clema- titis may be the cause of BEN. He noted that seeds from these plants, which grew abundantly in local wheat fields, comingled with wheat grain during the harvesting process. He administered Aristolochia seeds to animals, which developed renal damage, and speculated that human exposure to a toxic component of Aristolochia seeds could occur through ingestion of bread prepared with flour derived from contaminated grain. However, his field surveys and data failed to provide convincing evidence, and his astute observations were neglected for many decades. The clinical expression and pathological lesions observed at dif- ferent stages of Chinese herb nephropathy and BEN are strikingly similar, except for their rate of progression towards endstage renal failure, but recognition that aristolochic acid was implicated in the pathogenesis of BEN followed the finding by Grollman and col- leagues of aristolochic acid-​derived DNA adducts in renal cortical and urothelial tumour tissue of patients, with dominance of A:T and T:A transversions in the TP53 tumour suppressor gene mutational spectrum. The evidence has been further strengthened by the obser- vation that mutational spectra in urothelial cancers among BEN pa- tients resemble the mutational ‘signature’ observed in cultured cells and rodents treated with aristolochic acid. Genetic factors Support for a genetic component to aetiology includes observa- tions that the disease clearly affects particular families, and that some ethnic populations who have lived in endemic areas for gen- erations do not develop BEN. The mode of inheritance has not yet been established and possible causative gene(s) have not been identified, but a locus in the region between 3q25 and 3q26 has SLOVENIA HUNGARY CROATIA BOSNIA SERBIA ROMANIA BULGARIA ALBANIA MONTENEGRO Sava Zagreb Danube Sarajevo Sofia Sava M o rav a D a n u b e Belgrade Fig. 21.9.2.4  Foci of Balkan endemic nephropathy.

section 21  Disorders of the kidney and urinary tract 4962 been incriminated. However, some observations are inconsistent with a genetic basis. First, BEN is observed in individuals who have immigrated into the Balkan area from regions without the disorder, and in previously unaffected families who have lived for at least 15 years in endemic areas. Second, BEN does not develop in members from previously affected families who have left en- demic areas early in life or who spent less than 15 years in these areas. An obvious unifying hypothesis is that the disease occurs in genetically predisposed individuals who are chronically exposed to aristolochic acid. Pathology In the early stages of disease, renal histology reveals focal cortical tubular atrophy, interstitial oedema, and peritubuloglomerular sclerosis with limited mononuclear cell infiltration. Narrowing and endothelial swelling of interstitial capillaries (e.g. capillary sclerosis) is also described. In advanced cases, marked tubular at- rophy and interstitial fibrosis develop along with focal segmental glomerular changes and global sclerosis. There is an extremely high incidence of cellular atypia and urothelial carcinoma of the genitourinary tract. Clinical features BEN is a slowly progressive tubulointerstitial disease that may cul- minate in endstage renal disease. Clinical manifestations first appear between 30 and 50 years of age, with findings before the age of 20 being extremely rare. One of the first signs is tubular dysfunction, which is characterized by an increased excretion of low molecular weight proteins (such as β2-​microglobulin). Early tubular injury can also lead to renal glycosuria, aminoaciduria, and diminished ability to handle an acid load. Over a period of more than 20 years there is a progressive decrease in concentrating ability (resulting in polyuria) and in the glomerular filtration rate (resulting in endstage renal disease). Patients are usually without oedema and normo- tensive, with hypertension only developing with endstage disease. A normochromic normocytic anaemia occurs with early disease, which becomes increasingly pronounced as the disorder progresses. Urinary tract infection is rarely observed. Kidneys are of normal size early in the course of the disease, but a symmetrical reduction of kidney size with a smooth outline and normal pelvicalyceal system is subsequently observed in patients with late-​stage disease. Intrarenal calcifications are not seen. BEN is also associated with the development of transitional cell carcinoma of the renal pelvis or ureter, with studies noting a wide range in incidence (from 2 to nearly 50%). These tumours are gener- ally superficial and slow-​growing. Diagnosis and treatment The diagnosis of BEN is based on the presence of some combination of the following findings: • Symmetrically shrunken kidneys with absence of intrarenal calcifications • Farmers living in the villages where BEN occurs • Familial history positive for BEN • Mild tubular proteinuria and hyposthenuria (inability to concen- trate the urine normally) • Normochromic/​hypochromic anaemia occurring in patients with only slightly impaired renal function Since it has been demonstrated that Chinese herb nephropathy and Balkan endemic nephropathy have a common aetiological factor, i.e. aristolochic acid containing food (bread) or pills (slim- ming regimens), primary prevention can be considered. The high incidence of cellular atypia in the genitourinary tract suggests that regular surveillance should be performed for abnormal urinary cytologies. Whether bilateral native nephroureterectomies are required, particularly in those undergoing renal transplantation, is unclear. 5-​Aminosalicylic acid There is an association between the use of 5-​ASA in patients with chronic inflammatory bowel disease and the development of a par- ticular type of chronic tubulointerstitial nephritis. For many years, sulfasalazine, an azo-​compound derived from sulfapyridine and 5-​ASA, the latter being the pharmacologically active moiety, was the only valuable noncorticosteroid drug in the treatment of inflammatory bowel disease. Since the therapeutic- ally inactive sulfapyridine moiety was largely responsible for the mainly haematological side effects of sulfasalazine, this stimulated the development of several new 5-​ASA formulations (mesalazine, olsalazine, balsalazide) for topical and oral use. These new 5-​ASA products replaced sulfasalazine as the first-​line therapy for mildly to moderately active inflammatory bowel disease. However, a literature search revealed 17 published cases of renal impairment associated with 5-​ASA therapy in patients with inflammatory bowel disease, and in several it was shown that this did not recover completely on stopping the drug, even after a follow-​up period of several years. In a retrospective study, nephrologists reported 40 patients with inflam- matory bowel disease showing renal impairment, including 15 cases with interstitial nephritis and previous use of 5-​ASA. Stimulated by these findings we started a European prospective registration study aiming to register all patients with inflammatory bowel disease and renal impairment and to control for a possible association with 5-​ ASA therapy. A cohort of 1449 patients with inflammatory bowel disease seen during 1 year in the outpatient clinics of 28 European gastroenterology departments was investigated. Preliminary re- sults showed 30 patients (2%) with decreased renal function, and a possible association with 5-​ASA therapy was found in one-​half of them. A recent study estimated the incidence of clinical nephrotox- icity in patients taking 5-​ASA as 1 in 4000 patients/​year. However, determining the cause of renal disease in those with in- flammatory bowel disease is not straightforward. The most frequent renal complications are oxalate stones and their consequences, such as pyelonephritis, hydronephrosis, and (in the long term) amyloid- osis. Chronic inflammatory bowel disease is also associated with glomerulonephritis and minimal-​change glomerulonephritis, mem- branous, membranoproliferative, and focal glomerulosclerosis, and proliferative crescentic glomerulonephritis have all been reported. As for many drugs, reversible acute interstitial nephritis has been described with the use of 5-​ASA compounds. In view of this com- plexity, the association of 5-​ASA and chronic interstitial nephritis in patients with inflammatory bowel disease can be difficult to in- terpret, since renal involvement may be an extraintestinal mani- festation of the underlying disease. However, the particular form of chronic tubulointerstitial nephritis in patients with inflammatory bowel disease treated with 5-​ASA is characterized by an important cellular infiltration of the interstitium with macrophages, T cells, and also B cells (Fig. 21.9.2.5).

21.9.2  Chronic tubulointerstitial nephritis 4963 Pathogenesis and pathology That 5-​ASA causes renal disease is supported by the number of case reports in the literature of patients with inflammatory bowel disease using 5-​ASA as their only medication, the improvement (at least partially) of impaired renal function on stopping the drug, and a worsening after resuming 5-​ASA use. Furthermore, the molecular structure of 5-​ASA is very close to that of salicylic acid, phenacetin, and aminophenol, drugs with well-​documented nephrotoxic po- tential (Fig. 21.9.2.1). Calder and colleagues found that necrosis of the proximal convoluted tubules and papillary necrosis developed in rats after a single intravenous injection of 5-​ASA at doses of 1.4, 2.8, and 5.7 mmol/​kg body weight (high pharmacological doses). The mechanism of renal damage, possibly caused by 5-​ASA itself, may be analogous to that of salicylates by inducing hypoxia of renal tissues, either by uncoupling oxidative phosphorylation in renal mitochondria by inhibiting the synthesis of renal prostaglandins, or by rendering the kidney susceptible to oxidative damage by a redu- cing renal glutathione concentration after inhibition of the pentose phosphate shunt. Clinical features A typical case is shown in Fig. 21.9.2.5. An intriguing aspect of this type of toxic nephropathy is the documented persistence of the renal interstitium inflammation even several months/​years after first taking the drug. The disease is more prevalent in men, with a male-​ to-​female ratio of 15:2. The age of patients in reported cases ranges from 14 to 45 years. By contrast with analgesic nephropathy, where renal lesions are only observed after several years of analgesic abuse, interstitial nephritis associated with 5-​ASA was observed during the first year of treatment in 7 out of 17 reported cases; most of these patients had started 5-​ASA therapy with documented normal renal function. In several patients, particularly those in whom there was a delayed diagnosis of renal damage, recovery of renal function did not occur, and some needed renal replacement therapy. Diagnosis and treatment Since this type of chronic tubulointerstitial nephritis produces few if any symptoms, and if diagnosed at a late stage progresses to irrevers- ible chronic endstage renal disease, serum creatinine levels should be measured in any patient with inflammatory bowel disease treated with 5-​ASA at the start of the treatment, every 3 months for the re- mainder of the first year, and annually thereafter. The use of con- current immunosuppressive therapy, as is the case in severe forms of chronic inflammatory bowel disease, may necessitate extension to the period of intensive renal function monitoring. If serum cre- atinine increases, a renal biopsy is the only way to demonstrate the cause. Chronic interstitial nephritis in agricultural communities The main causes of CKD in developed countries are diabetes and hypertension, associated with ageing and obesity; this is also true in some developing countries. In addition to these ‘traditional’ causes, glomerular and tubulointerstitial diseases due to infections, C.P. man born 19.01.1971 0 2 4 6 8 10 12 1.1 10.6 4.9 4.2 Serum Creatinine (mg/dl) 32 mg/day HAEMODIALYSIS Methylprednisolone 16 mg/day Pentasa® 3x500 mg/day orally 4.0 3.9 3.8 03/10/91 15/03/92 23/02/94 02/03/94 22/11/94 02/12/94 06/01/95 01/05/96 01/12/96 08/05/99 22/12/94 31/12/94 05/08/00 16/08/01 4.3 5.3 Potassium (mEq/L): 03/08/02 5.4 15/03/05 7.3 HAEMODIALYSIS (a) (c) (c) (b) (b) 3.3 3.3 renal biopsy renal biopsy IBD diagnosis 2.6 2.8 Fig. 21.9.2.5  Nephrotoxicity in a patient treated with 5-​aminosalicylic acid for inflammatory bowel disease (IBD). (a) Evolution of renal failure. (b) First renal biopsy showing widening and massive cellular infiltration of the interstitium, tubular atrophy, and relative spacing of glomeruli. The cellular infiltration was identified using appropriate monoclonal antibodies and consisted not only of T cells and macrophages but also of B cells. (c) A second renal biopsy performed after the drug had been stopped for 8 months, when there was a modest improvement in renal function, again showed a significant cellular infiltration of the interstitium, tubular atrophy, and fibrosis. Thirteen years after the diagnosis of chronic interstitial nephritis was made in this young man, who had documented normal renal function at the start of treatment, haemodialysis had to be started. He is now on the waiting list for renal transplantation.

section 21  Disorders of the kidney and urinary tract 4964 nephrotoxic drugs, herbal medications, environmental toxins, and occupational exposure to pesticides—​the so-​called nontraditional causes—​contribute to the CKD burden in developing countries. However, since the 1990s, an increase in CKD prevalence not as- sociated with traditional risk factors has been reported, primarily affecting agricultural communities and male agricultural workers. This new disease, chronic interstitial nephritis in agricultural com- munities (CINAC), has become an important health problem in many countries, including El Salvador, Nicaragua, Guatemala, Costa Rica, Sri Lanka, Egypt, India, Tunisia, Senegal, and Peru. Epidemiology In Central America, growing numbers of CKD patients and in- creased CKD mortality have been observed over the last two dec- ades, particularly in Nicaragua and El Salvador. The Pan American Health Organization has reported CKD-​specific mortality (deaths per 100 000 population associated with CKD stages 3a, 3b, 4, and 5) in the region: Nicaragua (42.8), El Salvador (41.9), Guatemala (13.6), and Panama (12.3). These figures are four times the global CKD mortality rate, and up to 17 times greater than the lowest CKD mortality reported in the Americas region. As for gender, mortality rates in men are three times those of women. CKD in Central America affects mainly young men, between the third and fifth decades of life, working in agriculture (mainly sugarcane or other agricultural activities at lower altitudes and con- sequent higher temperatures). Women are less affected than men, but CKD prevalence in women is higher than CKD prevalence seen in international studies. Recent information demonstrated that CKD related mortality, rates in women and children in Ecuador and Nicaragua were up to 9 times higher was compared to control coun- tries in the area. This suggests that the heat stress hypothesis cannot fully explain this CINAC epidemy. In El Salvador farming communities the prevalence of CKD among adults is 15 to 21%. Of the patients studied, less than half have diabetes or hypertension; males predominate, and renal damage begins early in life. Women, men, adolescents, and children who live in farming communities are affected, whether they work in the fields or not; and people living in highlands and lowlands are all at risk. Environmental and occupational investigations demonstrate the presence of pesticides and heavy metals (cadmium and arsenic) in well water, dirt floors in homes, and farmlands (being more con- centrated in fields under cultivation). In addition, farmers carrying out intense physical activity during long hours exposed to high tem- peratures, with insufficient hydration and unprotected use of agro- chemical agents are more vulnerable to develop CINAC. Various terms are used for CINAC in the medical literature: CKD of unknown origin, CKD of uncertain origin, CKD of unknown aeti- ology, or agrochemical nephropathy. In some cases, it is named for the region or country where it appears: Central American nephrop- athy, Salvadoran agricultural nephropathy, Mesoamerican endemic nephropathy, chronic tubulointerstitial kidney disease of Central America, Udhanam endemic nephropathy (India), or Sri Lankan agricultural nephropathy. Diagnosis There is no consensus on a case definition for CINAC, The diag- nosis is presumed when patients fulfill CKD criteria in the absence of diabetes, hypertension, glomerular proteinuric disease, poly- cystic kidneys, obstructive uropathy, or other recognized causes, in conjunction with three general conditions—​poverty with all its repercussions, unhealthy working conditions, and a contaminated environment. In Sri Lanka, CINAC is defined as CKD in the absence of a past history of diabetes, chronic or severe arterial hypertension, snake bite, or glomerulonephritis or other urinary tract disease, and with normal glycosylated haemoglobin (<6.5%) and blood pressure less than 160/​100 mmHg in untreated patients or less than 140/​ 90 mmHg in patients receiving up to two antihypertensive drugs. Clinical features The disease emerges in the context of social determinants led by poverty and its consequences, and provokes a profound psycho- logical impact on patients and the community. CINAC is usu- ally asymptomatic and presents with slowly progressive renal impairment. Some of the general symptoms reported in early stages of the disease include arthralgia, asthenia, decreased libido, cramps, and fainting. Regarding renal symptoms, disorders of micturition are most common: nocturia, dysuria, post-​void dribbling, urinary hesi- tancy, and foamy urine. All symptoms appear as early as CKD stage 2 and tend to increase as the disease advances. Blood pressure is either normal or only mildly elevated. Tendon reflex abnormalities are seen as early as CKD stage 2. Sensorineural hearing loss may be evident. Fundoscopic examination, intraocular pressure, and visual fields tests are mostly normal. As for markers of renal damage, the urine sediment shows no significant abnormalities or dysmorphic erythrocytes. Proteinuria, mostly moderate, can be observed. Excretion of tubular proteins such as β2-​microglobulin and neutrophil gelatinase-​associated lipocalin (NGAL) are elevated, suggesting tubular dysfunction. Analysis of a 24-​h urinary collection typically shows polyuria char- acterized by hypermagnesuria, hyperphosphaturia, hypernatriuria, hyperkaliuria, and hypercalciuria. Fractional excretion of magne- sium and sodium is increased. Serum electrolytes reflect the excess excretion observed in urine. Blood osmolality is normal, as (usually) is the urinary osmolality. The predominant acid–​base balance dis- order reported is a metabolic alkalosis. Acid–​base and electrolyte disorders in urine and blood begin to appear in CKD stage 2. The absence of acidosis could indicate a relative conservation of the distal segment of the nephron, with bicarbonate reabsorption and hydrogen ion excretion. Renal ultrasound imaging shows increased echogenicity, a decreased corticomedullary ratio, and irregular renal margins. Renal Doppler ultrasonography reports normal blood flow in renal arteries, segmental arteries, and renal parenchyma. Doppler ultrasound examination of peripheral arteries is more likely to reveal changes of atherosclerosis in the tibial artery than the ca- rotid and aortoiliac arteries. One hypothesis for this selective damage to tibial arteries could be their greater occupational con- tact with toxic substances. Farmers’ legs, sometimes bare, are the parts most exposed to agrochemicals from spraying, which is done using backpack applicators at high ambient temperatures, with consequent vasodilation and opening of skin pores. Paddy farmers immerse their legs long periods in agrochemical rich muddy soil.

21.9.2  Chronic tubulointerstitial nephritis 4965 Pathogenesis and pathology The morphological pattern described is a chronic tubulointerstitial nephropathy with secondary glomerular and vascular damage. The main findings are interstitial fibrosis and tubular atrophy, with or without inflammatory monocyte infiltration. In addition, generalized sclerosis, increased glomerular size, collapse of some glomerular tufts, and lesions of extraglomerular blood vessels (such as intimal proliferation and thickening and vacuolization of the tunica media) are also observed. This pattern is consistent with tubulointerstitial nephritis, but in different degrees depending on sex (greater in males than females), occupation (greater in sugarcane agricultural workers than nonsugarcane agricultural workers, and lesser in nonagricultural workers) and CKD stage. There are nonspecific deposits of IgM, C3, and C1q in the glomeruli, but no immunoglobulin deposits in the tubules or interstitium. In add- ition to the known histopathology, a unique constellation of lesions was identified. At EM, proximal tubular cells (PTCs) demonstrated large dysmorphic lysosomes with a light-medium electron dense ma- trix containing dispersed dark electron-dense non-membrane bound ‘aggregates’, and were histologically associated with varying degrees of cellular/tubular atrophy, apparent cell fragments shedding and no to weak PTC proliferative capacity (Fig. 21.9.2.6). Aetiology Two aetiological hypotheses for CINAC in Central America—​both multifactorial but emphasizing different primary triggers—​have been proposed: one related to heat stress with repeated episodes of rhabdomyolysis and dehydration; the other related to toxic exposures (pesticides) at work and in the environment of agricultural commu- nities. In Sri Lanka, a similar hypothesis has been developed, in which multiple heavy metals act synergistically with agrochemicals such as glyphosate and their residues. A recent meta-analysis indicated that there is no consistent evidence to support an association between, CKD and heat stress/dehydration. In contrast, a consistent evidence for the adverse effect of agrochemicals and CKD was observed. The presence of extrarenal clinical manifestations (neurological, hearing, and lower limb arteries) supports arguments for a toxic causal factor (heavy metals, chemical or microbial substances), with (a) (b) (c) (d) 20 μm 3 μm 1 μm 30 μm * * * * * * Fig. 21.9.2.6  (a) Proximal tubule (asterisk) demonstrating accumulation of enlarged intracellular argyrophylic granules (Jones silver stain). (b) Fluorescent staining for the lysosomal marker Cathepsin B demonstrating increased fluorescence in some tubules (asterisks). Insert: Jones silver staining of the white marked region demonstrating that Cathepsin B positive granules are argyrophylic. (c) Electron microscopic image of proximal tubular cells containing enlarged dysmorphic granules, consistent with lysosomes, and containing dispersed electrondense aggregates. (d) detail of white marked region in c. Images from Sri Lankan CINAC patients.

section 21  Disorders of the kidney and urinary tract 4966 Table 21.9.2.2  Major organ manifestations of IgG4-​related disease Pancreas Type 1 autoimmune pancreatitis Salivary glands Sialadenitis Eye/​orbit/​lachrymal glands Orbital inflammation/​pseudotumour and dacryoadenitis Aorta/​artery/​ retroperitoneum Periaortitis/​periarteritis and retroperitoneal fibrosis Kidney Tubulointerstitial nephritis and pyelitis Lymph nodes Lymphadenopathy Lung Lung disease (inflammatory pseudotumour, alveolar interstitial disease, and pleuritis) Biliary system Sclerosing cholangitis and cholecystitis Liver Pseudotumour and hepatopathy Central/​peripheral nervous system Pachymeningitis and infraorbital nerve swelling Endocrine system Hypophysitis and thyroiditis Others Prostatitis, mastitis, mediastinitis, pericarditis, and skin (nodules and papules) Reprinted from Saeki T and Kawano M. (2014). IgG4-​related kidney disease. Kidney Int., 85(2), 251–​7. Copyright © 2014 International Society of Nephrology, with permission from Elsevier. the kidney being the organ in the body with the most pronounced damage in view of the combination of exposure to highly concen- trated, renally excreted toxins and dehydration in situations of pro- fuse sweating and low fluid intake in hot working conditions, when the kidney is working at maximal concentrating capacity for almost 12 h/​day. Genetic susceptibility could be a conditioning factor. Other factors are contributing to this cascade of events that make individuals in these communities particularly vulnerable to possible prior kidney damage. Those are low birth weight, malaria, hyperten- sion, diabetes, obesity, smoking habit, excessive alcohol consump- tion, and use of NSAIDs and nephrotoxic medicinal plants. This hypothesis gives a broader range to public health consider- ations and action, since it puts more emphasis on determinants that are both social (economic and social vulnerability of entire farming communities) and environmental (use and abuse of agrochemicals with little or no enforcement of existing internationally accepted re- gulations), with attention also paid to labour rights in the context of occupational health and safety. Prevention Common themes among the many recommendations made are the ur- gent need for more clearly focused biological–​epidemiological–​social research programmes. Different groups agree on a holistic approach to this most likely preventable disease. Although science has not yet pro- vided conclusive answers to aetiology, the hypothesized causal factors (particularly toxins) are potentially preventable, and there is scope for action on social and environmental determinants, workplace health and safety, health promotion at individual and community levels, early detection, and timely treatment. Surveillance systems must be re- inforced to assess CINAC trends and intervention impacts. IgG4-​related kidney disease IgG4-​related disease (IgG4-​RD) is a recently recognized clinico­ pathological entity characterized by a dense lymphoplasmacytic infiltrate that is rich in IgG4-​positive plasma cells with fibrosis, and usually an elevated serum IgG4 concentration. The condi- tion was first described in relation to the pancreas, but is now con- sidered to encompass various multiorgan inflammatory conditions (Table 21.9.2.2). IgG4-​related kidney disease refers to any form of renal involve- ment by IgG4-​RD, with the most common renal manifestation being IgG4-​related tubulointerstitial nephritis, which presents as acute or chronic renal insufficiency, renal mass lesions, or both, detectable by renal imaging (contrast CT scan). Pathogenesis Although several mechanisms, including autoimmunity, allergy, or innate immunity, have been discussed, the role of IgG4 in IgG4-​RD and the pathogenesis of IgG4-​RD is poorly understood. Predominance of a Th2-​cell response and activation of regulatory T cells at affected sites have been commonly confirmed in various or- gans in association with IgG4-​RD. Production of interleukin (IL)-​4, IL-​10, and transforming growth factor-​β (TGFβ) is also markedly increased in IgG4 tubulointerstitial nephritis compared with other types of tubulointerstitial disease. Pathology In the kidney, the dominant feature associated with IgG4-​RD is plasma cell-​rich tubulointerstitial nephritis with increased IgG4-​ positive plasma cells and fibrosis. A unique and characteristic ap- pearance is IgG4-​storiform fibrosis, with an irregularly whorled pattern (somewhat resembling that of a straw mat) of nests of in- flammatory cells with irregular fibres surrounding them. This is usually revealed by periodic acid–​methenamine silver staining, with the term ‘bird’s-​eye fibrosis’ coined because it resembles the ‘bird’s eye’ grain pattern of maple wood (Fig. 21.9.2.7). Various glomerular lesions, most commonly membranous nephropathy, are also reported concurrently with tubulointerstitial nephritis. Several radiological lesions within the kidney are diagnostic for IgG4-​RD affecting the kidney in the setting of extrarenal Fig. 21.9.2.7  Characteristic bird’s-​eye pattern (periodic acid–​ methenamine silver stain, magnification ×400). Nests of inflammatory cells with irregular fibres surrounding them. Reproduced with permission from Tang X et al. (2015). Evaluation of diagnostic criteria for IgG4-​related tubulointerstitial nephritis. Diagn Pathol, 10, 83. Copyright © Tang et al. 2015.

21.9.2  Chronic tubulointerstitial nephritis 4967 biopsy-​diagnosed IgG4-​RD. These renal lesions include small, low-​ attenuation lesions (typically bilateral and multiple, found in 65% of patients), significantly enlarged kidneys (20–​30%), or tumour masses. The term ‘IgG4-​related kidney disease’ has been proposed as a comprehensive term for the renal lesions associated with IgG4. Clinical features IgG4-​RD mainly affects middle-​aged to elderly men, many of whom have allergic conditions. Patients with IgG4-​RD often have lesions in several organs, with the salivary glands, lacrimal glands, lymph nodes, and pancreas being frequently affected. Systemic symptoms are relatively mild, and renal involvement usually be- comes clinically apparent when renal dysfunction and/​or renal radiographic abnormalities are detected, either during systematic examination for extrarenal IgG4-​RD or by chance. Oedema may be evident in patients with IgG4-​related kidney disease accompanied by glomerular lesions, or in patients with hydronephrosis due to retroperitoneal fibrosis. Polyclonal hypergammaglobulinaemia is a characteristic feature. Almost all patients with IgG4-​related kidney disease have an elevated serum IgG4 level, and 90% have an elevated serum total IgG level. Hypocomplementaemia and a high serum IgE level are characteristic, and eosinophilia is often evident. Although antinuclear antibodies and rheumatoid factors are often positive, anti-​DNA, anti-​SS-​A, anti-​SS-​B, anti-​ Sm, and anti-​RNP antibodies are usually negative. Proteinuria when present (±50%) is usually mild, but nephrotic-​range pro- teinuria may occur when membranous nephropathy is present. Progressive renal damage may occur, varying from subacute to slowly progressive. Diagnosis and treatment Diagnostic criteria for IgG4 tubulointerstitial nephritis and a diag- nostic algorithm using a set of diagnostic criteria for IgG4-​related kidney disease were proposed by a group from North America and the Japanese Society of Nephrology. As a mandatory criterion, they propose a renal histology picture rich in IgG4-​positive plasma cells (i.e. >10 IgG4+ plasma cells/​high power field in the most concen- trated fields). At least one other feature based on imaging, serology (an elevated serum IgG4 or total IgG level), or IgG4-​related involve- ment of another organ is required. An increase in the number of IgG4-​positive plasma cells may be a feature of myeloperoxidase–​ antineutrophil cytoplasmic antibody-​associated vasculitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, multicentric Castleman’s disease, lymphoproliferative disorders including malignant lymphoma, and some inflammatory conditions. IgG4 tubulointerstitial nephritis has a quick and favourable re- sponse to corticosteroid therapy, with the usual therapy being oral administration of prednisolone (0.6 mg/​kg per day) as induction therapy for 2 to 4 weeks, with the dose then gradually tapered to a low-​maintenance dose and continued for several years. Rapid recovery towards normal renal function is seen in most cases, but irreversible renal failure requiring maintenance haemo- dialysis can occur in patients with advanced renal damage before treatment. Relapse may occur in 20% of treated patients. The inci- dence of malignancy in patients with IgG4 tubulointerstitial neph- ritis is 3.5 times higher than that of the general population. Lithium Lithium is used extensively in the treatment of patients with manic-​ depressive psychosis. Different forms of renal effects/​injury have been described, most frequently nephrogenic diabetes insipidus, but also renal tubular acidosis, chronic interstitial nephritis, nephrotic syndrome, and focal segmental glomerular sclerosis/​global glom- erular sclerosis. Hyperparathyroidism is also observed in patients treated with lithium. Pathogenesis and pathology Lithium is eliminated from the body almost entirely by the kidney, being filtered at the glomerulus and reabsorbed in the proximal tu- bule, resulting in a clearance of one-​third of the normal creatinine clearance. It moves in and out of cells only slowly and accumulates in the kidney, particularly in the collecting tubule, entering these cells through sodium channels in the luminal membrane. Hence, its principal toxicity relates to distal tubular function, where inhibition of adenylate cyclase and generation of cyclic AMP result in down-​ regulation of aquaporin-​2, the collecting tubule water channel, and a decrease in antidiuretic hormone receptor density, leading to re- sistance to antidiuretic hormone. Further effects compound this. A low intracellular level of cyclic AMP leads to the increased cel- lular levels of glycogen observed in kidney biopsy specimens from patients taking lithium, as does the fact that lithium also directly inhibits enzymes involved in glycogen breakdown. The ensuing in- creased glycogen storage may interfere with distal tubular function and be responsible for the observation that polyuria and polydipsia in lithium-​treated patients is due to nephrogenic diabetes insipidus. The tubular defect in the distal nephron can also impair the ability to maximally acidify the urine. A lithium-​induced decrease in the activity of the H+-​ATPase pump in the collecting tubule may be re- sponsible for this defect. Lithium treatment has been aetiologically related to parathyroid hypertrophy and hyperfunction, the latter seeming to be due to an up- ward resetting of the level at which the plasma calcium concentration depresses parathyroid hormone release. Persistent hypercalcaemia (in 5–​10% of the patients) may exacerbate both the concentrating defect and the interstitial nephritis seen in lithium-​treated patients. Recently large dysmorphic lysosomes were found in the proximal tubular cells of 8 patients under chronic lithium treatment perfectly comparable with the abnormal lysosomes found in CINAC patients. Renal biopsies from patients taking lithium show a specific histo- logical lesion in the distal tubule and collecting duct. On light mi- croscopy there is swelling and vacuolization in cells associated with a considerable accumulation of periodic acid–​Schiff-​positive glycogen. This is present in all renal biopsies from patients taking lithium, appears within days after the administration of lithium, and disappears when lithium ingestion is ceased. Hestbech and colleagues were the first to suggest that progres- sive chronic interstitial lesions occurred in the kidneys of patients receiving lithium. However, a controlled study showed no dif- ference between biopsies from patients taking lithium and those from a group of patients who had affective disorders but were not doing so. Specifically, there was no difference in the incidence of glomerular sclerosis, interstitial fibrosis, tubular atrophy, cast for- mation, or interstitial volume, but there was a significant increase

section 21  Disorders of the kidney and urinary tract 4968 in the number of microcysts in the lithium-​treated patients. One reason why it has been difficult to determine the nature of lithium-​ induced chronic renal damage has been the lack, until recently, of an animal model in which lesions similar to those noted in human biopsies could be demonstrated. However, a recent study on lithium nephrotoxicity carried out in the rabbit showed clear-​cut evidence of progressive histological and functional impairment, with the de- velopment of significant interstitial fibrosis, tubular atrophy, glom- erular sclerosis, and cystic tubular lesions. A recent publication by Markowitz and colleagues revealed chronic tubulointerstitial neph- ropathy in 100% of 24 patients who had received lithium for sev- eral years, associated with cortical and medullary tubular cysts or dilatation. There was also a surprisingly high prevalence of focal segmental glomerulosclerosis and global glomerulosclerosis, some- times of equivalent severity to the chronic tubulointerstitial disease. Despite discontinuing lithium treatment, seven of nine patients with initial serum creatinine values above 2.5 mg/​dl (225 µmol/​litre) pro- gressed to endstage renal disease. A French follow-​up study of lithium-​treated patients demon- strated that the duration of lithium therapy and the cumulative dose of lithium were the major determinants of nephrotoxicity and estimated a prevalence of lithium-​related endstage renal failure in 2 of 1000 dialysis patients. Twelve out of 74 patients in this study reached endstage renal failure at a mean age of 65 years, with an average latency between onset of lithium therapy and endstage renal failure of 20 years. Lepkifker and colleagues retrospectively studied 114 subjects with major depressive or schizoaffective disorders who had been taken lithium for 4 to 30 years from 1968 to 2000. Long-​ term lithium therapy did not influence glomerular function in most patients, but 20% of those receiving long-​term lithium exhibited ‘creeping creatinine’ and developed chronic renal insufficiency. Clinical features Apart from acute lithium intoxication, chronic poisoning can occur in patients whose lithium dosage has been increased or in those with a decreased effective circulating volume, decreased sodium intake, diabetes mellitus, gastroenteritis, and renal failure, thereby resulting in an increase in serum lithium levels. Symptoms associated with poisoning include lethargy, drowsiness, coarse hand tremor, muscle weakness, nausea, vomiting, weight loss, polyuria, and polydipsia. Severe toxicity is associated with increased deep tendon reflexes, seizures, syncope, renal insufficiency, and coma. The commonest manifestation is altered mental status. Chronic lithium poisoning is frequently associated with electro- cardiographic changes, including ST-​segment depression and in- verted T waves in the lateral precordial leads. Lithium is concentrated within the thyroid and inhibits the synthesis and release of thyroxine, which can lead to hypothyroidism, and it may also cause thyrotoxi- cosis. Symptoms of hypercalcaemia may also be present, exacerbating the urinary concentrating defect already present in these patients. In patients with glomerular lesions such as minimal-​change or focal glomerular sclerosis, proteinuria generally begins within 1.5 to 10 months after the onset of therapy, completely or partially re- solving in most patients within 4 weeks after lithium is discontinued. Reinstitution of lithium has led to recurrent nephrosis in some cases. The hyperparathyroidism observed in patients receiving lithium treatment is characterized by elevated parathyroid hor- mone levels, hypercalcaemia, hypocalciuria, and normal serum phosphate levels, in contrast to primary hyperparathyroidism in which hypophosphataemia and hypercalciuria are seen. Diagnosis and treatment The severity of chronic lithium intoxication correlates directly with the serum lithium concentration and may be categorized as mild (1.5–​2.0 mmol/​litre), moderate (2.0–​2.5 mmol/​litre), or severe (>2.5 mmol/​litre). Polyuria and polydipsia due to nephrogenic diabetes insipidus and other acute manifestations of the effect of lithium on the kidney usually disappear rapidly if lithium is withdrawn. The decision about management, however, usually revolves around the relative benefit of the lithium in controlling and preventing the manifestation of manic-​depressive psychosis, and the disadvantage to the patient of the major side effect of lithium, that is, polyuria. In most cases, the lithium is so clearly beneficial that the polyuria is accepted as a side effect and treatment continued. It is likely that the serum concen- tration of lithium is important, and that renal damage is more prob- able if the serum concentration is consistently high, or if repeated episodes of lithium toxicity occur. The serum lithium concentration should therefore be monitored carefully (at least every 3 months) and maintained at the lowest level that will provide adequate control of psychiatric symptoms. Much more difficult to handle is the situation where a patient on long-​term lithium therapy is found to have impaired renal function for which there is no obvious alternative cause. As stated earlier, renal failure may progress even if lithium therapy is withdrawn, and in some patients the discontinuation of lithium can lead to a devastating deterioration in their psychiatric condition. The deci- sion as to whether or not to discontinue lithium should therefore be made after frank and open discussion, admitting all uncertainties, with the patient, psychiatric colleagues, and (if appropriate) rela- tives/​carers. Radiation nephropathy Radiation nephropathy is a renal disorder caused by ionizing ra- diation. The kidney may be injured by radiation administered to tumours within the kidney or nearby tissues (testis, ovary, retroperitoneum). Clinicians were aware of the potential adverse ef- fects of radiography on renal function from the beginning of the 20th century, and between 1940 and 1960 a significant number of cases were reported. In 1953, Luxton established the clinical features of the condition and defined the tolerance of the kidney to irradiation, leading to preventive shielding of the kidneys in patients receiving radiation therapy and to a marked decline in the frequency of radi- ation nephropathy. In recent years, however, total body irradiation preceding bone marrow transplantation has resulted in an increasing incidence of radiation nephropathy, with late chronic renal failure developing in 20% of patients who receive this treatment. Pathogenesis and pathology The radiation doses traditionally associated with radiation neph- ropathy were above 2000 rad (20 Gy) (less in children). By contrast, in patients receiving total body irradiation preceding bone marrow transplantation, renal impairment was observed after doses of 1000 to 1400 rad (10–​14 Gy). Fractionation, time, and effects of cytotoxic

21.9.2  Chronic tubulointerstitial nephritis 4969 chemotherapy can probably explain the differences. In laboratory rodents, fractionation of the total dose into multiple separated doses decreases the risk, probably due to repair of sublethal radiation damage during the time between the fractionated doses. Total body irradiation before bone marrow transplantation is usually adminis- tered over a short period, which does not allow sufficient time for the repair of radiation injury to the kidney. Moreover, the additional cytotoxic chemotherapy given to these patients potentiates the ef- fects of ionizing radiation. The precise pathogenesis of radiation nephropathy remains to be determined. The initial target of ionizing radiation within the kidney appears to be the endothelial cell. Radiation kills cells by damaging DNA, so that cell death after radiation is delayed until the cell divides. After the initial glomerular endothelial injury, vascular occlusion subsequently develops, leading to tubular at- rophy. Because inflammatory cells are not seen in the renal paren- chyma, the previously used terminology of ‘radiation nephritis’ is a misnomer. The pathological features of radiation nephropathy comprise a continuous spectrum of changes that vary in relation to the dose of irradiation administered and the time elapsed after exposure. Large doses are followed by complete atrophy, thickening of basement membranes, and interstitial fibrosis. Clinical features Radiation nephropathy can take several forms. Acute radiation nephropathy occurs between 6 and 12  months after radiation therapy and presents with hypertension, anaemia, and oedema. The severity of hypertension ranges from mild to malignant, and more than one-​half of the patients progress to chronic renal failure. Radiation nephropathy after total body irradiation before bone marrow transplantation most closely corresponds to this acute form of radiation nephropathy. A more insidious chronic form of radiation nephropathy develops over a period of several years and presents primarily with diminished glomerular filtration rate, hypertension, and (occasionally) protein- uria. Another subset of patients may develop hypertension within a few years of irradiation, evolving in some to malignant hyperten- sion with accelerated loss of renal function. Isolated persistent or intermittent proteinuria may also occur, frequently developing more than a decade after radiation exposure. Diagnosis and treatment Radiographic studies may help in the diagnosis of acute radiation nephropathy. CT scans with contrast demonstrate sharply de- marcated, dense, persistent nephrograms corresponding to the irradiated areas. The treatment of radiation nephropathy is supportive. Aggressive treatment of hypertension may slow the progression of renal disease, and the use of angiotensin-​converting enzyme inhibitors may have its classic renoprotective effect independent of antihypertensive action. Hypertension due to unilateral disease may respond to nephrectomy. Since radiation nephropathy is an irreversible process, preventive measures should be taken during the administration of radiation. This includes selective shielding of the kidneys and the use of frac- tionated doses. Patients exposed to additional nephrotoxins remain at an increased risk of toxic effects. Toxins Lead Lead toxicity affects many organs, resulting in encephalopathy, an- aemia, peripheral neuropathy, gout, and renal failure. It was the epi- demic of lead nephropathy in Queensland (Australia) that provided the strongest link between lead and chronic tubulointerstitial neph- ritis. Henderson noted an excess mortality due to chronic interstitial nephritis in Queensland but not in other parts of Australia, and cor- related the incidence of granular contracted kidneys at autopsy with the lead content of the skull in people from Queensland and Sydney, showing that this correlated closely with the incidence of renal failure. Exposure was due to the lead-​based paints used between 1890 and 1930, but recently the source of lead is industrial exposure. This type of exposure is often insidious and occurs over a very long period. Two studies have shown an inverse relationship between low-​level lead exposure and renal function in the general population. Recent studies have failed to show any effect on renal function 17 to 50 years after an episode of acute childhood plumbism, the difference with Henderson’s findings reflecting the greater lead burden in his study compared to the recent ones. Although low-​level lead exposure in the general population is associated with mild but significant depression of renal function, in particular in patients with hypertension, its role in the development of endstage renal disease is unclear. Pathogenesis and pathology The pathogenesis of renal disease seen in the context of lead exposure may be related to proximal tubule reabsorption of filtered lead, with subsequent accumulation in proximal tubule cells. Aminoaciduria, glycosuria, and phosphaturia representing Fanconi’s syndrome are observed after lead exposure, and thought to be related to an effect of lead on mitochondrial respiration and phosphorylation. Since lead is also capable of reducing 1,25-​dihydroxyvitamin D synthesis, prolonged hyperphosphaturia and hypophosphataemia caused by lead poisoning in children could result in bone demineralization and rickets. Chronic lead poisoning can affect glomerular func- tion. After an initial period of hyperfiltration, the glomerular filtra- tion rate is reduced and nephrosclerosis and chronic renal failure may ensue. Protracted lead exposure also interferes with the distal tubular secretion of urate, leading to hyperuricaemia and gout. Other pathophysiological mechanisms include the induction of oxi- dative stress and generation of free radicals, which in turn may result in high blood pressure, inflammation, apoptosis, and, ultimately, de- velopment of chronic renal lesions. Renal biopsies in patients with subclinical lead nephropathy and a mild to moderate decrease in glomerular filtration rate primarily show focal tubular atrophy and interstitial fibrosis with minimal cellular infiltration. Electron microscopy shows mitochondrial swelling, loss of cristae, loss of basal infoldings, and a lysosomal-​like structure containing dense bodies (not comparable to the lysosomal lesions observed in CINAC patients) in the proximal tubular cells. In Australian patients who died as a result of severe lead exposure, their kidneys were fibrotic and shrunken, the interstitium showed variable degrees of fibrosis with tubular dilatation, and the vessels had thickened muscular walls with subintimal hyaline deposition in afferent arterioles, but these findings in patients with endstage renal failure were nonspecific.

section 21  Disorders of the kidney and urinary tract 4970 Clinical features Renal failure becomes apparent years after exposure and is asso- ciated with gout in most, if not all, cases. Hypertension is also a very common feature of lead nephropathy, and an association be- tween hypertension without renal failure and low-​level lead ex- posure has gained increasing recognition in recent years. Although hyperuricaemia is common in renal failure, gout is less so and its presence should raise the possibility of lead nephropathy. However, whether chronic lead nephropathy exists as a clinical entity has been questioned. Many studies of occupational lead poisoning have not taken into account the coexposure to other toxins such as cadmium. Additionally, the relationship between early markers of renal tubular dysfunction, such as the urinary excretion of low molecular weight proteins or N-​acetyl β-​d-​glucosaminidase, to the subsequent devel- opment of renal failure remains to be determined. Diagnosis and treatment The diagnosis of lead nephropathy should be considered in any pa- tient with progressive renal failure, mild to moderate proteinuria, significant hypertension, a history of gout, and an appropriate his- tory of exposure. As the blood lead level only reflects recent lead exposure, and is usually normal in patients with chronic renal failure due to their pre- viously sustained low-​level lead exposure, the diagnosis has to be based on measurement of the body lead burden. The test of choice is the ethylenediaminetetraacetic acid (EDTA) mobilization test. This involves the administration of 2 g of EDTA intramuscularly in two divided doses 8 to 12 h apart, and collection of three consecutive 24-​h urine samples. A cumulative excretion of more than 600 µg is suggestive for a high body lead burden. Renal failure in itself does not increase body lead load but it does delay the excretion of lead. There is very little experience of the therapeutic use of EDTA in patients with chronic renal failure. Wedeen and colleagues treated eight industrially exposed patients with EDTA injections three times weekly for 6 to 15 months, all having mild renal failure with glom- erular filtration rates of around 50 ml/​min before treatment; four patients improved with a 20% increase in their glomerular filtration rate. Results from studies in Taiwan indicate that low-​level environ- mental lead exposure accelerates progressive diabetic nephropathy as well as CKD in patients without diabetes, and that repeated che- lation therapy may improve renal function and slow the progression of renal insufficiency. Cadmium Cadmium is a cumulative environmental pollutant and accumulates in the human body after inhalation or gastrointestinal absorption. Due to its various applications and increased industrial production, it has been released into the environment in much larger amounts from the 1950s onwards, particularly in Belgium and Japan, which are among the most important cadmium-​producing countries worldwide. However, the atmospheric emissions of cadmium from zinc smelters have been reduced since the 1970s. Currently, normal cadmium values are set at 0.1 to 0.8 µg/​litre (nonsmokers) in blood, and 0.02 to 0.7 µg/​g creatinine in urine. Cadmium is a highly toxic metal and it has long been recognized that high-​level exposure after inhalation or ingestion can give rise to nephrotoxicity, and that this effect is usually considered to be the earliest and most important feature from the point of view of health. When exposed to high levels of cadmium in the workplace (cad- mium in renal cortex >100–​400 µg/​kg wet weight), workers have developed tubular proteinuria, renal glycosuria, aminoaciduria, hypercalciuria, phosphaturia, and polyuria, and in a few severe cases (long-​standing high exposure and urinary excretion >20 µg/​g cre- atinine and β2-​microglobulin >1500 µg/​g creatinine), renal damage may progress to an irreversible reduction in glomerular filtration. Signs of distal tubular damage such as a cadmium-​induced inhib- ition of antidiuretic hormone-​stimulated ion transport have also been reported. The extent to which chronic low-​level environmental exposure to cadmium affects renal function is much less clear. The Cadmibel study, in which a random sample of 1699 subjects was recruited from four areas of Belgium with varying degrees of cadmium pol- lution, showed that (after standardization for several confounding factors) five markers of renal dysfunction (retinol binding protein, N-​acetyl-​β-​glucosaminidase, β2-​microglobulin, amino acids, and calcium) were significantly associated with urinary cadmium ex- cretion. There was a 10% probability of these variables being ab- normal when urinary cadmium levels exceeded 2 to 4 µg/​24 h. However, in a 5-​year follow-​up of a subcohort from the Cadmibel study, the so-​called Pheecad study, in which 593 individuals with the highest urinary cadmium excretion were re-​examined on average 5 years later, it was demonstrated that the subclinical tubular effects previously documented were not associated with deterioration in glomerular filtration rate. Hence, in the envir- onmentally cadmium-​exposed population, the renal effects due to cadmium appear to be weak, stable, and even reversible. These findings in environmentally exposed subjects may reasonably be extrapolated to the current, moderately exposed, occupational population, where, in various epidemiological studies, increased cadmium levels/​exposure have repeatedly been associated with disturbed levels of markers of early renal dysfunction, but without evidence for accelerated progression towards chronic renal failure. Recent findings point to the importance of coexposure as it was shown that moderate occupational lead exposure increases the renal response to low levels of cadmium as indicated by the in- creased strength of the association between cadmium in blood and urine and early renal biomarkers of dysfunction (i.e. N-​acetyl-​ β-​glucosaminidase, intestinal alkaline phosphatase, and retinol binding protein). Other studies reported that the presence of dia- betes, increased levels of tissue antimetallothionein-​1 antibodies, and/​or concomitant exposure to organic arsenic, also hold an in- creased risk for cadmium-​induced renal dysfunction. There is no specific treatment for cadmium-​induced renal disease, other than supportive care and change of residence area, to avoid further excessive cadmium exposure. Metabolic disorders Chronic hypokalaemia Several renal abnormalities, most of which are reversible with po- tassium repletion, can be induced by hypokalaemia. Vasopressin-​ resistant impairment of the ability to concentrate the urine, increased renal ammonia production, enhanced bicarbonate reabsorption,

21.9.2  Chronic tubulointerstitial nephritis 4971 altered sodium reabsorption, and hyperkalaemic nephropathy have all been described. Persistent hypokalaemia can induce a variety of changes in renal function, impairing tubular transport and possibly inducing chronic tubulointerstitial disease and cyst formation. Hypokalaemic neph- ropathy in humans produces characteristic vacuolar lesions in the epithelial cells of the proximal tubule and (occasionally) the distal tubule, abnormalities which probably require about 1  month to develop. More severe changes occur if prolonged hypokalaemia is maintained, including interstitial fibrosis, tubular atrophy, and cyst formation that is most prominent in the renal medulla. The patho- genesis of these changes is not well understood. Renal growth accelerates when rats are placed on a potassium-​ deficient diet, and within 8 days there is a 25% increase in kidney mass. The changes are most prominent in the outer medulla, es- pecially the inner stripe, where hyperplastic enlarged collecting duct cells form cellular outgrowths that project into the lumen causing partial obstruction. If the potassium-​deficient state per- sists, then cellular infiltrates appear in the renal interstitial com- partment and tubulointerstitial fibrosis develops. It has been proposed that some of these pathological changes may be ini- tiated by the high levels of ammonia generated in potassium-​ deficiency states and may be mediated through the activation of the alternate complement pathway. In support of this hypothesis is the finding that bicarbonate supplementation sufficient to sup- press renal ammoniagenesis attenuates the renal enlargement and tubulointerstitial disease: against it are reports that increased renal ammoniagenesis induced by acid loading causes renal enlarge- ment without cellular proliferation or interstitial disease. A recent paper provides results consistent with a sustained role for insulin-​ like growth factor-​1 (IGF-​1) in promoting the marked tubular epi- thelial cell hypertrophy and hyperplasia that occurs in the inner stripe of the outer medulla of the kidney with chronic potassium depletion. The same study also showed that potassium depletion causes a selective increase in the renal expression of TGFβ in the hypertrophied nonhyperplastic thick ascending limb, but, unlike IGF-​1, it is absent from the hyperplastic collecting duct cells. This might be responsible for preventing the conversion of the mito- genic stimulus of IGF-​1 into a hypertrophic one. It is possible that TGFβ causes the prominent interstitial infiltrate that develops in chronic hypokalaemia, since this growth factor is a well-​known chemoattractant for macrophages. A study has shown that angiotensin receptor blockade ameliorates tubulointerstitial injury induced by chronic potassium deficiency, and the same authors also showed that endothelin-​1 can mediate hypokalaemic renal injury in two different ways, by directly stimu- lating endothelin-​A receptors and by locally promoting endogenous endothelin-​1 production via endothelin-​B receptors, hence endothelin-​A and -​B receptor blockade may be renoprotective in hypokalaemic nephropathy. Hyperoxaluria Hyperoxaluria may be primary or acquired. The primary form is a rare inherited disorder due to an enzymatic abnormality in the metabolism of glyoxylic acid. The acquired forms of hyperoxaluria are more common and result either from the ingestion of oxalate precursors, such as ethylene glycol and ascorbic acid, and exposure to methoxyflurane anaesthesia, or from increased absorption from the intestinal tract in those with inflammatory bowel disease or who have undergone small-​bowel resection. Oxalate is the salt forming ion of oxalic acid, which is widely distributed in both plants and animals. Oxalic acid may form ox- alate salts with various cations, such as sodium, potassium, mag- nesium, and calcium. Although sodium oxalate, potassium oxalate, and magnesium oxalate are water soluble, calcium oxalate is nearly insoluble. Excretion of oxalate occurs primarily by the kidneys via glomerular filtration and tubular secretion. Since ox- alate can bind with calcium in the kidney, increased urinary ox- alate excretion (hyperoxaluria) leads to urinary calcium oxalate supersaturation, resulting in the formation and putative retention of calcium oxalate crystals in renal tissue. This first occurs in the proximal tubules, where oxalate is secreted, and these calcium ox- alate crystals may contribute to the formation of diffuse renal cal- cifications (nephrocalcinosis) and renal stones (nephrolithiasis, of which c.75% are predominantly composed of calcium oxalate) (see Chapter 21.14). If the overload is insidious and chronic, then inflam- matory cell infiltration, oedema, interstitial fibrosis, tubular atrophy, and dilatation result in chronic tubulointerstitial nephritis with progressive renal failure. Up to now, many (if not all) preventive or therapeutic strategies fail in their compliance or effectiveness, hence stone recurrence is still very common. Recently, experimental data in a rat model of secondary hyperoxaluria has provided evidence that lanthanum carbonate can efficiently bind oxalate in the intestine and decrease nephrocalcinosis. Clinical confirmation is needed, but lanthanum carbonate might be a promising therapy for secondary hyperoxaluria. Hypercalcaemia Prolonged elevation of urinary and serum calcium levels may re- sult in the deposition of calcium in the kidney, which also occurs in some clinical conditions not associated with hypercalcaemia. Calcium is most concentrated in the medulla, where degeneration and tubular necrosis begins due to intracellular overload, with damage to mitochondria and other critical organelles. Reactive in- flammatory changes occur in the adjacent interstitium, and necrotic cells may cause intratubular obstruction and tubular atrophy. The final results of these changes are focal areas of tubular atrophy, inter- stitial fibrosis, and a mononuclear cell infiltrate. See Chapter 21.14 for further discussion. Hyperuricaemia/​hyperuricosuria There are three different types of renal disease induced by abnormal uric acid metabolism: acute uric acid nephropathy, chronic urate nephropathy, and uric acid stone disease, the last being discussed in Chapter 21.14. The kidneys are mainly responsible for the excretion of uric acid and are a primary target organ affected in disorders of urate metab- olism. Renal lesions result from the crystallization of uric acid either in the urinary outflow tract or in the renal parenchyma. The deter- minants of uric acid solubility are its concentration and the pH of the medium in which it is dissolved, hence the supersaturation of fluid within the renal tubules as excreted uric acid becomes concentrated in the medulla, and the acidification of the urine in the distal tubule, are both conducive to the precipitation of uric acid. The major sites of urate deposition are the renal medulla, the collecting tubules, and the urinary tract. The pKa of uric acid is 5.7, and at the acid pH of

section 21  Disorders of the kidney and urinary tract 4972 the fluid in the distal tubule the bulk of filtered urate will be present in its nonionized form as uric acid, whereas at the more alkaline pH of the blood and interstitium it is in its ionized form as urate salts. Acute uric acid nephropathy Acute uric acid nephropathy is an uncommon condition caused by the precipitation of birefringent uric acid crystals in the col- lecting tubules, with consequent tubular obstruction, dilatation, and inflammation. This can occur in disorders associated with an increased production of uric acid (e.g. myeloproliferative or lymphoproliferative disorders, tumour lysis syndrome, chronic haemolytic anaemia, psoriasis, or the Lesch–​Nyhan syndrome) or when there is increased renal clearance of uric acid (e.g. inherited or acquired defects of tubular urate transport or uricosuric drugs). In those prone to acute uric acid nephropathy, management centres on prophylaxis with a plentiful fluid intake, with or without alkalinization of the urine, and pretreatment with allopurinol or recombinant urate oxidase enzyme (rasburicase). Presentation of acute uric acid nephropathy is with acute kidney injury, with urine microscopy revealing plentiful birefringent crystals. Chronic urate nephropathy The principal renal lesion in chronic hyperuricaemia is the depos- ition of microtophi of amorphous urate crystals in the interstitium, with a surrounding giant cell reaction. This results in a sec- ondary chronic inflammatory response similar to that seen with microtophus formation elsewhere in the body, potentially leading to interstitial fibrosis and chronic renal failure. Uric acid is an independent risk factor for cardiovascular death and major clinical events. Hyperuricaemia induces endothelial dys- function, and uric acid regulates critical proinflammatory path- ways in vascular smooth muscle cells, possibly having a role in the vascular changes associated with hypertension and vascular dis- ease. It also accelerates renal progression in the remnant kidney model via a mechanism linked to high systemic blood pressure and cyclooxygenase-​2 (COX-​2)-​mediated thromboxane-​induced vas- cular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression, but clinical evidence linking chronic renal failure to gout is weak, and the long-​ standing notion that chronic renal disease is common in patients with hyperuricaemia has been questioned in the light of prolonged follow-​up studies of renal function in people with this condition. Renal dysfunction could be documented only when the serum urate concentration was more than 10 mg/​dl (600 µmol/​litre) in women and more than 13 mg/​dl (780 µmol/​litre) in men for prolonged periods. Furthermore, the deterioration of renal function in those with hyperuricaemia of a lower magnitude has been attributed to the higher than expected occurrence of hypertension, diabetes mellitus, abnormal lipid metabolism, and nephrosclerosis. Nonetheless, it seems reasonable to prescribe allopurinol (in a dose appropriate to the level of renal function) to those very rare patients with bi- opsy evidence of ‘gouty nephropathy’, and possibly to patients with chronic renal failure who have a grossly elevated serum urate. There is an association between severe lead intoxication, chronic renal failure, and gout (saturnine gout) (see earlier discussion). It has also been suggested that there might be an association between renal disease and hyperuricaemia in those with a past history of ex- posure to lead and consequent subclinical lead toxicity (saturnine nephropathy). Evidence for this association is not clear cut, nor is the mechanism whereby lead exposure might aggravate hyperuricaemia and renal failure. FURTHER READING Sarcoidosis Kettritz R, et  al. (2006). The protean face of sarcoidosis revisited. Nephrol Dial Transplant, 21, 2690–​4. Korzets Z, et al. (1985). Acute renal failure due to sarcoid granuloma- tous infiltration of the renal parenchyma. Am J Kidney Dis, 6, 250–​3. Analgesic nephropathy Blohme I, Johansson S (1981). Renal pelvic neoplasms and atyp- ical urothelium in patients with end-​stage analgesic nephropathy. Kidney Int, 20, 671–​5. Chang SH, Mathew TH, McDonald SP (2008). Analgesic nephropathy and renal replacement therapy in Australia: trends, comorbidities and outcomes. Clin J Am Soc Nephrol, 3, 768–​76. De Broe M, Elseviers, MM (1998). Analgesic Nephropathy. New England Journal Of Medicine, 338(7), 446–52. De Broe ME, Elseviers MM (2009). Over-​the-​counter analgesic use. J Am Soc Nephrol, 20, 2098–​103. Duggin GG (1996). Combination analgesic-​induced kidney dis- ease: the Australian experience. Am J Kidney Dis, 28 Suppl 1, S39–​47. Fored CM, et al. (2001). Acetaminophen, aspirin, and chronic renal failure. N Engl J Med, 345, 1801–​8. Henrich WL, et  al. (2006). Non-​contrast-​enhanced computerized tomography and analgesic-​related kidney disease: report of the na- tional analgesic nephropathy study. J Am Soc Nephrol, 17, 1472–​80. Ibanez L, et al. (2005). Case-​control study of regular analgesic and nonsteroidal anti-​inflammatory use and end-​stage renal disease. Kidney Int, 67, 2393–​8. Mihatsch MJ, Khanlari B, Brunner FP (2006). Obituary to analgesic nephropathy: an autopsy study. Nephrol Dial Transplant, 21, 3139–​45. Mihatsch MJ, et al. (1983). Capillary sclerosis of the urinary tract and analgesic nephropathy. Clin Nephrol, 20, 285–​301. Perneger TV, Whelton PK, Klag MJ (1994). Risk of kidney failure as- sociated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med, 331, 1675–​9. Stewart JH, et al. (2003). Cancers of the kidney and urinary tract in patients on dialysis for end-​stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand. J Am Soc Nephrol, 14, 197–​207. van der Woude FJ, et al. (2007). Analgesics use and ESRD in younger age: a case-​control study. BMC Nephrol, 8, 15. Aristolochic acid nephropathy—​Chinese herb nephropathy Cosyns JP, et al. (1994). Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int, 45, 1680–​8. Cosyns JP, et al. (1999). Urothelial lesions in Chinese-​herb nephrop- athy. Am J Kidney Dis, 33, 1011–​17. Diamond JR, Pallone TL (1994). Acute interstitial nephritis following use of tung shueh pills. Am J Kidney Dis, 24, 219–​21. Gökmen MR, et al. (2013). The epidemiology, diagnosis, and man- agement of aristolochic acid nephropathy: a narrative review. Ann Intern Med, 158, 469–​77. Vanherweghem JL, et al. (1993). Rapidly progressive interstitial fibrosis in young women:  association with slimming regimen including Chinese herbs. Lancet, 341, 387–​91.

21.9.2  Chronic tubulointerstitial nephritis 4973 Yang CS, et al. (2000). Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis, 35, 313–​18. Aristolochic acid nephropathy—​Balkan endemic nephropathy Arlt VM, et  al. (2007). Aristolochic acid mutagenesis:  molecular clues to the aetiology of Balkan endemic nephropathy-​associated urothelial cancer. Carcinogenesis, 28, 2253–​61. Batuman V (2006). Fifty years of Balkan endemic nephropathy: daunting questions, elusive answers. Kidney Int, 69, 644–​6. De Broe M (2012). Chinese nephropathy and Balkan endemic nephrop- athy towards a single entity, aistolochic acid nephropathy. Kidney Int, 81, 513–15. Dimitrov P, et al. (2006). Clinical markers in adult offspring of families with and without Balkan endemic nephropathy. Kidney Int, 69, 723–​9. Gluhovschi G, et al. (2011). Fifty years of Balkan endemic nephropathy in Romania: some aspects of the endemic focus in the Mehedinti county. Clin Nephrol, 75, 34–​48. Grollman AP, et al. (2007). Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A, 104, 12129–​34. Stefanovic V, et al. (2006). Etiology of Balkan endemic nephropathy and associated urothelial cancer. Am J Nephrol, 26, 1–​11. Voice TC, et al. (2006). Evaluation of the hypothesis that Balkan en- demic nephropathy is caused by drinking water exposure to con- taminants leaching from Pliocene coal deposits. J Expo Sci Environ Epidemiol, 16, 515–​24. 5-​Aminosalicylic acid Calder IC, et al. (1972). Nephrotoxic lesions from 5-​aminosalicylic acid. BMJ, 1, 152–​4. Gisbert JP, González-​Lama Y, Maté J (2007). 5-​Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis, 13, 629–​38. Muller AF, et al. (2005). Experience of 5-​aminosalicylate nephrotox- icity in the United Kingdom. Aliment Pharmacol Ther, 21, 1217–​24. World MJ, et al. (1996). Mesalazine-​associated interstitial nephritis. Nephrol Dial Transplant, 11, 614–​21. Chronic interstitial nephritis in agricultural
communities (CINAC) Almaguer M, Herrera R, Orantes CM (2014). Chronic kidney disease of unknown etiology in agricultural communities. MEDICC Rev, 16, 9–​15. Herrera R, et al. (2014). Clinical characteristics of chronic kidney dis- ease of nontraditional causes in Salvadoran farming communities. MEDICC Rev, 16, 39–​47. Jayasumana C, Gunatilake S, Senanayake P (2014). Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epi- demic of chronic kidney disease of unknown etiology in Sri Lanka? Int J Environ Res Public Health, 11, 2125–​47. Jayasumana C, et al. (2017). Chronic interstitial nephritis in agricul- tural communities a worldwide epidemic with social occupational and environmental determinants. Nephrol Dial Trans, 32, 234–41. Jha V, et al. (2013). Chronic kidney disease: global dimension and per- spective. Lancet, 382, 260–​72. Johnson R, Wesseling C, Newman LS (2019). Chronic kidney disease of unknown cause in agricultural communities. N Eng J Med, 380, 1843–52. Kumagai Y, Pi J (2004). Molecular basis for arsenic induced alteration in nitric oxide production and oxidative stress: implication of endo- thelial dysfunction. Toxicol Appl Pharmacol, 198, 50–​7. López-​Marín L, et al. (2014). Histopathology of chronic kidney dis- ease of unknown etiology in Salvadoran agricultural communities. MEDICC Rev, 16, 49–​54. Orantes CM, et  al. (2014). Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities. MEDICC Rev,
16, 2–​30. Ordunez P, et al. (2018). Chronic kidney disease mortality trends in selected Central America countries, 1997-2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities. J Epi Com Health, 72, 280–6. Silva LC, Ordúñez P (2014). Chronic kidney disease in Central American agricultural communities:  challenges for epidemiology and public health. MEDICC Rev, 16, 66–​71. Vervaet B, et al. (2019). Chronic interstitial nephritis in agricultural communities: a toxin induced lysosomal tubulopathy. Kidney Int
(in press). IgG4-​related kidney disease Cornell LD (2012). IgG4-​related kidney disease. Semin Diagn Pathol, 29, 245–​50. Kawano M, et al. (2011). Proposal for diagnostic criteria for IgG4-​ related kidney disease. Clin Exp Nephrol, 15, 615–​26. Raissian Y, et al. (2011). Diagnosis of IgG4-​related tubulointerstitial nephritis. J Am Soc Nephrol, 22, 1343–​52. Saeki T, Kawano M (2014). IgG4-​related kidney disease. Kidney Int, 85, 251–​7. Saeki T, et al. (2010). Clinicopathological characteristics of patients with IgG4-​related tubulointerstitial nephritis. Kidney Int, 78, 1016–​23. Stone JH, Zen Y, Deshpande V (2012). IgG4-​related disease. N Engl J Med, 366, 539–​51. Tang X, et al. (2015). Evaluation of diagnostic criteria for IgG4-​related tubulointerstitial nephritis. Diagn Pathol, 10, 83. Yamaguchi Y, et al. (2012). Characteristic tubulointerstitial nephritis in IgG4-​related disease. Hum Pathol, 43, 536–​49. Lithium Boton R, Gaviria M, Battle CD (1987). Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis, 10, 329–​45. Grünfeld JP, Rossier BC (2009). Lithium nephrotoxicity revisited. Nat Rev Nephrol, 5, 270–​6. Lepkifker E, et  al. (2004). Renal insufficiency in long-​term lithium treatment. J Clin Psychiatry, 65, 850–​6. Markowitz GS, et  al. (2000). Lithium nephrotoxicity:  a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol, 11, 1439–​48. Presne C, et al. (2003). Lithium-​induced nephropathy: rate of progres- sion and prognostic factors. Kidney Int, 64, 585–​92. Wolf ME, et al. (1997). Lithium therapy, hypercalcemia, and hyper- parathyroidism. Am J Ther, 4, 323–​5. Radiation nephropathy Cohen EP (2000). Radiation nephropathy after bone marrow trans- plantation. Kidney Int, 58, 903–​18. Luxton RW (1961). Radiation nephritis: a long-​term study of fifty-​four patients. Lancet, 2, 1221. Toxins Buchet JP, et al. (1990). Renal effects of cadmium body burden of the general population. Lancet, 336, 699–​702.

section 21  Disorders of the kidney and urinary tract 4974 Evans M, Elinder CG (2011). Chronic renal failure from lead: myth or evidence-​based fact? Kidney Int, 79, 272–​9. Farkas WR, Stanawitz T, Schneider M (1978). Saturnine gout: lead-​induced formation of guanine crystals. Science, 199,
786–​7. Hambach R, et al. (2013). Co-​exposure to lead increases the renal re- sponse to low levels of cadmium in metallurgy workers. Toxicol Lett, 222, 233–​8. Hotz P, et al. (1999). Renal effects of low-​level environmental cadmium exposure: 5-​year follow-​up of a subcohort from the Cadmibel study. Lancet, 354, 1508–​13. Lin JL, et al. (2003). Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med, 348, 277–​86. Lin JL, et al. (2006). Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes. Kidney Int, 69, 2049–​56. Robijn S, et al. (2013). Lanthanum carbonate inhibits intestinal oxalate absorption and prevents nephrocalcinosis after oxalate loading in rats. J Urol, 189, 1960–​6. Soderland P, et al. (2010). Chronic kidney disease associated with environmental toxins and exposures. Adv Chronic Kidney Dis, 17, 254–​64. Staessen JA, et al. (1992). Impairment of renal function with increasing blood lead concentrations in the general population. N Engl J Med, 327, 151–​6. Staessen JP, et al. (1996). Public health implications of environmental exposure to cadmium and lead:  an overview of epidemiological studies in Belgium. J Cardiovasc Risk, 3, 26–​41. Metabolic disorders Benabe JE, Martinez-​Maldonado M (1978). Hypercalcemic nephrop- athy. Arch Intern Med, 138, 777–​9. Cremer W, Bock KD (1976). Symptoms and course of chronic hypo- kalemic nephropathy in man. Clin Nephrol, 7, 112–​19. Duffy WB, Senekjian HO, Knight TF (1981). Management of asymp- tomatic hyperuricemia. JAMA, 246, 2215–​16. Hestbech J, et al. (1977). Chronic renal lesions following long-​term treatment with lithium. Kidney Int, 12, 205–​13. Johnson RJ, et al. (1999). Reappraisal of the pathogenesis and conse- quences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis, 33, 225–​34. Kang DH, et al. (2002). A role for uric acid in the progression of renal disease. J Am Soc Nephrol, 13, 2888–​97. Robijn S, et al. (2013). Lanthanum carbonate inhibits intestinal oxalate absorption and prevents nephrocalcinosis after oxalate loading in rats. J Urol, 189, 1960–66. Suga S, et al. (2002). Angiotensin II type 1 receptor blockade ameli- orates tubulointerstitial injury induced by chronic potassium defi- ciency. Kidney Int, 61, 951–​8. Torres VE, et al. (1990). Association of hypokalemia, aldosteronism, and renal cysts. N Engl J Med, 322, 345–​51.

A multiple risk factor approach

A multiple risk factor approach

AAV with anti- GBM disease

AAV with anti- GBM disease

ANCA and complement

ANCA and complement

21.10.2  The kidney in systemic vasculitis 4989 renal histology. It is a less common feature of the medium-​vessel vasculitides (polyarteritis nodosa and Kawasaki’s disease) and is rare in large-​vessel vasculitis. AAV is the most frequent cause of renal vasculitis and is the focus of this chapter, although other causes of renal vasculitis will also be discussed. Historical perspective The subgroups within primary systemic vasculitis were initially described as discrete clinicopathological syndromes:  Henoch–​ Schönlein purpura in 1837, polyarteritis nodosa in 1866, Takayasu’s arteritis in 1910, MPA in 1923, Wegener’s granulomatosis in 1936, and Churg–​Strauss angiitis in 1951. An international consensus on the definitions and terminology of vasculitis was achieved in Chapel Hill (North Carolina) in 1992, and updated in 2012, when several syndromes were renamed using descriptive rather than eponymous terms. There are no diagnostic criteria developed for clinical use, but criteria for clinical trials based on ANCA, histology, and clinical fea- tures have been effective. In the 1980s, the association of ANCA with Wegener’s granulomatosis and MPA was reported and the target autoantigens, proteinase 3 (PR3-​ANCA) and myeloperoxidase (MPO-​ANCA), identified. The availability of ANCA testing has been a major advance in the diagnosis and monitoring of vasculitis and has provided insights into pathogenesis and classification. Before 1960, systemic vasculitis with renal involvement was usually fatal. High-​dose corticosteroids were partially effective in the short term, but it was the introduction of immunosuppres- sive therapy, and particularly cyclophosphamide, during the next decade that enabled sustained control of vasculitis to be achieved. An increasing awareness of the late toxicity of cyclophosphamide, particularly infertility and bladder and haematological malignan- cies, in the 1980s encouraged the development of strategies to min- imize cyclophosphamide exposure. Several additional agents have been introduced with the aim of improving control of fulminant or refractory disease, or reducing steroid or immunosuppressive exposure, and these include plasma exchange, intravenous im- munoglobulin, tumour necrosis factor-​α (TNFα) blockade, and lymphocyte depletion. Rituximab, a B-​cell-​depleting monoclonal antibody, was licensed for the treatment of GPA and MPA in 2011, and apart from glucocorticoids remains the only licensed treat- ment for vasculitis. Aetiology, genetics, pathogenesis, and pathology Genetics Genome-​wide association studies have revealed that polymorphisms of α1-​antitrypsin, PR3, and HLA DP antigens are associated with PR3-​ANCA positive disease, and of HLA DQ antigens with MPO-​ ANCA. Other polymorphisms, including cytotoxic T-​lymphocyte-​ associated antigen 4 (CTLA4), tyrosine-​protein phosphatase nonreceptor type 2, the third complement component, and the FcγRIII immunoglobulin receptor have been found in candidate gene studies. There is a modestly increased relative risk of family members having vasculitis, but familial cases are rare. Environment and drugs Occupational exposure to silica and other industrial dusts increases the risk of MPO-​ANCA vasculitis, and an increased incidence of MPO-​ANCA vasculitis was reported after the Kobe earthquake in 1995. Drug exposure to hydralazine, penicillamine, minocycline, and the combination of cocaine and levamisole, has also been associated with MPA. Chronic nasal exposure to cocaine can produce necrosis and inflammation difficult to differentiate from localized GPA. Disease associations ANCA vasculitis occurs in the setting of chronic infections, including tuberculosis, infective endocarditis, and cystic fibrosis, and with cancer, in particular epithelial malignancies. Control of the precipitating path- ology usually results in resolution of the vasculitis. One-​third of pa- tients with antiglomerular basement membrane (anti-​GBM) disease have concurrent ANCA positivity and features of extrarenal vasculitis. MPO-​ANCA occurring in 20% of lupus nephritis patients has been attributed to cross-​reactive antidouble-​stranded DNA antibodies, but a pauci-​immune necrotizing glomerulonephritis can occur in sys- temic lupus erythematosus associated with ANCA. Co-​occurrence of ANCA vasculitis with antiphospholipid antibodies is associated with extensive tissue necrosis and digital infarction. ANCA and complement The pathogenetic role of ANCA remains controversial because this pathology can occur without circulating ANCA, immune deposits are rarely present, and ANCA often persist without disease activity. Table 21.10.2.1  The classification of primary systemic vasculitis, updated in the 2012 Chapel Hill Consensus statement Predominant size of vessel involved Subgrouping ANCA-​associated vasculitis Immune complex Small Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) IgA vasculitis (formerly Henoch–​Schönlein purpura) Microscopic polyangiitis Cryoglobulinaemia Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–​Strauss syndrome) Antiglomerular basement membrane disease Hypocomplementaemic urticarial vasculitis Medium Polyarteritis nodosa Kawasaki’s disease Large Giant cell arteritis Takayasu’s arteritis

ANCA- associated vasculitis

ANCA- associated vasculitis

Aetiology and pathology—

Aetiology and pathology—

Aetiology, genetics, pathogenesis,and pathology

Aetiology, genetics, pathogenesis,and pathology

Aetiology

Aetiology

Areas of uncertainty or controversy

Areas of uncertainty or controversy

21.10.1  Diabetes mellitus and the kidney 4985 surveillance and eye screening for these patients also confers benefit in terms of limb and sight preservation. A multiple risk factor approach As the outlook for patients with diabetic nephropathy is poor, many national guidelines now suggest a multiple risk factor approach to management. However, many patients with advanced diabetic nephropathy referred to renal units in Europe and the United States of America have inadequate blood pressure control, low use of therapies of proven benefit (e.g. β-​blockers, ACE inhibitors, lipid-​ lowering therapy, and low-​dose aspirin), and poor assessment of comorbidities such as retinopathy and foot care. The Steno 2 study in 160 moderately albuminuric type 2 dia- betic patients involved a multifactorial intervention for 7 to 8 years that addressed glycaemia, blood pressure (using renin–​angiotensin system blocking agents in all), serum lipid lowering, low-​dose as- pirin, smoking cessation, reduction of dietary fat and salt, exercise, and antioxidant vitamins. Compared to routine care this significantly reduced the development of severely elevated albuminuria and the composite cardiovascular outcome of fatal and nonfatal myocar- dial infarction and stroke, myocardial revascularization (surgical or percutaneous), and peripheral vascular surgery or amputation. The SHARP (Study of Heart And Renal Protection) trial demonstrated a 2% absolute risk reduction in cardiovascular endpoints in patients with CKD (many of whom had diabetes) treated with a combination of simvastatin and ezetimibe. There is, therefore, a real challenge for our patients as well as their carers to implement multiple therapies in a way that will facilitate compliance and deliver long-​term benefit. Prognosis Moderately albuminuric type 1 and type 2 patients have a two-​ to fourfold increased mortality, mainly from cardiovascular disease. The reported relative mortality for European 40-​year-​old type 1 pa- tients with clinical proteinuria in Denmark was between 80 and 100 times that of the nondiabetic population, while the World Health Organization study revealed a three-​ to fourfold excess for severely elevated albuminuric patients with type 2 diabetes. Data from the FinnDiane and Pittsburgh Epidemiology Studies and Joslin Clinic cohorts also showed that the excess cardiovascular mortality associ- ated with type 1 diabetes is confined to those patients who develop elevated albuminuria; normoalbuminuric individuals have a mor- tality risk indistinguishable from the background population. Most of these deaths are due to stroke or myocardial infarction. In Finland, type 1 patients with nephropathy have a 10-​fold relative risk for both stroke and myocardial infraction compared to nondiabetic controls. The UKPDS cohort demonstrated an annual mortality of 4.6% for those with severely increased albuminuria, and almost 20% for those with a serum creatinine greater than 175 µmol/​litre or in endstage renal disease (Fig. 21.10.1.4), cardiovascular disease being the main cause of death. Pima Indians also show an increase in mortality with increasing ACR, but the causes of death are some- what different to white Europid patients; vascular disease is much less prevalent in Native Americans, although more frequent in those with diabetic nephropathy. In a largely white Europid population in the United Kingdom, a reduced eGFR of less than 60 ml/​min per 1.73 m2 conferred a more than threefold increased hazard ratio for cardiovascular mortality irrespective of albuminuria status. Survival on dialysis remains worse for patients with diabetes com- pared to those without, but they are improving; around 37% are alive after 5 years in American registries compared to 44% for hyperten- sive renal disease and 54% for glomerulonephritis. Overall survival for diabetic patients is best in those who have an early successful kidney transplant. Areas of uncertainty or controversy Should we screen for diabetic nephropathy? Due to the strong associations between an increase in UAER and car- diovascular disease, a case for screening for diabetic nephropathy can Table 21.10.1.4  Cross-​tabulation of latest classification of chronic kidney disease and historical definition of diabetic kidney disease GFR stage, description and definition Albuminuria stage, description, and definition A1—​(Normal) <3.0 mg/​mmol
<30 mg/​g A2—​moderate increase (microalbuminuria) <3.0–​30 mg/​mmol; <30–​299 mg/​g A3—​severe increase (macroalbuminuria) > 30 mg/​mmol; >300 mg/​g G1 (normal) >90 ml/​min per 1.73 m2 At risk of DKD Possible DKD (probable if DR) Probable DKD (consider other causes albuminuria in type 2) G2 (mild reduction) 60–​89 ml/​min per 1.73 m2 At risk of DKD Possible DKD (probable if DR) Probable DKD (consider other causes albuminuria in type 2) G3a (mild–​moderate reduction)
45–​59 ml/​min per 1.73 m2 Possible DKD
(probable if DR) Probable DKD (definite if DR) DKD G3b (moderate–​severe reduction)
30–​44 ml/​min per 1.73 m2 Possible DKD (probable if DR) Probable DKD (definite if DR) DKD G4 (severe reduction) 15–​29 ml/​min per 1.73 m2 Possible DKD (probable if DR) Probable DKD (definite if DR) DKD G5 (kidney failure) <15–​29 ml/​min
per 1.73 m2 Possible DKD (probable if DR) Probable DKD (definite if DR) DKD DKD, diabetic kidney disease; DR, diabetic retinopathy.

Blood pressure control

Blood pressure control

21.10.1  Diabetes mellitus and the kidney 4981 of moderately increased albuminuria or progression of retinop- athy. However, the study was closed early because of excess car- diac deaths and it was not powered for microvascular endpoints. Nonetheless, there is now debate as to the role of intensive glucose control in people with type 2 diabetes, and a recognition that tar- gets will need to be adjusted for the individual taking into account comorbidities and age. There is continuing controversy as to whether intensive glycaemic control alone can prevent the progression of moderately increased albuminuria to severely increased albuminuria. Careful analysis of the DCCT cohort failed to show an impact, but a post hoc ana- lysis of the Joslin Clinic nephropathy cohort demonstrated a slower progression in terms of rate of loss of GFR in those with better gly- caemic control. It is likely that other factors such as blood pres- sure control are of more importance for progression once UAER exceeds 30 to 40 mg/​day. Results from the DCCT/​EDIC cohort have shown a reduction in the number of patients in the intensively treated versus conventional arm who went on to develop an esti- mated glomerular filtration rate (eGFR) of less than 60 ml/​min per 1.73 m2 (incident rates of 1.6 vs 3.0/​1000 person years; P = 0.006), but no effect on rates of endstage renal disease, partly because of the remarkably few individuals who reached this endpoint (8 vs 16 respectively; P = 0.10). The UKPDS showed a positive benefit of intensive therapy on the rate of doubling of serum creatinine at 12 years (0.91% vs 3.52%; P <0.003) in patients with type 2 dia- betes, but the numbers were also very small. A meta-​analysis has shown no effect of intensive glycaemic control on hard nephrop- athy endpoints in type 2 diabetes. Pancreas transplantation in type 1 patients has demonstrated that long-​term (10 years) complete gly- caemic normalization can reverse established pathological changes in native (nontransplanted) glomeruli. Thus glomerulopathy may take as long to reverse as it does to develop, and many studies of intensive control to date may have been of too short a duration, and glycaemic correction inadequate. Blood pressure control There have been many studies of antihypertensive therapy in diabetic nephropathy. For clarity, these will be dealt with under three head- ings:  primary prevention (of moderately increased albuminuria), secondary prevention (of severely increased albuminuria), and ter- tiary prevention (of endstage renal disease and death). Primary prevention The EURODIAB Controlled Trial of Lisinopril in Insulin-​ dependent Diabetes (EUCLID) studied normotensive type 1 diabetic patients with a UAER between 5 and 20 µg/​min and dem- onstrated a significant reduction in albuminuria after 2 years, but no impact on the numbers developing moderately increased albu- minuria. This finding has been confirmed recently by the Diabetic Retinopathy Candesartan Trials (DIRECT) and RASS (Renin–​ Angiotensin System Study) studies. The Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) studied 1204 hyper- tensive type 2 patients with normoalbuminuria and demonstrated a significant reduction in the numbers developing moderately increased albuminuria after 3 years on trandolapril (6%), com- pared to verapamil (11.9%), or placebo (10%). The HOPE and ADVANCE studies also showed a significant benefit in patients at high cardiovascular risk. However, these findings were not con- firmed in normotensive or well-​controlled hypertensive patients in DIRECT. In the UKPDS, the number of hypertensive patients developing a urinary albumin concentration of more than 50 mg/​ litre at 6 years was 2.3% in the tight (blood pressure 144/​82 mmHg) and 12.5% in the less tight (blood pressure 154/​87 mmHg) groups (P <0.009). Secondary prevention Most studies have shown a short-​ to medium-​term benefit of antihypertensive therapy on UAER in the moderately increased albuminuric range, with drugs blocking the renin–​angiotensin system seeming to be more effective. In mainly European patients with type 1 diabetes, a meta-​analysis has shown an adjusted risk reduction of more than 60% for the de- velopment of severely increased albuminuria comparing ACE in- hibitors with placebo. The angiotensin II receptor blocker irbesartan has demonstrated a similar magnitude of effect in moderately in- creased albuminuric type 2 diabetic patients. Thus, blockade of the renin–​angiotensin system by any means appears to confer benefit in terms of a reduction in the numbers of patients developing severely Table 21.10.1.3  Comparison of intensive versus conventional therapy in the prevention of moderately increased albuminuria in type 1 (DCCT + EDIC) and newly diagnosed type 2 (UKPDS) patients Study Number Ethnicity Duration of study (years) Achieved HbA1c Moderately severe albuminuria Intensive (%) Conventional (%) Intensive (%) Conventional (%) RRR (%) DCCT European (96%) 9 7.2 (normal <6.05) 9.1 (UAER

40 mg/​day)   No retinopathy   726 15 27 44   Retinopathy   715 27 42 35 EDIC 1112 8 8.0 8.2 6.8 15.8 57 UKPDS 3867 European 81% Indian Asian 10% Afro-​ Caribbean 8% 9 7.0 (normal 6.2) 7.9 19.2 (UAC 50 mg/​litre) 25.4 24 DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications Study; RRR, relative risk reduction; UAC, urinary albumin concentration, annual; UAER, urinary albumin excretion rate, annual 4-​h collections (biannual for EDIC); UKPDS, United Kingdom Prospective Diabetes Study.

Blood pressure

Blood pressure

Box 21.10.1.1 Aetiopathological factors for nephro

Box 21.10.1.1 Aetiopathological factors for nephropathy

Box 21.10.1.2 Clinical features suggestive of nond

Box 21.10.1.2 Clinical features suggestive of nondiabeticrenal disease

21.10.1  Diabetes mellitus and the kidney 4983 estimate, although the UKPDS suggests that rates are similar to type 1 (Table 21.10.1.2). Up to 7% of newly diagnosed type 2 patients in the United Kingdom will have a urinary albumin concentration above 50 mg/​litre, and 1% will be above 300 mg/​litre. Some studies have reported a reduction in UAER with initial glycaemic correc- tion, but many patients have a sustained increase suggesting estab- lished nephropathology at diagnosis. GFR As previously mentioned, GFR at diagnosis of type 1 and type 2 diabetes is increased in 40 to 45% of patients. It returns to normal in most following glycaemic correction, although a significant minority maintain persistently high values (hyperfiltration). In nondiabetic humans, the GFR declines by 1 ml/​min per year after the age of 40, and it does so also in normotensive diabetic patients who have normal UAER. As the UAER approaches and exceeds the severely elevated albuminuria threshold, there tends to be a steady decline. This is particularly so in hypertensive patients, in whom the rate of loss of GFR varies considerably. In those with poorly con- trolled hypertension, the average decline was 10 ml/​min per year in historical series, leading to endstage renal disease in 7 to 10 years. More recently, the rate of decline is 2–​4 ml/​min per year in patients with well-​controlled systemic blood pressure, effectively delaying endstage renal disease by 15–​20 years. Patients with type 2 diabetes and a normal UAER tend to have a much slower rate of loss of GFR. It is now recommended that all people with diabetes have an eGFR performed annually using the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-​EPI) equations. Blood pressure In patients with type 1 diabetes, blood pressure is virtually always normal at diagnosis. This is not the case in type 2 diabetes, where over one-​third will have blood pressure higher than 160/​95 mmHg and many more are hypertensive by recent criteria. Type 1 patients who go on to develop moderately elevated albuminuria have signifi- cantly higher blood pressures than those who remain with a normal UAER, although the averages remain below 140/​90 mm Hg in both groups. Patients with newly developed moderately elevated albu- minuria show a steady increase in blood pressure such that over 45% exceed 140/​90 mmHg within 4 years. Most type 1 and type 2 patients with severely elevated albuminuria are hypertensive and on therapy. Clinical concomitants of nephropathy Many patients with diabetic nephropathy will also have retinopathy and neuropathy, which will tend to progress. Both of these com- plications can be reversed or at least ameliorated by improved gly- caemic control. There is an increased incidence of cardiovascular, cerebrovascular, and peripheral vascular disease; intensive manage- ment of modifiable cardiovascular risk factors is essential (see later). Amputation rates in patients with diabetic nephropathy are high; careful foot surveillance and preventative podiatry are essential. Differential diagnosis It is important to remember that not all renal or urinary tract dis- ease in diabetic patients is due to diabetic nephropathy. Urinary tract infection is more common in diabetic women compared to age-​matched nondiabetic controls. Infection is often asymptom- atic and culture should always be performed in any patient with an isolated positive urinalysis for protein, blood, leucocytes, or nitrite. A positive result is much more likely if two or more of these tests are positive. Papillary necrosis has been described in women with long-​ standing type 1 diabetes and is a recognized complication of hyperosmolar coma in patients with both types of diabetes. Atheromatous renovascular disease is also common in diabetes, but the precise prevalence of functionally significant renal artery sten- osis is uncertain. Whereas the vast majority of type 1 patients with moderately in- creased albuminuria who undergo renal biopsy are found to have histologically proven diabetic glomerulopathy, the situation is less certain in type 2 diabetes. Up to 10% of such patients have evi- dence of nondiabetic pathologies, many have nonspecific ischaemic changes, and only a few have classic diabetic lesions. The presence of diabetic retinopathy is helpful as those with it are almost certain to have diabetic glomerulopathy and those without it much less so. Even so, there are few cases of specifically treatable glomerular dis- ease in those with nondiabetic lesions, hence management is un- likely to be significantly different; although those with nonclassic lesions tend to have slower rates of decline of GFR and may be at lower risk of endstage renal disease. Clinical investigation Type 2 diabetes is becoming more common and as a result the chance of concomitant nondiabetic renal or urological disease is increased. The need to exclude urinary tract infection has already been mentioned. Current United Kingdom guidelines suggest investigation and possible referral of all diabetic pa- tients with persistent nonvisible or visible haematuria. An atyp- ical presentation of proteinuria, or an unusual clinical course such as rapidly deteriorating GFR, or the presence of features of other systemic diseases should prompt referral and inves- tigation (Box 21.10.1.2). Current United Kingdom guidelines suggest expert review of all with an eGFR of less than 30 ml/​ min per 1.73 m2. Box 21.10.1.2  Clinical features suggestive of nondiabetic renal disease • Increased UAER/​clinical proteinuria/​nephrotic syndrome in absence of retinopathy • Low GFR with normal UAER • Rapidly declining GFR (>15 ml/​min per year or >25% in 1 year) • Rapidly increasing proteinuria • Refractory hypertension (use of four or more agents)—​consider renal artery stenosis • Presence of active urinary sediment (red cells, cellular casts) • Signs or symptoms of other systemic disease • A greater than 30% reduction in GFR within 2–​3 months of initiation of renin–​angiotensin system blocking agents—​consider renal artery stenosis

Box 21.10.2.1 Clinical features that should raise

Box 21.10.2.1 Clinical features that should raise suspicionof vasculitis

CONTENTS

Contents

Contents Volume 1 List of abbreviations  xxxv List of contributors  xlv SECTION 1 Patients and their treatment Section editors: John D. Firth, Christopher P. Conlon,
and Timothy M. Cox 1.1 On being a patient  3 Christopher Booth† 1.2 A young person’s experience of chronic
disease  6 1.3 What patients wish you understood  8 Rosamund Snow† 1.4 Why do patients attend and what do they want from the consultation?  14 Des Spence 1.5 Medical ethics  20 Mike Parker, Mehrunisha Suleman, and Tony Hope 1.6 Clinical decision-​making  26 Timothy E.A. Peto and Philippa Peto SECTION 2 Background to medicine Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 2.1 Science in medicine: When, how, and what  33 William F. Bynum 2.2 Evolution: Medicine’s most basic science  39 Randolph M. Nesse and Richard Dawkins 2.3 The Global Burden of Disease: Measuring the health of populations  43 Theo Vos, Alan Lopez, and Christopher Murray 2.4 Large-​scale randomized evidence: Trials and meta-​analyses of trials  51 Colin Baigent, Richard Peto, Richard Gray, Natalie Staplin, Sarah Parish, and Rory Collins 2.5 Bioinformatics  67 Afzal Chaudhry 2.6 Principles of clinical pharmacology and drug therapy  71 Kevin O’Shaughnessy 2.7 Biological therapies for immune, inflammatory, and allergic diseases  100 John D. Isaacs and Nishanthi Thalayasingam 2.8 Traditional medicine exemplified by traditional Chinese medicine  108 Fulong Liao, Tingliang Jiang, and Youyou Tu 2.9 Engaging patients in therapeutic development  118 Emil Kakkis and Max Bronstein 2.10 Medicine quality, physicians, and patients  124 Paul N. Newton 2.11 Preventive medicine  127 David Mant 2.12 Medical screening  137 Nicholas Wald and Malcolm Law 2.13 Health promotion  152 Evelyne de Leeuw † It is with great regret that we report that Christopher Booth died on 13 July, 2012 and Rosamund Snow died on 2 February, 2017.

Contents xiv 2.14 Deprivation and health  157 Harry Burns 2.15 How much should rich countries’ governments spend on healthcare?  161 Allyson M. Pollock and David Price 2.16 Financing healthcare in low-​income developing countries: A challenge for equity in health  168 Luis G. Sambo, Jorge Simões, and Maria do Rosario O. Martins 2.17 Research in the developed world  177 Jeremy Farrar 2.18 Fostering medical and health research in resource-​constrained countries  181 Malegapuru W. Makgoba and Stephen M. Tollman 2.19 Regulation versus innovation in medicine  185 Michael Rawlins 2.20 Human disasters  188 Amartya Sen 2.21 Humanitarian medicine  193 Amy S. Kravitz 2.22 Complementary and alternative medicine  201 Edzard Ernst SECTION 3 Cell biology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 3.1 The cell  209 George Banting and Jean Paul Luzio 3.2 The genomic basis of medicine  218 Paweł Stankiewicz and James R. Lupski 3.3 Cytokines  236 Iain B. McInnes 3.4 Ion channels and disease  246 Frances Ashcroft and Paolo Tammaro 3.5 Intracellular signalling  256 R. Andres Floto 3.6 Apoptosis in health and disease  266 Mark J. Arends and Christopher D. Gregory 3.7 Stem cells and regenerative medicine  281 Alexis J. Joannides, Bhuvaneish T. Selvaraj, and
Siddharthan Chandran 3.8 The evolution of therapeutic antibodies  296 Herman Waldmann and Greg Winter 3.9 Circulating DNA for molecular diagnostics  299 Y.M. Dennis Lo and Rossa W.K. Chiu SECTION 4 Immunological mechanisms Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 4.1 The innate immune system  307 Paul Bowness 4.2 The complement system  315 Marina Botto and Matthew C. Pickering 4.3 Adaptive immunity  325 Paul Klenerman and Constantino López-​Macias 4.4 Immunodeficiency  337 Sophie Hambleton, Sara Marshall, and Dinakantha S. Kumararatne 4.5 Allergy  368 Pamela Ewan 4.6 Autoimmunity  379 Antony Rosen 4.7 Principles of transplantation immunology  392 Elizabeth Wallin and Kathryn J. Wood SECTION 5 Principles of clinical oncology Section editors: John D. Firth, Christopher P. Conlon, and Timothy M. Cox 5.1 Epidemiology of cancer  411 Anthony Swerdlow and Richard Peto 5.2 The nature and development of cancer: Cancer mutations and their implications  445 James D. Brenton and Tim Eisen 5.3 The genetics of inherited cancers  456 Rosalind A. Eeles 5.4 Cancer immunity and immunotherapy  471 Charles G. Drake 5.5 Clinical features and management  487 Tim Eisen and Martin Gore† 5.6 Systemic treatment and radiotherapy  497 Rajesh Jena and Peter Harper † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contents xv 5.7 Medical management of breast cancer  505 Tim Crook, Su Li, and Peter Harper SECTION 6 Old age medicine Section editor: Finbarr C. Martin 6.1 Ageing and clinical medicine  511 Claire Steves and Neil Pendleton 6.2 Frailty and sarcopenia  521 Andrew Clegg and Harnish Patel 6.3 Optimizing well-​being into old age  532 Steve Iliffe 6.4 Older people and urgent care  539 Simon Conroy and Jay Banerjee 6.5 Older people in hospital  548 Graham Ellis, Alasdair MacLullich, and Rowan Harwood 6.6 Supporting older peoples’ care in surgical and oncological services  563 Jugdeep Dhesi and Judith Partridge 6.7 Drugs and prescribing in the older patient  571 Miles Witham, Jacob George, and Denis O’Mahony 6.8 Falls, faints, and fragility fractures  579 Fiona Kearney and Tahir Masud 6.9 Bladder and bowels  589 Susie Orme and Danielle Harari 6.10 Neurodegenerative disorders in older people  601 John Hindle 6.11 Promotion of dignity in the life and death of older patients  612 Eileen Burns and Claire Scampion SECTION 7 Pain and palliative care Section editor: Bee Wee 7.1 Introduction to palliative care  623 Susan Salt 7.2 Pain management  629 Marie Fallon 7.3 Symptoms other than pain  634 Regina McQuillan 7.4 Care of the dying person  639 Suzanne Kite and Adam Hurlow SECTION 8 Infectious diseases Section editor: Christopher P. Conlon 8.1 Pathogenic microorganisms and the host  651

8.1.1 Biology of pathogenic microorganisms  651 Duncan J. Maskell and James L.N. Wood

8.1.2 Clinical features and general management of patients with severe infections  656 Peter Watkinson and Duncan Young 8.2 The patient with suspected infection  662

8.2.1 Clinical approach  662 Christopher J. Ellis

8.2.2 Fever of unknown origin  664 Steven Vanderschueren

8.2.3 Nosocomial infections  669 Ian C.J.W. Bowler and Matthew Scarborough

8.2.4 Infection in the immunocompromised host  673 Jon Cohen and Elham Khatamzas

8.2.5 Antimicrobial chemotherapy  684 Maha Albur, Alasdair MacGowan, and Roger G. Finch 8.3 Immunization  706 David Goldblatt and Mary Ramsay 8.4 Travel and expedition medicine  713 Susanna Dunachie and Christopher P. Conlon 8.5 Viruses  723

8.5.1 Respiratory tract viruses  723 Malik Peiris

8.5.2 Herpesviruses (excluding Epstein–​Barr virus)  734 J.G.P. Sissons†

8.5.3 Epstein–​Barr virus  754 Alan B. Rickinson and M.A. Epstein

8.5.4 Poxviruses  764 Geoffrey L. Smith

8.5.5 Mumps: Epidemic parotitis  769 B.K. Rima

8.5.6 Measles  772 Hilton C. Whittle and Peter Aaby

8.5.7 Nipah and Hendra virus encephalitides  784 C.T. Tan † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016.

Contents xvi

8.5.8 Enterovirus infections  787 Philip Minor and Ulrich Desselberger

8.5.9 Virus infections causing diarrhoea and vomiting  797 Philip R. Dormitzer and Ulrich Desselberger

8.5.10 Rhabdoviruses: Rabies and rabies-​related lyssaviruses  805 Mary J. Warrell and David A. Warrell

8.5.11 Colorado tick fever and other arthropod-​borne reoviruses  819 Mary J. Warrell and David A. Warrell

8.5.12 Alphaviruses  821 Ann M. Powers, E.E. Ooi, L.R. Petersen, and D.J. Gubler

8.5.13 Rubella  827 Pat Tookey and J.M. Best

8.5.14 Flaviviruses excluding dengue  830 Shannan Lee Rossi and Nikos Vasilakis

8.5.15 Dengue  845 Bridget Wills and Yee-​Sin Leo

8.5.16 Bunyaviridae  852 James W. Le Duc and D.A. Bente

8.5.17 Arenaviruses  862 Jan H. ter Meulen

8.5.18 Filoviruses  870 Jan H. ter Meulen

8.5.19 Papillomaviruses and polyomaviruses  877 Raphael P. Viscidi, Chen Sabrina Tan, and
Carole Fakhry

8.5.20 Parvovirus B19  886 Kevin E. Brown

8.5.21 Hepatitis viruses (excluding hepatitis C virus)  889 Matthew Cramp, Ashwin Dhanda, and
Nikolai V. Naoumov

8.5.22 Hepatitis C virus  896 Paul Klenerman, Katie J.M. Jeffery, Ellie J. Barnes, and
Jane Collier

8.5.23 HIV/​AIDS  901 Sarah Fidler, Timothy E.A. Peto, Philip Goulder, and Christopher P. Conlon

8.5.24 HIV in low-​ and middle-​income countries  933 Alison D. Grant and Kevin M. De Cock

8.5.25 HTLV-​1, HTLV-​2, and associated diseases  941 Kristien Verdonck and Eduardo Gotuzzo

8.5.26 Viruses and cancer  945 Robin A. Weiss

8.5.27 Orf and Milker’s nodule  947 Emma Aarons and David A. Warrell

8.5.28 Molluscum contagiosum  949 David A. Warrell and Christopher P. Conlon

8.5.29 Newly discovered viruses  951 Susannah J.A. Froude and Harriet C. Hughes 8.6 Bacteria  958

8.6.1 Diphtheria  959 Delia B. Bethell and Tran Tinh Hien

8.6.2 Streptococci and enterococci  965 Dennis L. Stevens and Sarah Hobdey

8.6.3 Pneumococcal infections  975 Anthony Scott

8.6.4 Staphylococci  991 Kyle J. Popovich, Robert A. Weinstein, and Bala Hota

8.6.5 Meningococcal infections  1010 Petter Brandtzaeg

8.6.6 Neisseria gonorrhoeae  1025 Jackie Sherrard and Magnus Unemo

8.6.7 Enterobacteria and bacterial food poisoning  1032 Hugh Pennington

8.6.8 Pseudomonas aeruginosa  1041 G.C.K.W. Koh and Sharon J. Peacock

8.6.9 Typhoid and paratyphoid fevers  1044 Christopher M. Parry and Buddha Basnyat

8.6.10 Intracellular klebsiella infections (donovanosis and rhinoscleroma)  1051 John Richens and Nicole Stoesser

8.6.11 Anaerobic bacteria  1055 Anilrudh A. Venugopal and David W. Hecht

8.6.12 Cholera  1060 Aldo A.M. Lima and Richard L. Guerrant

8.6.13 Haemophilus influenzae  1066 Esther Robinson

8.6.14 Haemophilus ducreyi and chancroid  1071 Nigel O’Farrell

8.6.15 Bordetella infection  1073 Cameron C. Grant

8.6.16 Melioidosis and glanders  1076 Sharon J. Peacock

8.6.17 Plague: Yersinia pestis  1081 Michael Prentice

8.6.18 Other Yersinia infections: Yersiniosis  1086 Michael Prentice

8.6.19 Pasteurella  1088 Marina S. Morgan

8.6.20 Francisella tularensis infection  1091 Petra C.F. Oyston

Contents xvii

8.6.21 Anthrax  1094 Arthur E. Brown

8.6.22 Brucellosis  1102 Juan D. Colmenero and Pilar Morata

8.6.23 Tetanus  1109 C. Louise Thwaites and Lam Minh Yen

8.6.24 Clostridium difficile  1115 David W. Eyre and Mark H. Wilcox

8.6.25 Botulism, gas gangrene, and clostridial gastrointestinal infections  1120 Dennis L. Stevens, Michael J. Aldape, and Amy E. Bryant

8.6.26 Tuberculosis  1126 Richard E. Chaisson and Jean B. Nachega

8.6.27 Disease caused by environmental mycobacteria  1150 Jakko van Ingen

8.6.28 Leprosy (Hansen’s disease)  1154 Diana N.J. Lockwood

8.6.29 Buruli ulcer: Mycobacterium ulcerans infection  1167 Bouke de Jong, Françoise Portaels, and Wayne M. Meyers

8.6.30 Actinomycoses  1170 Klaus P. Schaal

8.6.31 Nocardiosis  1176 Roderick J. Hay

8.6.32 Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection)  1179 Andrew F. Woodhouse

8.6.33 Lyme borreliosis  1181 Gary P. Wormser, John Nowakowski, and
Robert B. Nadelman

8.6.34 Relapsing fevers  1188 David A. Warrell

8.6.35 Leptospirosis  1198 Nicholas P.J. Day

8.6.36 Nonvenereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta  1204 Michael Marks, Oriol Mitjà, and David Mabey

8.6.37 Syphilis  1210 Phillip Read and Basil Donovan

8.6.38 Listeriosis  1223 Herbert Hof

8.6.39 Legionellosis and Legionnaires’ disease  1226 Diego Viasus and Jordi Carratalà

8.6.40 Rickettsioses  1230 Karolina Griffiths, Carole Eldin, Didier Raoult, and Philippe Parola

8.6.41 Scrub typhus  1252 Daniel H. Paris and Nicholas P.J. Day

8.6.42 Coxiella burnetii infections (Q fever)  1257 Thomas J. Marrie

8.6.43 Bartonellas excluding B. bacilliformis  1262 Bruno B. Chomel, Henri-​Jean Boulouis, Matthew J. Stuckey, and Jean-​Marc Rolain

8.6.44 Bartonella bacilliformis infection  1272 A. Llanos-​Cuentas and C. Maguiña-​Vargas

8.6.45 Chlamydial infections  1278 Patrick Horner, David Mabey, David Taylor-​Robinson, and Magnus Unemo

8.6.46 Mycoplasmas  1295 Jørgen Skov Jensen and David Taylor-​Robinson

8.6.47 A checklist of bacteria associated with infection
in humans  1307 John Paul 8.7 Fungi (mycoses)  1338

8.7.1 Fungal infections  1338 Roderick J. Hay

8.7.2 Cryptococcosis  1359 William G. Powderly, J. William Campbell, and
Larry J. Shapiro

8.7.3 Coccidioidomycosis  1361 Gregory M. Anstead

8.7.4 Paracoccidioidomycosis  1364 M.A. Shikanai-​Yasuda

8.7.5 Pneumocystis jirovecii  1371 Robert F. Miller and Christopher P. Eades

8.7.6 Talaromyces (Penicillium) marneffei infection  1375 Romanee Chaiwarith, Khuanchai Supparatpinyo, and Thira Sirisanthana

8.7.7 Microsporidiosis  1378 Louis M. Weiss 8.8 Protozoa  1384

8.8.1 Amoebic infections  1384 Richard Knight

8.8.2 Malaria  1395 Nicholas J. White and Arjen M. Dondorp

8.8.3 Babesiosis  1414 Philippe Brasseur

8.8.4 Toxoplasmosis  1416 Oliver Liesenfeld and Eskild Petersen

8.8.5 Cryptosporidium and cryptosporidiosis  1424 Simone M. Cacciò

8.8.6 Cyclospora and cyclosporiasis  1432 Paul Kelly and Ralph Lainson† † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contents xviii

8.8.7 Cystoisosporiasis  1436 Louis M. Weiss

8.8.8 Sarcocystosis (sarcosporidiosis)  1438 John E. Cooper

8.8.9 Giardiasis and balantidiasis  1440 Lars Eckmann and Martin F. Heyworth

8.8.10 Blastocystis infection  1449 Richard Knight

8.8.11 Human African trypanosomiasis  1451 Reto Brun and Johannes Blum

8.8.12 Chagas disease  1459 Michael A. Miles

8.8.13 Leishmaniasis  1467 Antony D.M. Bryceson and Diana N.J. Lockwood

8.8.14 Trichomoniasis  1475 Jane Schwebke 8.9 Nematodes (roundworms)  1478

8.9.1 Cutaneous filariasis  1478 Gilbert Burnham

8.9.2 Lymphatic filariasis  1487 Richard Knight

8.9.3 Guinea worm disease (dracunculiasis)  1495 Richard Knight

8.9.4 Strongyloidiasis, hookworm, and other gut strongyloid nematodes  1500 Michael Brown

8.9.5 Gut and tissue nematode infections acquired
by ingestion  1506 Peter L. Chiodini

8.9.6 Angiostrongyliasis  1516 Richard Knight 8.10 Cestodes (tapeworms)  1520

8.10.1 Cestodes (tapeworms)  1520 Richard Knight

8.10.2 Cystic hydatid disease (Echinococcus
granulosus)  1529 Pedro L. Moro, Hector H. Garcia, and
Armando E. Gonzalez

8.10.3 Cysticercosis  1533 Hector H. Garcia and Robert H. Gilman 8.11 Trematodes (flukes)  1540

8.11.1 Schistosomiasis  1540 David Dunne and Birgitte Vennervald

8.11.2 Liver fluke infections  1551 Ross H. Andrews, Narong Khuntikeo,
Paiboon Sithithaworn, and Trevor N. Petney

8.11.3 Lung flukes (paragonimiasis)  1558 Udomsak Silachamroon and Sirivan Vanijanonta

8.11.4 Intestinal trematode infections  1562 Alastair McGregor 8.12 Nonvenomous arthropods  1568 John Paul 8.13 Pentastomiasis (porocephalosis,
linguatulosis/​linguatuliasis, or tongue
worm infection)  1582 David A. Warrell SECTION 9 Sexually transmitted diseases Section editor: Jackie Sherrard 9.1 Epidemiology of sexually transmitted infections  1589 David Mabey and Anita Vas-​Falcao 9.2 Sexual behaviour  1597 Catherine H. Mercer and Anne M. Johnson 9.3 Sexual history and examination  1600 Gary Brook, Jackie Sherrard, and Graz A. Luzzi 9.4 Vaginal discharge  1603 Paul Nyirjesy 9.5 Urethritis  1606 Patrick Horner 9.6 Genital ulceration  1610 Patrick French and Raj Patel 9.7 Anogenital lumps and bumps  1613 Henry J.C. de Vries and Charles J.N. Lacey 9.8 Pelvic inflammatory disease  1622 Jonathan D.C. Ross 9.9 Principles of contraception  1626 Zara Haider Index

Contents xix Volume 2 List of abbreviations  xxxv List of contributors  xlv SECTION 10 Environmental medicine, occupational medicine, and poisoning Section editor: Jon G. Ayres 10.1 Environmental medicine, occupational medicine, and poisoning—​Introduction  1637 Jon G. Ayres 10.2 Occupational health  1638

10.2.1 Occupational and environmental health  1638 Raymond Agius and Debasish Sen

10.2.2 Occupational safety  1652 Lawrence Waterman

10.2.3 Aviation medicine  1656 Michael Bagshaw

10.2.4 Diving medicine  1664 David M. Denison and Mark A. Glover

10.2.5 Noise  1671 David Koh and Tar-​Ching Aw†

10.2.6 Vibration  1673 Tar-​Ching Aw† 10.3 Environment and health  1677

10.3.1 Air pollution and health  1677 Om P. Kurmi, Kin Bong Hubert Lam, and Jon G. Ayres

10.3.2 Heat  1687 Michael A. Stroud

10.3.3 Cold  1689 Michael A. Stroud

10.3.4 Drowning  1691 Peter J. Fenner

10.3.5 Lightning and electrical injuries  1696 Chris Andrews

10.3.6 Diseases of high terrestrial altitudes  1701 Tyler Albert, Erik R. Swenson, Andrew J. Pollard, Buddha Basnyat, and David R. Murdoch

10.3.7 Radiation  1709 Jill Meara

10.3.8 Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions  1713 Peter J. Baxter

10.3.9 Bioterrorism  1718 Manfred S. Green 10.4 Poisoning  1725

10.4.1 Poisoning by drugs and chemicals  1725 John A. Vale, Sally M. Bradberry, and D. Nicholas Bateman

10.4.2 Injuries, envenoming, poisoning, and allergic reactions caused by animals  1778 David A. Warrell

10.4.3 Poisonous fungi  1817 Hans Persson and David A. Warrell

10.4.4 Poisonous plants  1828 Michael Eddleston and Hans Persson 10.5 Podoconiosis (nonfilarial elephantiasis)  1833 Gail Davey SECTION 11 Nutrition Section editor: Katherine Younger 11.1 Nutrition: Macronutrient metabolism  1839 Keith N. Frayn and Rhys D. Evans 11.2 Vitamins  1855 Tom R. Hill and David A. Bender 11.3 Minerals and trace elements  1871 Katherine Younger 11.4 Severe malnutrition  1880 Alan A. Jackson 11.5 Diseases of affluent societies and the need for dietary change  1891 J.I. Mann and A.S. Truswell 11.6 Obesity  1903 I. Sadaf Farooqi 11.7 Artificial nutrition support  1914 Jeremy Woodward † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contents xx SECTION 12 Metabolic disorders Section editor: Timothy M. Cox 12.1 The inborn errors of metabolism: General aspects  1929 Timothy M. Cox and Richard W.E. Watts† 12.2 Protein-​dependent inborn errors of metabolism  1942 Georg F. Hoffmann and Stefan Kölker 12.3 Disorders of carbohydrate metabolism  1985

12.3.1 Glycogen storage diseases  1985 Robin H. Lachmann and Timothy M. Cox

12.3.2 Inborn errors of fructose metabolism  1993 Timothy M. Cox

12.3.3 Disorders of galactose, pentose, and pyruvate metabolism  2003 Timothy M. Cox 12.4 Disorders of purine and pyrimidine metabolism  2015 Anthony M. Marinaki, Lynette D. Fairbanks, and Richard W.E. Watts† 12.5 The porphyrias  2032 Timothy M. Cox 12.6 Lipid disorders  2055 Jaimini Cegla and James Scott 12.7 Trace metal disorders  2098

12.7.1 Hereditary haemochromatosis  2098 William J.H. Griffiths and Timothy M. Cox

12.7.2 Inherited diseases of copper metabolism:
Wilson’s disease and Menkes’ disease  2115 Michael L. Schilsky and Pramod K. Mistry 12.8 Lysosomal disease  2121 Patrick B. Deegan and Timothy M. Cox 12.9 Disorders of peroxisomal metabolism in adults  2157 Anthony S. Wierzbicki 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias  2174 Sonia Fargue, Dawn S. Milliner, and Christopher J. Danpure 12.11 A physiological approach to acid–​base disorders: The roles of ion transport and body fluid compartments  2182 Julian Seifter 12.12 The acute phase response, hereditary periodic fever syndromes, and amyloidosis  2199

12.12.1 The acute phase response and C-​reactive protein  2199 Mark B. Pepys

12.12.2 Hereditary periodic fever syndromes  2207 Helen J. Lachmann, Stefan Berg, and Philip N. Hawkins

12.12.3 Amyloidosis  2218 Mark B. Pepys and Philip N. Hawkins 12.13 α1-​Antitrypsin deficiency and the serpinopathies  2235 David A. Lomas SECTION 13 Endocrine disorders Section editor: Mark Gurnell 13.1 Principles of hormone action  2245 Rob Fowkes, V. Krishna Chatterjee, and Mark Gurnell 13.2 Pituitary disorders  2258

13.2.1 Disorders of the anterior pituitary gland  2258 Niki Karavitaki and John A.H. Wass

13.2.2 Disorders of the posterior pituitary gland  2277 Niki Karavitaki, Shahzada K. Ahmed, and John A.H. Wass 13.3 Thyroid disorders  2284

13.3.1 The thyroid gland and disorders of thyroid function  2284 Anthony P. Weetman and Kristien Boelaert

13.3.2 Thyroid cancer  2302 Kristien Boelaert and Anthony P. Weetman 13.4 Parathyroid disorders and diseases altering calcium metabolism  2313 R.V. Thakker 13.5 Adrenal disorders  2331

13.5.1 Disorders of the adrenal cortex  2331 Mark Sherlock and Mark Gurnell

13.5.2 Congenital adrenal hyperplasia  2360 Nils P. Krone and Ieuan A. Hughes 13.6 Reproductive disorders  2374

13.6.1 Ovarian disorders  2374 Stephen Franks, Kate Hardy, and Lisa J. Webber

13.6.2 Disorders of male reproduction and male hypogonadism  2386 P.-​M.G. Bouloux

13.6.3 Benign breast disease  2406 Gael M. MacLean † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018.

Contents xxi

13.6.4 Sexual dysfunction  2408 Ian Eardley 13.7 Disorders of growth and development  2416

13.7.1 Normal growth and its disorders  2416 Gary Butler

13.7.2 Normal puberty and its disorders  2428 Fiona Ryan and Sejal Patel

13.7.3 Normal and abnormal sexual differentiation  2435 S. Faisal Ahmed and Angela K. Lucas-​Herald 13.8 Pancreatic endocrine disorders and multiple endocrine neoplasia  2449 B. Khoo, T.M. Tan, and S.R. Bloom 13.9 Diabetes and hypoglycaemia  2464

13.9.1 Diabetes  2464 Colin Dayan and Julia Platts

13.9.2 Hypoglycaemia  2531 Mark Evans and Ben Challis 13.10 Hormonal manifestations of nonendocrine disease  2541 Thomas M. Barber and John A.H. Wass 13.11 The pineal gland and melatonin  2553 J. Arendt and Timothy M. Cox SECTION 14 Medical disorders in pregnancy Section editor: Catherine Nelson-​Piercy 14.1 Physiological changes of normal pregnancy  2563 David J. Williams 14.2 Nutrition in pregnancy  2568 David J. Williams 14.3 Medical management of normal pregnancy  2575 David J. Williams 14.4 Hypertension in pregnancy  2583 Fergus McCarthy 14.5 Renal disease in pregnancy  2589 Kate Wiles 14.6 Heart disease in pregnancy  2597 Catherine E.G. Head 14.7 Thrombosis in pregnancy  2606 Peter K. MacCallum and Louise Bowles 14.8 Chest diseases in pregnancy  2613 Meredith Pugh and Tina Hartert 14.9 Liver and gastrointestinal diseases of pregnancy  2619 Michael Heneghan and Catherine Williamson 14.10 Diabetes in pregnancy  2627 Bryony Jones and Anne Dornhorst 14.11 Endocrine disease in pregnancy  2638 David Carty 14.12 Neurological conditions in pregnancy  2642 Pooja Dassan 14.13 The skin in pregnancy  2648 Gudula Kirtschig and Fenella Wojnarowska 14.14 Autoimmune rheumatic disorders and vasculitis in pregnancy  2655 May Ching Soh and Catherine Nelson-​Piercy 14.15 Maternal infection in pregnancy  2671 Rosie Burton 14.16 Fetal effects of maternal infection  2678 Lawrence Impey 14.17 Blood disorders in pregnancy  2687 David J. Perry and Katharine Lowndes 14.18 Malignant disease in pregnancy  2696 Robin A.F. Crawford 14.19 Maternal critical care  2701 Rupert Gauntlett 14.20 Prescribing in pregnancy  2706 Lucy MacKillop and Charlotte Frise 14.21 Contraception for women with medical diseases  2711 Aarthi R. Mohan SECTION 15 Gastroenterological disorders Section editor: Jack Satsangi 15.1 Structure and function of the gastrointestinal tract  2721 Michael E.B. FitzPatrick and Satish Keshav† 15.2 Symptoms of gastrointestinal disease  2727 Jeremy Woodward 15.3 Methods for investigation of
gastroenterological disease  2734

15.3.1 Colonoscopy and flexible sigmoidoscopy  2734 James E. East and Brian P. Saunders † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contents xxii

15.3.2 Upper gastrointestinal endoscopy  2740 James E. East and George J. Webster

15.3.3 Radiology of the gastrointestinal tract  2748 Fiachra Moloney and Michael Maher

15.3.4 Investigation of gastrointestinal function  2757 Jervoise Andreyev 15.4 Common acute abdominal presentations  2765

15.4.1 The acute abdomen  2765 Simon J.A. Buczacki and R. Justin Davies

15.4.2 Gastrointestinal bleeding  2771 Vanessa Brown and T.A. Rockall 15.5 Immune disorders of the gastrointestinal tract  2783 Joya Bhattacharyya and Arthur Kaser 15.6 The mouth and salivary glands  2797 John Gibson and Douglas Robertson 15.7 Diseases of the oesophagus  2828 Rebecca C. Fitzgerald and Massimiliano di Pietro 15.8 Peptic ulcer disease  2849 Joseph Sung 15.9 Hormones and the gastrointestinal tract  2862

15.9.1 Hormones and the gastrointestinal tract  2862 Rebecca Scott, T.M. Tan, and S.R. Bloom

15.9.2 Carcinoid syndrome  2870 B. Khoo, T.M. Tan, and S.R. Bloom 15.10 Malabsorption  2875

15.10.1 Differential diagnosis and investigation of malabsorption  2875 Alastair Forbes and Victoria Mulcahy

15.10.2 Bacterial overgrowth of the small
intestine  2879 Stephen J. Middleton and Raymond J. Playford

15.10.3 Coeliac disease  2884 Peter D. Mooney and David S. Sanders

15.10.4 Gastrointestinal lymphomas  2892 Kikkeri N. Naresh

15.10.5 Disaccharidase deficiency  2902 Timothy M. Cox

15.10.6 Whipple’s disease  2909 Florence Fenollar and Didier Raoult

15.10.7 Effects of massive bowel resection  2911 Stephen J. Middleton, Simon M. Gabe, and
Raymond J. Playford

15.10.8 Malabsorption syndromes in the tropics  2916 Vineet Ahuja and Govind K. Makharia 15.11 Crohn’s disease  2925 Miles Parkes and Tim Raine 15.12 Ulcerative colitis  2937 Jeremy Sanderson and Peter Irving 15.13 Irritable bowel syndrome  2951 Adam D. Farmer and Qasim Aziz 15.14 Colonic diverticular disease  2960 Nicolas C. Buchs, Roel Hompes, Shazad Q. Ashraf, and
Neil J.McC. Mortensen 15.15 Congenital abnormalities of the gastrointestinal tract  2967 Holm H. Uhlig 15.16 Cancers of the gastrointestinal tract  2977 Peter L. Labib, J.A. Bridgewater, and Stephen P. Pereira 15.17 Vascular disorders of the gastrointestinal tract  2997 Ray Boyapati 15.18 Gastrointestinal infections  3008 Sarah O’Brien 15.19 Miscellaneous disorders of the bowel  3025 Alexander Gimson 15.20 Structure and function of the liver, biliary tract, and pancreas  3032 William Gelson and Alexander Gimson 15.21 Pathobiology of chronic liver disease  3043 Wajahat Z. Mehal 15.22 Presentations and management of liver disease  3049

15.22.1 Investigation and management of
jaundice  3049 Jane Collier

15.22.2 Cirrhosis and ascites  3058 Javier Fernández and Vicente Arroyo

15.22.3 Portal hypertension and variceal bleeding  3068 Marcus Robertson and Peter Hayes

15.22.4 Hepatic encephalopathy  3080 Paul K. Middleton and Debbie L. Shawcross

15.22.5 Liver failure  3089 Jane Macnaughtan and Rajiv Jalan

15.22.6 Liver transplantation  3100 John G. O’Grady 15.23 Hepatitis and autoimmune liver disease  3108

15.23.1 Hepatitis A to E  3108 Graeme J.M. Alexander and Kate Nash

Contents xxiii

15.23.2 Autoimmune hepatitis  3119 G.J. Webb and Gideon M. Hirschfield

15.23.3 Primary biliary cholangitis  3127 Jessica K. Dyson and David E.J. Jones

15.23.4 Primary sclerosing cholangitis  3135 Kate D. Lynch and Roger W. Chapman 15.24 Other liver diseases  3142

15.24.1 Alcoholic liver disease  3142 Ewan Forrest

15.24.2 Nonalcoholic fatty liver disease  3147 Quentin M. Anstee and Christopher P. Day

15.24.3 Drug-​induced liver disease  3155 Guruprasad P. Aithal

15.24.4 Vascular disorders of the liver  3166 Alexander Gimson

15.24.5 The liver in systemic disease  3169 James Neuberger

15.24.6 Primary and secondary liver tumours  3178 Graeme J.M. Alexander, David J. Lomas,
William J.H. Griffiths, Simon M. Rushbrook, and Michael E.D. Allison

15.24.7 Liver and biliary diseases in infancy and childhood  3191 Richard J. Thompson 15.25 Diseases of the gallbladder and biliary tree  3196 Colin Johnson and Mark Wright 15.26 Diseases of the pancreas  3209

15.26.1 Acute pancreatitis  3209 R. Carter, Euan J. Dickson, and C.J. McKay

15.26.2 Chronic pancreatitis  3218 Marco J. Bruno and Djuna L. Cahen

15.26.3 Tumours of the pancreas  3227 James R.A. Skipworth and Stephen P. Pereira Index Volume 3 List of abbreviations  xxxv List of contributors  xlv SECTION 16 Cardiovascular disorders Section editor: Jeremy Dwight 16.1 Structure and function  3241

16.1.1 Blood vessels and the endothelium  3241 Keith Channon and Patrick Vallance

16.1.2 Cardiac physiology  3253 Rhys D. Evans, Kenneth T. MacLeod,
Steven B. Marston, Nicholas J. Severs, and Peter H. Sugden 16.2 Clinical presentation of heart disease  3276

16.2.1 Chest pain, breathlessness, and fatigue  3276 Jeremy Dwight

16.2.2 Syncope and palpitation  3284 K. Rajappan, A.C. Rankin, A.D. McGavigan, and S.M. Cobbe 16.3 Clinical investigation of cardiac disorders  3294

16.3.1 Electrocardiography  3294 Andrew R. Houghton and David Gray

16.3.2 Echocardiography  3314 James D. Newton, Adrian P. Banning, and
Andrew R.J. Mitchell

16.3.3 Cardiac investigations: Nuclear, MRI, and CT  3326 Nikant Sabharwal, Andrew Kelion, Theodoros Karamitos, and Stefan Neubauer

16.3.4 Cardiac catheterization and angiography  3339 Edward D. Folland 16.4 Cardiac arrhythmias  3350 Matthew R. Ginks, D.A. Lane, A.D. McGavigan, and
Gregory Y.H. Lip 16.5 Cardiac failure  3390

16.5.1 Epidemiology and general pathophysiological classification of heart failure  3390 Theresa A. McDonagh and Kaushik Guha

16.5.2 Acute cardiac failure: Definitions, investigation, and management  3397 Andrew L. Clark and John G.F. Cleland

16.5.3 Chronic heart failure: Definitions, investigation, and management  3407 John G.F. Cleland and Andrew L. Clark

Contents xxiv

16.5.4 Cardiorenal syndrome  3421 Darren Green and Philip A. Kalra

16.5.5 Cardiac transplantation and mechanical circulatory support  3428 Jayan Parameshwar and Steven Tsui 16.6 Valvular heart disease  3436 Michael Henein 16.7 Diseases of heart muscle  3459

16.7.1 Myocarditis  3459 Jay W. Mason and Heinz-​Peter Schultheiss

16.7.2 The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular  3468 Oliver P. Guttmann and Perry Elliott

16.7.3 Specific heart muscle disorders  3489 Oliver P. Guttmann and Perry Elliott 16.8 Pericardial disease  3501 Michael Henein 16.9 Cardiac involvement in infectious
disease  3509

16.9.1 Acute rheumatic fever  3509 Jonathan R. Carapetis

16.9.2 Endocarditis  3519 James L. Harrison, John L. Klein, William A. Littler, and Bernard D. Prendergast

16.9.3 Cardiac disease in HIV infection  3534 Peter F. Currie

16.9.4 Cardiovascular syphilis  3539 Krishna Somers 16.10 Tumours of the heart  3544 Thomas A. Traill 16.11 Cardiac involvement in genetic disease  3551 Thomas A. Traill 16.12 Congenital heart disease in the adult  3559 S.A. Thorne 16.13 Coronary heart disease  3596

16.13.1 Biology and pathology of atherosclerosis  3596 Robin P. Choudhury, Joshua T. Chai, and
Edward A. Fisher

16.13.2 Coronary heart disease: Epidemiology and prevention  3603 Goodarz Danaei and Kazem Rahimi

16.13.3 Management of stable angina  3616 Adam D. Timmis

16.13.4 Management of acute coronary syndrome  3626 Rajesh K. Kharbanda and Keith A.A. Fox

16.13.5 Percutaneous interventional cardiac procedures  3655 Edward D. Folland

16.13.6 Coronary artery bypass and valve surgery  3666 Rana Sayeed and David Taggart 16.14 Diseases of the arteries  3674

16.14.1 Acute aortic syndromes  3674 James D. Newton, Andrew R.J. Mitchell, and
Adrian P. Banning

16.14.2 Peripheral arterial disease  3680 Janet Powell and Alun Davies

16.14.3 Cholesterol embolism  3688 Christopher Dudley 16.15 The pulmonary circulation  3691

16.15.1 Structure and function of the pulmonary circulation  3691 Nicholas W. Morrell

16.15.2 Pulmonary hypertension  3695 Nicholas W. Morrell 16.16 Venous thromboembolism  3711

16.16.1 Deep venous thrombosis and pulmonary embolism  3711 Paul D. Stein, Fadi Matta, and John D. Firth

16.16.2 Therapeutic anticoagulation  3729 David Keeling 16.17 Hypertension  3735

16.17.1 Essential hypertension: Definition, epidemiology, and pathophysiology  3735 Bryan Williams and John D. Firth

16.17.2 Essential hypertension: Diagnosis, assessment, and treatment  3753 Bryan Williams and John D. Firth

16.17.3 Secondary hypertension  3778 Morris J. Brown and Fraz A. Mir

16.17.4 Mendelian disorders causing
hypertension  3796 Nilesh J. Samani and Maciej Tomaszewski

16.17.5 Hypertensive urgencies and emergencies  3800 Gregory Y.H. Lip and Alena Shantsila 16.18 Chronic peripheral oedema and lymphoedema  3811 Peter S. Mortimer 16.19 Idiopathic oedema of women  3823 John D. Firth

Contents xxv SECTION 17 Critical care medicine Section editor: Simon Finfer 17.1 The seriously ill or deteriorating patient  3829 Carole Foot and Liz Hickson 17.2 Cardiac arrest  3839 Gavin D. Perkins, Jasmeet Soar, Jerry P. Nolan, and
David A. Gabbott 17.3 Anaphylaxis  3849 Anthony F.T. Brown 17.4 Assessing and preparing patients with medical conditions for major surgery  3860 Tom Abbott and Rupert Pearse 17.5 Acute respiratory failure  3867 Susannah Leaver, Jeremy Cordingley, Simon Finney, and Mark Griffiths 17.6 Circulation and circulatory support in the critically ill  3881 Michael R. Pinsky 17.7 Management of raised intracranial pressure  3892 David K. Menon 17.8 Sedation and analgesia in the ICU  3898 Michael C. Reade 17.9 Metabolic and endocrine changes in acute and chronic critical illness  3906 Eva Boonen and Greet Van den Berghe 17.10 Palliative and end-​of-​life care in the ICU  3914 Phillip D. Levin and Charles L. Sprung 17.11 Diagnosis of death and organ donation  3918 Paul Murphy 17.12 Persistent problems and recovery after critical illness  3925 Mark E. Mikkelsen and Theodore J. Iwashyna SECTION 18 Respiratory disorders Section editor: Pallav L. Shah 18.1 Structure and function  3933

18.1.1 The upper respiratory tract  3933 Pallav L. Shah, J.R. Stradling, and S.E. Craig

18.1.2 Airways and alveoli  3937 Peter D. Wagner and Pallav L. Shah 18.2 The clinical presentation of respiratory disease  3947 Samuel Kemp and Julian Hopkin 18.3 Clinical investigation of respiratory disorders  3956

18.3.1 Respiratory function tests  3956 G.J. Gibson

18.3.2 Thoracic imaging  3970 Susan J. Copley and David M. Hansell

18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992 Pallav L. Shah 18.4 Respiratory infection  4004

18.4.1 Upper respiratory tract
infections  4004 P. Little

18.4.2 Pneumonia in the normal host  4008 Wei Shen Lim

18.4.3 Nosocomial pneumonia  4022 Wei Shen Lim

18.4.4 Mycobacteria  4026 Hannah Jarvis and Onn Min Kon

18.4.5 Pulmonary complications of HIV
infection  4031 Julia Choy and Anton Pozniak 18.5 The upper respiratory tract  4040

18.5.1 Upper airway obstruction  4040 James H. Hull and Matthew Hind

18.5.2 Sleep-​related breathing disorders  4048 Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind 18.6 Allergic rhinitis  4059 Stephen R. Durham and Hesham A. Saleh 18.7 Asthma  4067 Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow 18.8 Chronic obstructive pulmonary
disease  4098 Nicholas S. Hopkinson 18.9 Bronchiectasis  4142 R. Wilson and D. Bilton 18.10 Cystic fibrosis  4151 Andrew Bush and Caroline Elston

Contents xxvi 18.11 Diffuse parenchymal lung diseases  4166

18.11.1 Diffuse parenchymal lung disease: An introduction  4166 F. Teo and A.U. Wells

18.11.2 Idiopathic pulmonary fibrosis  4177 P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells

18.11.3 Bronchiolitis obliterans and cryptogenic
organizing pneumonia  4185 Vasilis Kouranos and A.U. Wells

18.11.4 The lung in autoimmune rheumatic disorders  4191 M.A. Kokosi and A.U. Wells

18.11.5 The lung in vasculitis  4200 G.A. Margaritopoulos and A.U. Wells 18.12 Sarcoidosis  4208 Robert P. Baughman and Elyse E. Lower 18.13 Pneumoconioses  4219 P.T. Reid 18.14 Miscellaneous conditions  4235

18.14.1 Diffuse alveolar haemorrhage  4235 S.J. Bourke and G.P. Spickett

18.14.2 Eosinophilic pneumonia  4238 S.J. Bourke and G.P. Spickett

18.14.3 Lymphocytic infiltrations of the
lung  4241 S.J. Bourke

18.14.4 Hypersensitivity pneumonitis  4244 S.J. Bourke and G.P. Spickett

18.14.5 Pulmonary Langerhans’ cell
histiocytosis  4256 S.J. Bourke

18.14.6 Lymphangioleiomyomatosis  4257 S.J. Bourke

18.14.7 Pulmonary alveolar proteinosis  4259 S.J. Bourke

18.14.8 Pulmonary amyloidosis  4261 S.J. Bourke

18.14.9 Lipoid (lipid) pneumonia  4263 S.J. Bourke

18.14.10 Pulmonary alveolar microlithiasis  4265 S.J. Bourke

18.14.11 Toxic gases and aerosols  4267 Chris Stenton

18.14.12 Radiation pneumonitis  4271 S.J. Bourke

18.14.13 Drug-​induced lung disease  4272 S.J. Bourke 18.15 Chronic respiratory failure  4282 Michael I. Polkey and P.M.A. Calverley 18.16 Lung transplantation  4292 P. Hopkins and A.J. Fisher 18.17 Pleural diseases  4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell 18.18 Disorders of the thoracic cage and diaphragm  4328 John M. Shneerson and Michael I. Polkey 18.19 Malignant diseases  4338

18.19.1 Lung cancer  4338 S.G. Spiro and N. Navani

18.19.2 Pulmonary metastases  4360 S.G. Spiro

18.19.3 Pleural tumours  4361 Y.C. Gary Lee

18.19.4 Mediastinal tumours and cysts  4368 Y.C. Gary Lee and Helen E. Davies SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function  4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand 19.2 Clinical presentation and diagnosis of rheumatological disorders  4386 Christopher Deighton and Fiona Pearce 19.3 Clinical investigation  4395 Michael Doherty and Peter C. Lanyon 19.4 Back pain and regional disorders  4406 Carlo Ammendolia and Danielle Southerst 19.5 Rheumatoid arthritis  4415 Kenneth F. Baker and John D. Isaacs 19.6 Spondyloarthritis and related conditions  4441 Jürgen Braun and Joachim Sieper 19.7 Infection and arthritis  4457 Graham Raftery and Muddassir Shaikh 19.8 Reactive arthritis  4464 Carmel B. Stober and Hill Gaston 19.9 Osteoarthritis  4470 Andrew J. Barr and Philip G. Conaghan

Contents xxvii 19.10 Crystal-​related arthropathies  4482 Edward Roddy and Michael Doherty 19.11 Autoimmune rheumatic disorders and vasculitides  4495

19.11.1 Introduction  4495 David A. Isenberg and Ian Giles

19.11.2 Systemic lupus erythematosus and related disorders  4499 Anisur Rahman and David A. Isenberg

19.11.3 Systemic sclerosis (scleroderma)  4513 Christopher P. Denton and Carol M. Black

19.11.4 Sjögren’s syndrome  4532 Wan-​Fai Ng

19.11.5 Inflammatory myopathies  4537 Ingrid E. Lundberg, Hector Chinoy, and
Robert Cooper

19.11.6 Large vessel vasculitis  4546 Raashid Luqmani and Cristina Ponte

19.11.7 ANCA-​associated vasculitis  4556 David Jayne

19.11.8 Polyarteritis nodosa  4569 Loïc Guillevin

19.11.9 Small vessel vasculitis  4573 Richard A. Watts

19.11.10 Behçet’s syndrome  4579 Sebahattin Yurdakul, Izzet Fresko, and
Hasan Yazici

19.11.11 Polymyalgia rheumatica  4584 Bhaskar Dasgupta and Eric L. Matteson

19.11.12 Kawasaki disease  4590 Brian W. McCrindle 19.12 Miscellaneous conditions presenting to the rheumatologist  4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo SECTION 20 Disorders of the skeleton Section editor: Cyrus Cooper 20.1 Skeletal disorders—​general approach and clinical conditions  4615 B. Paul Wordsworth and M.K. Javaid 20.2 Inherited defects of connective tissue:
Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum  4670 N.P. Burrows 20.3 Osteomyelitis  4688 Martin A. McNally and Anthony R. Berendt 20.4 Osteoporosis  4696 Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper 20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans  4703 Gavin Clunie 20.6 Bone cancer  4709 Helen Hatcher SECTION 21 Disorders of the kidney and
urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin 21.2 Electrolyte disorders  4729

21.2.1 Disorders of water and sodium homeostasis  4729 Michael L. Moritz and Juan Carlos Ayus

21.2.2 Disorders of potassium homeostasis  4748 John D. Firth 21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington 21.4 Clinical investigation of renal disease  4781 Andrew Davenport 21.5 Acute kidney injury  4807 John D. Firth 21.6 Chronic kidney disease  4830 Alastair Hutchison 21.7 Renal replacement therapy  4861

21.7.1 Haemodialysis  4861 Robert Mactier

21.7.2 Peritoneal dialysis  4874 Simon Davies

21.7.3 Renal transplantation  4879 Nicholas Torpey and John D. Firth 21.8 Glomerular diseases  4909

21.8.1 Immunoglobulin A nephropathy and IgA
vasculitis (HSP)  4909 Jonathan Barratt and John Feehally

21.8.2 Thin membrane nephropathy  4918 Peter Topham and John Feehally

Contents xxviii

21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919 Moin Saleem and Lisa Willcocks

21.8.4 Membranous nephropathy  4928 An S. De Vriese and Fernando C. Fervenza

21.8.5 Proliferative glomerulonephritis  4933 Alan D. Salama and Mark A. Little

21.8.6 Membranoproliferative glomerulonephritis  4937 Tabitha Turner-​Stokes and Mark A. Little

21.8.7 Antiglomerular basement membrane
disease  4943 Mårten Segelmark and Thomas Hellmark 21.9 Tubulointerstitial diseases  4951

21.9.1 Acute interstitial nephritis  4951 Simon D. Roger

21.9.2 Chronic tubulointerstitial nephritis  4956 Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers, and
Benjamin Vervaet 21.10 The kidney in systemic disease  4975

21.10.1 Diabetes mellitus and the kidney  4975 Rudolf Bilous

21.10.2 The kidney in systemic vasculitis  4988 David Jayne

21.10.3 The kidney in rheumatological
disorders  5001 Liz Lightstone and Hannah Beckwith

21.10.4 The kidney in sarcoidosis  5012 Ingeborg Hilderson and Jan Donck

21.10.5 Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

21.10.6 Haemolytic uraemic syndrome  5027 Edwin K.S. Wong and David Kavanagh

21.10.7 Sickle cell disease and the kidney  5032 Claire C. Sharpe

21.10.8 Infection-​associated nephropathies  5034 A. Neil Turner

21.10.9 Malignancy-​associated renal disease  5041 A. Neil Turner

21.10.10 Atherosclerotic renovascular disease  5044 Philip A. Kalra and Diana Vassallo 21.11 Renal diseases in the tropics  5049 Vivekanand Jha 21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld 21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin 21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and Fredric L. Coe 21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet 21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko 21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty 21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart 21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley Index Volume 4 List of abbreviations  xxxv List of contributors  xlv SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay 22.1 Introduction to haematology  5169 Chris Hatton 22.2 Haematopoiesis  5172

22.2.1 Cellular and molecular basis of haematopoiesis  5172 Paresh Vyas and N. Asger Jakobsen

22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181 Wendy N. Erber

Contents xxix 22.3 Myeloid disease  5189

22.3.1 Granulocytes in health and disease  5189 Joseph Sinning and Nancy Berliner

22.3.2 Myelodysplastic syndromes  5197 Charlotte K. Brierley and David P. Steensma

22.3.3 Acute myeloid leukaemia  5205 Nigel Russell and Alan Burnett

22.3.4 Chronic myeloid leukaemia  5213 Mhairi Copland and Tessa L. Holyoake†

22.3.5 The polycythaemias  5227 Daniel Aruch and Ronald Hoffman

22.3.6 Thrombocytosis and essential thrombocythaemia  5239 Daniel Aruch and Ronald Hoffman

22.3.7 Primary myelofibrosis  5247 Evan M. Braunstein and Jerry L. Spivak

22.3.8 Eosinophilia  5254 Peter F. Weller

22.3.9 Histiocytosis  5259 Chris Hatton 22.4 Lymphoid disease  5263

22.4.1 Introduction to lymphopoiesis  5263 Caron A. Jacobson and Nancy Berliner

22.4.2 Acute lymphoblastic leukaemia  5269 H. Josef Vormoor, Tobias F. Menne, and
Anthony V. Moorman

22.4.3 Hodgkin lymphoma  5280 Vijaya Raj Bhatt and James O. Armitage

22.4.4 Non-​Hodgkin lymphoma  5288 Vijaya Raj Bhatt and James O. Armitage

22.4.5 Chronic lymphocytic leukaemia  5302 Clive S. Zent and Aaron Polliack

22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310 S. Vincent Rajkumar and Robert A. Kyle 22.5 Bone marrow failure  5325

22.5.1 Inherited bone marrow failure syndromes  5325 Irene Roberts and Inderjeet S. Dokal

22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336 Judith C.W. Marsh, Shreyans Gandhi,
and Ghulam J. Mufti

22.5.3 Paroxysmal nocturnal haemoglobinuria  5348 Lucio Luzzatto 22.6 Erythroid disorders  5354

22.6.1 Erythropoiesis  5354 Vijay G. Sankaran

22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359 David J. Weatherall† and Chris Hatton

22.6.3 Anaemia as a challenge to world health  5366 David J. Roberts and David J. Weatherall†

22.6.4 Iron metabolism and its disorders  5371 Timothy M. Cox and John B. Porter

22.6.5 Anaemia of inflammation  5402 Sant-​Rayn Pasricha and Hal Drakesmith

22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407 A.V. Hoffbrand

22.6.7 Disorders of the synthesis or function of haemoglobin  5426 Deborah Hay and David J. Weatherall†

22.6.8 Anaemias resulting from defective maturation
of red cells  5450 Stephen J. Fuller and James S. Wiley

22.6.9 Disorders of the red cell membrane  5456 Patrick G. Gallagher

22.6.10 Erythrocyte enzymopathies  5463 Alberto Zanella and Paola Bianchi

22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472 Lucio Luzzatto

22.6.12 Acquired haemolytic anaemia  5479 Amy Powers and Leslie Silberstein 22.7 Haemostasis  5490

22.7.1 The biology of haemostasis and
thrombosis  5490 Gilbert C. White, II, Harold R. Roberts,
and Nigel S. Key

22.7.2 Evaluation of the patient with a bleeding tendency  5509 Trevor Baglin

22.7.3 Thrombocytopenia and disorders of platelet function  5520 Nicola Curry and Susie Shapiro

22.7.4 Genetic disorders of coagulation  5532 Eleanor S. Pollak and Katherine A. High

22.7.5 Acquired coagulation disorders  5546 T.E. Warkentin † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017. † It is with great regret that we report that David J. Weatherall died on 8 December, 2018.

Contents xxx 22.8 Transfusion and transplantation  5563

22.8.1 Blood transfusion  5563 D.S. Giovanniello and E.L. Snyder

22.8.2 Haemopoietic stem cell transplantation  5579 E.C. Gordon-​Smith and Emma C. Morris SECTION 23 Disorders of the skin Section editor: Roderick J. Hay 23.1 Structure and function of skin  5591 John A. McGrath 23.2 Clinical approach to the diagnosis of skin disease  5596 Vanessa Venning 23.3 Inherited skin disease  5602 Thiviyani Maruthappu and David P. Kelsell 23.4 Autoimmune bullous diseases  5612 Kathy Taghipour and Fenella Wojnarowska 23.5 Papulosquamous disease  5621 Christopher E.M. Griffiths 23.6 Dermatitis/​eczema  5630 Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay 23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria  5639 Volha Shpadaruk and Karen E. Harman 23.8 Disorders of pigmentation  5677 Eugene Healy 23.9 Photosensitivity  5688 Hiva Fassihi and Jane McGregor 23.10 Infections of the skin  5695 Roderick J. Hay 23.11 Sebaceous and sweat gland disorders  5699 Alison M. Layton 23.12 Blood and lymphatic vessel disorders  5709 Peter S. Mortimer and Roderick J. Hay 23.13 Hair and nail disorders  5724 David de Berker 23.14 Tumours of the skin  5732 Edel O’Toole 23.15 Skin and systemic diseases  5743 Clive B. Archer and Charles M.G. Archer 23.16 Cutaneous reactions to drugs  5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee 23.17 Management of skin disease  5761 Rod Sinclair SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease  5775 Alastair Compston and Christopher Kennard 24.2 Mind and brain: Building bridges
between neurology, psychiatry, and psychology  5778 Adam Zeman 24.3 Clinical investigation of neurological disease  5781

24.3.1 Lumbar puncture  5781 R. Rhys Davies and Andrew J. Larner

24.3.2 Electrophysiology of the central and peripheral nervous systems  5785 Christian Krarup

24.3.3 Imaging in neurological diseases  5802 Andrew J. Molyneux, Shelley Renowden, and
Marcus Bradley

24.3.4 Investigation of central motor pathways:
Magnetic brain stimulation  5817 K.R. Mills 24.4 Higher cerebral function  5821

24.4.1 Disturbances of higher cerebral function  5821 Peter J. Nestor

24.4.2 Alzheimer’s disease and other dementias  5830 Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness  5860

24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson

24.5.2 Narcolepsy  5882 Matthew C. Walker

24.5.3 Sleep disorders  5886 Paul J. Reading

24.5.4 Syncope  5896 Andrew J. Larner

24.5.5 The unconscious patient  5901 David Bates

Contents xxxi

24.5.6 Brainstem death and prolonged disorders of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.6 Disorders of the special senses  5913

24.6.1 Visual pathways  5913 Sara Ajina and Christopher Kennard

24.6.2 Eye movements and balance  5922 Michael Strupp and Thomas Brandt

24.6.3 Hearing loss  5931 Linda Luxon 24.7 Disorders of movement  5937

24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937 Mark J. Edwards and Penelope Talelli

24.7.2 Parkinsonism and other extrapyramidal diseases  5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri

24.7.3 Movement disorders other than Parkinson’s disease  5956 Bettina Balint and Kailash Bhatia

24.7.4 Ataxic disorders  5976 Nicholas Wood 24.8 Headache  5987 Peter J. Goadsby 24.9 Brainstem syndromes  6006 David Bates 24.10 Specific conditions affecting the central nervous system  6010

24.10.1 Stroke: Cerebrovascular disease  6010 J. van Gijn (revised by Peter M. Rothwell)

24.10.2 Demyelinating disorders of the central nervous system  6026 Alasdair Coles and Siddharthan Chandran

24.10.3 Traumatic brain injury  6042 Tim Lawrence and Laurence Watkins

24.10.4 Intracranial tumours  6048 Jeremy Rees

24.10.5 Idiopathic intracranial hypertension  6054 Alexandra Sinclair 24.11 Infections of the central nervous system  6060

24.11.1 Bacterial infections  6060 Diederik van de Beek and Guy E. Thwaites

24.11.2 Viral infections  6082 Fiona McGill, Jeremy Farrar, Bridget Wills, Menno
De Jong, David A. Warrell, and Tom Solomon

24.11.3 Intracranial abscesses  6097 Tim Lawrence and Richard S.C. Kerr

24.11.4 Neurosyphilis and neuro-​AIDS  6100 Hadi Manji

24.11.5 Human prion diseases  6109 Simon Mead and R.G. Will 24.12 Disorders of cranial nerves  6120 Robert D.M. Hadden 24.13 Disorders of the spinal cord  6127

24.13.1 Diseases of the spinal cord  6127 Anu Jacob and Andrew J. Larner

24.13.2 Spinal cord injury and its management  6135 Wagih El Masri(y) and Michael Barnes 24.14 Diseases of the autonomic nervous system  6150 Christopher J. Mathias and David A. Low 24.15 The motor neuron diseases  6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw 24.16 Diseases of the peripheral nerves  6176 Robert D.M. Hadden 24.17 Inherited neurodegenerative diseases  6197 Swati Sathe 24.18 Disorders of the neuromuscular junction  6295 David Hilton-​Jones and Jacqueline Palace 24.19 Disorders of muscle  6304

24.19.1 Structure and function of muscle  6304 Michael G. Hanna and Enrico Bugiardini

24.19.2 Muscular dystrophy  6310 Kate Bushby and Chiara Marini-​Bettolo

24.19.3 Myotonia  6328 David Hilton-​Jones

24.19.4 Metabolic and endocrine disorders  6334 David Hilton-​Jones and Richard Edwards

24.19.5 Mitochondrial disease  6343 Patrick F. Chinnery and D.M. Turnbull 24.20 Developmental abnormalities of the central nervous system  6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth 24.21 Acquired metabolic disorders and the nervous system  6368 Neil Scolding 24.22 Neurological complications of systemic disease  6376 Neil Scolding

Contents xxxii 24.23 Paraneoplastic neurological syndromes  6384 Jeremy Rees 24.24 Autoimmune encephalitis and Morvan’s syndrome  6393 Camilla Buckley and Angela Vincent SECTION 25 Disorders of the eye Section editor: Christopher P. Conlon 25.1 The eye in general medicine  6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw SECTION 26 Psychiatric and drug-​related disorders Section editor: Michael Sharpe 26.1 General introduction  6445 Michael Sharpe 26.2 The psychiatric assessment of the medical patient  6447 Jane Walker, Roger Smyth, and Michael Sharpe 26.3 Common psychiatric presentations in medical patients  6454

26.3.1 Confusion  6454 Bart Sheehan and Thomas Jackson

26.3.2 Self-​harm  6457 Kate E.A. Saunders and Keith Hawton

26.3.3 Medically unexplained symptoms  6460 Michael Sharpe

26.3.4 Low mood  6462 Jane Walker 26.4 Psychiatric treatments in the medically ill  6465

26.4.1 Psychopharmacology in medical practice  6465 Philip J. Cowen

26.4.2 Psychological treatments  6470 Michael Sharpe and Simon Wessely 26.5 Specific psychiatric disorders  6475

26.5.1 Delirium  6475 Bart Sheehan

26.5.2 Dementia  6478 Bart Sheehan

26.5.3 Organic psychoses  6482 Curtis McKnight and Jason Caplan

26.5.4 Alcohol misuse  6486 Jonathan Wood

26.5.5 Substance misuse  6490 Stephen Potts

26.5.6 Depressive disorder  6493 Joseph Cerimele and Lydia Chwastiak

26.5.7 Bipolar disorder  6498 Kate E.A. Saunders and John Geddes

26.5.8 Anxiety disorders  6501 Ted Liao and Steve Epstein

26.5.9 Acute stress disorder, adjustment disorders,
and post-​traumatic stress disorder  6506 Jonathan I. Bisson

26.5.10 Eating disorders  6509 Christopher G. Fairburn

26.5.11 Schizophrenia  6513 Stephen M. Lawrie

26.5.12 Somatic symptom and related
disorders  6517 Michael Sharpe

26.5.13 Personality disorders  6520 Iain Jordan 26.6 Changing unhealthy behaviours  6524

26.6.1 Brief interventions for excessive alcohol consumption  6524 Amy O’Donnell, Eileen Kaner, and Nick Heather

26.6.2 Obesity and weight management  6529 Susan Jebb and Paul Aveyard

26.6.3 Smoking cessation  6533 Paul Aveyard 26.7 Psychiatry, liaison psychiatry, and
psychological medicine  6536 Michael Sharpe SECTION 27 Forensic medicine Section editor: John D. Firth 27.1 Forensic and legal medicine  6541 Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and
Steven B. Karch

Contents xxxiii SECTION 28 Sport and exercise medicine Section editor: John D. Firth 28.1 Sport and exercise medicine  6565 Cathy Speed SECTION 29 Biochemistry in medicine Section editor: Christopher P. Conlon 29.1 The use of biochemical analysis for diagnosis
and management  6577 Brian Shine and Nishan Guha SECTION 30 Acute medicine Section editor: John D. Firth 30.1 Acute medical presentations  6591 Sian Coggle, Elaine Jolly, and John D. Firth 30.2 Practical procedures  6644 Elaine Jolly, Sian Coggle, and John D. Firth Index

Clinical features

Clinical features

Clinical features—

Clinical features—

Clinical investigation

Clinical investigation

Copyright

Copyright

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2020 The moral rights of the authors have been asserted First Edition published in 1983 Second Edition published in 1987 Third Edition published in 1996 Fourth Edition published in 2003 Fifth Edition published in 2010 Sixth Edition published in 2020 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2018933144 Set ISBN: 978–0–19–874669–0 Volume 1: 978–0–19–881533–4 Volume 2: 978–0–19–881535–8 Volume 3: 978–0–19–881537–2 Volume 4: 978–0–19–884741–0 Only available as part of a set Printed in Malaysia by Vivar Printing Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Criteria for diagnosis

Criteria for diagnosis

Disease associations

Disease associations

Disorders of renal calcium handling, urinary stone

Disorders of renal calcium handling, urinary stones, and nephrocalcinosis 5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan,

Disorders of tubular electrolyte handling Nine V.A

Disorders of tubular electrolyte handling Nine V.A.M. Knoers and Elena N. Levtchenko

Do drugs that block the renin– angiotensin systemp

Do drugs that block the renin– angiotensin systemprevent or only delay the development of nephropathy?Can they reverse established nephropathy?

Drugs and the kidney 5150 Aine Burns and Caroline

Drugs and the kidney 5150 Aine Burns and Caroline Ashley

ESSENTIALS Musculoskeletal symptoms can occur in a variety of diseases, or as drug side effects. Presentations and conditions discussed in this section include: Multisystem diseases—​adult-​onset Still’s disease (including macrophage activation syndrome as sequelae), acute sarcoid arth- ritis, amyloidosis Paraneoplastic syndromes—​hypertrophic pulmonary osteoar­thro­ pathy, remitting seronegative symmetrical synovitis with pitting oe- dema, tumour-​induced osteomalacia Skin manifestations of rheumatic disease—​panniculitis, neutrophilic dermatoses, multicentric reticulohistiocytosis Primary joint pathology and synovial disorders—​pigmented vilonodular synovitis, synovial osteochondromatosis, Charcot
joint Rheumatic manifestations of haematological disease—​ haemophilia, sickle cell disease, leukaemia, lymphoma, and poly- neuropathy, organomegaly, endocrinopathy, M-​protein, and skin abnormalities Rheumatic manifestations of metabolic disease—​hereditary haemo- chromatosis, Wilson’s disease Disorders of the spine and axial skeleton—​Tietze’s syndrome, diffuse idiopathic skeletal hyperostosis, and alkaptonuria Drug-​induced rheumatic syndromes—​statin-​induced myop- athy, drug-​induced tendinopathy, drug-​induced lupus, allopurinol hypersensitivity Multisystem diseases Adult-​onset Still’s disease Adult-​onset Still’s disease (AOSD) is a rare, idiopathic, multisystem inflammatory disorder characterized by quotidian fever, evanescent rash, and inflammatory arthritis. The condition was first proposed as a separate disease entity by Eric Bywaters in 1971, who described the clinical syndrome in 14 adult patients, and named it adult-​onset Still’s due to similarities with paediatric Still’s disease, described by George Still in 1897 and now known as systemic onset juvenile idiopathic arthritis. Adult-​onset Still’s disease effects approximately 0.1 to 1 per 100 000 population. It is more common in females than males, and is most frequent in younger age groups, with 75% of patients with disease onset between the ages of 16 and 35 years. There appears to be no ethnic predisposition and there are no known human leuko- cyte antigen (HLA) associations. Adult-​onset Still’s disease is often classified under the spectrum of autoinflammatory disease, as an idiopathic febrile syndrome, but unlike other diseases in this category an underlying molecular mechanism has not been clearly defined. It is clear that macrophage activation is prominent in the immunopathogenesis, and patho- genic roles of inflammatory cytokines IL-​1β, IL-​6, IFN-​γ, TNFα, and IL-​18 have been demonstrated. Adult-​onset Still’s disease is a clinical diagnosis and can be as- sisted by Yamaguchi 1992 and Fautrel 2002 criteria (Table 19.12.1). The fever, which for diagnosis must rise to more than 39oC, typically appears in the evening (Fig. 19.12.1). The articular manifestations most frequently involve symmetrical inflamma- tory arthritis affecting the knees, wrists, and ankles, however small joint polyarthritis involving the proximal interphalangeal or metacarpophalangeal joints has frequently been described. Compared to other inflammatory arthropathies there is more fre- quent structural damage in the carpus, including pericapitate joint space narrowing and ankylosis. The skin eruption in adult-​onset Still’s disease is transient, hence called evanescent, and is usually present in the evening accom- panying febrile periods. It typically affects the trunk and proximal limbs, is non​pruritic, ‘salmon pink’, maculopapular, and may display Koebner’s phenomenon (Fig. 19.12.2). In large case series organ manifestations include splenomegaly in 44%, pleuritis in 26% and pericarditis in 24%. Large pleural effu- sions and cardiac tamponade have been reported. Laboratory features in adult-​onset Still’s disease reflect sys- temic inflammation, with anaemia of chronic disease, reactive thrombocytosis, high C-​reactive protein and erythrocyte sedimen- tation rate (ESR). There is usually a marked neutrophil leucocytosis and mixed derangement in liver function tests. There are no specific autoimmune tests, but negative antinuclear antibodies (ANA) and rheumatoid factor (RF) form part of the historical diagnostic criteria to ensure exclusion of alternative diagnoses such as systemic lupus erythematosus (SLE) and systemic rheumatoid arthritis (RA). 19.12 Miscellaneous conditions presenting to
the rheumatologist Stuart Carter, Lisa Dunkley, and Ade Adebajo

19.12  Miscellaneous conditions presenting to the rheumatologist 4599 The mechanism for marked hyperferritinaemia is unclear, al- though it is likely driven by macrophage activity and inflammatory cytokines. It is usually more than five times the upper limit of normal laboratory measurements. This is not specific to the condition and hence not a diagnostic test alone, but is a useful biomarker during treatment as levels normalize with remission. In health 50–​80% of ferritin is glycosylated, a mechanism that appears to be impaired in adult-​onset Still’s disease, producing glycosylated ferritin levels below 20%. The combination of serum ferritin more than five times upper limit of normal laboratory measurements and glycosylated ferritin less than 20% has a specificity of 93% for adult-​onset Still’s disease, although the test is not widely available. Macrophage activation syndrome is a well-​recognized life threatening manifestation of adult-​onset Still’s disease, affecting 12–​15% of cases and carrying a significant mortality, reported between 10–​22%. In this condition activated tissue macrophages phagocytose haemopoetic cells in bone marrow and the reticulo- endothelial system. Macrophage activation syndrome can be a presenting feature of adult-​onset Still’s disease, making diagnosis challenging as sec- ondary haemophagocytic lymphohistiocytosis caused by other conditions (including malignancy, infection, and systemic lupus erythematosus) has common clinical and laboratory abnormal- ities to adult-​onset Still’s disease, including high spiking fever, hyperferritinaemia, and liver dysfunction. Clinicians should be alerted to the condition if a patient develops a non​remitting fever, neurological dysfunction, hepatosplenomegaly, lymphadenop- athy, accompanied by pancytopenia (or normalization from a pre- vious high level), falling ESR (caused by hypofibrinogenaemia), hypertriglyceridaemia, hyponatraemia, hypoalbuminaemia, and worsening liver dysfunction. Treatment of adult-​onset Still’s disease is dependent upon disease manifestations and severity. While non​steroidal anti-​inflammatories have been used as first-​line historically, only 20% of patients re- spond, and corticosteroids are usually required. Combination methotrexate and corticosteroids is an effective first-​line treatment and steroid-​sparing strategy. In recent years, anti-​TNF antagonists (etanercept, adalimumab, infliximab), IL-​1 antagonists (anankinra, canakinumab, rilonacept) and IL-​6 antagonists (tocilizumab) are now recommended ahead of alternative treatments such as leflunomide, azathioprine, ciclosporin, cyclophosphamide, or intra- venous immunoglobulins in severe or methotrexate refractory cases. In cases of macrophage activation syndrome there is no defined treatment protocol, but aggressive immunosuppression is needed, commonly with high dose intravenous glucocorticoids, intravenous immunoglobulins and immunosuppression with ciclosporin and/​or biologic agents anakinra or tocilizumab. Table 19.12.1  Yamaguchi 1992 and Fautrel 2002 diagnostic criteria for adult-​onset Still’s disease Yamaguchi, 1992 Fautrel, 2002 ≥5 (2 must be major) ≥4 major criteria, or 3 major
and 2 minor Major Major • Fever >39°C ≥1 week • Spiking fever ≥39°C • Arthralgia ≥2 weeks • Arthralgia • Typical rash • Transient erythema • Leukocytosis >10 000/​mm3, >80% • Pharyngitis polymorphs • Polymorphs ≥80% Minor • Glycosylated ferritin ≤20% • Sore throat • Lymphadenopathy Minor • Hepatomegaly or splenomegaly • Maculopapular rash • Abnormal liver function tests • Leukocytosis >10 000/​mm3 • Negative antinuclear factor and rheumatoid factor Exclusion criteria • Infection • Malignancy (lymphoma) • Other rheumatic disease (systemic vasculitis) AM PM AM PM AM PM AM PM AM PM AM PM 39 38 37 36 Time Temperature °C Fig. 19.12.1  Quotidian fever typical of adult-​onset Still’s disease consisting of daily spiking temperatures above 39°C in the evening, returning to baseline levels in the morning. Fig. 19.12.2  The rash of adult-​onset Still’s disease. © American College of Rheumatology.

section 19  Rheumatological disorders 4600 Acute sarcoid arthritis Löfgren described a unique presentation of acute sarcoid arthritis in 1953, with a triad of bi-​hilar lymphadenopathy, arthritis and ery- thema nodosum (Fig. 19.12.3), now known as Löfgren’s syndrome, which is considered pathognomonic of the condition, making tissue biopsy to secure a diagnosis redundant, unlike many other mani- festations of sarcoidosis. Tissue biopsy should be sought if there are atypical features, to exclude alternative diagnoses such as lymphoma and tuberculosis. Epidemiological studies in sarcoidosis have described articular symptoms in up to 25% of cases, most frequent among Caucasians and rare in Japanese populations. Typical Löfgren’s syndrome presents with lower limb oligoarthro­ pathy, most frequently with diffuse ankle swelling, although peri- articular inflammation where joint range of motion is maintained and ultrasound demonstrates no intra-​articular abnormality is a well-​recognized variant. Tenosynovitis is often frequently encoun- tered in ultrasound studies. Other joint involvement in order of fre- quency includes the knee, wrist, and metacarpophalangeal joints. The most frequent skin abnormality in acute sarcoid arthropathy is erythema nodosum, but this is not present in all cases, and was only present in 53% of Löfgren’s original cohort. Lupus pernio, granulomatous skin lesions, and inflammatory papules developing within scars and tattoos have also been reported. Additional features in Löfgren’s syndrome may include fever in up to two-​thirds. A few patients display respiratory symptoms including cough and dyspnoea, hepatomegaly, inflammatory eye disease, and rarely peripheral lymphadenopathy, splenomegaly, hypercalcaemia, and salivary gland hypertrophy. Serum angiotensin converting en- zyme levels are elevated in 50% of patients. Most patients with Löfgren’s syndrome improve rapidly with non​steroidal anti-​inflammtory drugs (NSAIDs) or oral cortico- steroid treatment. Long-​term prognosis is good, with most achieving treatment free remission within the first year of diagnosis. Only a few patients progress to chronic arthropathy in which methotrexate is the first-​line recommended disease-​modifying antirheumatic drug (DMARD). Predictors of poor prognosis and disease persistence include absence of erythema nodosum, pulmonary infiltrates on chest X-​ray, presence of splenomegaly, and absence of bi-​hilar lymphadenopathy on chest X-​ray. Amyloidosis Systemic amyloidosis consists of a group of conditions causing extracellular deposition of insoluble fibrillar proteins in the extra- cellular space, including in joints and periarticular tissue. The conditions are categorized depending on the fibril precursor re- sponsible for the amyloid protein deposition, which produce a recognizable clinical syndrome and set of complications, al- though there is considerable overlap. The precursors responsible in non​hereditary amyloidosis are serum amyloid A in secondary (AA) amyloidosis, immunoglobulin light chains in amyloid light-​chain (AL) amyloidosis, and dialysis-​associated β-​2 microglobulin in β-​2M amyloidosis. Secondary (AA) amyloidosis The most frequent causes of secondary amyloidosis are chronic inflammatory diseases, chronic infections and malignancies, in cases where inflammatory disease is poorly controlled and there is a persistent acute phase response. Rheumatic disease including rheumatoid arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis account for 70% of cases, with a reported prevalence of 3–​6% in all inflammatory arthropathies. Other important condi- tions which cause amyloidosis that is seen in the rheumatology clinic include autoinflammatory syndromes and systemic vasculitides. Secondary amyloidosis should be considered in patients with rheumatic disease with evidence of longstanding uncontrolled in- flammatory activity. The combination of renal dysfunction and proteinuria is found in 97% of patients at diagnosis, and the renal prognosis is poor, with 40% progression to end-​stage renal failure requiring renal replacement therapy. Alongside renal abnormalities hepatosplenomegaly is common. Gastrointestinal involvement oc- curs in advanced disease and manifests as malabsorption, pseudo-​ obstruction, or nausea and vomiting from mucosal infiltration. Amyloid light-​chain (AL) amyloidosis In amyloid light-​chain (AL) amyloidosis, rheumatic manifestations are uncommon. The principle causes of morbidity are renal dysfunc- tion with nephrotic syndrome, congestive cardiac failure, painful sensory peripheral neuropathy, and hepatomegaly. However, pa- tients can present to the rheumatology clinic in a variety of ways. A classical presentation is ‘shoulder pad sign’, caused by infiltration of the glenohumeral joint and capsule, causing pain, stiffness, swelling, and limitation. In combination with macroglossia and ‘racoon eyes’, caused by periorbital ecchymosis, this triad is considered pathog- nomonic of amyloid light-​chain amyloidosis. Peripheral articular symptoms occur in 9% of patients, which may produce inflamma- tory joint stiffness mimicking rheumatoid arthritis. Infiltration of muscles of mastication can cause jaw claudication mimicking tem- poral arteritis. Infiltration of exocrine glands can lead to sicca symp- toms mimicking Sjogren’s syndrome. Carpal tunnel syndrome is also common. β-​2M amyloidosis Historically, this condition caused substantial morbidity in long-​ term haemodialysis patients, but it is no longer seen with use of Fig. 19.12.3  Erythema nodosum on the shins. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press.

19.12  Miscellaneous conditions presenting to the rheumatologist 4601 modern high flux dialysis membranes that clear β-​2 microglobulin from the circulation more effectively. In contrast to AL and AA amyloidosis, in dialysis-​related amyloidosis β-​2 microglobulin de- position outside of the musculoskeletal system is rare. Involvement of the musculoskeletal system caused a persistent, erosive, sym- metrical large and small joint polyarthropathy, and tenosynovitis. Carpal tunnel syndrome was common and often a presenting fea- ture. Deposition in periarticular bone manifested as erosive disease in both the axial and appendicular skeleton, leading to pathological fractures. Paraneoplastic syndromes Hypertrophic osteoarthropathy Hypertrophic osteoarthropathy (HOA) is a syndrome caused by periostosis and soft tissue hypertrophy at the distal extremities, causing a combination of finger clubbing, bone and joint pain, and synovial effusions. It is a well described indicator of serious underlying pathology, including lung cancer, and can precede the secondary cause by several years. The condition was initially called hypertrophic ‘pulmonary’ osteoarthropathy due to its association with pulmonary malig- nancy (predominantly squamous cell carcinoma), bronchiectasis, cystic fibrosis, and lung abscess. However, the ‘pulmonary’ was re- moved with recognition that hypertrophic osteoarthropathy could be caused by extrapulmonary conditions including congenital heart disease, inflammatory bowel disease, and head and neck cancers. Although there is a spectrum of severity, clubbing is usually ob- vious and bone pain can be elicited by palpation of the affected areas. Periosteal reaction is often visible on plain radiographs and uptake in bone scintigraphy can be seen in a periosteal distribution in distal long bones (Fig. 19.12.4). Hypertrophic osteoarthropathy can also be associated with acanthosis palmaris, a hyperkeratoic condition affecting the palm, causing accentuation of the dermatoglyphic lines and leading to a velvety, ridged appearance described as ‘tripe palms’. Acanthosis palmaris alone is a paraneoplastic sign, often found in lung or gas- tric malignancy. Management involves seeking and treating the underlying diag- nosis, which may cause hypertrophic osteoarthropathy to remit. It responds well to NSAIDs as first-​line agents. Refractory cases have been successfully treated with the bisphosphonates pamidronate and zolendronate, and with the somatostatin analogue octerotide. Remitting seronegative symmetrical synovitis with pitting oedema Remitting seronegative symmetrical synovitis with pitting oedema is descriptive of a clinical presentation of acute polyarthritis de- scribed in 1985. Patients present with a symmetrical small joint polyarthritis, with gross swelling and pitting oedema in the dorsum of the hands and/​or feet. The condition is non​erosive, autoantibody negative, and responds well to low dose corticosteroid, typically 10 mg daily. Malignancy was reported in 25% of 89 patients in five case series, with a mixture of solid and haemopoeitic malignancy, suggesting overrepresentation of malignancy in this condition, al- though it does tend to occur in older age groups (over 70 years) and is more common in men. Tumour-​induced osteomalacia Tumour-​induced osteomalacia is caused by occult tumours with relatively heterogeneous histopathology usually found in bones in the lower extremities or peripheral soft tissues. The tumours secrete fibroblast growth factor-​23 (FGF-​23, also known as phosphatonin), which causes excess secretion of phosphate from the proximal tu- bule of the kidney. The diagnosis is challenging as tumour sites may be asymptom- atic, with most symptoms mediated by ectopic hormone production and progressing gradually, often leading to diagnostic delay by sev- eral years. Symptoms are often non​specific, including malaise and myalgia, but presence of bone pain and low trauma fracture prompts further investigation. Biochemical analysis shows hypophosphataemia, inappropriately low or normal 1, 25 dihydroxyvitamin D, hyperphosphaturia, and elevated levels of FGF-​23. Plain radiographs reveal features of osteomalacia with cortical thinning, coarsened trabeculae, and pseudofractures. To locate le- sions octreotide scintigraphy or positron emission tomography (PET) is required, followed by structural imaging with CT or MRI to characterize the lesion. Other causes of genetic and acquired hypophosphataemia should be excluded. Complete excision of the tumour allows resolution of the bio- chemical abnormalities, and provides excellent long-​term prog- nosis. If surgery is not possible due to lesion location or inability to locate the lesion, medical treatment is indicated. This includes high dose phosphate and 1,25 dihydroxyvitamin D replacement, with regular monitoring of serum calcium levels. Subcutaneous adminis- tration of octreotide is successful in some cases. Fig. 19.12.4  Radiography of distal tibia showing the periosteal reaction (arrow). Reproduced from Rosencow, III EC (2010). Mayo Clinic Challenging Images for Pulmonary Board Review. © Mayo Foundation for Medical Education and
Research, by permission of Oxford University Press.

section 19  Rheumatological disorders 4602 Skin manifestations of rheumatic disease Panniculitis Panniculitis describes a heterogeneous group of conditions character- ized by inflammatory lesions affecting subcutaneous adipose tissue. They are subcategorized into four histological subtypes, mostly septal or mostly lobular, with or without vasculitis. The range of possible diagnoses includes leukocytoclastic vasculitis, erythema nodosum, rheumatoid nodules, cutaneous polyarteritis nodosa, gout panniculitis, subcutaneous sarcoidosis, and lupus erythematosus profundus. The most common panniculitis is erythema nodosum (mostly septal without vasculitis). This is characterized by painful, symmet- rical subcutaneous nodules usually over 1 cm affecting the lower extremities and more uncommonly the forearms (see Fig. 19.12.3). They appear as bright red nodules, progressing to purple, followed by yellow/​green colouration, spontaneously resolving over 3–​6 weeks without a scar. The skin lesions are frequently accompanied by fever, arthralgia and fatigue, and may be accompanied by abdom- inal pain and diarrhoea. It is most common in females between the second and fourth decades of life. In children erythema nodosum is most commonly associated with streptococcal infection, but in adults medications, sarcoid- osis and inflammatory bowel diseases are the most common causes (Table 19.12.2). The rheumatic diseases most frequently associated with the condition are sarcoidosis (in Löfgren’s syndrome), Behçet’s disease, and Takayasu’s arteritis. Important differentials to con- sider are Mycobacterium tuberculosis, Mycoplasma pneumonia, Hodgkins and non-​Hodgkin’s lymphoma. Neutrophilic dermatoses Neutrophilic dermatoses are characterized by skin infiltration by polymorphonuclear leukocytes. The archetypal conditions presenting to rheumatology are pyoderma gangrenosum and Sweet’s syndrome, disease associations of which are shown in Table 19.12.3. Pyoderma gangrenosum Pyoderma gangrenosum is a rare disease with a UK incidence of 0.63 per 100 000 person-​years. It has a variety of clinical presenta- tions including classical ulcerating lesions and atypical bulbous, pustular and granulomatous subtypes (Figs. 19.12.5 and 19.12.6). Table 19.12.2  Conditions associated with erythema nodosum Infections • Streptococcus sp. • Tuberculosis • Yersinia sp. • Atypical pneumonia — Mycoplasma pneumonia — Chlamydia psitacci • Infectious mononucleosis Malignancy • Hodgkin’s lymphoma • Non-​Hodgkin’s lymphoma • Leukaemia Autoimmune conditions • Ulcerative colitis • Crohn’s disease • Behçet’s disease • Reactive arthritis Miscellaneous • Sarcoidosis Drugs • Sulfonamides, e.g. sulphasalazine • Celecoxib • Furosemide • Bumetanide • Gliclazide • Penicillin • Oral contraceptives Table 19.12.3  Disease associations of Pyoderma gangrenosum and Sweet’s syndrome Pyoderma gangrenosum Sweet’s syndrome Rheumatic disease • Rheumatoid arthritis • Ankylosing spondylitis • Systemic lupus erythematous • Behçet’s disease • Relapsing polychondritis • Systemic lupus erythematous Gastrointestinal • Inflammatory bowel disease (Ulcerative colitis > Crohn’s disease) • Inflammatory bowel disease (Crohn’s disease > Ulcerative colitis) Infections • HIV • Hepatitis B • HIV Haematological • Monoclonal gammopathy of uncertain significance (MGUS) • Waldenstrom macroglobulinaemia • Myelofibrosis • Non-​Hodgkin’s lymphoma • Acute myeloid leukaemia • Chronic lymphocytic leukaemia • Non-​Hodgkins lymphoma • Multiple myeloma • Myelodysplastic syndrome • Hairy cell leukaemia • Mixed cryoglobulinaemia Solid tumours • Prostate • Colon • Bladder • Breast • Lung • Ovary • Prostate • Colon • Renal • Lung Endocrine • Pregnancy • Pregnancy • Hashimoto’s thyroiditis Drug-​induced • Granulocyte colony stimulating factor (G-​CSF) • All-​trans retinoic acid • Granulocyte colony stimulating factor (G-​CSF) • Bortezomab • Imatinib • Co-​trimoxazole Miscellaneous • Sarcoidosis • Pyoderma gangrenosum and acne (PAPA) syndrome • Takayasu’s arteritis • Relapsing polychondritis

19.12  Miscellaneous conditions presenting to the rheumatologist 4603 Ulcerative or classical lesions may develop after minor trauma or surgery, a phenomenon known as pathergy, which produces a small red-​blue pustule, which then enlarges and ulcerates. The ul- cers classically have a raised edge with a blue or violaceous border, a steep and undermined internal margin with purulent exudates. Elliptical tissue biopsies which include the floor and margin of the lesions are recommended for diagnostic purposes. Histopathology demonstrates destruction of adnexal glands and follicular units by neutrophillic inflammation with haemorrhage and necrosis. Folliculitis and granulomas may be found in pustular and granu- lomatous variants respectively. Topical treatment for mild lesions includes potent steroid pre- parations and tacrolimus, but systemic treatment is usually re- quired: high dose oral prednisolone (1–​2 mg/​kg/​day) and ciclosporin are used most frequently, with mycophenolate mofetil, azathioprine, and tacrolimus commonly used alternatives. Patients with coex- istent inflammatory bowel disease and rheumatoid arthritis can be successfully treated with anti-​TNF agents. Sweet’s syndrome Robert Sweet described the syndrome, otherwise known as acute fe- brile neutrophilic dermatosis, in 1964. It is characterized by acute onset fever, peripheral neutrophilia and painful erythematous, ir- regular papules or plaques, the histology of which demonstrates neutrophilic inflammation in the papillary dermis. Skin lesions are accompanied by dermal oedema and are distributed most frequently on the face, neck, upper limbs and trunk (Fig. 19.12.7). Lesions may also occur on the lower limb indistinguishable from erythema nodosum. Arthralgia, myalgia, lethargy, and painful red eyes are commonly reported. Treatment for Sweet’s syndrome importantly includes treatment of underlying disease (Table 19.12.3), which may drive activity of skin lesions. Given the many disease associations, the diagnostic work-​up includes seeking an underlying cause and exclusion of malignancy, before proceeding with empirical treatment. However, Sweet’s syndrome responds very well to high dose oral corticoster- oids (prednisolone 1 mg/​kg/​day), which is first-​line therapy. A third of patients show persistent disease after corticosteroid tapering at 4–​6 weeks, requiring second-​line, steroid-​sparing treatment. If pa- tients have underlying inflammatory bowel disease or rheumatoid arthritis, anti-​TNF agents should be considered. Dapsone, colchi- cine, NSAIDs, and ciclosporin are alternative agents, which are used second line in idiopathic cases. Case reports have demonstrated benefit with anakinra and rituximab in refractory disease. Multicentric reticulohistiocytosis Multicentric reticulohistiocytosis is a rare disease of unknown aeti- ology presenting most commonly in women in the fourth decade, with an erosive and destructive symmetrical small joint polyarthritis and progressive papulonodular skin lesions. Joint disease com- monly affects the distal interphalangeal joint, distinguishing it from rheumatoid arthritis. It may produce a rapidly progressive arth- ritis mutilans, and juxta-​articular erosion which can mimic gout radiographically. A  wide variety of malignancies, both solid and haemopoeitic, have been identified in up to 25% of patients in some case series, raising the possibility of paraneoplastic pathogenesis. Fig. 19.12.5  Pyoderma gangrenosum. Fig. 19.12.6  Ulcerating pyoderma gangrenosum. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press. Fig. 19.12.7  Rash of Sweet’s syndrome. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press.

section 19  Rheumatological disorders 4604 Nodules and arthritis present simultaneously in approximately 20% of patients, but there may be an interval between arthritis onset and skin disease of a few years. Skin nodules occur most fre- quently on the face and dorsum of the hand. Distal limb nodules can occur in a periungual distribution, causing a ‘coral bead’ ap- pearance of the nail bed (Fig. 19.12.8). In addition to the skin, papulonodular lesions frequently affect the oropharyngeal and nasal mucosal. Constitutional symptoms such as fever, malaise, and weight loss are often present. Major organ disease is infre- quent, but most commonly affects the heart and lungs, manifesting as pericardial effusion, pleural effusion, or pulmonary fibrosis. Diagnosis can be achieved by skin or synovial biopsy, clas- sically revealing a multinucleated giant cell inflammation with eosinophilic periodic acid–​Schiff (PAS) positive ‘ground glass’ cytoplasm. There is no treatment consensus because the rarity of multicentric reticulohistiocytosis prevents rigorous clinical trials. Modern approaches mimic ‘treat to target’ rheumatoid arthritis regimen, with first-​line use of corticosteroids and disease-​modifying antirheumatic drugs, in which methotrexate, hydroxychloroquine, and azathioprine have been most commonly used with variable success. Likewise, both joint and skin disease, refractory to cor- ticosteroid and disease-​modifying antirheumatic drugs, have been successfully treated with anti-​TNF agents etanercept, adalimumab and infliximab, and IL-​6 blockade with tocilizumab in case reports and small case series. Bisphosphonates including alendronic acid, pamidronate, and zolendronate have also shown benefit. Primary joint pathology and synovial disorders Pigmented villonodular synovitis Pigmented vilonodular synovitis is an aggressive and locally in- vasive synovial proliferation of unknown aetiology, considered to have both inflammatory and tumour-​like characteristics. The hyperplastic synovium is pigmented due to haemosiderin con- taining multinucleated giant cells and macrophages, which are thought to mediate joint destruction by local metalloproteinase and cytokine production. Diffuse, localized, and extra-​articular subtypes have been described, with diffuse and localized forms affecting all or part of the contiguous synovium respectively, and the extra-​articular subtype commonly causing tenosynovitis or bursitis. In extra-​articular manifestations, nodular tendon lesions com- monly affect the extensor tendons of the wrist and—​although painless—​may restrict movement. Treatment is by surgical ex- cision, which allows histological confirmation of the diagnosis. Recurrence is rare. Diffuse and localized intra-​articular lesions occur most com- monly as a monoarthritis of the knee, hip, or ankle of adult men aged between 20 and 50 years. Slow evolution of pain, swelling, and a gradual reduction in the range of movement can lead to diagnostic delay. Aspiration of serosanguineous fluid in the absence of trauma should raise the suspicion. MRI is the optimal imaging study, cap- able of demonstrating synovial proliferation in some cases. Intra-​articular steroid administration gives only short-​lived re- lief, and surgical excision is the treatment of choice. In the event of a recurrence (40% in diffuse cases), radioisotope synovectomy with Yttrium may be used. Joint replacement may be required in advanced cases. Primary synovial osteochondromatosis This is a rare condition with an incidence of 1 in 100 000, occurring most commonly in men between the ages of 30 and 50 years, in an otherwise normal joint. It is a benign neoplastic process involving subsynovial cartilage and synovial hyperplasia. The process leads to formation of hyaline cartilage chondromas, which may detach from the synovium and ossify, forming intra-​articular loose bodies. Usually multiple calcified periarticular bodies are formed, ranging from 1 mm to 3 cm in size (Fig. 19.12.9). The condition can also be extra-​articular, affecting bursae and tendon sheaths. Intra-​articular disease is typically monoarticular, with the knee affected in 50% of cases, but other commonly affected sites include (a) (b) (c) Fig. 19.12.8  Smooth, reddish brown papules and nodules on the ear (a) and fingers (b, c) in multicentric reticulohistiocytosis. Reproduced from Burge S et al. (2016). Oxford Handbook of Medical Dermatology, 2nd edn, by permission of Oxford University Press.

19.12  Miscellaneous conditions presenting to the rheumatologist 4605 hip, shoulder, elbow, and ankle. The symptoms include joint pain, swelling, restricted range of motion, and locking suggestive of intra-​ articular loose bodies. The current treatment of choice is surgical synovectomy and removal of loose bodies. Malignant transform- ation to chondrosarcoma is rare. Charcot joint Charcot’s osteoarthropathy is a deformity of the foot and ankle re- sulting from peripheral neuropathy (Figs. 19.12.10 and 19.12.11). Originally described by Charcot in tabes dorsalis, the most common cause today is diabetes mellitus type 1 and 2, occurring in type 1 diabetes most commonly in the fifth decade, and in type 2 the sixth decade. Leprosy is a frequent cause in endemic areas. Charcot joints commonly present with a unilateral, erythema- tous, swollen foot, with pain in only 30% at presentation and recent trauma reported by up to 53% of patients. There are five anatom- ical classifications, describing the clinical patterns and distribution of bones and joints affected (Table 19.12.4). Types 2 and 3 are most common; hindfoot involvement (Type 4 and 5) is associated with poorer prognosis. The natural progression of disease can be described in four stages. Stage 0 is characterized by inflammatory foot oedema and erythema with normal plain radiographs; stage I  by bone dis- solution; stage II by bone coalescence; and stage III by bone re- modelling. In early disease (stage 0), MRI is the most sensitive imaging modality to detect changes such as soft tissue oedema, joint effusions, subchondral bone marrow oedema, and to exclude osteomyelitis. The mainstay of Charcot joint management is offloading with casting therapy, which has been shown to limit bone and joint destruction and reduce progression to deformity. Gradual and Fig. 19.12.9  Osteochondromatosis: lateral radiograph of the knee showing extensive periarticular chondral-​type soft tissue calcifications (arrows) typical of synovial osteochondromatosis. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology,
4th edn, by permission of Oxford University Press. Fig. 19.12.10  Charcot ankle joint. Reproduced from Jolly E et al. (eds) (2016). Training in Medicine, by permission of Oxford University Press. Fig. 19.12.11  Charcot foot. There is marked disruption of the midfoot in this patient with diabetes. There is a divergent Lis Franc dislocation and fragmentation of the midfoot bones. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press. Table 19.12.4  Anatomical subtypes of Charcot osteoarthropathy Subtype Joints/​bones involved Type 1 Metatarsophalangeal and interphalangeal joints Type 2 Tarsometatarsal joints Type 3 Naviculocuneiform, talonavicular, and calcaneocuboid joints Type 4 Ankle and subtalar joints Type 5 Calcaneum

section 19  Rheumatological disorders 4606 smooth transition to footwear and rehabilitation to progressive weightbearing is important to prevent further damage. Evidence for bisphosphonate and calcitonin use is weak. They have been success- fully used to reduce bone turnover, but this does not appear to trans- late into improved clinical outcomes. Teriparatide use is currently being evaluated in a randomized controlled trial. Rheumatology and haematology Haemophilia Haemophilias are a group of X-​linked recessive disorders, re- sulting in factor VIII deficiency in haemophilia A and factor IX in haemophilia B (Christmas disease). Haemarthrosis is the main musculoskeletal manifestation, occurring spontaneously in major forms (factor VIII levels <1% of normal), minor trauma in mod- erate forms (1–​5% of normal) and major trauma in mild forms (>5% of normal). Symptoms of haemarthrosis include rapid swelling of the in- volved joint, usually preceded by tingling or burning and joint stiffness. It most commonly occurs in knees, ankles, and elbows. Presence of iron and haemosiderin deposition in synovium results in proliferation of synovial fibroblasts, neovascularization, and activation of inflammatory cytokines, leading to joint damage. Prophylactic factor replacement between 2 and 18  years of age prevents disabling joint complications. Without this, acute haemarthroses begin from around five years of age. In acute haemarthrosis ultrasonography is useful to differen- tiate haemarthrosis from soft tissue or subperiosteal haemorrhage. Management of acute haemarhroses includes rest, ice, and immo- bilization, factor replacement, followed by joint aspiration in large, tense joint effusions. Synovial fluid should be sent for microscopy, culture, and sensitivity to exclude septic arthritis, the incidence of which is 40 times higher in haemophilia than the general popula- tion. After adequate factor replacement, physiotherapy aids restor- ation of normal range of motion and prevents joint contractures. Systemic or intraarticular steroid are not recommended. Analgesics including NSAIDs, COX-​2 inhibitors, and opiates in severe cases are helpful to manage pain. Advanced haemophilic arthropathy may develop in severe cases requiring early joint replacement. In selected patients with trouble- some, recurrent haemarthrosis, synovectomy or angiographic em- bolization may be considered to prevent severe joint damage. Sickle cell disease Sickle cell disease encompasses a group of inherited haemo­ globinopathies characterized by abnormal β-​globin chain produc- tion, resulting in structurally abnormal, sickled red blood cells. Musculoskeletal pain is very common as a consequence of self-​ limiting vaso-​occlusive episodes, causing tissue ischaemia, which may manifest between six months and four years with sickle cell dactylitis or hand-​foot syndrome, caused by infarction of diaphyses in the bones of the hands and feet. Avascular necrosis of the fem- oral head or humeral head can also occur in up to one-​third of pa- tients, manifesting during painful vaso-​occlusive crises affecting the epiphyses. Management of mild cases includes oral hydration and NSAIDs, with severe cases requiring intravenous fluids, NSAIDs, and opiate analgesia. Osteomyelitis is 100 times more prevalent than the general population due to a combination of medullary bone infarction, hyposplenism and impaired humoral immunity. This should be considered in the presence of bone pain or prolonged pain crises (>2 weeks) accompanied by fever. Frequently encountered organ- isms include Salmonella sp. and Staphylococcus aureus, typically affecting femoral, tibial, and humeral shafts. Septic arthritis may complicate up to 20% of cases of osteomyelitis. Hyperuricaemia occurs in up to 40% of patients and may result in clinical gout. Leukaemia Arthritis is common in leukaemia, particularly in childhood leu- kaemia. It occurs due to bone marrow and joint infiltration by leu- kaemic cells, and may lead to a misdiagnosis of juvenile idiopathic arthritis. Rarely, a frank inflammatory leukaemic arthritis can de- velop. Clinical patterns of arthritis include asymmetrical large joint oligoarthritis or distal, symmetrical polyarthritis. It is well recognized that musculoskeletal involvement may pre- cede the diagnosis of leukaemia by weeks to months, requiring a high index of suspicion and vigilance during treatment of the ini- tial arthritis. Diagnostic clues indicating leukaemia include a dis- proportionate amount of pain to clinical findings, nocturnal pain, fever, cytopenia, lytic lesions, and a poor response to NSAIDs and corticosteroids. Lymphoma Arthritis is an uncommon feature of lymphomas, but may be a presenting feature in non-​Hodgkin’s lymphoma in absence of other symptoms. This can mimic rheumatoid arthritis with a small joint polyarthritis, and some patients are found to be rheumatoid factor and anticyclic citrullinated peptide antibody positive. Atypical lymphocytes are detectable in synovial fluid in up to 60%.  POEMS POEMS refers to an uncommon disorder that may present to any specialty, depending on the dominant feature in the spectrum of polyneuropathy, organomegaly, endocrinopathy, M-​protein (i.e. a monoclonal paraproteinaemia), and skin abnormalities. Papilloedema, extravascular volume overload (peripheral oedema, pleural effusion, ascites, pericardial effusion), sclerotic bone lesions, and thrombocytosis are also well recognized features. Neuropathy is the most common manifestation, classically a symmetrical sensorimotor demyelinating peripheral neuropathy. Osteosclerotic bone lesions occur in most cases. Hepatomegaly is found in up to 78% and splenomegaly in up to 70%. Endocrine abnormalities include hypogonadism, thyroid disorders, diabetes mellitus, hyperprolactinaemia, and adrenal insufficiency. The paraprotein is almost exclusively a lambda monoclone. Skin changes may manifest as hyperpigmentation, new haemagioma formation, telangiectasia, flushing, thickening (which may resemble sclero- derma) and acryocyanosis. Serum vascular endothelial growth factor (VEGF) levels are markedly elevated in POEMS. Radiographs may show single or multiple osteosclerotic lesions with unusual patterns of proliferative change, both of which are unexpected in myeloma. Bone marrow bi- opsy demonstrates megakaryocyte hyperplasia and clustering, with

19.12  Miscellaneous conditions presenting to the rheumatologist 4607 two-​thirds having plasma cell clonal expansion with lambda expres- sion in over 90%. Treatment is directed at the principal presenting features. The paraproteinaemia may require melphalan and corticosteroid. Serum levels of VEGF correlate with clinical course and response to therapy. Remission in POEMS has been reported after treatment with a VEGF-​blocking monoclonal antibody, bevacizumab. Rheumatology and metabolic disorders Hereditary haemochromatosis This is a group of inherited iron storage disorders, most commonly involving autosomal recessive inheritance of a C282Y mutation, with the remaining 5% of cases involving a heterozygous C282Y/​H63D mutation. 80% of patients develop a progressive, non​inflammatory arthropathy, typically mimicking the distribution of calcium pyro- phosphate arthritis, with second and third metacarpophalangeal joints affected most frequently (Fig. 19.12.12). The proximal interphalangeal joints and wrists are also frequently affected, with shoulders, knees, ankles, elbows also involved. Non​specific symptoms at onset including fatigue and abdominal pain lead to diagnostic delay. The classical radiographic features are those of calcium pyrophos- phate arthritis with hook-​like osteophytes and chondrocalcinosis, which may be detectable in knee meniscal cartilage, the triangular ligament of the wrist, pubic symphysis, and spine. The joint disease is irreversible, with no impact from serum iron reduction following phlebotomy. NSAIDs, COX-​2 inhibitors, colchicine, and intra-​ articular steroids give short-​term relief. Wilson’s disease A  rare genetic disorder of copper metabolism, Wilson’s disease typically presents between the second and third decades of life with three neurological presentations:  a dystonic syndrome, an ataxic syndrome, or a Parkinsonian syndrome. Most patients pre- senting with neurological symptoms have asymptomatic liver disease. Musculoskeletal involvement is present in two-​thirds of patients, and typically manifests as development of early degen- erative arthritis due to copper deposition in the synovium or sec- ondary chondrocalcinosis. Hypermobility and osteopenia are also frequently reported. Characteristic radiological features include fluffy periostitis at the greater trochanter and inferior aspect of the calcaneus, and cor- ticated ossicles near affected joints. Diagnosis requires measuring urinary 24 hour copper excretion, serum caeruloplasmin, slit lamp examination for Kayser-​Fleischer rings (present in 98% of patients with neurological disease), and genetic testing for ATP7B mutations. Treatment includes using copper chelators penicillamine or trientine, which increase copper excretion. These can be used in combination with zinc which inhibits intestinal copper absorption. Disorders of the spine and axial skeleton Tietze’s syndrome Tietze’s syndrome is a rare benign condition, also known as chondropathia tuberosa, affecting middle-​aged men and women, characterized by anterior chest pain associated with focal tender- ness and swelling over the second or third sternocostal joint. Pain is typically exacerbated by coughing and deep inspiration. It is differ- entiated from costochondritis by the presence of swelling. Tietze’s syndrome is a diagnosis of exclusion, and imaging must be performed to exclude serious underlying pathology. Plain radio- graphs are insufficient to assess the sternocostal joint, even on ob- lique views, due to the overlying structures. A combination of CT and MRI imaging helps identify serious differentials such as osteo- myelitis and bone tumours, including primary chondrosarcomas and metastases from bronchogenic or breast carcinoma. Anterior chest wall pain is present in up to one-​third of patients (of which a proportion have swelling) with early seronegative spondyloarthropathy and may predate onset of spinal pain and stiff- ness. Rarer conditions such as SAPHO should be considered in cases of multiple swellings and presence of hyperostosis and osteitis on imaging (see next section). Tietze’s is commonly self-​limiting, requiring symptomatic treat- ment with NSAIDs, but in some cases the condition may last for years, when local injection with lidocaine or corticosteroid may pro- vide symptomatic relief. Diffuse idiopathic skeletal hyperostosis Diffuse idiopathic skeletal hyperostosis (DISH) is an idiopathic condition which is commonly asymptomatic, twice as common in males, and has increasing prevalence with age. It is characterized by ossification of ligaments and entheses in the axial skeleton and peripheral sites. The spine is principally affected, leading to bony bridges (entheso­ phytes) between adjacent verterbrae, most commonly in the lower thoracic and upper lumbar verterbrae. Cervical spine involvement is well described and can lead to large osteophytes capable of causing dysphagia and airway obstruction requiring surgery. Spinal symp- toms include pain and restriction, which may mimic seronegative spondyloarthropathy. Fig. 19.12.12  Iron fist sign in hereditary haemochromatosis. Contrast the normal clenched fist on the left with the abnormal fist on the right, caused by arthritis of the second and third metacarpophalangeal joints. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press.

section 19  Rheumatological disorders 4608 Peripheral ossification can also occur in peripheral joints, ligaments and entheses, including the shoulder, elbow, knee, metacarpophalangeal joints, and calcaneus. Phalangeal tufting and an increase in the cortical thickness of the tubular bones of the hand is recognized. Articular osteophytes are classically para-​articular and distinguishable from osteoarthritic osteophytes. Classical radiographic changes include ossification of the anterior longitudinal ligament, visible as ossifications on lateral radiographs, likened to ‘flowing candle wax’. There is preservation of the vertebral cartilage and vertebral disc height (Fig. 19.12.13). Diffuse idiopathic skeletal hyperostosis is distinguishable from ankylosing spondylitis by the age of the patient at symptom onset, by typical radiographic features (Table 19.12.5), and the lack of as- sociation with HLA-​B27. There is no specific treatment for diffuse idiopathic skeletal hyperostosis. The natural history is similar to ankylosing spondylitis in terms of progression, reaching advanced disease after ten years. Treatment strategies are similar to those for osteoarthritis, including physiotherapy, topical NSAIDs, and analgesia. Corticosteroid injec- tion can be considered for painful peripheral entheseal involvement. Diffuse idiopathic skeletal hyperostosis is associated with obesity, dyslipidaemia, hypertension, impaired glucose tolerance, hyperuricaemia, and hyperinsulinaemia, hence management in- cludes testing for these known metabolic associations and instigating secondary prevention measures. Alkaptonuria Alkaptonuria is a Mendelian autosomal recessive disorder resulting from absence of homogentisate 1,2 dioxygenase, which is important in the metabolism of phenylalanine, leading to accumulation of homogentisic acid in tissues. It is rare worldwide with an estimated prevalence of 1 in 250 000–​1 000 000, but it is more common in the Dominican Republic, India, Jordan and most prevalent in Slovakia (1 in 19 000). Deposition of homogentisic acid occurs in bone, joints, ten- dons, cartilage and heart valves, and accumulation in urine leads to dark urine, which turns to black on standing. Although urine discolouration is evident from birth, its significance is rarely rec- ognized, leading to delay in diagnosis until on average the fourth decade, when patients typically present with musculoskeletal prob- lems including spinal deformity, presenting with back pain and restriction due to the development of ochronosis (darkening of con- nective tissue, from homogentisic acid deposition) and ochronotic osteoarthropathy. A  large joint inflammatory arthritis affecting knees, shoulder, hips, elbows, and ankles occurs later in the disease process. Classical physical signs include evidence of homogentisic acid in tissues, which manifests as black, blue, or yellow pigmen- tation of ear cartilage and sclera. Valvular heart disease and renal stones are late complications. In those affected, homogentisic acid is measureable in urine, which is absent in healthy individuals. Radiographic features in- clude chondocalcinosis of intervertebral discs, ossification of liga- ments, and osteoporotic verterbral fractures. Although there is no cure, treatments can be targeted towards reducing the accumulation of homogentisic acid and its metabol- ites, including treatment with Vitamin C and Nitisone. Drug-​induced rheumatic syndromes Statin-​induced myopathy Statin-​induced myopathy encompasses a spectrum of clinical prob- lems including asymptomatic rise in serum creatine kinase, myalgia, myositis, and rhabdomyolysis. In the United Kingdom, the inci- dence of statin-​induced myopathy is 1.2 per 10 000 person-​years, with incidence of rhabdomyolysis with simvastatin, atorvastatin, or pravastatin monotherapy 0.44 per 10 000 person-​years. Symptoms include muscle aches, cramps, tenderness, or weak- ness, which usually develop after taking statins for six months and persist after withdrawal of the drug for an average of 2.3 months. Rarely, patients can have persistent myotoxicity after withdrawal of Fig. 19.12.13  Diffuse idiopathic skeletal hyperostosis. This lateral view of the lumbar spine reveals the classic flowing mature ossification of the anterior longitudinal ligament. Note the preservation of disc spaces. Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology,
4th edn, by permission of Oxford University Press. Table 19.12.5  Factors differentiating diffuse idiopathic skeletal hyperostosis from established ankylosing spondylitis Diffuse idiopathic skeletal hyperostosis Ankylosing spondylitis (Established disease) • Elderly males • Male 20–​30 yrs • HLA-​B27 negative • HLA-​B27 80–​85% • Anterior longitudinal ligament ossification—​‘flowing candle wax’ • Romanus lesions—​‘shiny corners’ • Squaring vertebral bodies • Preserved disc space • Disc space ossification • No sacroiliac joint abnormality • Bilateral sacroiliac abnormality (narrowing, sclerosis, erosion, fusion) • Non​marginal osteophytes • Marginal osteophytes • Preserved facet joints • Facet joint erosion

19.12  Miscellaneous conditions presenting to the rheumatologist 4609 the statin, which raises the possibility of anti-​HMG-​CoA reductase associated immune-​mediated necrotizing myopathy, which often requires immunosuppressive treatment. Risk factors that have been linked to development of statin-​ induced myopathy include female gender, advanced age, multiple comorbidities, impaired renal or liver function, and alcohol ex- cess. Untreated hypothyroidism, hyperthyroidism, hyperpara- thyroidism and vitamin D deficiency are known to cause myalgia and mildly elevated creatine kinase and need to be excluded. Important drug interactions with ciclosporin, amiodarone, macrolide antibiotics, and warfarin should be considered, which can cause elevated statin levels and myotoxicity by P450 cyto- chrome inhibition. It is recommended that hydrophilic statins (pravastatin, rosuvastatin and fluvastatin) are used in patients with existing muscle disease, rather than lipophilic statins (simvastatin, atorvastatin, lovastatin) which are more likely to penetrate muscle and produce myopathy. If serum creatine kinase is more than ten times the upper limit of normal, assessment of renal function, urine myoglobin, and urine output should be performed urgently to confirm or refute presence of rhabdomyolysis. If muscle symptoms and elevated creatine kinase persist despite withdrawal of the statin, or if muscle weakness pre- dominates, further assessment is needed to exclude primary muscle disease or autoimmune myopathy, including serology, electromyog- raphy, and muscle biopsy. Drug-​induced tendinopathy Drug-​induced tendinopathy is caused by four main classes of drug: quinolones, statins, systemic glucocorticoids, and aromatase inhibitors. The most common site is the Achilles tendon, often pre- senting with abrupt onset localized pain, with warmth erythema and swelling. A positive Thompson’s test (absent plantarflexion on squeezing the calf) identifies tendon rupture, which can be con- firmed by ultrasound or MRI imaging. The incidence of quinolone tendinopathy is estimated to be 0.5–​2% of quinolone prescriptions. 90% of lesions effect the Achilles tendon (resulting in rupture in 41% of cases), with the remaining 10% of cases involving the rotator cuff, extensor tendons of the wrist, finger and thumb flexors, or quadricipital tendons. Risk factors in- clude age above 60 years, renal impairment, and concomitant gluco- corticoid treatment. Statin tendinopathy usually causes unilateral Achilles tendino­ pathy, of which one-​third result in tendon rupture. Risk factors include advanced age and concomitant quinolone therapy. Systemic glucocorticoids may also result in Achilles, patellar, or quadricipital tendon rupture, which may be seen after just four months treatment, although thought to be a consequence of longer-​ term treatment affecting collagen integrity. Local steroid injections for the management of tenosynovitis can result in tendon rupture, although this is rare, occurring in only 0.1% of injections. Decreased collagen tensile strength in animal models after local injection sup- ports the recommendation of rest and avoidance of excess load bearing after a local injection. Aromatase inhibitors are capable of producing small joint syno- vitis and tenosynovitis of the wrist and hands, including both trigger finger and De Quervain’s tenosynovitis, which may occur after just two weeks of treatment. Management includes withdrawal of the offending drug. In cases of Achilles tendinopathy without rupture, initial offloading may be achieved by activity modification and orthotic heel inserts. This should be followed by early physiotherapy guided rehabilitation, including eccentric exercises. Tendon rupture requires orthopaedic management, which may well be conservative in the first instance, with surgery reserved for isolated cases. Drug-​induced lupus Drug-​induced lupus is a well-​recognized phenomenon reported in the treatment with over 80 different medications (Table 19.12.6). Securing the diagnosis is challenging, as there are many shared symptoms, signs, and laboratory parameters with idiopathic sys- temic lupus erythematosus. The risk of developing drug-​induced lupus varies with drug, estimated to be less than 1% with most known associated medications, increasing to 5–​8% with hydralazine and up to 20% per year with procainamide treatment. In contrast to idiopathic systemic lupus erythematosus, drug-​ induced lupus occurs more frequently in older patients, reflecting increased medication use in this population. The most common manifestations include serositis, fever, myalgia, and arthritis. Cutaneous involvement is atypical in drug-​induced lupus, in con- trast to malar rash, discoid rash, photosensitivity, alopecia, and oral ulcers frequently encountered in idiopathic systemic lupus erythematosus. ANA antibodies are usually positive in drug-​induced lupus, antihistone antibodies in more than 95%, but anti-​dsDNA anti- bodies in less than 5%. In patients with drug-​induced lupus and anti-​ dsDNA antibodies, the crithidia assay may be positive due to cross reactivity with antihistone antibodies. However, the presence of antihistone antibodies in drug-​induced lupus is not a differentiating feature, as they are also present in up to 75% of cases of idiopathic systemic lupus erythematosus. More recently, the anti-​TNF drugs infliximab, adalimumab and etanercept have also been shown to cause drug-​induced Table 19.12.6  Medications reported to cause drug-​induced lupus Commonly cause
drug-​induced lupus • Procainamide • Hydralazine Less common causes Antibiotics • Isoniazid • Minocycline Anticonvulsants • Phenytoin, carbamazepine Antirheumatic drugs • Anti-​TNF—​infliximab, etanercept, adalimumab • Sulfasalazine • Penicillamine Cardiac drugs • Statins—​simvastatin, lovastatin • β-blockers—​propranolol, atenolol, metoprolol • Methyldopa • Hydrochlorthiazide • Quinidine Antipsychotics • Chlorpromazine

section 19  Rheumatological disorders 4610 lupus, with a phenotype more similar to idiopathic systemic lupus erythematosus than ‘classical drug-​induced lupus’ (Table 19.12.7). It is thought that some of these cases may represent ‘unmasking’ of idiopathic systemic lupus erythematosus by anti-​TNF therapy, and some cases of drug-​induced autoimmunity. This phenom- enon is rare, however, with 0.2–​0.4% of patients receiving anti-​ TNF treatment estimated to develop symptoms consistent with drug-​induced lupus. Management for all drug-​induced lupus involves withdrawal of the drug. Symptoms gradually improve over weeks. NSAIDs can be used to manage arthralgia. Corticosteroids are used in more severe manifestations, but are not required long term. Allopurinol hypersensitivity Allopurinol hypersensitivity is rare, with the incidence of severe cutaneous adverse reactions of 0.69 per 1000 person-​years, but im- portant to recognize due to the severity of cutaneous manifestations that can result and the significant mortality (9–​20%). Manifestations of allopurinol hypersensitivity include maculopapular eruptions, Stevens–​Johnson syndrome/​toxic epidermal necrolysis (SJS/​TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and allopurinol hypersensitivity syndrome. Allopurinol hypersensitivity syndrome is characterized by rash (including TEN, erythema multiforme, diffuse maculopapular or exfoliative dermatitis), eosinophilia, leucocytosis, fever, acute hepatocellular injury, and progressive renal failure. It typ- ically develops a month after allopurinol initiation, with most cases manifesting in the first six months of treatment. Risk fac- tors include higher starting dose, baseline renal impairment, concomitant diuretics and presence of HLA-​B*58:01 allele, which is more prevalent in Asian populations. It is likely that all these factors contribute to sustained accumulation of the metabolite of allopurinol, oxypurinol, pre-​disposing to development of allopur- inol hypersensitivity. The current recommendations to avoid adverse events with allo- purinol treatment include a maximum starting dose of 100 mg daily (reduced to 50 mg in patients with creatine kinased stage 4 = eGFR 15–​30 ml/​min/​1.73 m2), careful monitoring of renal function after initiation and dose escalation to allow early detection of renal im- pairment, prompt dose reduction, and consideration of alternative urate lowering drugs. Miscellaneous infections Whipple’s disease Whipple’s disease, caused by Tropheryma whipplei, classically pre- sents in middle-​aged men with a prodromal arthritis, before devel- opment of abdominal pain, diarrhoea, and weight loss. An acute or subacute migratory polyarthritis may precede bowel symptoms by years, and typically involves the ankles, knees, shoulders, and el- bows. However, a symmetrical small joint polyarthritis can mimic rheumatoid arthritis, leading to immunosuppressive treatment. Several cases have been reported where escalation to anti-​TNF treat- ment has revealed bowel symptoms leading to the diagnosis, and the development of significant gastrointestinal symptoms during initiation of immunosuppression and poor response to treatment should prompt consideration of the diagnosis. The polymerase chain Table 19.12.7  Differentiating features between classical drug-​induced lupus, idiopathic systemic lupus erythematosus, and anti-​TNF-​associated drug-​induced lupus Classical drug-​induced lupus Anti-​TNF-​associated
drug-​induced lupus Idiopathic systemic lupus erythematosus Demographics Mean age at onset 50–​70 yrs 50 yrs 20–​30 yrs Gender distribution Female = male Female 5:1 Male Female 9:1 Male Clinical presentation Rash/​cutaneous involvement <5% 67–​73% 54–​70% Arthritis 20% 31–​52% 83% Glomerulonephritis <5% 7–​9% 34% Serositis 50% 12–​18% 28% Neuropsychiatric <5% 3% 12% Fever/​constitutional 45% 23% 42% Laboratory abnormalities ANA

99% 79–​100% 99% Crithidia ‘False positive’ due to antihistone antibodies –​ Positive Anti-​DsDNA abs <5% 72–​92% 50–​70% Antihistone abs 95% 17–​57% 75% Low complement <1% 59% 50% Leukopenia 15% 14% 56% Thrombocytopenia <5% 6% 31%

19.12  Miscellaneous conditions presenting to the rheumatologist 4611 reaction can detect bacteria in stool and saliva cultures, but duo- denal biopsy showing periodic acid–​Schiff-​staining macrophages is diagnostic. Treatment requires a long course of antibiotics, between one and two years’ duration. Chikungunya Chikungunya (‘to walk bent over’ in Kimakonde language) is a single stranded RNA alphavirus transmitted by Aedes mosquitos. Originally isolated in Tanzania, global expansion of disease has led to increasing cases in Africa, spread to Southeast Asia, the Pacific Islands, Europe, the Caribbean, northern South America, and the United States of America. Chikungunya presents with an acute phase of fever, severe arth- ralgia, myalgia, headache, and a maculopapular rash, which usually resolves within 14  days. Diagnosis is made by detection of chi- kungunya RNA by RT-​PCR in the acute phase (days 0–​7 post in- fection), with ELISA for IgM and IgG antibodies detectable in the subacute (days 7–​14) and chronic phases of illness (day 14 onwards). Leukopenia (both lymphopenia and neutropenia), thrombocyto- penia, increased aminotransferases, and increased LDH may be present. Incapacitating arthralgia is found in 99% of patients in the acute phase of chikungunya, which usually develops within minutes to hours of a prodromal fever. After resolution of fever, headache, rash and myalgia, arthralgia may persist for up to several years, or re-​emerge during the chronic phase. The arthritis may commonly mimic and even fulfil EULAR/​ACR 2010 criteria for rheumatoid arthritis (with negative anticyclic citrullinated peptide and rheuma- toid factor antibodies), with a symmetrical small joint polyarthritis, capable of causing erosive damage in a minority. Involvement of the knees, hips, elbows, sternoclavicular, temporomandibular joints, and tenosynovitis have also been reported. There is no effective antiviral treatment. Initial treatment is supportive with rest and NSAIDs. In persistent inflammatory arthritis mimicking rheumatoid arthritis, a combination of intra-​ articular and oral steroids, disease-​modifying antirheumatic drugs including methotrexate, sulfasalazine, and hydroxychloroquine have been used. FURTHER READING Gillmore JD, Hawkins PN (2013). Pathophysiology and treatment of systemic amyloidosis. Nat Rev Nephrol, 9, 574–​86. Islam AD, et al. (2013). Multicentric reticulohistiocytosis: a rare yet challenging disease. Clin Rev Allergy Immunol, 45, 281–​9. Kadavath S, Efthimiou P (2015). Adult-​onset Still’s disease-​ pathogenesis, clinical manifestations, and new treatment options. Ann Med, 47, 6–​14. Katz U, Zandman-​Goddard G (2010). Drug-​induced lupus: an update. Autoimmun Rev, 10, 46–​50. Kirchgesner T, et al. (2014). Drug-​induced tendinopathy: from physi- ology to clinical applications. Joint Bone Spine, 81, 485–​92. Mader R, Verlaan JJ, Buskila D (2013). Diffuse idiopathic skeletal hyperostosis: clinical features and pathogenic mechanisms. Nat Rev Rheumatol, 9, 741–​50. Manger B, Schett G (2014). Paraneoplastic syndromes in rheuma- tology. Nat Rev Rheumatol, 10, 662–​70. Morais SA, et al. (2016). Musculoskeletal complications of haemato- logical disease. Rheumatology (Oxford), 55, 968–​81. Perfetto F, et  al. (2010). Systemic amyloidosis:  a challenge for the rheumatologist. Nat Rev Rheumatol, 6, 417–​29. Petrova NL, Edmonds ME (2013). Medical management of Charcot arthropathy. Diabetes Obes Metab, 15, 193–​7. Phornphutkul C, et al. (2002). Natural history of alkaptonuria. N Engl J Med, 347, 2111–​21. Puechal X (2013). Whipple’s disease. Ann Rheum Dis, 72, 797–​803. Salles M, et al. (2011). The SAPHO syndrome: a clinical and imaging study. Clin Rheumatol, 30, 245–​9. Sathasivam S (2012). Statin induced myotoxicity. Eur J Intern Med, 23, 317–​24. Stamp LK, Day RO, Yun J (2016). Allopurinol hypersensi- tivity:  investigating the cause and minimizing the risk. Nat Rev Rheumatol, 12, 235–​42. Ungprasert P, Crowson CS, Matteson EL (2016). Clinical characteris- tics of sarcoid arthropathy: a population-​based study. Arthritis Care Res, 68, 695–​9. Wallach D, Vignon-​Pennamen MD (2015). Pyoderma gangrenosum and Sweet syndrome: the prototypic neutrophilic dermatoses. Br J Dermatol, doi: 10.1111/​bjd.13955

SECTION 20 Disorders of the skeleton Section editor: Cyrus Cooper 20.1 Skeletal disorders—​general approach and clinical conditions   4615 B. Paul Wordsworth and M.K. Javaid 20.2 Inherited defects of connective tissue:
Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum   4670 N.P. Burrows 20.3 Osteomyelitis   4688 Martin A. McNally and Anthony R. Berendt 20.4 Osteoporosis   4696 Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper 20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans   4703 Gavin Clunie 20.6 Bone cancer   4709 Helen Hatcher

ESSENTIALS

ESSENTIALS

section 21  Disorders of the kidney and urinary tract 5012 Systemic sclerosis DeMarco PJ, et  al. (2002). Predictors and outcome of scleroderma renal crisis: the high-​dose versus low-​dose D-​penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum, 46, 2983–​9. Denton C, et al. (2009). Renal complications and scleroderma renal crisis. Rheumatology (Oxford), 48, iii32–​5. Kowal-​Bielecka O, et al. (2009). EULAR recommendations for the treat- ment of systemic sclerosis: a report from the EULAR Scleroderma trials and research group (EUSTAR). Ann Rheum Dis, 68, 620–​8. Nagaraja V (2019). Management of scleroderma renal crisis. Curr Opin Rheumatol, 31, 223–30. Penn H, et al. (2007). Scleroderma renal crisis: patient characteristics and long-​term outcomes. Q J Med, 100, 485–​94. Steen VD (1994). Renal involvement in systemic sclerosis. Clin Dermatol, 12, 253–​8. Steen VD (2001). Treatment of systemic sclerosis. Am J Clin Dermatol, 2, 315–​25. Teixeira L, et al. (2008). Mortality and risk factors of scleroderma renal crisis: a French retrospective study in 50 patients. Ann Rheum Dis, 67, 110–​16. Rheumatoid arthritis Adu D, et al. (1993). Glomerulonephritis in rheumatoid arthritis. Br J Rheumatol, 32, 1008–​11. Boers M (1990). Renal disorders in rheumatoid arthritis. Semin Arthritis Rheum, 20, 57–​68. Esteve V, et al. (2006). Renal involvement in amyloidosis. Clinical out- comes, evolution and survival. Nefrologia, 26, 212–​17. Hall CL, et al. (1987). The natural course of gold nephropathy: long term study of 21 patients. BMJ, 295, 745–​84. Hall CL, et al. (1988). Natural course of penicillamine nephropathy: a long term study of 33 patients. BMJ, 296, 1085–​6. Harper L, et al. (1997). Focal segmental necrotizing glomeruloneph- ritis in rheumatoid arthritis. QJM, 90, 125–​32. Honkanen E, et al. (1987). Membranous glomerulonephritis in rheuma- toid arthritis not related to gold or D-​penicillamine therapy: a report of four cases and review of the literature. Clin Nephrol, 27, 87–​93. Kuznetsky KA, et  al. (1986). Necrotizing glomerulonephritis in rheumatoid arthritis. Clin Nephrol, 26, 257–​64. Stokes MB, et al. (2005). Development of glomerulonephritis during anti-​TNF-​alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant, 20, 1400–​6. Uda H, et al. (2006). Two distinct clinical courses of renal involvement in rheumatoid patients with AA amyloidosis. J Rheumatol, 33, 1482–​7. Sjögren’s syndrome Goules A, et al. (2019). Renal involvement in primary Sjogren’s syn- drome: natural history and treatment outcome. Clin Exp Rheumatol, 37 Suppl 118(3), 123–32. Shioji R, et al. (1970). Sjogrens syndrome and renal tubular acidosis. Am J Med, 48, 456–​63. Tu W, et al. (1968). Interstitial nephritis in Sjogren’s syndrome. Ann Intern Med, 69, 1163–​70. Mixed connective tissue disease Kitridou R, et al. (1986). Renal involvement in mixed connective tissue disease:  a longitudinal clinicopathologic study. Semin Arthritis Rheum, 16, 135–​45. Sharp G, et al. (1972). Mixed connective tissue disease-​ an appar- ently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med, 52, 148–​59. Drug nephrotoxicity Clive D, Stoff J (1984). Renal syndromes associated with anti-​ inflammatory drugs. N Engl J Med, 310, 563–​72. De Broe M, Elseviers M. (2009). Over the counter analgesic use. J Am Soc Nephrol, 20, 2098–​103. Elseviers M, et al. (1995). High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure. Kidney Int, 48, 1316–​23. Joint Formulary Committee. British national formulary (online). BMJ Group and Pharmaceutical Press, London. https://​www. medicinescomplete.com/​mc/​bnf/​current/​ Pusey C, Saltissi D, Bloodworm L (1983). Drug associated acute inter- stitial nephritis: clinical and pathological features and the response to high dose steroid therapy. Q J Med, 52, 194–​211. Sandler D, Burr F, Weinberg C (1991). Nonsteroidal anti-​ inflammatory drugs and risks for chronic renal disease. Ann Int Med, 115, 165–​72. Savill J, Chia Y, Pusey C (1988). Minimal change nephropathy and pemphigus vulgaris associated with penicillamine treatment of rheumatoid arthritis. Clin Nephrol, 29, 267–​70. 21.10.4  The kidney in sarcoidosis Ingeborg Hilderson and Jan Donck ESSENTIALS Sarcoidosis is associated with a broad spectrum of renal manifest- ations, but clinically important disease occurs in few patients. The most common cause of renal dysfunction is abnormal calcium me- tabolism:  untreated chronic hypercalcaemia and hypercalciuria causes progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal in- sufficiency is unusual. A range of glomerulopathies can be associated with sarcoidosis. When treatment is required, steroids are the first line, with various steroid-​sparing agents used in cases that are refractory. Introduction Sarcoidosis is a multisystem inflammatory disease characterized by the presence of noncaseating epithelioid granulomas. These granulomas can resolve without sequelae or result in the devel- opment of fibrosis. The disease has a benign course with spontan- eous resolution in up to two-​third of cases. However, in one-​third a chronic disorder develops, leading to significant organ impair- ment. Sarcoidosis most frequently involves the lungs, but may af- fect any organ system. The most common sites of extrapulmonary disease include skin, eyes, liver, spleen, peripheral lymph nodes,

21.10.4  The kidney in sarcoidosis 5013 central nervous system, and heart. The incidence of renal in- volvement remains unclear. There is a great difference in reported prevalence due to the heterogeneity of renal manifestations and the often insidious nature of the disease. Clinical presentations Sarcoidosis is associated with a broad spectrum of renal mani- festations, but clinically important disease occurs in only a few patients. The most prevalent cause of renal dysfunction is a dis- ordered calcium metabolism. Interstitial granulomatous neph- ritis is the most typical histological finding, but development of renal insufficiency is unusual. Finally, there is a wide range of glomerulopathies associated with sarcoidosis. Different types of renal sarcoidosis can coexist. Calcium metabolism Epidemiology Hypercalcaemia occurs in approximately 10 to 20% of patients with sarcoidosis and hypercalciuria is found in up to 50% of patients. Pathogenesis In sarcoidosis and other granulomatous diseases there is an in- creased activity of 1-​α-​hydroxylase, which is synthetized by granulomas and activated macrophages. This enzyme activity is re- sponsible for the increase in 1,25-​dihydroxy vitamin D (calcitriol) and is resistant to negative feedback mechanisms. Calcitriol aug- ments the gastrointestinal calcium absorption, stimulates the osteoclast activity and bony reabsorption, and increases renal tubular calcium reabsorption. The net result is hypercalcaemia, which is known to cause renal dysfunction by several different mechanisms (Box 21.10.4.1). The rise in calcitriol suppresses the production of the parathy- roid hormone. Along with an increased renal calcium load, this results in hypercalciuria. Untreated, chronic hypercalcaemia and hypercalciuria causes a progressive tubulointerstitial inflamma- tion with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease in sarcoidosis. Furthermore, hypercalciuria predisposes to nephrolithiasis and ob- structive uropathy. Interstitial nephritis with granuloma formation Epidemiology Granulomatous interstitial nephritis is the most common renal le- sion seen on biopsy, but in only a few patients does this cause clin- ically significant disease. The true incidence is unknown, but in autopsy studies of patients with sarcoidosis, a granulomatous infil- trate is found in the kidneys in 7 to 23%. Clinical course Granulomatous interstitial nephritis is usually present when the initial diagnosis of systemic sarcoidosis is made and rarely de- velops in patients who have longstanding sarcoidosis. Most often there is diffuse active sarcoidosis, although isolated renal disease is an accepted entity. Interstitial nephritis has an insidious na- ture and is asymptomatic until late in the course of the disease when severe kidney dysfunction develops as a result of progres- sive fibrosis. It has a highly variable course with a tendency to wax and wane, either spontaneously or under treatment. Relapses are frequent. Diagnosis Screening for renal disease is important. Renal function tests, measurement of serum calcium, and urine analysis should be performed systematically both during initial evaluation and the follow-​up of patients with sarcoidosis. Whenever granuloma- tous interstitial nephritis is suspected, a histopathological con- firmation should be attempted. Noncaseating granulomas are the hallmark of the disease, but they are nonspecific (Fig. 21.10.4.1). Box 21.10.4.1  Mechanisms of renal dysfunction caused by hypercalcaemia • Vasoconstriction of the afferent arteriole, causing a decrease in glom- erular filtration • Inhibition of Na+/​K+-​ATPase leading to urinary sodium wasting with polyuria and dehydration • Decreased sensitivity to antidiuretic hormone • Acute tubular necrosis (a) (b) (c) Fig. 21.10.4.1  Granulomatous interstitial nephritis. (a) On the left there is a localized inflammation of the renal parenchyma, which is not present on the right (haematoxylin and eosin stain, original magnification ×100). (b) Further magnification of the inflammation. There is a granulomatous infiltration with central collections of histiocytes surrounded by lymphocytes (haematoxylin and eosin stain, original magnification ×200). (c) Confirmation of the histiocytic character of the inflammation by an immunohistochemical staining with antibodies directed against CD68 (anti-​CD68 stain, original magnification ×200). Courtesy of Prof. Dr. E. Lerut, University of Leuven, Belgium.

section 21  Disorders of the kidney and urinary tract 5014 Especially in case of isolated renal disease, other reasons of granu- lomatous infiltration should be excluded (Table 21.10.4.1). The absence of kidney biopsy findings does not exclude the diagnosis as renal sarcoidosis can be focal in nature and the typical lesions can easily be missed in biopsy. The urinary manifestations are also nonspecific: there is often mild proteinuria, or less frequently aseptic pyuria or nonvisible haematuria. In some cases, the urine sediment is bland. Glomerular disease Membranous nephropathy is the most common glomerular manifestation of sarcoidosis, although its incidence is very low. Some case reports suggest an association between sarcoidosis and focal segmental sclerosis, mesangioproliferative glomerulo- nephritis, IgA nephropathy, and crescentic glomerulonephritis, but a definitive causal relationship to these conditions has not been proven. Tubular dysfunction Tubular dysfunction is frequently associated with hypercalcaemia and granulomatous interstitial nephritis. It may present as isolated proximal or distal tubular acidosis, Fanconi’s syndrome, urinary concentration deficits, or metabolic alkalosis. Obstructive and vascular uropathy Obstructive uropathy usually results from nephrolithiasis, but in patients with sarcoidosis, obstruction may also be due to retroperi- toneal fibrosis or lymphadenopathy. Renal artery stenosis caused by granulomatous angiitis is an extremely rare complication of sarcoid- osis, often accompanied by arterial hypertension. Treatment Treatment is always required for renal disease, as it is for cardiac, ocular, and neurological manifestations of sarcoidosis, given the substantial risk of end-​organ damage. However, there is no standard of care and little is known about the optimal dose and duration of treatment. Hypercalcaemia and hypercalciuria Glucocorticoids are the mainstay of treatment (Table 21.10.4.2) as they block the 1-​α-​hydroxylase activity and diminish the in- testinal calcium absorption and bony resorption. Most often, a starting dose of prednisolone of 0.3 to 0.5 mg/​kg once daily is re- commended, followed by a taper to a maintenance dose of 5–​10 mg once daily. The total duration of treatment should be at least 12 months. Chloroquine is an alternative treatment. The optimal dose is unknown, but a daily dosage of 250 to 500 mg is most often used. Retinal toxicity is the major concern. Hydroxychloroquine (recommended daily dosing is 200–​400 mg) is slightly less ef- fective, but carries a lesser risk of retinopathy. Ketoconazole in a daily dose of 600–​800 mg can also be used. Hepatic toxicity is the major limiting side effect. The effect of these alternative forms of treatment is less predictable and slower than treatment with corticoids. Preventive measures such as ensuring adequate oral hydration, a low dietary intake of calcium, vitamin D, and oxalate, as well as the limitation of sunlight exposure play additional supportive roles. Thiazide use should be avoided given the substantial risk of aggra- vating hypercalcaemia. Interstitial nephritis with granuloma formation Glucocorticoids Glucocorticoids are the cornerstone of treatment (Table 21.10.4.3). Most authors recommend a starting dose of 0.5 to 1 mg per kg pred- nisone once daily, depending on the severity of the disease. The ini- tial dose should be maintained for 4 weeks to allow improvement and/​or stabilization of renal function. Most patients respond rapidly to treatment but a full recovery of renal function is rare. Patients with a poor response after 1 month tend to have a worse renal out- come and are more susceptible to relapse. After 4 weeks of treat- ment, the dose can be tapered by 5 mg each week until a daily dose of 5 to 10 mg is reached. There is an increased risk of relapse if corticosteroids are tapered too quickly. In this eventuality, the dose should be augmented to the last dose that was effective, with an increase to the initial dose if there is no improvement after 4 weeks. Subsequent tapering should be more gradual. However, in some patients it is impos- sible to taper the glucocorticoids adequately. Given the many side effects of a prolonged treatment with high-​dose glucocorticoids, Table 21.10.4.1  Differential diagnosis of granulomatous nephritis Diagnosis Example Drug reaction β-​lactam antibiotics, nonsteroidal
anti-​inflammatory drugs Infections Tuberculosis, chronic fungal infection Autoimmune disorders Sarcoidosis, granulomatosis with polyangiitis Neoplasia Lymphoma Foreign body reaction Heroin Table 21.10.4.2  Treatment of hypercalcaemia and hypercalciuria in sarcoidosis Standard of care: glucocorticoids Starting dose: 0.3–​0.5 mg/​kg per day Maintenance dose: 5–​10 mg/​day Total duration of treatment: at least 12 months Alternatives Chloroquine Dose: 250–​500 mg/​day Hydroxychloroquine Dose: 200–​400 mg/​day Ketoconazole Dose: 600–​800 mg/​day Preventive measures Limit sunlight exposure Low dietary intake of calcium, vitamin D, and oxalate Adequate oral hydration Avoid thiazide use

21.10.4  The kidney in sarcoidosis 5015 a steroid-​sparing agent (azathioprine or mycophenolate mofetil) can be added, with the intention of subsequently reducing the glucocorticoid dose. The ideal duration of maintenance therapy is unknown. A total duration of treatment of 18 to 24 months seems necessary to be ef- fective and to prevent relapse. For the few patients who suffer fre- quent relapses, lifelong treatment with low-​dose glucocorticoids may be required. There are, however, important side effects from long-​term steroid use which need to be balanced against the risk of progression to endstage renal disease. Azathioprine and mycophenolate mofetil Azathioprine and mycophenolate mofetil can be used as steroid-​ sparing agents or in patients with failure of or a strong contraindi- cation to continued corticosteroids. Treatment with these drugs should only be started after at least 1 month of treatment with cor- ticosteroids, since this duration is needed to allow improvement or stabilization of renal function. The daily dose of azathioprine is 2 mg per kg, mycophenolate mofetil is dosed at 1 g, twice a day. However, it should be pointed out that the evidence in support of these second-​ line agents is very limited. Tumour necrosis factor-​α inhibitors Tumour necrosis factor (TNF) is thought to be a major player in sar- coidosis through its role in the maintenance of granuloma forma- tion. TNFα inhibitors have therefore been suggested as appropriate treatment in cases of steroid-​resistant sarcoidosis. They should only be used when at least one other immunosuppressive agent has been tried, or in patients who have developed severe steroid toxicity. Evidence is scarce. Infliximab is usually given in a dosage of 3 to 5 mg per kg at weeks 0, 2, and 6, followed by 3 to 5 mg per kg every 6 to 8 weeks thereafter. Adalimumab could be an interesting option for patients intolerant of infliximab, but more research is needed before its use can be advocated. Etanercept seems to have no bene- ficial effect in patients with sarcoidosis, as in other granulomatous diseases. Kidney transplantation Endstage renal disease secondary to sarcoidosis is very uncommon. One concluded that renal transplantation can be carried out safely with excellent graft and patient survival, although there was a rela- tively high rate of renal recurrence (17%). A short delay between the last episode of sarcoidosis and renal transplantation was a risk factor for recurrence. Experimental therapy With recognition of the role of cytokines in the pathogenesis of sar- coidosis, other immunosuppressive drugs including thalidomide, pentoxifylline, and rituximab have been proposed as steroid-​sparing agents, but more data are needed before their use can be advocated. Conclusion Sarcoidosis may affect any organ, including the kidney. Disordered calcium metabolism is the most common cause of renal failure. Granulomatous interstitial nephritis is the most typical histological finding, but development of renal insufficiency is rare. The lack of large, randomized controlled treatment trials limits therapeutic options. Corticosteroids remain the cornerstone of treatment. The role of corticosteroid-​sparing medications continues to evolve. FURTHER READING Berliner AR, Haas M, Choi MJ (2006). Sarcoidosis: the nephrologist’s perspective. Am J Kidney Dis, 48, 856–​70. Hilderson I, et al. (2014). Treatment of renal sarcoidosis: is there a guideline? Overview of the different treatment options. Nephrol Dial Transplant, 29, 1841–​7. Mahévas M, et  al. (2009). Renal sarcoidosis:  clinical, laboratory, and histologic presentation and outcome in 47 patients. Medicine (Baltimore), 88, 98–​106. Rajakariar R, et al. (2006). Sarcoid tubulo-​interstitial nephritis: long-​ term outcome and response to corticosteroid therapy. Kidney Int, 70, 165–​9. Table 21.10.4.3  Treatment of granulomatous interstitial nephritis in sarcoidosis Step 1: glucocorticoids Starting dose: • Major organ impairment: —  Oral prednisone 1 mg/​kg per day Or —  Intravenous pulse methylprednisolone (3 days), followed by oral
prednisone 1 mg/​kg per day • Milder disease: oral prednisone 0.5 mg/​kg per day Keep initial dose for 4 weeks, if renal function does not stabilize/​improve continue to step 2 After 4 weeks of treatment, reduce dose by 5 mg a week Maintenance dose: 5–​10 mg daily Relapse: • Augment prednisone to the last dose that was effective and continue for 4 weeks • No improvement after 4 weeks: augment corticoids to the starting dose and continue for 4 weeks • Subsequent tapering: more gradual Total duration of treatment: 18–​24 months Step 2: add another immunosuppressive agent Failure of corticosteroids Relative contraindication to corticosteroids Impossibility to taper the corticosteroids Azathioprine Dose: 2 mg/​kg per day Mycophenolate mofetil Dose: 1 g, twice a day Subsequently reduce the corticosteroids by 5 mg a week until a daily dose of 5–​10 mg is reached Step 3: add a TNFα inhibitor—​infliximab Steroid-​resistant sarcoidosis when at least one other immunosuppressive agent has been tried Severe steroid toxicity Dose: 2–​5 mg/​kg at weeks 0, 2, and 6 and every 6 to 8 weeks thereafter Experimental therapy Thalidomide, pentoxifylline, rituximab, etc.

Environment and drugs

Environment and drugs

Epidemiology

Epidemiology

FURTHER READING

FURTHER READING

section 21  Disorders of the kidney and urinary tract 4986 be made with some confidence, although the evidence base for bene- ficial intervention at lower levels of albuminuria is not secure. Current recommendations from national diabetes associations advise at least annual screening, based on the diagnostic flowchart shown in Fig. 21.10.1.3. Extrapolating the known effects of ACE inhibitors on a re- duction of UAER to a possible prevention of severe albuminuria and thus endstage renal disease has led several authors to propose a poten- tial cost benefit from the early use of these agents. However, there are no consistent data showing a benefit of these drugs in terms of pre- vention of moderately increased albuminuria in normoalbuminuric patients with normal or well-​controlled blood pressures. Can glycaemic control reverse established
nephropathy? The DCCT was inconclusive, but data from clinic populations and following pancreas transplantation suggest benefit, at least in type 1 diabetes. The situation in type 2 is much less certain. Why does intensive glycaemic control fail to completely prevent development of moderately increased albuminuria? Glycaemia is one of many factors leading to nephropathy, so correc- tion of this alone may not be enough. Moreover, even in the DCCT complete glycaemic normalization was not achieved. It is possible that newer insulins and delivery systems with continuous glucose monitoring may make sustained normoglycaemia more easily achievable and enable us to test its effectiveness. Do drugs that block the renin–​angiotensin system prevent or only delay the development of nephropathy? Can they reverse established nephropathy? The data are not conclusive, partly because of the relatively short duration of many trials, but most studies show a benefit in terms of reduction of UAER. For those with severely elevated albuminuria and CKD stage 3 and beyond, there is no doubt that renin–​angiotensin system blocking drugs delay endstage renal disease. For moderately increased albu- minuria, there are no studies of sufficient power to confirm benefit on hard clinical endpoints such as mortality or endstage renal dis- ease. Primary prevention of moderately increased albuminuria using renin–​angiotensin system blockade has only been shown in hypertensive type 2 patients or those at high cardiovascular risk. Likely developments in the near future Hyperglycaemia is thought to lead to nephropathy through sev- eral pathways, as outlined in Box 21.10.1.1. There are develop- ments in most of these fields, with the following being studied in trials: pyridoxamine and other inhibitors of glycation; atrasentan and other endothelin inhibitors; allopurinol; antifibrotic agents; al- dosterone antagonists; and inhibitors of inflammatory pathways. FURTHER READING ACCORD Study Group (2008). Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med, 358, 2545–​59. ACCORD Study Group (2010). Effects of intensive blood-​pressure control in type 2 diabetes mellitus. N Engl J Med, 362, 1575–​85. Adler AI, et al. (2003). Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Study (UKPDS 64). Kidney Int, 63, 225–​32. American Diabetes Association. (2015). Executive summary: stand- ards of medical care in diabetes—​2015. Diabetes Care, 38 Suppl 1, S4. Bilous R (2008). Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabetic Med, 25 Suppl 2, 25–​9. Bilous R, et al. (2009). Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: 3 randomised trials. Ann Intern Med, 151, 11–​20. DCCT/​EDIC Research Group (2003). Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progres- sion of diabetic nephropathy. JAMA, 290, 2159–​67. 0.1% (0.0% to 0.1%) 0.1% (0.1% to 0.2%) 2.0% (1.9% to 2.2%) 1.4% (1.3% to 1.5%) 3.0% (2.6% to 3.4%) 4.6% (3.6% to 5.7%) D E A T H 19.2% (14.0% to 24.4%) 2.8% (2.5% to 3.2%) 2.3% (1.5% to 3.0%) No nephropathy Microalbuminuria Macroalbuminuria Elevated plasma creatinine or renal replacement therapy 0.3% (0.1% to 0.4%) Fig. 21.10.1.4  Annual transition rates and 95% confidence interval through stages of nephropathy in 5097 newly diagnosed type 2 diabetic patients in the UKPDS.

21.10.1  Diabetes mellitus and the kidney 4987 DCCT/​EDIC Research Group (2011). Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med, 365, 2366–​76. Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent dia- betes mellitus. N Engl J Med, 329, 977–​86. Finne P, et al. (2005). Incidence of end stage renal disease in patients with type 1 diabetes. JAMA, 294, 1782–​7. Forbes JM, Cooper ME (2013). Mechanisms of diabetic complications. Physiol Rev, 93, 137–​88. Fullerton B, et al. (2014). Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev, 2, CD009122. Gaede P, et al. (2008). Effect of multifactorial interventions on mor- tality in type 2 diabetes. N Engl J Med, 358, 580–​91. Gaston RS, et al. (2004). Transplantation in the diabetic patient with advanced chronic kidney disease: a task force report. Am J Kidney Dis, 44, 529–​42. He F, et al. (2002). Diabetic retinopathy in predicting diabetic neph- ropathy in patients with type 2 diabetes and renal disease: a meta-​ analysis. Diabetologia, 56, 457–​66. Hellemons ME, et al. (2012) Validity of biomarkers predicting onset or progression of nephropathy in patients with type 2 diabetes: a sys- tematic review. Diabetic Med, 29, 567–​77. Hemmingsen B, et al. (2011). Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-​analysis and trial sequential analysis of randomised clinical trials. BMJ, 343, d6898. Hovind P, et  al. (2004). Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes mellitus: inception cohort study. BMJ, 328, 1105–​8. International Diabetes Federation (2017). Diabetes atlas, 8th edition. https://diabetesatlas.org JBS3 Board (2014). Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart, 100, ii1–​i67. Kato M, et  al. (2014). Diabetic nephropathy—​emerging epigenetic mechanisms. Nat Rev Nephrol, 10, 517–​30. Kidney Disease Outcomes Quality Initiative (2012). KDOQI Clinical Practice Guidelines for diabetes and chronic kidney disease: 2012 update. Am J Kid Dis, 60, 850–​86. Mahmoodi BK, et al. (2012). Associations of kidney disease measures with mortality and endstage renal disease with and without hyper- tension: a meta-​analysis. Lancet, 380, 1649–​61. Mann JF, et al. (2009). Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-​blind, controlled trial. Lancet, 372, 547–​53. Marshall SM, Flyvbjerg A (2006). Prevention and early detection of vascular complications of diabetes. BMJ, 333, 475–​80. Mauer M, et  al. (2009). Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med, 361, 40–​51. Molitch ME, et al. (2004). Nephropathy in diabetes. Diabetes Care, 27 Suppl 1, S79–​83. Mooyaart AL, et al. (2011). Genetic associations in diabetic nephrop- athy: a meta-​analysis. Diabetologia, 54, 544–​53. Olsen S, Mogensen CE (1996). How often is NIDDM complicated with non-​diabetic renal disease? An analysis of renal biopsies and the lit- erature. Diabetologia, 39, 1638–​45. Orchard TJ, et al. (2010). In the absence of renal disease, 20 year mor- tality risk in type 1 diabetes is comparable to that in the general population: a report from the Pittsburgh epidemiology of diabetes complications study. Diabetologia, 53, 2312–​19. Palmer SC, et al (2015). Comparative safety and efficacy of blood pres- sure lowering agents in adults with diabetic kidney disease: a net- work meta-​analysis. Lancet, 385, 2047–​56. Parving H-​H, et  al. (2012). Cardiorenal end points in a Trial of Aliskiren for type 2 diabetes. N Engl J Med, 367, 2204–​13. Pavkov ME, et  al. (2006). Increasing incidence of proteinuria and declining incidence of end stage renal disease in diabetic Pima Indians. Kidney Int, 70, 1840–​6. Robertson LM, Waugh N, Robertson A (2006). Protein restriction for diabetic renal disease. Cochrane Database Syst Rev, 2, CD002181. Rossing P (2006). Prediction, progression and prevention of diabetic nephropathy. Diabetologia, 49, 11–​19. Rule AD (2010). The CKD-​EPI equation for estimating GFR from serum creatinine: real improvement or more of the same? Clin J Am Soc Nephrol, 5, 951–​3. Stehouwer CDA (2004). Endothelial dysfunction in diabetic neph- ropathy: state of the art and potential significance for non-​diabetic kidney disease. Nephrol Dial Transplant, 19, 778–​81. Strippoli GFM, et al. (2004). Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ, 329, 828–​40. Study of Heart and Renal Protection website. http://​www.sharpinfo. org The Renal Association (2018). UK Renal Registry: 20th annual report of the Renal Association. Nephron, 139 Suppl 1, 1–​372. Tuttle KR, et al. (2014). Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care, 37, 2864–​83. UK Prospective Diabetes Study Group (1998). Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 352, 837–​53. UK Prospective Diabetes Study Group (1998). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ, 317, 703–​13. Upadhyay A (2012). Lipid lowering therapy in persons with chronic kidney disease: a systematic review and meta-​analysis. Ann Intern Med, 157, 251–​62. US Renal Data System (2014). 2014 USRDS annual data report. Volume 1:  chronic kidney disease. National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda. http://​www.usrds.org/​adr/​htm US Renal Data System (2018). 2018 USRDS annual data report. Volume 2:  end stage renal disease (ESRD) in the United States. National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda. https://www.usrds.org/adr.aspx White SA, Shaw JA, Sutherland DER (2009). Pancreas transplantation. Lancet, 373, 1808–​17. Wolf G, Chen S, Ziyadeh FN (2005). From the periphery of the glom- erular capillary wall towards the centre of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes, 54, 1626–​34.

Fig. 21.10.1.1 Schematic of a glomerulus. In diabe

Fig. 21.10.1.1 Schematic of a glomerulus. In diabetes, there is relativeafferent arteriolar dilatation and angiotensin II- induced efferent arteriolarconstriction. This leads to increased glomerular capillary flow andpressure resulting in elevated GFR (hyperfiltration) and increased albuminfiltration. Blockade of the renin– angiotensin system dilates the efferentarteriole and reduces GFR and capillary pressure.

Fig. 21.10.1.2 (a) Glomerulus from patient with ty

Fig. 21.10.1.2 (a) Glomerulus from patient with type 1 diabetes andseverely increased albuminuria (haematoxylin and eosin stain). Noteafferent (A) and efferent (E) arteriolar hyalinosis, thickened and splitBowman’s capsule (B), and mesangial expansion (M). (b) Glomerulusfrom patient with type 1 diabetes and severely increased albuminuria(toluidine blue stain) showing typical nodule (N). Note centralaccumulation of matrix material with surrounding nuclei.

21.10.1  Diabetes mellitus and the kidney 4979 increased albuminuria (microalbuminuria), and severely increased albuminuria (clinical proteinuria) (Table 21.10.1.1). Selecting only population-​based cohorts with good patient ascertainment gives prevalence rates for moderately increased albuminuria of between 5 and 21% for type 1, and 11 to 42% for type 2 diabetes. Reported annual incidence rates are around 2% for type 1 patients (Table 21.10.1.2). For severely increased albuminuria, the prevalence is 6.4% in type 1 patients in the United Kingdom, with a range from 5 to 33% worldwide for type 2. A cumulative incidence of approxi- mately 20% after 20 years’ duration was found in type 1 diabetic cohorts of the Steno Hospital in Denmark and Joslin Clinic in the United States of America, and similar figures have been reported for patients with type 2 diabetes in the United States of America (25%) and Germany (27%). More recent data from patients prospectively studied from diag- nosis of type 1 diabetes in Scandinavia have revealed lower cumu- lative incidences of 15% after 20 years (Denmark) and 11% after 30 years (Sweden). There have also been reductions in the num- bers of patients with type 1 diabetes entering renal replacement therapy programmes in the United States of America (incident rate in 1995–​1999 was 7.1% vs 3.9% in 2000–​2004) although this re- duction is not seen in African Americans who continue to show a year-​on-​year increase. The cumulative incidence of endstage renal disease secondary to type 1 diabetes in Finland is only 7.8% after 30 years. The situation for type 2 diabetes is less clear as far as mod- erately and severely increased albuminuria are concerned, al- though the transition rates are similar to type 1 at 1 to 2% per year. A  population-​based study in the United States of America has suggested that fewer patients with type 2 diabetes presented with clinical proteinuria at diagnosis in the 1990s compared to 30 years previously. Analysis of the UKPDS cohort has suggested a cumula- tive incidence of a urinary albumin concentration between 50 and 299 mg/​litre (moderately increased albuminuria) of 42% at 20 years and severely increased albuminuria of 20% after 20 years. Almost 20% of adults with diabetes in the 2007 to 2012 NHANES cohort in the United States of America had a diagnosis of chronic kidney dis- ease (CKD), and 30% had moderately increased albuminuria. Diabetes was given as the primary renal diagnosis in 38% of prevalent patients and 47% of incident patients receiving renal re- placement therapy in the US population in 2016. The corresponding figures in the United Kingdom in 2017 were 18% (prevalent cases) and 29% (incident cases). In considering these figures, however, it is important to note that the reliability of clinician-assigned ‘pri- mary cause’ of end stage renal failure is not well established; that diagnosis of diabetic nephropathy is rarely established by renal bi- opsy; and that many patients may be more properly described as having end stage renal failure with diabetes as perhaps one of sev- eral aetiological factors, rather than end stage renal failure caused by diabetes. There is dramatic variation in the risk of moderately and severely elevated albuminuria, and of endstage renal disease, in different ethnic subgroups. In the United States of America, there is a four- fold increased prevalence of African American and native American patients on renal replacement therapy compared to white patients. The increase is threefold for those of Hispanic origin. A similar in- creased risk has been reported for South Asian populations in the United Kingdom. Many countries have disease registers of patients entering renal replacement therapy and in 2009 to 2010, prevalence rates of 51 to 63% for diabetes were reported for Mexico, Singapore, Malaysia, and New Zealand, with incident rates of 49 to 66%. Pacific Islanders and Maori people in New Zealand are much more prone to renal disease and diabetes than those of European extraction. The reasons for the excess risk of endstage renal disease in these groups is unclear but may be genetic, related to increased rates of hyper- tension, or the result of fetal programming. There are intriguing data suggesting that the number and size of glomeruli is different in Australian aborigines compared to white Europid patients. 50 microns (a) (b) Fig. 21.10.1.2  (a) Glomerulus from patient with type 1 diabetes and severely increased albuminuria (haematoxylin and eosin stain). Note afferent (A) and efferent (E) arteriolar hyalinosis, thickened and split Bowman’s capsule (B), and mesangial expansion (M). (b) Glomerulus from patient with type 1 diabetes and severely increased albuminuria (toluidine blue stain) showing typical nodule (N). Note central accumulation of matrix material with surrounding nuclei.

Fig. 21.10.1.4 Annual transition rates and 95% con

Fig. 21.10.1.4 Annual transition rates and 95% confidence interval through stages of nephropathy in 5097 newlydiagnosed type 2 diabetic patients in the UKPDS.

Fig. 21.10.2.1 Glomerular histology of ANCA- assoc

Fig. 21.10.2.1 Glomerular histology of ANCA- associated vasculitis. (a) A glomerulus showing focal necrosiswith an early crescentic reaction (arrow). (b) Glomerular macrophage infiltration (brown) illustrated by CD68staining. (c) Severe glomerular involvement with widespread necrosis, a circumferential crescent, and collapse ofthe glomerular tuft. (d) Massive periglomerular leucocyte infiltration occurring around an affected glomerulus.

Fig. 21.10.2.2 Magnetic resonance angiogram demons

Fig. 21.10.2.2 Magnetic resonance angiogram demonstrating bilateralrenal artery stenosis (arrows) in a patient with Takayasu’s arteritis.

section 21  Disorders of the kidney and urinary tract 4992 ANCA-​associated vasculitis Following a prodromal phase of several months with constitutional symptoms such as fever, night sweats, polymyalgia, and weight loss, patients present either with an extrarenal manifestation, or symptoms of constitutional disturbance, or evidence of nephritis. Nonrenal spe- cialties receiving vasculitis referrals, such as ear, nose, and throat medi- cine, need an awareness of the potential for systemic disease and access to ANCA testing and urgent nephrology referral (Box 21.10.2.1). Because renal vasculitis is asymptomatic until clinical features of renal insufficiency develop, the absence of specific symptoms of renal dis- ease often result in diagnostic delay. In consequence, patients with renal-​limited vasculitis present with more advanced renal failure. The average delay from onset of symptoms to diagnosis has short- ened from longer than 1 year in the 1990s to less than 6 months. During this phase, urinary abnormalities will be present and should therefore be sought in all patients with unexplained illness, or where there is a suspicion of vasculitis. Glomerular haematuria may be visible or nonvisible and is accompanied by subnephrotic proteinuria, but may be confused with prostatic disease or urinary tract infection. The pres- ence of red cell casts on urine microscopy reflects severe glomerular injury and is associated with crescentic glomerulonephritis. Atypical presentations including ‘failure to thrive’ and unexpected asymptom- atic renal impairment are more common in elderly patients. Renal vasculitis is more common in elderly patients with AAV, being present in 95%. Pulmonary involvement, typically with radio- logical infiltrates, reflects alveolar capillaritis in both GPA and MPA. The term pulmonary–​renal syndrome is used to describe the clinical presentation of alveolar haemorrhage with crescentic glomerulo- nephritis. Other pulmonary features common in AAV include pul- monary fibrosis, bronchiectasis, and cavitating disease: these may precede or be detected at the same time as nephritis. Renal vasculitis commonly presents with the syndrome of rapidly progressive glomerulonephritis, that is, deteriorating renal function and crescentic glomerulonephritis on kidney biopsy. AAV accounts for 50 to 80% of cases of this syndrome and is differentiated from other causes by serological testing and renal immunofluorescence studies (Table 21.10.2.2). AAV with anti-​GBM disease About 5% of patients with AAV present with simultaneous renal vasculitis and anti-​GBM disease. They are older, have more severe renal disease, and are more likely to have pulmonary involvement than other AAV patients. The serology demonstrates ANCA posi- tivity, usually MPO-​ANCA, and anti-​GBM antibodies. Renal hist- ology reveals an aggressive crescentic glomerulonephritis, typically involving all glomeruli with linear IgG deposition on immunofluor- escence. When presenting in renal failure, such patients are more likely to recover renal function than in pure anti-​GBM disease. However, after the initial presentation, unlike in anti-​GBM disease, they can follow a relapsing course with persisting ANCA positivity. See Chapter 21.8.7 for further discussion of anti-​GBM disease. IgA vasculitis (Henoch–​Schönlein purpura) IgA vasculitis, although most frequent in children, occurs in adults, when it often pursues a relapsing course. By definition, extrarenal features of vasculitis including purpura, arthritis, and gastrointes- tinal involvement are present, but differentiation from other vascu- litic syndromes requires the demonstration of IgA deposition on skin or renal biopsy. A short prodromal period of 1 to 2 weeks with pur- pura often associated with a bacterial upper respiratory tract infec- tion are typical of IgA vasculitis. Purpura predominates in the lower limbs, then the upper limbs, then the trunk, and may coalesce and ulcerate. Some 50% of adults will have evidence of renal involvement, but it is important to recognize that this may be delayed by 2 to 4 weeks from the cutaneous presentation. Purpura is also common in cryoglobulinaemia, when digital ischaemia, livedo reticularis, neur- opathy, and other organ manifestations may also be seen. The renal presentation of IgA vasculitis overlaps with that of IgA nephropathy but is more likely to pursue a rapidly progressive course and to have extracapillary glomerular necrosis with crescents on biopsy. Polyarteritis nodosa Patients present with constitutional features of weight loss, fever, and night sweats, with specific symptoms depending on the ves- sels involved. Myalgia and muscle tenderness due to muscle in- volvement is common, as is abdominal pain due to intestinal ischaemia. Involvement of the skin can produce livedo reticularis, bullous/​vesicular eruptions, and ulcers, and aneurysms can some- times form palpable nodules when they occur in subcutaneous tis- sues. Infarction of peripheral nerves presents with mononeuritis multiplex. Ischaemia in the kidney frequently manifests with hypertension:  regional infarction—​presenting with loin pain and haematuria—​is rarely seen. Virtually any organ can be involved, with presentations ranging from myocardial ischaemia to orchitis. The association of polyarteritis nodosa with microscopic vessel involvement, such as necrotizing glomerulonephritis, has been called ‘polyangiitis overlap syndrome’, but is now classified as MPA. Takayasu’s arteritis Some 20% of patients with Takayasu’s arteritis have renal arterial disease causing renal artery stenosis, hypertension, reduced renal size, and renal impairment (Fig. 21.10.2.2). See Chapter 19.11.6 for further discussion of Takayasu’s arteritis. Fig. 21.10.2.2  Magnetic resonance angiogram demonstrating bilateral renal artery stenosis (arrows) in a patient with Takayasu’s arteritis.

Foreword

Foreword

Foreword Professor Sir John Bell, Regius Professor of Medicine, University of Oxford In 1983, David Weatherall, John Ledingham, and David Warrell launched the first edition of the Oxford Textbook of Medicine. That era of medicine looked entirely different from today but the need for a scholarly repository of medical knowledge remains as important as ever. Medicine is now firmly in a digital age; sources of information abound and are readily available and the field is moving so quickly that it is harder than ever to provide up to date relevant informa- tion for the profession. Despite this, the sixth edition of the Oxford Textbook of Medicine still provides the foundation of knowledge upon which good clinical practice is based. Never before has there been such a rapid advance of medical know- ledge and practice. Since the first edition of the Oxford Textbook of Medicine, medical practice has reduced cardiovascular mortality by up to 70% in Western countries, there are now multiple new ther- apies for diseases such as rheumatoid arthritis and multiple scler- osis, disorders where the descriptions of therapeutic options in the first edition were necessarily brief. Cancer is now increasingly man- aged with immune and targeted therapies. Whole new diseases have appeared (Hepatitis C and HIV) and have been either controlled or conquered with drug therapy. The sequencing of the human genome seemed an impossible dream in 1983 while today we have sequenced more than a million genomes and have had insights into rare disease and cancer that were unimaginable then. Life expectancy has risen by nine years for men and ten for women in the United Kingdom, creating a demographic shift that will fundamentally change society and medicine forever. The pace of change has been dramatic. The Oxford Textbook of Medicine gained a reputation by moving medical practice forward from the Oslerian view of medicine ori- ginally expounded in his text book the Principles and Practice of Medicine into an era of more molecular and scientifically based understanding of disease. Constrained by the lack of tools for ex- ploring the molecular basis of pathogenesis, Osler was limited in how he could describe the world of disease, largely based on bed- side observations or those from the post-​mortem room. The Oxford Textbook of Medicine shifted this focus and aligned it with the emerging field of molecular medicine which has begun to create a new taxonomy of disease but also an approach to therapy which is based on pathogenesis. There has been a wave of new information, with new insights appearing weekly into the underlying molecular events associated with disease. Diseases characterized by phenotype are now broken down into multiple subtypes and disease is being individualized. This is rapidly leading to a very significant change in our perception of pathogenesis as well as the classification and nomenclature of disease, all crucial roles for a textbook of medicine. We now are aware that many of the classic definitions of diseases such as diabetes or cancer were descriptions of phenotypic charac- teristics. Interrogation of these disorders at a molecular level has demonstrated that these terms mask disease subtypes defined by molecular pathology where natural history and response to therapy may differ. Combine this with the explosion of new diseases coming from studies of rare disease and there is a challenge to conventional disease nomenclature. This molecular precision creates real oppor- tunities for targeted highly effective therapies, but it also creates challenges for the model of drug discovery when novel treatments can only be used in increasingly small patient populations. These are major issues for medicine, health systems, but also textbooks such as this one where, historically, the stewardship of disease nomenclature has been maintained. The therapeutic options available to practising clinicians have also advanced beyond all recognition since the first edition of the Oxford Textbook of Medicine. We have seen an era of biologic therapy which has provided important new therapeutic alternatives for many hard-​ to-​treat diseases including cancer. We are now entering a new era where modalities such as gene therapy and interfering RNA thera- peutics have demonstrated their utility in the clinic. Similarly, an era of cell therapy has also begun which will provide important new alternatives to some diseases. These new therapeutic alterna- tives and other opportunities for improving healthcare using med- ical technology or novel diagnostics such as sequencing also bring with them the challenge of how healthcare systems can continue to be affordable, either for individuals in private healthcare settings, or in state-​funded, single-​payer systems. In this context, it is remark- able that the authors and editors of the Oxford Textbook of Medicine have managed to sustain both its relevance and the accuracy of its content. The pace at which our understanding of disease, our therapeutic options, and our healthcare systems are likely to change makes it nearly impossible for a textbook of medicine to be truly comprehen- sive given the speed of change, the impact of new innovations and the multiple additional sources of information available to practi- tioners. The Oxford Textbook of Medicine has provided remarkable levels of detail in this rapidly changing world but, more importantly, the textbook continues to provide a source for readers to access information on the fundamental features of disease. This founda- tional knowledge remains crucial to our ability to understand, diag- nose, and treat patients whether they are in the developing world or

Foreword vi Western healthcare systems. Having a source of such information across all major diseases accessible in a single source remains the bedrock of both teaching and practising medicine. The foundations provided by the Oxford Textbook of Medicine form a core of know- ledge which practising clinicians will continue to need. The editors of this edition have been faithful to the vision of the original three editors. Science, in all its forms, is at the heart of our understanding of disease and has enabled progress in clinical medi- cine to occur at a remarkable pace. By providing a textbook that describes the foundations of our understanding of disease and its management, the editors have successfully given us an authoritative text which practising clinicians will find invaluable to support their day-​to-​day decisions. David Weatherall, one of the three original editors and who died in 2018, would be gratified by this new edition.

GFR

GFR

Genetics

Genetics

Glycaemic control and blood pressure

Glycaemic control and blood pressure

Glycaemic control

Glycaemic control

Granulomata

Granulomata

section 21  Disorders of the kidney and urinary tract 4990 Experimental studies have demonstrated unequivocally that ANCA induce neutrophil activation, superoxide and cytokine release, and can cause neutrophil-​mediated endothelial cytotoxicity. ANCA re- quire neutrophil priming with TNF, which leads to translocation of PR3 or MPO from primary cytoplasmic granules to the cell mem- brane. In addition to binding to cell surface autoantigens, ligation of the Fc component of the ANCA antibody to neutrophil Fc re- ceptors is necessary for intracellular signalling and cell activation. Both spontaneous and induced animal models have demonstrated the ability of ANCA to cause a pauci-​immune renal vasculitis in sus- ceptible animal strains. There is increased glomerular deposition of alternative complement components, and complement factor 5 receptor inhibition has abrogated experimental MPO-​ANCA vas- culitis. A positive feedback loop between neutrophil and alterna- tive complement pathway activation has been proposed. Neutrophil extracellular traps (NETs) containing PR3 and MPO are found in the circulation and renal lesions and promote autoantigen presenta- tion to the immune system; penicillamine promotes NET formation that has led to vasculitis in experimental models. Pathology AAV predominantly affects small blood vessels, capillaries, arteri- oles, and venules, but may also affect muscular arteries and (rarely) larger arteries and the heart. Capillaritis in the glomerular tuft re- sults in capillary thrombosis and infarction. This appears on biopsy as segmental fibrinoid necrosis and a secondary crescentic reaction within Bowman’s capsule, containing monocytes and epithelial cells (Figs. 21.10.2.1a and 21.10.2.1b), which progresses to involve the whole tuft and destroy the glomerulus (Fig. 21.10.2.1c). In addition, there is periglomerular and tubulointerstitial inflammation, which may contain giant cells (Fig. 21.10.2.1d). Extraglomerular arter- itis is seen in 15% of cases and frank granulomata occur rarely in GPA. There is considerable variety in the severity and proportion of fibrotic lesions between glomeruli. Obsolescent glomeruli and fi- brotic crescents reflect previous vasculitic events and are associated with tubulointerstitial scarring. Capillaritis in pulmonary alveoli causes capillary rupture and haemorrhage into the alveolar space. Granulomata The ANCA autoantigen PR3 is abundantly expressed in granuloma- tous lesions in close proximity to mature dendritic cells capable of antigen presentation. The inflammatory infiltrate at such foci is neu- trophil rich, and interventions which deplete neutrophils, including experimental chemokine blockade or the drugs cyclophospha- mide and deoxyspergualin, are effective therapies. T cells in granu- lomatous lesions are over-​represented by a CD4+, CD28− subset which release γ-​interferon and TNFα and have cytotoxic potential. A pathogenetic role for cytotoxic T cells has been shown in larger-​ vessel arteritis, and similar mechanisms are likely to be important in smaller-​vessel disease. Circulating markers of T-​cell activation are elevated, including the soluble interleukin-​2 receptor. The efficacy of B-​cell-​depleting therapies has focused attention on B cells, which (b) (a) (d) (c) Fig. 21.10.2.1  Glomerular histology of ANCA-​associated vasculitis. (a) A glomerulus showing focal necrosis with an early crescentic reaction (arrow). (b) Glomerular macrophage infiltration (brown) illustrated by CD68 staining. (c) Severe glomerular involvement with widespread necrosis, a circumferential crescent, and collapse of the glomerular tuft. (d) Massive periglomerular leucocyte infiltration occurring around an affected glomerulus.

Growth factors

Growth factors

Haemodynamic factors

Haemodynamic factors

Half title

Half title

Oxford Textbook of Medicine

Hyperglycaemia

Hyperglycaemia

IgA vasculitis (Henoch– Schönlein purpura)

IgA vasculitis (Henoch– Schönlein purpura)

Introduction

Introduction

section 21  Disorders of the kidney and urinary tract 4988 21.10.2  The kidney in systemic vasculitis David Jayne ESSENTIALS Systemic vasculitis can occur as a primary autoimmune disorder, or as a secondary manifestation of another disease process (related to infection, malignancy, chronic inflammatory disorder, or drugs). Primary systemic vasculitis is classified according to the predominant size of the blood vessel involved and the presence of circulating antineutrophil cytoplasm autoantibodies (ANCA). Incidence and prevalence rates are between 15 and 20 per million and 200 to 400 per million population, respectively. Vasculitic syndromes frequently involve the kidney, causing tissue infarction, loss of function, and rapid progression to endstage renal disease within weeks or months. They account for 5% of cases of endstage renal failure. ANCA-​associated vasculitis (AAV) is the most common cause of renal vasculitis and has been the focus for most research. Management aims for an early diagnosis, recovery of renal function, and prevention of renal relapse. Small-​vessel vasculitides—​renal disease is common. There are two subgroups: AAV, which comprises three syndromes: granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis), micro- scopic polyangiitis (MPA), and eosinophilic granulomatosis with angiitis (EGPA, formerly Churg–​Strauss syndrome). The second sub- group is immune complex vasculitis and comprises IgA vasculitis (formerly Henoch–​Schönlein purpura), antiglomerular basement membrane disease, and cryoglobulinaemia: these are ANCA nega- tive and characterized by immune complex deposition. Medium-​ and larger-​vessel vasculitides—​renal disease is uncommon in the medium-​vessel disorders polyarteritis nodosa (ANCA nega- tive) and Kawasaki’s disease, and rare in the large-​vessel disorders, giant cell arteritis and Takayasu’s arteritis. Aetiology and pathogenesis—​there is a complex genetic contribution to AAV, and rare drug-​induced forms. Neutrophil dysregulation is as- sociated with ANCA and alternative complement pathway activation. Pathology—​the typical renal lesion of small-​vessel vasculitis is a neutrophil-​dominant glomerular capillaritis leading to segmental necrotizing glomerulonephritis with epithelioid crescent forma- tion. Glomerular immune deposits are scanty or absent in AAV (‘pauci-​immune’). Clinical presentation—​the diagnosis of vasculitis is often delayed for many months because initial symptoms such as fever, night sweats, polymyalgia, and weight loss are nonspecific. Patients with vasculitis present with (1) persistent symptoms of constitutional disturbance; (2) nonrenal vasculitic manifestations, the nature of which may indi- cate a specific diagnosis, for example, upper respiratory tract symp- toms or signs (GPA), ‘maturity-​onset’ asthma (EGPA), or mononeuritis multiplex (MPA); or (3)  features of renal insufficiency. AAV is the most common cause of rapidly progressive glomerulonephritis—​ crescentic glomerulonephritis with renal failure—​and should be considered in any unexplained case of acute renal impairment, es- pecially when nonvisible haematuria with proteinuria is present and the kidneys are of normal size on ultrasound examination. Patients with renal-​limited vasculitis present with more advanced renal failure than those with extrarenal disease because they are asymptomatic until symptoms of renal insufficiency develop. Diagnosis—​this depends on the recognition of patterns of clinical features, supported by serology, histology, and imaging, and the ex- clusion of secondary causes. ANCA positivity, confirmed by a positive proteinase 3 ANCA (PR3-​ANCA) or myeloperoxidase ANCA (MPO-​ ANCA), has a predictive value of over 95% for the diagnosis of AAV with renal involvement in a patient with suspected nephritis. The diagnosis of polyarteritis nodosa is usually made by demonstration of aneurysms of medium-​sized muscular arteries on angiography, or when biopsy of affected tissue reveals fibrinoid necrosis of involved vessels, accompanied by a marked inflammatory response. Other in- vestigations determine the extent and severity of systemic disease. Management—​combination therapy with cyclophosphamide or rituximab and high-​dose oral prednisolone leads to control of ac- tive disease in 80 to 90% of patients, but is complicated by toxicity, particularly cytopenias and infection. Azathioprine, methotrexate, or mycophenolate mofetil in combination with low-​dose prednisolone or rituximab are used to maintain remission after 3 to 6 months, and mycophenolate mofetil may also be considered for the induction of remission in MPO-​ANCA-​associated renal disease. High-​dose intravenous methylprednisolone is widely used as initial therapy for renal vasculitis, and plasma exchange improves the chances of renal recovery in patients with severe renal impairment. Careful follow-​up of patients in experienced centres with regular moni- toring of blood counts, biochemical indices, inflammatory markers (erythrocyte sedimentation rate and C-​reactive protein), and ANCA permits the prevention and early detection of drug-​related toxicity and infection, and the early diagnosis and treatment of disease re- lapse. Collaborative research networks have facilitated randomized controlled trials and the development of evidence-​based treatment guidelines. Disease relapse—​this is seen in 50% of patients by 5 years and is more common in PR3-​ANCA-​positive patients, in the presence of persisting ANCA positivity, and after withdrawal of immunosuppressive drugs. Rituximab is the first choice for relapsing or refractory disease: patients then require long-​term therapy as subsequent relapses are likely. Prognosis—​patient survival in AAV with renal involvement is 83 and 73% at 1 and 5 years, respectively, with a high serum creatinine at diagnosis, older age, and extensive extrarenal vasculitis indicating a poorer prognosis. Fifty per cent of those presenting with a serum creatinine greater than 500 μmol/​litre will be alive and off dialysis at 1 year of follow-​up. Introduction Renal involvement is common in primary systemic vasculitis af- fecting small blood vessels and is subdivided into those asso- ciated with antineutrophil cytoplasm autoantibodies (ANCA) (Table 21.10.2.1) (ANCA-​associated vasculitis (AAV): comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA)) and those without ANCA but with immune complex deposition on

Investigation

Investigation

Jonathan Barratt and John Feehally 21.8.2 Thin mem

Jonathan Barratt and John Feehally 21.8.2 Thin membrane nephropathy 4918 Peter Topham and John Feehally

section 21  Disorders of the kidney and urinary tract 4918 21.8.2  Thin membrane nephropathy Peter Topham and John Feehally ESSENTIALS Thin membrane nephropathy is a common autosomal dominant glomerular disorder that results in persistent nonvisible haema- turia and is pathologically characterized by the presence of dif- fuse and uniform thinning of the glomerular basement membrane. Recent genetic studies have identified mutations in the COL4A3 and COL4A4 genes in 40% of affected families. There is no specific treat- ment. Prognosis is excellent for most people, but a few cases with progressive renal impairment have been described. Introduction and definition Thin membrane nephropathy (TMN) is an autosomal dominant condition diagnosed by examination of a renal biopsy by electron microscopy, which shows glomerular basement membranes (GBMs) that are thin but otherwise morphologically normal. Historically, the term ‘benign familial haematuria’ was used in the era before the GBM abnormality had been identified. About 30 to 50% of cases of TMN have an identifiable family history of haematuria. Aetiology, genetics, and pathogenesis The similarity between the basement membrane changes seen in early Alport’s syndrome and those seen in TMN suggested the presence of a similar underlying genetic defect. It has been demonstrated that 50% of families with TMN have haematuria that segregates with the COL4A3/​COL4A4 locus, and identical mutations have been described in both TMN and autosomal recessive Alport’s syndrome. TMN pa- tients with these mutations can therefore be considered as carriers of autosomal recessive Alport’s syndrome. A significant number of dif- ferent COL4A3 and COL4A4 mutations have been identified in fam- ilies with TMN, most being single nucleotide substitutions that are different in each family. In some families, linkage with the COL4A3 andCOL4A4 genes has not been found; some of these cases may be ex- plained by de novo mutations or incomplete penetrance, but it is prob- able that the remainder are due to the presence of other TMN loci. Pathology The pathological findings in TMN are limited to diffuse thinning of the GBM which is otherwise morphologically normal (Fig. 21.8.2.1). This contrasts with Alport’s syndrome in which the GBM is thick- ened and lamellated and the normal lamina densa of the GBM is dis- rupted. The normal range for GBM thickness must be determined in each laboratory because of the influence of techniques used for fixing the biopsy, but normal GBM thickness is typically 350 to 450 nm and a reduction to less than 250 nm involving over 50% of the GBM is diagnostic of TMN. Clinical features TMN is common and accounts for 20 to 25% of patients presenting to a nephrologist with isolated nonvisible haematuria. Autopsy and kidney transplant donor studies suggest it may be present in 5 to 9% of the population. It is an autosomal dominant condition but may (a) GBM U GBM EP EP U GBM (b) Fig. 21.8.2.1  Thin membrane nephropathy. Electron micrographs contrasting (a) glomerular basement membrane (GBM) of normal thickness (350–​450 nm) with (b) uniform membrane thinning (150–​200 nm) in thin membrane nephropathy. Space between the heads of the short arrows defines GBM width. Ep, visceral epithelial cells; U, urinary space. Magnification ×20 000.

Likely developments in the near future

Likely developments in the near future

List of abbreviations xxxv

List of abbreviations xxxv

Abbreviations 5-​FU 5-​fluorouracil 5-​HIAA 5-​hydroxyindoleacetic acid 5-​HT 5-​hydroxytryptamine 5-​HT 5-​hydroxytryptamine AAA acquired aplastic anaemia AAFB acid-​ and alcohol-​fast bacilli AASLD American Association for the Study of Liver Diseases AAV antineutrophil cytoplasm autoantibody-associated vasculitis (also aplastic anaemia ABC ATP-​binding cassette ABCDE airway, breathing, circulation, disability, and exposure ABG arterial blood gas ABMR antibody-​mediated rejection ABPA allergic bronchopulmonary aspergillosis ABPM ambulatory blood pressure measurement ACE angiotensin-​converting enzyme AChE acetylcholinesterase, define at first mention ACPA anticitrullinated peptide/​protein antibodies ACR American College of Rheumatology (also albumin:creatinine ratio) ACS acute coronary syndromes ACTH adrenocorticotropic hormone AD Alzheimer’s disease ADEM acute disseminated encephalomyelitis ADH antidiuretic hormone ADL activities of daily living ADME absorption, distribution, metabolism, and excretion ADPKD autosomal dominant polycystic kidney disease ADR adverse drug reaction ADRT advanced decision to refuse treatment AECA antiendothelial cell antibodies AF atrial fibrillation AFP α-​fetoprotein AGT alanine–​glyoxylate aminotransferase aGVHD acute graft-​versus-​host disease AHA American Heart Association aHUS atypical haemolytic uraemic syndrome AIF apoptosis-​inducing factor AIHA autoimmune haemolytic anaemia AIN acute interstitial nephritis AIP autoimmune pancreatitis (also acute interstitial pneumonia) AIS androgen insensitivity syndromes AKI acute kidney injury ALD alcoholic liver disease ALF acute liver failure ALL acute lymphoblastic leukaemia alloSCT allogeneic stem cell transplantation ALP alkaline phosphatase ALS amyotrophic lateral sclerosis ALT alanine aminotransferase AMA antimitochondrial antibody AML acute myeloid leukaemia AMLR autologous mixed lymphocyte reactions AMT Abbreviated Mental Test ANA antinuclear autoantibodies ANC absolute neutrophil count ANCA antineutrophil cytoplasmic antibodies ANP atrial natriuretic peptide AOSD adult-​onset Still’s disease AP alternative pathway APA aldosterone-​producing adenoma APC antigen presenting cell APCM active physiological conservative management APL acute promyelocytic leukaemia APS antiphospholipid syndrome APTT activated partial thromboplastin time AR androgen receptor ara-​C cytosine arabinoside ARB angiotensin receptor blocker ARDS adult respiratory distress syndrome ARF acute renal failure ARH autosomal recessive hypercholesterolaemia ARPKD autosomal recessive polycystic kidney disease ART antiretroviral therapy ARVC arrhythmogenic right ventricular cardiomyopathy ARVD atherosclerotic renovascular disease AS ankylosing spondylitis ASAS Assessment of SpondyloArthritis International Society ASCT autologous stem cell transplantation ASD atrial septal defect ASH Action on Smoking and Health ASOT antistreptolysin O titre AST aspartate aminotransferase ATG antithymocyte globulin ATP adenosine triphosphate ATRA all-​trans-​retinoic acid AV aortic valve AVN arteriovenous nipping

Abbreviations xxxvi AVSD atrioventricular septal defect AZA azacitidine BCAA branched-​chain amino acid BCC basal cell carcinoma BCG bacillus Calmette–​Guérin BEN Balkan endemic nephropathy BH4 tetrahydrobiopterin BHS British Hypertension Society BICC betaferon in chronic viral cardiomyopathy BKV BK polyomavirus BM bone marrow BMD bone mineral density BMF bone marrow failure BMI body mass index BMP bone morphogenic protein BNF British National Formulary BNP B-​type natriuretic peptide BOS bronchiolitis obliterans syndrome BP blood pressure BPG biphosphoglycerate BRAO branch artery occlusion BRVO branch retinal vein occlusion BSEP haemolysis, elevated liver enzymes, and low platelet count BSP bromosulphthalein BTS British Thoracic Society BUN blood urea nitrogen CA carbohydrate antigen CABG coronary artery bypass grafting CAF Comprehensive Assessment for Frailty CAH congenital adrenal hyperplasia CAM Confusion Assessment Method CAMT congenital amegakaryocytic thrombocytopenia CAP community-​acquired pneumonia CAPS cryopyrin-​associated periodic syndromes CaR calcium-​sensing receptor CAT COPD assessment test CBT cognitive behaviour therapy CCB calcium channel blocker CCK cholecystokinin CCP anticyclic citrullinated peptide CCQ Clinical COPD questionnaire CCV clathrin-​coated vesicles CCyR complete cytogenetic response CD cluster of differentiation CDA congenital dyserythropoietic anaemia CDC donation after circulatory death CEA carcinoembryonic antigen CETP cholesteryl ester transfer protein CF cystic fibrosis CFA cryptogenic fibrosing alveolitis cfDNA cell-​free DNA CFS Clinical Frailty Scale CFTR cystic fibrosis transmembrane regulator CFU colony forming unit CGA comprehensive geriatric assessment CGRP calcitonin gene-​related peptide cGVHD chronic graft-​versus-​host disease CHAD cold haemagglutinin disease CHD coronary heart disease CHF congestive heart failure CHM Commission on Human Medicines CINAC chronic interstitial nephritis in agricultural communities CINCA chronic infantile neurological, cutaneous, and articular syndrome CISN coumarin-​induced skin necrosis CK creatine kinase CKD chronic kidney disease CKD-​EPI Chronic Kidney Disease Epidemiology Collaboration CLL chronic lymphocytic leukaemia CML chronic myeloid leukaemia CMR cardiac magnetic resonance CMS congenital myasthenic syndrome CMT Charcot–​Marie–​Tooth disease CMV cytomegalovirus CNI calcineurin inhibitor CNS central nervous system CNSHA congenital non-​spherocytic haemolytic anaemia CO cardiac output CoA coenzyme A COPD chronic obstructive pulmonary disease COX cyclooxygenase CPAP continuous positive airway pressure CPM central pontine myelosis CPP central precocious puberty CPPS chronic pelvic pain syndrome CPR cardiopulmonary resuscitation CR complete remission CRDQ Chronic Respiratory Disease Questionnaire CREST calcinosis, Raynaud’s, oesophageal dysmotility, sclerodactyly, telangiectasia CRF chronic renal failure CRH corticotropin-​releasing hormone CRIM cross-​immunoreactive material CRP C-​reactive protein CRT cardiac resynchronization therapy CS continuous smokers CSF cerebrospinal fluid/​colony-​stimulating factor CT computed tomography CTA computed tomography angiography CTCA computed tomography coronary angiography CTD connective tissue disease CTEPH chronic thromboembolic pulmonary hypertension CTL cytotoxic T-​lymphocyte CVD cardiovascular disease CVID common variable immunodeficiency CVS chorionic villus sampling CXR chest radiograph CYP cytochrome P450 CZT cadmium zinc telluride DAEC diffusely adherent Escherichia coli DALY disability-​adjusted life year DAMP damage-​associated molecular pattern DASH Dietary Approaches to Stop Hypertension DAT direct antiglobulin test

  Abbreviations xxxvii DBA Diamond–​Blackfan anaemia DBD donation after brain death DBP diastolic blood pressure DC dyskeratosis congenita (also dendritic cell) DCA directional coronary atherectomy DCCT Diabetes Control and Complications Trial DCD donation after circulatory death DCI decompression illness dcSSc diffuse cutaneous systemic sclerosis DCT distal convoluted tubule DDAVP 1-​deamino-​8-​d-​arginine vasopressin DDD dense deposit disease DECAF dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation DGP deamidated gliadin peptide DHG dihydroxyglutarate DIC disseminated intravascular coagulation DIC disseminated intravascular coagulation DILI drug-​induced liver injury DILV double-​inlet left ventricle DIP desquamative interstitial pneumonia DISC death-​initiating signalling complex DISH diffuse idiopathic skeletal hyperostosis DLB dementia with Lewy bodies DLBCL diffuse large B-​cell lymphoma DMARD disease-​modifying antirheumatic drug DMD disease-​modifying drugs (can also mean Duchenne muscular dystrophy) DMSA dimercaptosuccinic acid DNACPR do-​not-​attempt-​cardiopulmonary resuscitation DNR do not resuscitate DOAC direct oral anticoagulant DOCA desoxycorticosterone DOPPS Dialysis Outcomes and Practice Patterns Study DORV double-​outlet right ventricle DPI dry powder inhalers DRE digital rectal examination DRESS drug reaction with eosinophilia and systemic symptoms dRTA distal renal tubular acidosis DSA donor-​specific antibodies DTC direct to consumer DTPA diethylenetriaminepentaacetic acid DVT deep vein thrombosis DXA dual energy X-​ray absorptiometry EACTS European Association for Cardio-​Thoracic Surgery EAggEC enteroaggregative Escherichia coli EANM European Association of Nuclear Medicine EAPCI European Association of Percutaneous Cardiovascular Interventions EASL European Association for the Study of the Liver EATL enteropathy-​associated T-​cell lymphoma EBV Epstein–​Barr virus ECD extended criteria donor ECF extracellular fluid ECG electrocardiogram ECLAM European community lupus activity measure ECM extracellular matrix ECV extracellular volume EDMD Emery–​Dreifuss muscular dystrophy EDRF endothelial-​derived relaxing factor EDTA European Dialysis and Transplant Association EDV end-​diastolic volume EEG electroencephalography EELV end expiratory lung volume EGF epidermal growth factor eGFR estimated glomerular filtration rate EGPA eosinophilic granulomatosis with polyangiitis EIEC enteroinvasive Escherichia coli EIS endoscopic injection sclerotherapy ELCA excimer laser coronary atherectomy ELISA enzyme-​linked immunosorbent assay EM erythema multiforme (also electron microscopy) EMA endomysial antibody EMG electromyography EMS early morning urethral smear ENA extractable nuclear antigens ENaC epithelial sodium channel ENT ear, nose, or throat EOL end of life EoO eosinophilic oesophagitis EPCR endothelial cell protein C receptor EPEC enteropathogenic Escherichia coli EPO erythropoietin ER endoplasmic reticulum ERA European Renal Association ERC endoscopic retrograde cholangiography ERCP endoscopic retrograde cholangiopancreatography ERNV equilibrium radionuclide ventriculography ERS European Respiratory Society ESA erythropoiesis-​stimulating agent ESC European Society of Cardiology ESGE European Society of Gastrointestinal Endoscopy ESH European Society of Hypertension ESKD end-​stage kidney disease ESR erythrocyte sedimentation rate ESRD end-​stage renal disease ESS EULAR sicca score ESWL extracorporeal shock-​wave lithotripsy ETEC enterotoxigenic Escherichia coli EUS endoscopic ultrasonography EVLP ex-​vivo lung perfusion EVO endoscopic variceal obturation FA Fanconi’s anaemia FACIT fibril-​associated collagen with interrupted triple FAK focal adhesion kinase FAP familial adenomatous polyposis FBC full blood count FCAS familial cold autoinflammatory syndrome FCHL familial combined hyperlipidaemia FDA Food and Drug Administration FDG fluorodeoxyglucose FDG-​PET fluorodeoxyglucose-​positron emission tomography FDP fibrinogen-​degradation product FEV forced expiratory volume FEV1 forced expiratory volume in 1 s

Abbreviations xxxviii FFR fractional flow reserve FGF fibroblast growth factor FH familial hypercholesterolaemia FISH fluorescent in situ hybridization FL follicular lymphoma FLC free light chain FMF familial Mediterranean fever FMTC familial medullary thyroid carcinoma FNAB fine needle aspiration biopsy FNH focal nodular hyperplasia FOB faecal occult blood FODMAPs fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FRC functional residual capacity FSGS focal segmental glomerulosclerosis FSH follicular stimulating hormone FTD frontotemporal dementia FVC forced vital capacity FVU first voided urine G6PD glucose-​6-​phosphate dehydrogenase GABA γ-​aminobutyric acid GAD generalized anxiety disorder GALT gut-​associated lymphoid tissue GAVE gastric antral vascular ectasia GBD Global Burden of Disease GBM glomerular basement membrane G-​CSF granulocyte colony-​stimulating factor GCA giant cell arteritis GCS Glasgow Coma Score GDF growth differentiation factors GEP gastroenteropancreatic GFB glomerular filtration barrier GFR glomerular filtration rate GH growth hormone GI gastrointestinal GIB gastrointestinal bleeding GIE glucocorticoid inhibitory element GIP gastric inhibitor peptide GIST gastrointestinal stromal tumour GLP glucagon-​like peptide GM-​CSF granulocyte–​macrophage colony-​stimulating factor GM/​MS gas chromatography–​mass spectrometry GN glomerulonephritis GnRH gonadotropin-​releasing hormone GOLD Global Initiative for Obstructive Lung Disease GOMMID glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits GORD gastro-​oesophageal reflux disease GOV gastro-​oesophageal varices GP glycoprotein (also general practitioner) GPA granulomatosis with polyangiitis GPCR G-​protein-​coupled-​receptors GPI glycosylphosphatidylinositol GRACE Global Registry of Acute Coronary Events GRADE Grading of Recommendations, Assessment, Development and Evaluations GRHPR glyoxylate/​hydroxypyruvate reductase GSD glycogen storage disease GSGS focal segmental glomerulosclerosis GSH glutathione GU gonococcal urethritis GUM genitourinary medicine GVHD graft-​versus-​host disease GVL graft-​versus-​leukaemia GWAS genome-​wide association study H&E haematoxylin and eosin stain HAART highly active antiretroviral therapy HAND HIV-​associated neurocognitive disorder HAV hepatitis A virus HBc hepatitis B core HBeAG hepatitis B e antigen HBIg hepatitis B immunoglobulin HBPM home blood pressure measurement HBsAG hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCG human chorionic gonadotropin HCV hepatitis C virus HD haemodialysis HDF haemodiafiltration HDL high-​density lipoprotein HDL-​C high-​density lipoprotein cholesterol HDU high-​dependency unit HDV hepatitis D virus HE hepatic encephalopathy or hereditary elliptocytosis HELLP haemolysis, elevated liver enzymes and low platelets HES hypereosinophilic syndrome hESC human embryonic stem cell HETE hydroxyeicosatetraenoic acid HEV hepatitis E virus HF haemofiltration HFA Heart Failure Association HFnEF heart failure with a normal ejection fraction HFOV high-​frequency oscillatory ventilation HFV high-​frequency ventilation HHT hereditary haemorrhagic telangiectasis/​ 15-​hydroxy-​5,8,10-​hepatrotrienoic acid HHV human herpesvirus HIF hypoxia-​inducible factors HIV human immunodeficiency virus HIV-​OL human immunodeficiency virus oral lesion HK high molecular weight kininogen HL hepatic lipase HLA human leucocyte antigen HLH haemophagocytic lymphohistiocytosis HLHS hypoplastic left heart syndrome HMA hypomethylating agent HOGA 4-​hydroxy-​2-​oxoglutarate aldolase HPA hypothalamic-​pituitary-​adrenal HPG hypothalamic-​pituitary-​gonadal HPLC high-​performance liquid chromatography HPP hereditary pyropoikilocytosis HPRT hypoxanthine-​guanine phosphoribosyltransferase HPV human papillomavirus

  Abbreviations xxxix HRA high-​resolution anoscopy HRCT high-​resolution computed tomography HRT hormone replacement therapy HS hereditary spherocytosis HSC haematopoietic stem cell or hepatic stellate cell HSCT haemopoietic stem cell transplantation HSP Henoch–​Schönlein purpura HSPC haematopoietic stem and progenitor cell HSV herpes simplex virus HUS haemolytic uraemic syndrome HUV hypocomplementaemic urticarial vasculitis IADL instrumental activities of daily living IAS insulin autoimmune syndrome IBD irritable bowel disease IBS irritable bowel syndrome IBS-​C irritable bowel syndrome with constipation IBS-​D irritable bowel syndrome with diarrhoea IBS-​M irritable bowel syndrome with alternating constipation and diarrhoea IC intercalated cell ICAM intercell adhesion molecules ICD implantable cardioverter-​defibrillator ICP intracranial pressure ICS inhaled oral corticosteroids ICU intensive care unit IDA iminodiacetic acid IDL intermediate-​density lipoprotein IEC intestinal epithelial cell IF intrinsic factor IFG impaired fasting glucose IFN interferon Ig immunoglobulin IgAN immunoglobulin A nephropathy IgE immunoglobulin E IGF insulin-​like growth factors IgG4-​RD immunoglobulin G4-​related disease IgG4-​SC immunoglobulin G4-​related sclerosing cholangitis IGV isolated gastric varices IHD ischaemic heart disease IHME Institute for Health Metrics and Evaluation IIH idiopathic intracranial hypertension IIP idiopathic interstitial pneumonias IL interleukin ILC innate lymphoid cell ILD interstitial lung disease IMA inferior mesenteric artery INR international normalized ratio IPAF interstitial pneumonitis with autoimmune features IPEX immunodysregulation polyendocrinopathy enteropathy X-​linked IPF idiopathic pulmonary fibrosis IPI International Prognostic Index iPSC induced pluripotent stem cell IPSID immunoproliferative small intestinal disease IRIDA iron-​refractory iron deficiency anaemia IRIS immune reconstitution inflammatory syndrome IRM immunoradiographic assay IRV Inspiratory and expiratory reserve volume ISH International Society of Hypertension ISHLT International Society for Heart and Lung Transplantation ISIS International Study of Infarct Survival ISWT incremental shuttle walking test ITP immune thrombocytopenia ITU intensive care unit IV intravenous IVC inferior vena cava IVF in vitro fertilization IVIG intravenous immunoglobulin IVU intravenous urography JE Japanese encephalitis JIA juvenile idiopathic arthritis JNC Joint National Committee KDIGO Kidney Disease: Improving Global Outcomes LA left atrium LAMA long-​acting antimuscarinic agents LBBB left bundle branch block LCAT lecithin–​cholesterol acyltransferase LCH Langerhans’ cell histiocytosis lcSSc limited cutaneous systemic sclerosis LDH lactate dehydrogenase LDL low-​density lipoprotein LDL-​C low-​density lipoprotein cholesterol LFT liver function test LGE late gadolinium enhancement LGMD limb-​girdle muscular dystrophy LGV lymphogranuloma venereum LH luteinizing hormone LIC liver iron content LINQ Lung Information Needs Questionnaire LIP lymphocytic interstitial pneumonia LKM liver–​kidney microsomal LMICs low-​ and middle-​income countries LMN lower motor neuron LMWH low molecular weight heparin LMWP low molecular weight protein LOLA l-​ornithine l-​arginine LP lumbar puncture LPL lipoprotein lipase LPLR lipoprotein lipase receptor LTOT long-​term oxygen therapy LV left ventricle LVDD left ventricular diastolic dysfunction LVEF left ventricular ejection fraction LVOT left ventricular outflow tract LVRS lung volume reduction surgery LVSD left ventricular systolic dysfunction MAG3 mercaptoacetyltriglycine MAGIC MAGnesium in Coronaries MAHA microangiopathic haemolytic anaemia MALT mucosa-​associated lymphoid tissue MAO monoamine oxidase inhibitor MAP mean arterial pressure MAPK mitogen-​activated protein kinase MBD mineral and bone disorder M-​CSF macrophage colony-​stimulating factor

Abbreviations xl MCHC mean cell haemoglobin concentration MCL mantle cell lymphoma MCNS minimal change nephrotic syndrome MCpEF myocarditis with preserved left ventricular ejection fraction MCV mean corpuscular volume MDE myeloma-​defining event MDI metered dose inhalers MDRD Modification of Diet in Renal Disease MDS myelodysplastic syndrome MED minimal erythema dose MELD Model for End-​Stage Liver Disease MEN multiple endocrine neoplasia MERFF myoclonic epilepsy and ragged red fibres mESC mouse embryonic stem cell MGRS monoclonal gammopathy of renal significance MGUS monoclonal gammopathy of undetermined significance MHC major histocompatibility complex MHRA Medicines and Healthcare Products Regulatory Agency MIC minimum inhibitory concentration MIDD monoclonal immunoglobulin deposition diseases MKD mevalonate kinase deficiency MM malignant melanoma MMA methylmalonic acid MMF mycophenolate mofetil MMP matrix metalloproteinase MMR mismatch repair MN membranous nephropathy MND motor neuron disease MoCA Montreal Cognitive Assessment MPA microscopic polyangiitis MPO myeloperoxidase MPS mucopolysaccharidosis (also myocardial perfusion scintigraphy) MR magnetic resonance MRA magnetic resonance angiography (can also be medicine regulatory authority) MRC Medical Research Council MRCP magnetic resonance cholangiopancreatography MRI magnetic resonance imaging MRSA methicillin-​resistant Staphylococcus aureus MS multiple sclerosis MS/​MS tandem mass spectroscopy MSA multiple-​system atrophy MSC mesenchymal stromal cell MSH melanocyte-​stimulating hormone MSU midstream urine MTC medullary thyroid carcinoma mTOR mammalian target of rapamycin MUS medically unexplained symptoms MWS Muckle–​Wells syndrome NAAT nucleic acid amplification testing NABQI N-​acetyl-​p-​benzoquinone imine NADH reduced nicotinamide-​adenine dinucleotide NADPH reduced nicotinamide-​adenine dinucleotide phosphate NAFLD nonalcoholic fatty liver disease NAIT neonatal alloimmune thrombocytopenia NASH nonalcoholic steatohepatitis NCAM neural-​cell adhesion molecule NEP neutral endopeptidase NET neuroendocrine tumour or neutrophil extracellular trap NETT National Emphysema Therapy Trial NEWS National Early Warning Score NGF nerve growth factor NGS next-​generation sequencing NHDL-​C non-​high-​density lipoprotein cholesterol NHL non-​Hodgkin’s lymphoma NHS National Health Service (UK) NICE National Institute for Health and Care Excellence NIPPV non-​invasive nasal positive-​pressure ventilation NIPT non-​invasive prenatal testing NIV non-​invasive ventilation NK natural killer NKT natural killer T NLST National Lung Screening Trial NMS neuroleptic malignant syndrome NMSC non-​melanoma skin cancer NNH number needed to harm NNT number needed to treat NOTT Nocturnal Oxygen Treatment Trial NREM non-​rapid eye movement NRT nicotine replacement therapy NSAID non-​steroidal anti-​inflammatory drug NSCLC non-​small cell lung cancer NSIP non-​specific interstitial pneumonia NSTEMI non-​ST-​elevation myocardial infarction NTD neural tube defect NTM non-​tuberculous mycobacterial NT-​proBNP N-​terminal B-​type natriuretic peptide NYHA New York Heart Association OAF osteoclast-​activating factor OAPR odds of being affected given a positive result OB obliterative bronchiolitis OCD obsessive–​compulsive disorder OCT optical coherence tomography OD once daily OECD Organisation for Economic Cooperation and Development OED other eating disorders OLP oral lichen planus OMIM Online Mendelian Inheritance in Man OMT optimal medical therapy OPAT outpatient parenteral antibiotic therapy OR odds ratio OS overall survival OSA obstructive sleep apnoea OTB oral tuberculosis PA pernicious anaemia (also pulmonary artery) PACAP pituitary adenylate cyclase activating polypeptide PAF platelet activating factor PAH polycyclic aromatic hydrocarbons (can also mean pulmonary hypertension)

  Abbreviations xli PAOP pulmonary artery occlusion pressure PAS periodic acid–​Schiff PASI Psoriasis Area and Severity Index PASP pulmonary artery systolic pressure PBD polyglucosan body disease PBM peripheral blood mononuclear cell PCC prothrombin complex concentrate PCH paroxysmal cold haemoglobinuria (also pulmonary capillary haemangiomatosis) PCI percutaneous coronary intervention PCNSL primary central nervous system lymphoma Pco partial pressure of carbon dioxide PCP Pneumocystis jirovecii pneumonia PCR polymerase chain reaction (also protein:creatinine ratio) PCT proximal convoluted tubule PCV pneumococcal conjugate vaccine PCWP pulmonary capillary wedge pressure PD peritoneal dialysis (also Parkinson’s disease) PDA patent ductus arteriosus PDC pyruvate dehydrogenase complex PDD Parkinson’s disease dementia PDGF platelet-​derived growth factor PE pleural effusion (can also mean pulmonary embolism) PEACH Pelvic Inflammatory Disease Evaluation and Clinical Health PEEP positive end expiratory pressure PEF peak expiratory flow PEG percutaneous endoscopic gastrostomy PET position emission tomography PFO patent foramen ovale PFS progression-​free survival PGK phosphoglycerate kinase PHARC polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract PICS post-​intensive care syndrome PID pelvic inflammatory disease PIGN postinfectious glomerulonephritis PK pyruvate kinase PKD pyruvate kinase deficiency (also polycystic kidney disease) PKU phenylketonuria PLA2R phospholipase A2 receptor PMN polymorphonuclear neutrophil PMR polymyalgia rheumatica PNH paroxysmal nocturnal haemoglobinuria Po2 partial pressure of oxygen POC point of care POMC pro-​opiomelanocortin PP polypeptide PPI proton pump inhibitor ppm parts per million PPS Palliative Performance Scale PPV porcine parvovirus PR3 proteinase 3 PRCA pure red cell aplasia PRI population reference intake PRPP phosphoribosyl pyrophosphate PRR pattern-​recognition receptor PRrP parathyroid-​hormone-​related protein PSA prostate-​specific antigen PSC primary sclerosing cholangitis PSP primary spontaneous pneumothorax PT prothrombin time PTC percutaneous transhepatic cholangiography PTCA percutaneous transluminal coronary angioplasty PTH parathyroid hormone PTHrP PTH/​PTH-​related peptide PTLD post-​transplant lymphoproliferative disorder PTP post-​transfusion purpura PTSD post-​traumatic stress disorder PUVA psoralen ultraviolet A PV pemphigus vulgaris (also plasmas viscosity test) PVE prosthetic valve endocarditis PVOD pulmonary veno-​occlusive disease PVR pulmonary vascular resistance PYY peptide tyrosine-​tyrosine QALY quality-​adjusted life year RA rheumatoid arthritis (can also mean right atrium) RAAS renin–​angiotensin–​aldosterone system RAS renin–​angiotensin system (also renal artery stenosis or restrictive allograft syndrome RAVV right atrioventricular valve RBBB right bundle branch block RBF rat bite fevers RCA right coronary artery RCC renal cell carcinoma RCDP rhizomelic chondrodysplasia punctata RCT randomized controlled trial RDA recommended dietary allowance REM rapid eye movement RF rheumatoid factor RI resistivity index RNA ribonucleic acid RNI reference nutrient intake RNP ribonucleoprotein ROC receiver–​operator characteristic RP ribosomal protein RRT renal replacement therapy RTA renal tubular acidosis RV residual volume (also right ventricle) RVOTO right ventricular outflow tract obstruction SA short-​axis SABR stereotactic ablative body radiotherapy SBP spontaneous bacterial peritonitis (also systolic blood pressure) SCC squamous cell carcinoma SCD sickle cell disease (also sudden cardiac death) SCI spinal cord injuries SCID severe combined immunodeficiency SCLC small cell lung cancer SCMR Society for Cardiovascular Magnetic Resonance SCN sickle cell nephropathy or severe congenital neutropenia sdLDL small dense low-​density lipoprotein SDS Shwachman–​Diamond syndrome

Abbreviations xlii SEER Surveillance, Epidemiology, and End Results SGRQ St George’s Respiratory Questionnaire SHBG sex hormone binding globulin SHEC Shiga toxin-​producing Escherichia coli SIADH syndrome of inappropriate antidiuretic hormone secretion SIRS systemic inflammatory response syndrome SLB surgical lung biopsy SLE systemic lupus erythematosus SM smouldering myeloma SMA superior mesenteric artery (also smooth muscle antibody) SMC smooth muscle cell sMDRD simplified Modification of Diet in Renal Disease SMR standardized mortality ratio SNGFR single-​nephron glomerular filtration rate SNP single nucleotide polymorphism SNS sympathetic nervous system SOD sphincter of Oddi disorder SPC Summary of Product Characteristics SPD storage pool deficiency SPECT single-​positron emission computed tomography SPF sun protection factor SSc systemic sclerosis SSD somatic symptom disorder SSFP steady-​state free precession SSRI selective serotonin reuptake inhibitor STEMI ST elevation myocardial infarction STI sexually transmitted infection STOPP/​START set of inappropriate combinations of medicines and disease (STOPP) and a set of recommended treatments for given conditions (START) suPAR soluble urokinase plasminogen activating receptor SVC superior vena cava SVR systemic vascular resistance TACE transarterial chemoembolization TAE transarterial embolization TALH thick ascending limb of Henle TAR thrombocytopenia with absent radii TAVI transcatheter aortic valve implantation TB tuberculosis TBLC transbronchial lung cryobiopsy TBM tuberculous meningitis TC total cholesterol TCA tricyclic antidepressant TCPC total cavopulmonary connection TCR T-​cell receptor TCT thrombin clotting time TdT terminal deoxyribonucleotidyl transferase TEC transient erythroblastopenia of childhood TEN toxic epidermal necrolysis TF transcription factor (also tissue factor) TFPI tissue factor pathway inhibitor TG triglyceride TGF transforming growth factor TGFα, TGFβ transforming growth factor-​α, -​β TGN trans Golgi network THR total hip replacement THRIVE Treatment of HDL to Reduce the Incidence of Vascular Events TIA transient ischaemic attack TIBC total iron-​binding capacity TIMI thrombolysis in myocardial infarction TINU tubulointerstitial nephritis uveitis TIPS transjugular intrahepatic portosystemic shunt TK tyrosine kinase TKI tyrosine kinase inhibitor TKR total knee replacement TLC total lung capacity TLR Toll-​like receptor TMA thrombotic microangiopathy t-​MDS therapy-​related myelodysplastic syndrome(s) TNF tumour necrosis factor TNFα tumour necrosis factor-​α tPA tissue plasminogen activator TPN total parenteral nutrition TPN total parenteral nutrition TRAIL TNF-​related apoptosis-​inducing ligand TRAPS tumour necrosis factor receptor-​associated periodic syndrome Treg regulatory T (cell) TROPHY Trial of Preventing Hypertension TSH thyroid-​stimulating hormone TTD thiazide-​type diuretic tTG tissue transglutaminase TTIP Transatlantic Trade and Investment Partnership TTKG transtubular potassium concentration gradient TTP thrombotic thrombocytopenic purpura TURBT transurethral resection of bladder tumour TV tricuspid valve UAER urinary albumin excretion rate UCB umbilical cord blood UDCA ursodeoxycholic acid UDP uridine diphosphate UI urinary incontinence UIP usual interstitial pneumonia UKELD United Kingdom Model for End-​Stage Liver Disease UKM urea kinetic modelling UKMEC UK Medical Eligibility Criteria UKPDS United Kingdom Prospective Diabetes Study ULN upper limit of normal UMN upper motor neuron UPR unfolded protein response URR urea reduction ratio URTI upper respiratory tract infection UTI urinary tract infection UV ultraviolet UVL ultraviolet light UVR ultraviolet radiation V/​Q ventilation/​perfusion VARD video-​assisted retroperitoneal debridement VATS video-​assisted thoracoscopic surgery VC vital capacity vCJD variant Creutzfeldt–​Jakob disease

  Abbreviations xliii VDRL Venereal Diseases Research Laboratory VEGF vascular endothelial growth factor VEOIBD very early-​onset inflammatory bowel disease VIP vasoactive intestinal peptide VKA vitamin K antagonist VLA vertical long axis VLCFA very long-​chain fatty acid VLDL very low-​density lipoprotein VSD ventricular septal defect VTE venous thromboembolism VWD von Willebrand’s disease VWF von Willebrand factor VZV varicella zoster virus WBC white blood cell WCC white cell count WGS whole genome sequencing WHO World Health Organization WM Waldenström’s macroglobulinaemia X-​ALD X-​linked adrenoleukodystrophy XLH X-​linked hypophosphataemia YLDs years lived with disability YLL years of life lost ZASP Z-​line associated protein

Contributors Peter Aaby Bandim Health Project, INDEPTH Network, Bissau, Guinea-​Bissau, West Africa 8.5.6: Measles Emma Aarons Consultant Virologist and Infectious Disease Physician, Rare and Imported Pathogens Laboratory, Public Health England, Salisbury, Wiltshire, UK 8.5.27: Orf and Milker’s nodule Tom Abbott William Harvey Research Institute, Queen Mary University of London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Ade Adebajo Faculty of Medicine, Dentistry and Health, University of Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist Raymond Agius Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health S. Faisal Ahmed School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Shahzada K. Ahmed Department of Otorhinolaryngology, Queen Elizabeth Hospital, Birmingham, UK 13.2.2: Disorders of the posterior pituitary gland Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in the tropics Guruprasad P. Aithal NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, The University of Nottingham, Nottingham, UK 15.24.3: Drug-​induced liver disease Sara Ajina Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.6.1: Visual pathways Tyler Albert VA Puget Sound Health Care System, Division of General Internal Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Maha Albur University of Bristol, Bristol, UK 8.2.5: Antimicrobial chemotherapy Michael J. Aldape Veterans Affairs Medical Center, Infectious Diseases Section, Boise, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Graeme J.M. Alexander UCL Professor, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK 15.23.1: Hepatitis A to E; 15.24.6: Primary and secondary liver tumours Michael E.D. Allison Liver Unit, Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK 15.24.6: Primary and secondary liver tumours Carlo Ammendolia Faculty of Medicine, University of Toronto, Toronto, Canada; Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Division of Rheumatology, Mount Sinai Hospital, Toronto, Canada 19.4: Back pain and regional disorders Chris Andrews Faculty of Medicine, University of Queensland, Herston, Qld 4029, Australia 10.3.5: Lightning and electrical injuries Ross H. Andrews Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Professor of Parasitology, Imperial College London, Faculty of Medicine, St Mary’s Campus, London, UK 8.11.2: Liver fluke infections Jervoise Andreyev Consultant Gastroenterologist, United Lincolnshire Hospitals Trust; Honorary Professor, The School of Medicine, University of Nottingham, UK 15.3.4: Investigation of gastrointestinal
function Gregory M. Anstead Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Immunosuppression and Infectious Diseases Clinics, Department of Medicine, South Texas Veterans Health Care System, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Quentin M. Anstee Professor of Experimental Hepatology and Honorary Consultant Hepatologist, Faculty of Medical Sciences, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Charles M.G. Archer Department of Dermatology, Oxford University Hospitals NHS Trust, Oxford, UK 23.15: Skin and systemic diseases Clive B. Archer Consultant Dermatologist and Honorary Senior Clinical Lecturer, St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust & King’s College London, Guy’s Hospital, London, UK 23.15: Skin and systemic diseases Michael J. Arden-​Jones  Consultant
Dermatologist, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Mark J. Arends University of Edinburgh Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK 3.6: Apoptosis in health and disease J. Arendt Emeritus Professor of
Endocrinology, University of Surrey,
Guildford, UK 13.11: The pineal gland and melatonin James O. Armitage The Joe Shapiro Professor of Medicine, Division of Oncology/​Hematology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Vicente Arroyo Professor of Medicine at the University of Barcelona Medical School; Chairman of the European Association
for the Study of the Liver Chronic Liver
Failure Consortium (EASL-​CLIF
Consortium) and President of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF), Barcelona, Spain 15.22.2: Cirrhosis and ascites Daniel Aruch Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Frances Ashcroft Professor of Physiology, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 3.4: Ion channels and disease Caroline Ashley Lead Specialist Pharmacist, Centre for Nephrology, Royal Free Hospital, London, UK 21.19: Drugs and the kidney Shazad Q. Ashraf Consultant Colorectal Surgeon, Department of Colorectal Surgery, Queen Elizabeth Hospital, Birmingham University Hospitals, Birmingham, UK 15.14: Colonic diverticular disease

Contributors xlvi Paul Aveyard Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management; 26.6.3: Smoking cessation Tar-​Ching Aw† Abu Dhabi National Oil Company, United Arab Emirates 10.2.5: Noise; 10.2.6 Vibration Jon G. Ayres Emeritus Professor of Environmental and Respiratory Medicine, Universty of Birmingham, Birmingham, UK 10.1: Environmental medicine, occupational medicine, and poisoning; 10.3.1: Air pollution and health Juan Carlos Ayus Renal Consultants of Houston, Houston, TX, USA; University of California Irvine, Orange, CA, USA 21.2.1: Disorders of water and sodium homeostasis Qasim Aziz Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 15.13: Irritable bowel syndrome Trevor Baglin Previously Cambridge Haemophilia and Thrombophilia Centre, Department of Haematology, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK 22.7.2: Evaluation of the patient with a bleeding tendency Michael Bagshaw Aviation Medicine, King’s College, London, UK 10.2.3: Aviation medicine Colin Baigent Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Kenneth F. Baker Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 19.5: Rheumatoid arthritis Bettina Balint Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, Queen Square, London, UK; Department of Neurology, University Hospital Heidelberg, University of Heidelberg, Germany 24.7.3: Movement disorders other than Parkinson’s disease Jay Banerjee College of Life Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Adrian P. Banning Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1 Acute aortic syndromes George Banting Medical Sciences Building, University of Bristol, Bristol, UK 3.1: The cell Thomas M. Barber University of Warwick, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK 13.10: Hormonal manifestations of non-​endocrine disease E.J. Barnes Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.5.22: Hepatitis C virus Michael Barnes University of Newcastle, Newcastle upon Tyne, UK; Christchurch Group, Janet Barnes Unit, Birmingham, UK 24.13.2: Spinal cord injury and its management Andrew J. Barr Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, UK 19.9: Osteoarthritis Jonathan Barratt Professor of Renal Medicine, University of Leicester; Honorary Consultant Nephrologist, University Hospitals of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP) Buddha Basnyat Oxford University Clinical Research Unit -​ Nepal; Patan Academy of Health Sciences, Nepal 8.6.9 Typhoid and paratyphoid fevers; 10.3.6: Diseases of high terrestrial altitudes D. Nicholas Bateman, Pharmacology, Toxicology and Therapeutics, University of Edinburgh, Edinburgh, UK 10.4.1: Poisoning by drugs and chemicals David Bates Clinical Neurology, Newcastle University, Newcastle on Tyne, UK 24.5.5: The unconscious patient; 24.9: Brainstem syndromes Robert P. Baughman University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Peter J. Baxter School of Clinical Medicine,
Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK 10.3.8: Disasters: Earthquakes, hurricanes, floods, and volcanic eruptions Hannah Beckwith Specialist Registrar, Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK 21.10.3: The kidney in rheumatological
disorders Diederik van de Beek Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.1: Bacterial infections David A. Bender University College London, London, UK 11.2: Vitamins D.A. Bente University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Anthony R. Berendt Oxford University Hospitals NHS Foundation Trust, Oxford, UK 20.3: Osteomyelitis Stefan Berg Consultant in Pediatric Rheumatology and Immunology, Queen Silvia Children’s Hospital, Goteborg, Sweden 12.12.2 Hereditary periodic fever syndromes David de Berker Bristol Dermatology
Centre, University Hospitals Bristol,
Bristol, UK 23.13: Hair and nail disorders Nancy Berliner H. Franklin Bunn Professor of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 22.3.1: Granulocytes in health and disease; 22.4.1: Introduction to lymphopoiesis Jessica Bertrand Experimental Orthopedics, University Hospital Magdeburg, Magdeburg, Germany 19.1: Joints and connective tissue—​structure
and function J.M. Best King’s College London, London, UK 8.5.13: Rubella Delia B. Bethell Oxford University Hospitals NHS Foundation Trust, Oxford, UK 8.6.1: Diphtheria Kailash Bhatia Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, UK 24.7.3: Movement disorders other than
Parkinson’s disease Vijaya Raj Bhatt Assistant Professor, Division of Hematology-​Oncology, University of Nebraska Medical Center, Omaha, NE, USA 22.4.3: Hodgkin lymphoma; 22.4.4: Non-​Hodgkin lymphoma Joya Bhattacharyya Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the gastrointestinal tract Paola Bianchi Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Rudolf Bilous Professor of Clinical Medicine, Newcastle University, Newcastle upon Tyne; Academic Centre, James Cook University Hospital, Middlesbrough, UK 21.10.1: Diabetes mellitus and the kidney D. Bilton Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.9: Bronchiectasis Jonathan I. Bisson Division of Psychological Medicine and Clinical Neurosciences, University of Cardiff, Cardiff, UK 26.5.9: Acute stress disorder, adjustment disorders, and post-​traumatic stress disorder Carol M. Black Newnham College, Cambridge, UK 19.11.3: Systemic sclerosis (scleroderma) S.R. Bloom Head of Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome Johannes Blum Medical Services, Swiss
Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis † It is with great regret that we report that Tar-Ching Aw died on 18 July, 2017.

Contributors xlvii Kristien Boelaert University of Birmingham, Birmingham, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Eva Boonen Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Christopher Booth† Wellcome Institute for the History of Medicine, Wellcome Building, London, UK 1.1: On being a patient Marina Botto Professor, Imperial College London, London, UK 4.2: The complement system Ralph Bouhaidar Consultant Forensic Pathologist, NHS Lothian; Honorary Senior Lecturer, Edinburgh University, Edinburgh; Training Programme Director for Forensic Histopathology (Scotland), UK 27.1: Forensic and legal medicine Henri-​Jean Boulouis Ecole Nationale Vétérinaire d’Alfort, Maisons-​Alfort, France 8.6.43: Bartonellas excluding B. bacilliformis P.-​M.G. Bouloux Centre for Neuroendocrinology, University College London Medical School, London, UK 13.6.2: Disorders of male reproduction and male hypogonadism S.J. Bourke Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.3: Lymphocytic infiltrations of the lung; 18.14.4: Hypersensitivity pneumonitis; 18.14.5: Pulmonary Langerhans’ cell histiocytosis; 18.14.6: Lymphangioleiomyomatosis; 18.14.7: Pulmonary alveolar proteinosis; 18.14.8: Pulmonary amyloidosis; 18.14.9: Lipoid (lipid) pneumonia; 18.14.10: Pulmonary alveolar microlithiasis; 18.14.12: Radiation pneumonitis; 18.14.13: Drug-​induced
lung disease Ian C.J.W. Bowler Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Louise Bowles Consultant Haematologist, Barts Health NHS Trust, London, UK 14.7: Thrombosis in pregnancy Paul Bowness Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK 4.1: The innate immune system Ray Boyapati Department of Gastroenterology, Monash Health, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Vic, Australia 15.17: Vascular disorders of the gastrointestinal tract Sally M. Bradberry NPIS (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Marcus Bradley North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases Tasanee Braithwaite Locum Consultant, Moorfields Eye Hospital NHS Foundation Trust, London, UK 25.1: The eye in general medicine Thomas Brandt Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Petter Brandtzaeg Emeritus Professor, Department of Paediatrics, Oslo University Hospital, Oslo, Norway 8.6.5: Meningococcal infections Philippe Brasseur Institut de Recherche pour le Développement, Dakar, Sénégal, West Africa 8.8.3: Babesiosis Jürgen Braun Medical Director, Rheumazentrum Ruhrgebiet, Herne, Germany; Chair of Rheumatology, Ruhr University, Bochum, Germany 19.6: Spondyloarthritis and related
conditions Evan M. Braunstein Hematology Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis James D. Brenton Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications J.A. Bridgewater Professor and Consultant in Medical Oncology, UCL Cancer Institute, London, UK 15.16: Cancers of the gastrointestinal tract Frank Bridoux Professor of Nephrology, Department of Nephrology, Hôpital Jean Bernard, Poitiers, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Charlotte K. Brierley Department of Haematology, Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 22.3.2: Myelodysplastic syndromes Alice Brockington University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Max Bronstein Advocacy and Science
Policy, Every Life Foundation, Washington, DC, USA 2.9: Engaging patients in therapeutic development Gary Brook London North West University Healthcare NHS Trust, London, UK 9.3: Sexual history and examination Arthur E. Brown Research Consultant, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand 8.6.21: Anthrax Anthony F.T. Brown Department of Emergency Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Qld, Australia 17.3: Anaphylaxis Kevin E. Brown Virus Reference Department, Public Health England, London, UK 8.5.20: Parvovirus B19 Michael Brown Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.9.4: Strongyloidiasis, hookworm, and other gut strongyloid nematodes Morris J. Brown Professor of Endocrine Hypertension, Queen Mary University of London, William Harvey Heart Centre, London, UK 16.17.3: Secondary hypertension Vanessa Brown Specialist Registrar, Royal Surrey County Hospital, Guildford, UK 15.4.2: Gastrointestinal bleeding Reto Brun Parasite Chemotherapy Unit, Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland 8.8.11: Human African trypanosomiasis Marco J. Bruno Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis Amy E. Bryant Research Professor, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, ID, USA 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Antony D.M. Bryceson London School of Hygiene and Tropical Medicine, London, UK 8.8.13: Leishmaniasis Nicolas C. Buchs Consultant Colorectal Surgeon, Clinic for Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland 15.14: Colonic diverticular disease Camilla Buckley MRC Clinician Scientist and Honorary Consultant, Department of Clinical Neurology, University of Oxford, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Simon J.A. Buczacki Honorary Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen Enrico Bugiardini MRC Centre for Neuromuscular Disease, University College London, London, UK 24.19.1: Structure and function of muscle Alan Burnett Former Professor of Haematology, Cardiff University, Cardiff, UK 22.3.3: Acute myeloid leukaemia Gilbert Burnham John Hopkins Bloomberg School of Public Health, Baltimore, MD, USA 8.9.1: Cutaneous filariasis Aine Burns Consultant Nephrologist and Director of Postgraduate Medical Education, Centre for Nephrology, Royal Free NHS Trust and University College Medical School, London, UK 21.19: Drugs and the kidney † It is with great regret that we report that Christopher Booth died on 13 July, 2012.

Contributors xlviii Eileen Burns Leeds Centre for Older People’s Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK 6.11: Promotion of dignity in the life and death of older patients Harry Burns University of Strathclyde, UK 2.14: Deprivation and health N.P. Burrows Consultant Dermatologist, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.2: Inherited defects of connective tissue: Ehlers–​Danlos syndrome, Marfan syndrome, and pseudoxanthoma elasticum Rosie Burton Khayelitsha District Hospital, Corner of Walter Sisulu and Streve Biko
Roads, Khayelitsha, Cape Town, Africa; Department of Medicine, University of Cape Town, Cape Town, Africa 14.15: Maternal infection in pregnancy Andrew Bush Imperial College London, London, UK; National Heart and Lung Institute, London, UK; Royal Brompton and Harefield NHS Foundation Trust, London, UK 18.10: Cystic fibrosis Kate Bushby Newcastle University John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Gary Butler University College London Hospital and UCL Great Ormond Street Institute of Child Health, London, UK 13.7.1: Normal growth and its disorders William F. Bynum Professor Emeritus, University College London, London, UK 2.1: Science in medicine: When, how,
and what Simone M. Cacciò European Union Reference Laboratory for Parasites, Department of Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy 8.8.5: Cryptosporidium and cryptosporidiosis Djuna L. Cahen Erasmus Medical Center, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands 15.26.2: Chronic pancreatitis P.M.A. Calverley School of Clinical Sciences, University of Liverpool, Liverpool, UK 18.15: Chronic respiratory failure Jason Caplan Dignity Health Medical Group; St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine; Phoenix, AZ, USA 26.5.3: Organic psychoses Jonathan R. Carapetis Telethon Kids Institute, University of Western Australia and Perth Children’s Hospital, Perth, Australia 16.9.1: Acute rheumatic fever Jordi Carratalà Department of Infectious Diseases, Hospital Universitari de Bellvitge -​ IDIBELL, Division of Health Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain 8.6.39: Legionellosis and Legionnaires’ disease R. Carter Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Stuart Carter Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Carty Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK 14.11: Endocrine disease in pregnancy Jaimini Cegla Imperial College London, London, UK 12.6: Lipid disorders Joseph Cerimele University of Washington, Washington, DC, USA 26.5.6: Depressive disorder Joshua T. Chai Department of Cardiovascular Medicine, University of Oxford,
Oxford, UK 16.13.1: Biology and pathology of
atherosclerosis Richard E. Chaisson Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA 8.6.26: Tuberculosis Romanee Chaiwarith Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Ben Challis University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia Siddharthan Chandran Euan MacDonald Centre for Clinical Brain Sciences (CCBS), University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine; 24.10.2: Demyelinating disorders of the central nervous system Keith Channon John Radcliffe Hospital, Oxford, UK 16.1.1: Blood vessels and the endothelium Roger W. Chapman Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis V. Krishna Chatterjee University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action Afzal Chaudhry Chief Clinical Information Officer, Cambridge University Hospitals, Cambridge, UK 2.5: Bioinformatics K. Ray Chaudhuri National Parkinson Foundation Centre of Excellence, King’s College, Denmark Hill Campus, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Patrick F. Chinnery University of Newcastle, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease Hector Chinoy University of Manchester, Manchester, UK 19.11.5: Inflammatory myopathies Peter L. Chiodini Hospital for Tropical Diseases, University College London Hospitals,
London, UK 8.9.5: Gut and tissue nematode infections acquired by ingestion Rossa W.K. Chiu Choh-​Ming Li Professor of Chemical Pathology, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Bruno B. Chomel School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Robin P. Choudhury University of Oxford, Oxford, UK 16.13.1: Biology and pathology of atherosclerosis Julia Choy National Health Service, London, UK 18.4.5: Pulmonary complications of HIV infection Lydia Chwastiak Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA 26.5.6: Depressive disorder Andrew L. Clark Chair of Clinical Cardiology
and Honorary Consultant Cardiologist,
Hull York Medical School, Castle Hill Hospital, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3: Chronic heart failure: Definitions, investigation, and management Andrew Clegg Academic Unit of Elderly Care and Rehabilitation, University of Leeds, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.2: Frailty and sarcopenia John G.F. Cleland National Heart and Lung Institute, Royal Brompton and Harefield Hospitals Trust London, UK; Hull York Medical School, University of Hull, Hull, UK 16.5.2: Acute cardiac failure: Definitions, investigation, and management; 16.5.3 Chronic heart failure: Definitions, investigation, and management Gavin Clunie Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.5: Osteonecrosis, osteochondrosis, and osteochondritis dissecans S.M. Cobbe Previously Consultant Cardiologist, Glasgow Royal Infirmary; former BHF Walton Professor of Medical Cardiology, University of Glasgow, Glasgow, UK 16.2.2: Syncope and palpitation Fredric L. Coe The University of Chicago Medicine, Chicago, IL, US 21.1: Structure and function of the kidney Sian Coggle Consultant Physician, Cambridge University Hospitals, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures Jon Cohen Brighton and Sussex Medical School, Brighton, UK 8.2.4: Infection in the immunocompromised host

Contributors xlix Alasdair Coles Cambridge School of Clinical Medicine, Cambridge, UK 24.10.2: Demyelinating disorders of the central nervous system Jane Collier Consultant Hepatologist, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus; 15.22.1: Investigation and management of jaundice Rory Collins Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Juan D. Colmenero Infectious Diseases Service, Regional University Hospital, Málaga, Spain 8.6.22: Brucellosis Alastair Compston Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK 24.1: Introduction and approach to the patient with neurological disease Juliet Compston University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 20.4: Osteoporosis Philip G. Conaghan Leeds University,
Leeds, UK 19.9: Osteoarthritis Christopher P. Conlon Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.4: Travel and expedition medicine; 8.5.23: HIV/​ AIDS; 8.5.28: Molluscum contagiosum Simon Conroy Department of Health Sciences, University of Leicester, Leicester, UK 6.4: Older people and urgent care Cyrus Cooper MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 20.4: Osteoporosis John E. Cooper University of Cambridge, Cambridge, UK 8.8.8: Sarcocystosis (sarcosporidiosis) Robert Cooper University of Liverpool, Liverpool, UK 19.11.5: Inflammatory myopathies Mhairi Copland Professor of Translational Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Susan J. Copley Imperial College Healthcare NHS Trust, London, UK 18.3.2: Thoracic imaging Jeremy Cordingley Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Philip J. Cowen University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.4.1: Psychopharmacology in medical practice Timothy M. Cox Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK 1.1: An older patient’s story; 12.1: The inborn errors of metabolism: General aspects; 12.3.1: Glycogen storage diseases; 12.3.2: Inborn errors of fructose metabolism; 12.3.3: Disorders of galactose, pentose, and pyruvate metabolism; 12.5: The porphyrias; 12.7.1: Hereditary haemochromatosis; 12.8: Lysosomal disease; 13.11: The pineal gland and melatonin; 15.10.5: Disaccharidase deficiency; 22.6.4: Iron metabolism and its disorders S.E. Craig Oxford Sleep Unit, Churchill Hospital, Oxford, UK 18.1.1: The upper respiratory tract Matthew Cramp South West Liver Unit and Peninsula Schools of Medicine and Dentistry, Derriford Hospital, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Robin A.F. Crawford Addenbrooke’s Hospital, Cambridge, UK 14.18: Malignant disease in pregnancy Daniel Creamer King’s College Hospital, London, UK 23.16: Cutaneous reactions to drugs Tim Crook North Middlesex Hospital,
London, UK 5.7: Medical management of breast cancer Paul Cullinan Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.7: Asthma Peter F. Currie Perth Royal Infirmary, Perth and Ninewells Hospital and Medical School, Dundee, UK 16.9.3: Cardiac disease in HIV infection Nicola Curry Consultant Haematologist, Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 22.7.3: Thrombocytopenia and disorders of
platelet function Goodarz Danaei Department of Global Health and Population, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA 16.13.2: Coronary heart disease: Epidemiology and prevention Christopher J. Danpure Emeritus Professor of Molecular Cell Biology, University College London, London, UK 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Bhaskar Dasgupta University of Essex, Essex, UK; Anglia Ruskin University, East Anglia, UK; Southend University Hospital NHS Foundation Trust, Essex, UK 19.11.11: Polymyalgia rheumatica Pooja Dassan Consultant Neurologist, Imperial College Healthcare NHS Trust and London
North West University Healthcare NHS Trust, London, UK 14.12: Neurological conditions in
pregnancy Andrew Davenport Professor of Dialysis and ICU Nephrology, UCL Department of Nephrology, Royal Free Hospital, University College London, London, UK 21.4: Clinical investigation of renal disease Gail Davey Centre for Global Health Research, Brighton and Sussex Medical School,
Brighton, UK 10.5: Podoconiosis Alun Davies Imperial College School of Medicine, London, UK 16.14.2: Peripheral arterial disease Helen E. Davies University Hospital of Wales, Cardiff, UK 18.19.4: Mediastinal tumours and cysts R Justin Davies Consultant Colorectal Surgeon, Cambridge Colorectal Unit, Addenbrooke’s Hospital, Cambridge, UK 15.4.1: The acute abdomen P.D.O. Davies Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK 8.6.27: Disease caused by environmental mycobacteria R. Rhys Davies Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture Simon Davies Professor of Nephrology and Dialysis Medicine, Institute for Science and Technology in Medicine, Keele University, Keele; Consultant Nephrologist, University Hospital of North Midlands, Stoke-​on-​Trent, UK 21.7.2: Peritoneal dialysis Richard Dawkins New College, University of Oxford, Oxford, UK 2.2: Evolution: Medicine’s most basic science Christopher P. Day Vice-​Chancellor and President, Newcastle University and Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 15.24.2: Non​alcoholic fatty liver disease Nicholas P.J. Day Mahidol-​Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.6.35: Leptospirosis; 8.6.41: Scrub typhus Colin Dayan University of Cardiff, Wales, UK 13.9.1: Diabetes Marc E. De Broe Professor of Medicine, Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Kevin M. De Cock Center for Global Health, Atlanta, GA, USA 8.5.24: HIV in low-​ and middle-​income
countries An S. De Vriese Division of Nephrology, AZ Sint-​Jan Brugge-​Oostende AV, Brugge, Belgium 21.8.4: Membranous nephropathy Patrick B. Deegan Consultant Metabolic Physician, Lysosomal Disorders Unit, Cambridge University Hospitals, Cambridge, UK 12.8 Lysosomal disease

Contributors l Christopher Deighton Royal Derby Hospital, Derby, UK 19.2 Clinical presentation and diagnosis of rheumatological disorders David M. Denison Emeritus Professor of Clinical Physiology, Royal Brompton Hospital and Imperial College London, London, UK 10.2.4: Diving medicine Christopher P. Denton Centre for Rheumatology, Division of Medicine, University College London (UCL) Medical School, Royal Free Hospital, London, UK 19.11.3: Systemic sclerosis (scleroderma) Ulrich Desselberger University of Cambridge, Cambridge, UK 8.5.8: Enterovirus infections; 8.5.9: Virus
infections causing diarrhoea and vomiting Patrick C. D’Haese Head of Laboratory of Pathophysiology, University of Antwerp, Campus Drie Eiken, Wilrijk, Belgium 21.9.2: Chronic tubulointerstitial nephritis Ashwin Dhanda Plymouth Hospitals NHS Trust, Plymouth, UK 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Jugdeep Dhesi Guys and St Thomas’ Hospitals, London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Euan J. Dickson Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis Michael Doherty University of Nottingham, Nottingham, UK 19.3: Clinical investigation; 19.10: Crystal-​related arthropathies Inderjeet S. Dokal Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts Health NHS Trust, London, UK 22.5.1: Inherited bone marrow failure
syndromes Jan Donck Department of Nephrology, AZ Sint-​ Lucas, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Arjen M. Dondorp Mahidol-​Oxford Tropical Medicine Research Unit, Bangkok,
Thailand 8.8.2: Malaria Basil Donovan University of New South Wales, NSW, Australia 8.6.37: Syphilis Philip R. Dormitzer Pfizer Vaccine Research and Development, Pearl River, NY, USA 8.5.9: Virus infections causing diarrhoea and vomiting Anne Dornhorst Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy Charles G. Drake New York Presbyterian and Columbia University Medical Center, New York, USA 5.4: Cancer immunity and immunotherapy Hal Drakesmith MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Christopher Dudley Consultant Nephrologist, The Richard Bright Renal Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 16.14.3: Cholesterol embolism Susanna Dunachie Oxford University Hospitals NHS Trust, Oxford, UK 8.4: Travel and expedition medicine Lisa Dunkley Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 19.12: Miscellaneous conditions presenting to the rheumatologist David Dunne University of Cambridge,
Cambridge, UK; Wellcome Trust-​Cambridge, Centre for Global Health Research, UK; CAPREx, THRiVE-​Cambridge, and Cambridge-​Africa 8.11.1: Schistosomiasis Stephen R. Durham National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, UK 18.6: Allergic rhinitis Jeremy Dwight John Radcliffe Hospital, Oxford, UK 16.2.1: Chest pain, breathlessness, and fatigue Jessica K. Dyson Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Christopher P. Eades University College London, London, UK 8.7.5: Pneumocystis jirovecii Ian Eardley St James’s Hospital, Leeds, UK 13.6.4: Sexual dysfunction James E. East Consultant Gastroenterologist, Translational Gastroenterology Unit, John Radcliffe Hospital; Associate Professor of Gastroenterology and Endoscopy, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 15.3.1: Colonoscopy and flexible
sigmoidoscopy; 15.3.2: Upper gastrointestinal endoscopy Lars Eckmann Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA 8.8.9: Giardiasis and balantidiasis Michael Eddleston Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 10.4.4: Poisonous plants Mark J. Edwards St George’s University of London, London, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Richard Edwards School of Clinical Sciences, University of Bristol, Bristol, UK 24.19.4: Metabolic and endocrine disorders Rosalind A. Eeles The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK 5.3: The genetics of inherited cancers Tim Eisen Department of Oncology, University of Cambridge, Cambridge, UK; Oncology Early Clinical Development, AstraZeneca, Cambridge, UK 5.2: The nature and development of cancer: Cancer mutations and their implications; 5.5: Clinical features and management; 21.18: Malignant diseases of the urinary tract Wagih El Masri(y) Keele University, Newcastle-​ under-​Lyme, UK; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK 24.13.2: Spinal cord injury and its management Carole Eldin University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Perry Elliott St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Christopher J. Ellis Heart of England Foundation Trust, Birmingham, UK; University of Birmingham, Birmingham, UK 8.2.1: Clinical approach Graham Ellis Monklands Hospital, Airdrie, Lanarkshire, UK 6.5: Older people in hospital Monique M. Elseviers Centre for Research and Innovation in Care (CRIC), University of Antwerp, Antwerp; Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium 21.9.2: Chronic tubulointerstitial nephritis Caroline Elston Respiratory Medicine and Adult Cystic Fibrosis, King’s College Hospital, London, UK 18.10: Cystic fibrosis M.A. Epstein Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK 8.5.3: Epstein–​Barr virus Steve Epstein MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington, DC, USA 26.5.8: Anxiety disorders Wendy N. Erber Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA, Australia 22.2.2: Diagnostic techniques in the assessment of haematological malignancies Ari Ercole Neurosciences Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Edzard Ernst Emeritus Professor, University of Exeter, Exeter, UK 2.22: Complementary and alternative medicine Andrew P. Evan Indiana University School of Medicine, Indianapolis, IN, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Mark Evans University of Cambridge Medical School, Cambridge, UK 13.9.2: Hypoglycaemia

Contributors li Rhys D. Evans Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK 11.1 Nutrition: Macronutrient metabolism; 16.1.2: Cardiac physiology Pamela Ewan Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.5: Allergy David W. Eyre Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 8.6.24 Clostridium difficile Lynette D. Fairbanks Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4 Disorders of purine and pyrimidine metabolism Christopher G. Fairburn Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.10: Eating disorders Carole Fakhry Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses Marie Fallon St Columba’s Hospice Chair of Palliative Medicine, University of Edinburgh, Edinburgh, UK 7.2: Pain management Sonia Fargue University of Alabama at Birmingham, Birmingham, AL, USA 12.10: Hereditary disorders of oxalate metabolism: The primary hyperoxalurias Adam D. Farmer Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London; Department of Gastroenterology, University Hospitals of North Midlands, Stoke-​on-​Trent, UK 15.13: Irritable bowel syndrome I. Sadaf Farooqi Wellcome-​MRC Institute of Metabolic Science, University of Cambridge, UK 11.6: Obesity Jeremy Farrar Wellcome Trust, London, UK 2.17: Research in the developed world; 24.11.2: Viral infections Ken Farrington Lister Hospital, East and North Hertfordshire NHS Trust, Stevenage, UK 21.3: Clinical presentation of renal disease Hiva Fassihi King’s College London,
London, UK 23.9: Photosensitivity John Feehally Emeritus Consultant Nephrologist, University Hospitals of Leicester; Honorary Professor of Renal Medicine, University of Leicester, Leicester, UK 21.8.1: Immunoglobulin A nephropathy and IgA vasculitis (HSP); 21.8.2: Thin membrane nephropathy Peter J. Fenner School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Qld, Australia 10.3.4: Drowning Florence Fenollar Aix-​Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, Marseille, France 15.10.6: Whipple’s disease Javier Fernández Consultant Hepatologist, Head of Liver ICU, Liver Unit, Hospital Clinic Barcelona; Associate Professor, University of Barcelona Medical School, Barcelona, Spain; Member of the European Foundation for the Study of Chronic Liver Failure (EF-​CLIF) 15.22.2: Cirrhosis and ascites Fernando C. Fervenza Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA 21.8.4: Membranous nephropathy Sarah Fidler Professor of HIV Medicine, Imperial College London, London, UK 8.5.23: HIV/​AIDS Richard E. Fielding Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon
Tyne, UK 21.3: Clinical presentation of renal disease Roger G. Finch Nottingham University Hospitals, NHS Trust, Nottingham, UK 8.2.5: Antimicrobial chemotherapy Simon Finney Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK 17.5: Acute respiratory failure Helen V. Firth Addenbrookes Hospital Cambridge, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system John D. Firth Consultant Physician and Nephrologist, Cambridge University
Hospitals, Cambridge, UK 16.16.1: Deep venous thrombosis and pulmonary embolism; 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment; 16.19: Idiopathic oedema of women; 21.2.2: Disorders of potassium homeostasis; 21.5: Acute kidney injury; 21.7.3: Renal transplantation; 30.1: Acute medical presentations; 30.2: Practical procedures A.J. Fisher Professor of Respiratory Transplant Medicine, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK 18.16: Lung transplantation Edward A. Fisher Departments of Medicine, Pediatrics, and Cell Biology, Smilow Research Centre, New York, NY, USA 16.13.1: Biology and pathology of atherosclerosis Rebecca C. Fitzgerald Professor of Cancer Prevention and MRC Programme Leader, MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre, Cambridge, UK 15.7: Diseases of the oesophagus Michael E.B. FitzPatrick Department of Gastroenterology, Oxford University Hospitals, Oxford; Senior Research Fellow, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract R. Andres Floto Molecular Immunity Unit, Department of Medicine, University of Cambridge, UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK 3.5: Intracellular signalling Edward D. Folland University of Massachusetts Medical School, MA, USA 16.3.4: Cardiac catheterization and angiography; 16.13.5: Percutaneous interventional cardiac procedures D. de Fonseka Academic Respiratory Unit, University of Bristol, Bristol, UK 18.17: Pleural diseases Carole Foot Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating patient Alastair Forbes Norwich Medical School,  University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption Ewan Forrest Consultant Hepatologist and Honorary Clinical Associate Professor, Department of Gastroenterology, Glasgow Royal Infirmary and the University of Glasgow, Glasgow UK 15.24.1: Alcoholic liver disease Rob Fowkes Royal Veterinary College,
London, UK 13.1: Principles of hormone action Keith A.A. Fox Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK 16.13.4: Management of acute coronary
syndrome Stephen Franks Imperial College London, London, UK 13.6.1: Ovarian disorders Keith N. Frayn Radcliffe Department of Medicine, University of Oxford, Oxford, UK 11.1: Nutrition: Macronutrient metabolism Patrick French Mortimer Market Centre, Central and North West London NHS Trust, London, UK; University College London, London, UK 9.6: Genital ulceration Izzet Fresko Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Peter S. Friedmann Emeritus Professor of Dermatology, University of Southampton, Southampton, UK 23.6: Dermatitis/​eczema Charlotte Frise Obstetric Medicine and Acute General Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20: Prescribing in pregnancy Susannah J.A. Froude Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Stephen J. Fuller Associate Professor, Medicine Sydney Medical School Nepean, The University of Sydney, Sydney, Australia 22.6.8: Anaemias resulting from defective maturation of red cells David A. Gabbott Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK 17.2: Cardiac arrest

Contributors lii Simon M. Gabe Consultant Gastroenterologist, Intestinal Failure and Academic Unit, St Mark’s Hospital, London, UK 15.10.7: Effects of massive bowel resection Patrick G. Gallagher Professor of Pediatrics, Genetics and Pathology, Yale University, New Haven, CT, USA 22.6.9: Disorders of the red cell membrane Shreyans Gandhi King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Hector H. Garcia Center for Global Health, Tumbes and Department of Microbiology, Universidad Peruana Cayetano Heredia, and Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus); 8.10.3: Cysticercosis Hill Gaston University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Rupert Gauntlett Critical Care Medicine and Obstetric Anaesthesia, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK 14.19: Maternal critical care John Geddes University of Oxford, Oxford, UK 26.5.7: Bipolar disorder William Gelson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.20: Structure and function of the liver, biliary tract, and pancreas Jacob George Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK 6.7: Drugs and prescribing in the older patient G.J. Gibson Newcastle University, Newcastle upon Tyne, UK 18.3.1: Respiratory function tests John Gibson Professor of Oral Medicine and Honorary Consultant in Oral Medicine, Institute of Dentistry, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK 15.6: The mouth and salivary glands J. van Gijn University Medical Center Utrecht, Utrecht, the Netherlands 24.10.1 Stroke: Cerebrovascular disease Ian Giles Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction Robert H. Gilman Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA 8.10.3: Cysticercosis Alexander Gimson Consultant Hepatologist, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 15.19: Miscellaneous disorders of the bowel; 15.20: Structure and function of the liver, biliary tract, and pancreas; 15.24.4: Vascular disorders of the liver Matthew R. Ginks Oxford University Hospitals NHS Trust, Oxford, UK 16.4: Cardiac arrhythmias D.S. Giovanniello Medical Director, American Red Cross, Biomedical Services, Connecticut Blood Services Region, Farmington, CT, USA 22.8.1: Blood transfusion Mark A. Glover Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.2.4: Diving medicine Peter J. Goadsby NIHR-​Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK 24.8: Headache David Goldblatt University College London, London, UK 8.3: Immunization Armando E. Gonzalez Center for Global Health, Tumbes, Universidad Peruana Cayetano Heredia, and Department of Veterinary Epidemiology and Economics, School of Veterinary Medicine, Universidad Nacional Mayor de San Marcos, Lima, Peru 8.10.2: Cystic hydatid disease (Echinococcus granulosus) E.C. Gordon-​Smith Professor of Haematology, St George’s Hospital, University of London, London, UK 22.8.2: Haemopoietic stem cell transplantation Martin Gore† The Royal Marsden, London, UK; The Institute of Cancer Research, University of London, London, UK 5.5: Clinical features and management Eduardo Gotuzzo Universidad Peruana Cayetano Heredia, Lima, Peru 8.5.25: HTLV-​1, HTLV-​2, and associated diseases Philip Goulder University of Oxford, Oxford, UK 8.5.23: HIV/​AIDS Alison D. Grant Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.5.24: HIV in low-​ and middle-​income
countries Cameron C. Grant The University of Auckland, New Zealand; Starship Children’s Health, Auckland, New Zealand 8.6.15: Bordetella infection David Gray Department of Cardiovascular Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK 16.3.1: Electrocardiography Richard Gray Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials John R. Graybill Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA 8.7.3: Coccidioidomycosis Darren Green Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.5.4: Cardiorenal syndrome Manfred S. Green Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.9: Bioterrorism Christopher D. Gregory University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, UK 3.6: Apoptosis in health and disease Christopher E.M. Griffiths Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK 23.5: Papulosquamous disease Karolina Griffiths University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Mark Griffiths Peri-​Operative Medicine, St Bartholomew’s Hospital, London, UK; Imperial College London, London, UK 17.5: Acute respiratory failure William J.H. Griffiths Consultant Hepatologist, Department of Hepatology, Addenbrooke’s Hospital, Cambridge, UK 12.7.1: Hereditary haemochromatosis; 15.24.6: Primary and secondary liver tumours J.P. Grünfeld Hôpital Universitaire Necker, Paris, France 21.12: Renal involvement in genetic disease D.J. Gubler Director, Program on Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore; Asian Pacific Institute of Tropical Medicine and Infectious Diseases, University of Hawaii, Honolulu 8.5.12: Alphaviruses Richard L. Guerrant Center for Global Health, School of Medicine, University of Virginia, VA, USA 8.6.12: Cholera Kaushik Guha Portsmouth Hospitals NHS Trust, Portsmouth, UK 16.5.1: Epidemiology and general pathophysiological classification of
heart failure Nishan Guha Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management Loïc Guillevin Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, INSERM U1060, Hôpital Cochin, Assistance Publique–​ Hôpitaux de Paris, University Paris Descartes, Paris, France 19.11.8: Polyarteritis nodosa Mark Gurnell University of Cambridge Medical School, Cambridge, UK 13.1: Principles of hormone action; 13.5.1 Disorders of the adrenal cortex Oliver P. Guttmann St Bartholomew’s Hospital, London, UK; Institute of Cardiovascular
Science, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular; 16.7.3: Specific heart muscle disorders Robert D.M. Hadden Consultant Neurologist, King’s College Hospital, London, UK 24.12: Disorders of cranial nerves; 24.16: Diseases of the peripheral nerves † It is with great regret that we report that Martin Gore died on 10 January, 2019.

Contributors liii Zara Haider Kingston Hospital NHS Trust, Surrey, UK 9.9: Principles of contraception Sophie Hambleton Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK; Paediatric Immunology and Infectious Diseases, Great North Children’s Hospital, Newcastle upon Tyne, UK 4.4: Immunodeficiency Freddie C. Hamdy Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 21.18: Malignant diseases of the
urinary tract Michael G. Hanna National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.19.1: Structure and function of muscle David M. Hansell Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK 18.3.2: Thoracic imaging Danielle Harari Guy’s and St Thomas’ Hospitals and King’s College London, London, UK 6.9: Bladder and bowels Kate Hardy Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, London, UK 13.6.1: Ovarian disorders Karen E. Harman Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Peter Harper London Oncology Centre, London, UK 5.6: Systemic treatment and radiotherapy; 5.7: Medical management of breast cancer Steve Harper Consultant Renal and Transplant Medicine, Southmead Hospital, Bristol; Honorary Professor, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Honorary Professor, School of Medicine, University of Exeter, Exeter, UK 21.1: Structure and function of the kidney James L. Harrison London Deanery, London, UK 16.9.2: Endocarditis Tina Hartert Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Christine Hartmann Institute of Musculoskeletal Medicine, University of Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Nicholas C. Harvey MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK 20.4: Osteoporosis Rowan Harwood Nottingham University Hospitals NHS Trust and University of Nottingham, Queens Medical Centre, Nottingham, UK 6.5: Older people in hospital Helen Hatcher Consultant Medical Oncologist, Cambridge University Hospitals, Cambridge, UK 20.6: Bone cancer Chris Hatton Cancer and Haematology Centre, Churchill Hospital, Oxford, UK 22.1: Introduction to haematology; 22.3.9: Histiocytosis; 22.6.2: Anaemia: Pathophysiology, classification, and clinical features Philip N. Hawkins Professor of Medicine, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.2 Hereditary periodic fever syndromes; 12.12.3 Amyloidosis Keith Hawton Centre for Suicide Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm Deborah Hay Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK 22.6.7: Disorders of the synthesis or function of haemoglobin; 22.6.9: Disorders of the red cell membrane Roderick J. Hay King’s College London,
London, UK 8.6.31: Nocardiosis; 8.7.1: Fungal infections; 23.6: Dermatitis/​eczema; 23.10: Infections of the skin; 23.12: Blood and lymphatic vessel disorders Peter Hayes Professor of Hepatology, Liver Unit, University of Edinburgh; and Royal Infirmary of Edinburgh, Edinburgh, UK 15.22.3: Portal hypertension and variceal
bleeding Catherine E.G. Head Consultant Cardiologist, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 14.6: Heart disease in pregnancy Eugene Healy Dermatopharmacology, Southampton General Hospital, University of Southampton, UK 23.8: Disorders of pigmentation Nick Heather Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption David W. Hecht Loyola University Health System, IL, USA 8.6.11: Anaerobic bacteria Thomas Hellmark Department of Clinical Sciences, Lund University, Lund, Sweden 21.8.7: Antiglomerular basement membrane
disease Michael Heneghan Professor of Hepatology and Consultant Hepatologist, Institute of Liver Studies, King’s College Hospital, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Michael Henein Umeå University, Sweden; Canterbury Christ Church University, Canterbury, UK 16.6: Valvular heart disease; 16.8: Pericardial disease Martin F. Heyworth Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8.8.9: Giardiasis and balantidiasis Liz Hickson Royal North Shore Hospital, NSW, Australia 17.1: The seriously ill or deteriorating
patient Tran Tinh Hien Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.1: Diphtheria Katherine A. High Professor of Pediatrics Emerita, Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; President and Head of R&D, Spark Therapeutics, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Ingeborg Hilderson Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium 21.10.4: The kidney in sarcoidosis Tom R. Hill Population Health Sciences
Institute, Newcastle University, Newcastle
upon Tyne, UK 11.2: Vitamins David Hilton-​Jones Muscular Dystrophy Campaign, Muscle and Nerve Centre, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, UK 24.18: Disorders of the neuromuscular junction; 24.19.3: Myotonia; 24.19.4 Metabolic and endocrine disorders Matthew Hind Royal Brompton Hospital
and National Heart and Lung Institute,
Imperial College School of Medicine, London, UK 18.5.1: Upper airway obstruction; 18.5.2: Sleep-​ related breathing disorders John Hindle Betsi Cadwaladr University Health Board, Llandudno Hospital; School of Psychology, Bangor University, Bangor, UK 6.10: Neurodegenerative disorders in
older people N. Hirani Royal Infirmary, Edinburgh, UK 18.11.2: Idiopathic pulmonary fibrosis Gideon M. Hirschfield Lily and Terry Horner
Chair in Autoimmune Liver Disease Research,
Toronto Centre for Liver Disease,
Department of Medicine, University of
Toronto, Toronto General Hospital, Toronto, Canada 15.23.2: Autoimmune hepatitis Sarah Hobdey Veterans Medical Hospital, Boise, ID, USA 8.6.2: Streptococci and enterococci Herbert Hof MVZ Labor Limbach, Heidelberg, Germany 8.6.38: Listeriosis A.V. Hoffbrand Emeritus Professor of Haematology, University College, London, UK 22.6.6: Megaloblastic anaemia and miscellaneous deficiency anaemias

Contributors liv Ronald Hoffman Albert A. and Vera G. List, Professor of Medicine, Division of Hematology/​ Oncology; Director, Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA 22.3.5: The polycythaemias; 22.3.6: Thrombocytosis and essential thrombocythaemia Georg F. Hoffmann Department of General Pediatrics, University of Heidelberg, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Tessa L. Holyoake† Professor of Experimental Haematology, Section of Experimental Haematology, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK 22.3.4: Chronic myeloid leukaemia Roel Hompes Consultant Colorectal Surgeon, Academic Medical Centre Amsterdam, University of Amsterdam, the Netherlands 15.14: Colonic diverticular disease Tony Hope St Cross College, University of Oxford, Oxford, UK 1.5: Medical ethics Julian Hopkin Medicine and Health, School of Medicine, Swansea University, Swansea, UK 18.2: The clinical presentation of respiratory disease P. Hopkins Medical Director, Queensland Lung Transplant Service, Chermside, Qld, Australia 18.16: Lung transplantation Nicholas S. Hopkinson National Heart and Lung Institute, Imperial College, London, UK 18.8: Chronic obstructive pulmonary disease Patrick Horner Population Health Sciences, University of Bristol, Bristol, UK 8.6.45: Chlamydial infections; 9.5: Urethritis Bala Hota Rush University, Chicago, IL USA 8.6.4: Staphylococci Andrew R. Houghton Grantham and District Hospital, Grantham, UK; University of Lincoln, Lincoln, UK 16.3.1: Electrocardiography Robert A. Huddart The Institute of Cancer Research, London, UK 21.18: Malignant diseases of the urinary tract Harriet C. Hughes Consultant Microbiology and Infectious Diseases, Public Health Wales, Cardiff, UK 8.5.29: Newly discovered viruses Ieuan A. Hughes University of Cambridge, Cambridge, UK 13.5.2: Congenital adrenal hyperplasia James H. Hull The Royal Brompton Hospital, London, UK 18.5.1: Upper airway obstruction Adam Hurlow Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person Jane A. Hurst Great Ormond Street Hospital, London, UK 24.20: Developmental abnormalities of the central nervous system Alastair Hutchison Medical Director and Professor of Renal Medicine, Dorset County Hospital, Dorchester, UK 21.6: Chronic kidney disease Peter J. Hutchinson University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Steve Iliffe Research Department of Primary Care and Population Health, University College London, London, UK 6.3: Optimizing well-​being into old age Lawrence Impey Obstetrics and Fetal Medicine, The Women’s Centre, John Radcliffe Hospital, Oxford, UK 14.16: Fetal effects of maternal infection Jakko van Ingen Radboud University Medical Centre, Nijmegen, the Netherlands 8.6.27: Disease caused by environmental mycobacteria Peter Irving Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis John D. Isaacs Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7 Biological therapies for immune, inflammatory, and allergic diseases; 19.5: Rheumatoid arthritis David A. Isenberg Centre for Rheumatology, Department of Medicine, University College London, London, UK 19.11.1: Introduction; 19.11.2: Systemic lupus erythematosus and related disorders Theodore J. Iwashyna Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Center for Clinical Management Research, Department of Veterans Affairs,
Ann Arbor, MI, USA; Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia 17.12: Persistent problems and recovery after critical illness Arnaud Jaccard Service d’hématologie clinique et de thérapie cellulaire, CHU de Limoges—​Hôpital Dupuytren, Limoges, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Alan A. Jackson Southampton General Hospital, Southampton, UK 11.4: Severe malnutrition Thomas Jackson Queen Elizabeth Hospital, Birmingham, UK 26.3.1: Confusion Anu Jacob National Neuromyelitis Optica Service, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.13.1: Diseases of the spinal cord Caron A. Jacobson Division of Hematologic Malignancies, Dana-​Farber Cancer Institute, Boston, MA, USA 22.4.1: Introduction to lymphopoiesis N. Asger Jakobsen Clinical Research Fellow, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Rajiv Jalan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Hannah Jarvis Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 18.4.4: Mycobacteria M.K. Javaid Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions David Jayne Professor of Clinical Autoimmunity, Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK 19.11.7: ANCA-​associated vasculitis; 21.10.2: The kidney in systemic vasculitis Susan Jebb Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK 26.6.2: Obesity and weight management Katie J.M. Jeffery Oxford University Hospitals NHS Foundation Trust, Department of Microbiology, John Radcliffe Hospital, Oxford, UK 8.5.22: Hepatitis C virus Rajesh Jena Cambridge University Hospitals, Cambridge, UK 5.6: Systemic treatment and radiotherapy Tom Jenkins University of Sheffield, Sheffield, UK 24.15: The motor neuron diseases Jørgen Skov Jensen Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark 8.6.46: Mycoplasmas Vivekanand Jha Executive Director, The George Institute for Global Health, New Delhi, India; Professor of Nephrology, University of Oxford, Oxford, UK 21.11: Renal diseases in the tropics Tingliang Jiang Professor, Department of Pharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Alexis J. Joannides University of Cambridge, Cambridge, UK 3.7: Stem cells and regenerative medicine Anne M. Johnson Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017.

Contributors lv Colin Johnson Emeritus Professor of Surgical Sciences, University of Southampton, Southampton, UK 15.15: Diseases of the gallbladder and biliary tree M.R. Johnson Professor of Neurology and Genomic Medicine, Faculty of Medicine, Department of Brain Sciences, Imperial College, London, UK 24.5.1: Epilepsy in later childhood and adulthood Elaine Jolly University of Cambridge, Cambridge, UK 30.1: Acute medical presentations; 30.2: Practical procedures D. Joly Necker-​Enfants Malades Hospital, Paris, France 21.12: Renal involvement in genetic disease Bryony Jones Imperial College Hospital, London, UK 14.10: Diabetes in pregnancy David E.J. Jones Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK 15.23.3: Primary biliary cholangitis Bouke de Jong Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Menno De Jong Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 24.11.2: Viral infections Iain Jordan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.5.13: Personality disorders Emil Kakkis Ultragenyx Pharmaceutical Inc., Novato, CA, USA 2.9: Engaging patients in therapeutic development Philip A. Kalra Consultant and Honorary Professor of Nephrology, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 16.5.4 Cardiorenal syndrome; 21.10.10: Atherosclerotic renovascular disease Eileen Kaner Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Theodoros Karamitos Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Niki Karavitaki Queen Elizabeth Hospital, Birmingham, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland Steven B. Karch Consultant in Cardiac Pathology and Toxicology, Berkeley, CA, USA 27.1: Forensic and legal medicine Fiona E. Karet Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 21.15: The renal tubular acidoses Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK 15.5: Immune disorders of the
gastrointestinal tract David Kavanagh Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome Fiona Kearney Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures David Keeling Oxford Haemophilia and Thrombosis Centre, Churchill Hospital, Oxford, UK 16.16.2: Therapeutic anticoagulation Andrew Kelion Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Julia Kelly Royal Brompton and Harefield NHS Trust, London, UK 18.5.2: Sleep-​related breathing disorders Paul Kelly Professor of Tropical Gastroenterology, Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; TROPGAN Group, Department of Internal Medicine, University of Zambia School of Medicine, Lusaka, Zambia 8.8.6: Cyclospora and cyclosporiasis David P. Kelsell London Medical School, London, UK 23.3: Inherited skin disease Samuel Kemp Royal Brompton Hospital, London, UK 18.2: The clinical presentation of respiratory disease Christopher Kennard Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.1: Introduction and approach to the patient with neurological disease; 24.6.1: Visual pathways Richard S.C. Kerr Oxford University Hospitals NHS Foundation Trust, Oxford, UK 24.11.3: Intracranial abscesses Satish Keshav† Department of Gastroenterology, Oxford University Hospitals NHS Foundation Trust, Oxford; Professor of Gastroenterology, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.1: Structure and function of the gastrointestinal tract Nigel S. Key Harold R. Roberts Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Rajesh K. Kharbanda John Radcliffe Hospital, Oxford, UK 16.13.4: Management of acute coronary syndrome Elham Khatamzas Regional Infectious Diseases Unit, NHS Lothian, Edinburgh, UK 8.2.4: Infection in the immunocompromised host Peng T. Khaw Professor and Consultant Ophthalmic Surgeon; Director of Research, Development and Innovation; Director, NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK 25.1: The eye in general medicine B. Khoo University College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.2: Carcinoid syndrome Nine V.A.M. Knoers Professor in Clinical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands 21.16: Disorders of tubular electrolyte handling Stefan Kölker Consultant, Pediatric Metabolic Medicine, University Children’s Hospital, Heidelberg; Department of General Pediatrics, Division of Inborn Metabolic Diseases, Heidelberg, Germany 12.2 Protein-​dependent inborn errors of metabolism Nils P. Krone University of Sheffield,
Sheffield, UK 13.5.2: Congenital adrenal hyperplasia Narong Khuntikeo Director, Cholangiocarcinoma Research Institute (CARI), Director, Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Faculty of Medicine, Khon Kaen University, Thailand; Associate Professor, Department of Surgery, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections Gudula Kirtschig Tübingen, Germany 14.13: The skin in pregnancy Suzanne Kite Leeds Teaching Hospitals NHS Trust, Leeds, UK 7.4: Care of the dying person John L. Klein Guy’s and St Thomas’ NHS Foundation Trust, London, UK 16.9.2: Endocarditis Paul Klenerman Nuffield Department of Medicine, University of Oxford, Oxford, UK 4.3: Adaptive immunity; 8.5.22: Hepatitis
C virus Richard Knight Department of Microbiology, University of Nairobi, Nairobi, Kenya 8.8.1: Amoebic infections; 8.8.10: Blastocystis infection; 8.9.2: Lymphatic filariasis; 8.9.3: Guinea worm disease (dracunculiasis); 8.9.6: Angiostrongyliasis; 8.10.1: Cestodes (tapeworms) David Koh PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, SSH School of Public Health, National University of Singapore, Singapore 10.2.5: Noise G.C.K.W. Koh Diseases of the Developing World, Alternative Drug Development, GlaxoSmithKline, UK 8.6.8: Pseudomonas aeruginosa M.A. Kokosi Royal Brompton and Harefield NHS Trust, London, UK 18.11.4: The lung in autoimmune rheumatic disorders Onn Min Kon Respiratory Medicine, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK 18.4.4: Mycobacteria † It is with great regret that we report that Satish Keshav died on 23 January, 2019.

Contributors lvi Adelheid Korb-​Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Vasilis Kouranos Royal Brompton and Harefield NHS Trust, London, UK 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia Christian Krarup Region Hovedstaden, Denmark 24.3.2: Electrophysiology of the central and peripheral nervous systems Amy S. Kravitz United States Agency for International Development (USAID), Washington DC, USA 2.21: Humanitarian medicine Dinakantha S. Kumararatne Depatment of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK 4.4: Immunodeficiency Om P. Kurmi Hyperbaric Medicine Unit,
St Richard’s Hospital, Chichester, UK 10.3.1: Air pollution and health Robert A. Kyle Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Peter L. Labib Clinical Research Fellow, Institute for Liver and Digestive Health, Royal Free Campus, University College London, London, UK 15.16: Cancers of the gastrointestinal tract Charles J.N. Lacey Hull York Medical School, University of York, York, UK 9.7: Anogenital lumps and bumps Helen J. Lachmann Senior Lecturer, National Amyloidosis Centre and Centre for Acute Phase Proteins, University College London Medical School, London, UK 12.12.2: Hereditary periodic fever syndromes Robin H. Lachmann Consultant in Inherited Metabolic Disease, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK 12.3.1: Glycogen storage diseases Ralph Lainson† Ex Director, the Wellcome Parisitology Unit, and research-worker, Department of Parasitology, Instiuto Evandro Chagas, Rodovia, Barro Levilầndia, Ananindeua, Pará, Brazil 8.8.6: Cyclospora and cyclosporiasis Kin Bong Hubert Lam University of Oxford, Oxford, UK 10.3.1: Air pollution and health D.A. Lane Faculty of Medicine, Department of Medicine, Imperial College London,
London, UK 16.4: Cardiac arrhythmias Peter C. Lanyon Nottingham University Hospitals Trust, Nottingham, UK 19.3: Clinical investigation Andrew J. Larner Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK 24.3.1: Lumbar puncture; 24.5.4: Syncope; 24.13.1: Diseases of the spinal cord Malcolm Law Wolfson Institute of Preventive Medicine, St Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2.12 Medical screening Tim Lawrence Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.3: Traumatic brain injury; 24.11.3: Intracranial abscesses Stephen M. Lawrie Division of Psychiatry, University of Edinburgh, Edinburgh, UK 26.5.11: Schizophrenia Alison M. Layton Harrogate and District NHS Foundation Trust, Harrogate, UK 23.11: Sebaceous and sweat gland disorders James W. Le Duc Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX, USA 8.5.16: Bunyaviridae Susannah Leaver St George’s NHS Foundation Trust, London, UK 17.5: Acute respiratory failure Y.C. Gary Lee Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, WA, Australia 18.17: Pleural diseases; 18.19.3 Pleural tumours; 18.19.4 Mediastinal tumours and cysts Haur Yueh Lee National Heart Centre Singapore, Singapore, China; Kings Drugs Reaction Group, King’s College London, London, UK 23.16: Cutaneous reactions to drugs Richard W.J. Lee Director, Uveitis and Scleritis Service, National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK 25.1: The eye in general medicine Evelyne de Leeuw Centre for Health Equity Training, Research and Evaluation, UNSW Sydney, South Western Sydney Local Health District, Ingham Institute, Australia 2.13: Health promotion Yee-​Sin Leo National Centre for Infectious Disease, Tan Tock Seng Hospital, Singapore; Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Lee Kong Chian School of Medicine, Singapore 8.5.15: Dengue Phillip D. Levin Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Elena N. Levtchenko Professor in Pediatric Nephrology, Catholic University Leuven, Leuven, the Netherlands 21.16: Disorders of tubular electrolyte handling Su Li Department of Epidemiology, Guangxi Medical University, Nanning, Guangxi, China 5.7: Medical management of breast cancer Fulong Liao Professor, Biomechanopharmacology, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine Ted Liao MedStar Georgetown University Hospital and Georgetown University School of Medicine, Washington DC, USA 26.5.8: Anxiety disorders Oliver Liesenfeld Roche Molecular Systems, Pleasanton, CA, USA 8.8.4: Toxoplasmosis Liz Lightstone, Professor of Renal Medicine, Centre for Inflammatory Disease, Faculty of Medicine, Imperial College London, London, UK 21.10.3: The kidney in rheumatological disorders Wei Shen Lim Consultant Respiratory Physician and Honorary Professor of Medicine, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK 18.4.2: Pneumonia in the normal host; 18.4.3: Nosocomial pneumonia Aldo A.M. Lima Biomedicine Center and Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil 8.6.12: Cholera Gregory Y.H. Lip Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, UK; Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark 16.4: Cardiac arrhythmias; 16.17.5: Hypertensive urgencies and emergencies Mark A. Little Professor of Nephrology and Consultant Nephrologist, Trinity Health Kidney Centre, Trinity College Dublin; Tallaght and Beaumont Hospitals, Dublin, Ireland 21.8.5: Proliferative glomerulonephritis; 21.8.6: Membranoproliferative glomerulonephritis P. Little University of Southampton, Southampton, UK 18.4.1: Upper respiratory tract infections William A. Littler The Priory Hospital, Birmingham, UK 16.9.2: Endocarditis A. Llanos-​Cuentas School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Y.M. Dennis Lo Li Ka Shing Professor of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, China 3.9: Circulating DNA for molecular diagnostics Diana N.J. Lockwood London School of Hygiene and Tropical Medicine, London, UK 8.6.28: Leprosy (Hansen’s disease); 8.8.13: Leishmaniasis David A. Lomas Vice Provost (Health) and Head of UCL Medical School, University College London, London, UK 12.13: α1-​Antitrypsin deficiency and the serpinopathies; 15.24.6 Primary and secondary liver tumours Alan Lopez University of Melbourne, Melbourne, Vic, Australia 2.3: The Global Burden of Disease: Measuring the health of populations † It is with great regret that we report that Ralph Lainson died on 5 May, 2015.

Contributors lvii Constantino López-Macias Mexican Society of Immunology, Mexico; University of Oxford, Oxford, UK 4.3: Adaptive immunity David A. Low Liverpool John Moores University, Liverpool, UK 24.14: Diseases of the autonomic nervous system Elyse E. Lower University of Cincinnati Medical Center, Cincinnati, OH, USA 18.12: Sarcoidosis Katharine Lowndes Department of Haematology, Royal Hampshire County Hospital, Winchester UK 14.17: Blood disorders in pregnancy Angela K. Lucas-​Herald School of Medicine, University of Glasgow, Royal Hospital for Children, Glasgow, UK 13.7.3: Normal and abnormal sexual differentiation Ingrid E. Lundberg Rheumatology Unit, Department of Medicine, Sloan, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden 19.11.5: Inflammatory myopathies James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, Human Genome Sequencing Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA 3.2: The genomic basis of medicine Raashid Luqmani Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, UK 19.11.6: Large vessel vasculitis Linda Luxon National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK 24.6.3: Hearing loss Jean Paul Luzio Cambridge Institute for Medical Research, Cambridge, UK 3.1: The cell Lucio Luzzatto Department of Haematology, Muhimbili University of Health and Allied Sciences Dar es Salaam, Tanzania 22.5.3: Paroxysmal nocturnal haemoglobinuria; 22.6.11: Glucose-​6-​phosphate dehydrogenase deficiency Graz A. Luzzi Wycombe General Hospital, High Wycombe, UK 9.3: Sexual history and examination Kate D. Lynch Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford; Nuffield Department of Medicine, University of Oxford, Oxford, UK 15.23.4: Primary sclerosing cholangitis David Mabey Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta; 8.6.45: Chlamydial infections; 9.1: Epidemiology of sexually transmitted infections Peter K. MacCallum Senior Lecturer in Haematology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK 14.7: Thrombosis in pregnancy Alasdair MacGowan Department of Medical Microbiology, North Bristol NHS Trust, Bristol, UK 8.2.5: Antimicrobial chemotherapy Lucy Mackillop Obstetric Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 14.20 Prescribing in pregnancy Gael M. MacLean Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.6.3: Benign breast disease Kenneth T. MacLeod National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Alasdair MacLullich Edinburgh University, Edinburgh, UK 6.5: Older people in hospital Jane Macnaughtan Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK 15.22.5: Liver failure Robert Mactier Consultant Nephrologist, Glasgow Renal and Transplant Unit, South Glasgow University Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK 21.7.1: Haemodialysis C. Maguiña-​Vargas School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru 8.6.44: Bartonella bacilliformis infection Michael Maher Professor of Radiology, University College Cork and Consultant Radiologist, Cork University Hospital and Mercy University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract Malegapuru W. Makgoba National Health Ombud, Pretoria, South Africa; College of Health Science, University of KwaZulu-​Natal, Durban, South Africa; National Planning Commission of South Africa; Universities of Natal and KwaZulu-​Natal, Durban, South Africa; MRC (SA), Cape Town, South Africa 2.18: Fostering medical and health research in resource-​constrained countries Govind K. Makharia Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India 15.10.8: Malabsorption syndromes in
the tropics Hadi Manji The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 24.11.4: Neurosyphilis and neuro-​AIDS J.I. Mann Edgar Diabetes and Obesity Research Centre (EDOR), Department of Human Nutrition, University of Otago, Dunedin, New Zealand 11.5: Diseases of affluent societies and the need for dietary change David Mant University of Oxford, Oxford, UK 2.11: Preventive medicine G.A. Margaritopoulos Royal Brompton and Harefield NHS Trust, London, UK 18.11.5: The lung in vasculitis Anthony M. Marinaki Purine Research Laboratory, Viapath, St Thomas’ Hospital, London, UK 12.4: Disorders of purine and pyrimidine metabolism Chiara Marini-​Bettolo Newcastle University
John Walton Centre for Muscular Dystrophy Research, Newcastle upon Tyne Hospital NHS Foundation Trust, Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK 24.19.2: Muscular dystrophy Michael Marks Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Paul Marks Honorary Consultant Neurosurgeon, Harrogate District Hospital, Harrogate;
Her Majesty’s Senior Coroner for the City
of Kingston upon Hull and the County of
the East Riding of Yorkshire; Vice President, Faculty of Forensic and Legal Medicine,
London, UK; Honorary Professor of Neurosurgery, College of Medicine,
University of Malawi, Malawi 27.1: Forensic and legal medicine Thomas J. Marrie Department of Medicine, Dalhousie University, Nova Scotia, Canada 8.6.42: Coxiella burnetii infections (Q fever) Judith C.W. Marsh King’s College Hospital, King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Sara Marshall Wellcome Trust, London, UK 4.4: Immunodeficiency Steven B. Marston National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Maria do Rosario O. Martins University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Thiviyani Maruthappu Kelsell Group, Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London, Queen Mary University of London, London, UK 23.3: Inherited skin disease Duncan J. Maskell University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms N.A. Maskell Academic Respiratory Unit,
University of Bristol, UK 18.17: Pleural diseases Jay W. Mason Cardiology Division, University
of Utah College of Medicine, Salt Lake City, UT, USA 16.7.1: Myocarditis Tahir Masud Nottingham University Hospitals Trust, Nottingham, UK 6.8: Falls, faints, and fragility fractures Christopher J. Mathias Stoke Poges, UK 24.14: Diseases of the autonomic nervous
system

Contributors lviii Fadi Matta Associate Professor, Department of Osteopathic Medical Specialties, Collage of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Eric L. Matteson Division of Rheumatology, Divisions of Rheumatology and Epidemiology, Mayo Clinic College of Medicine, Rochester, MN, USA 19.11.11: Polymyalgia rheumatica Kieran McCafferty Consultant Nephrologist, Barts Health NHS Trust, London, UK 21.17: Urinary tract obstruction Fergus McCarthy Division of Women’s Health, Women’s Health Academic Centre KHP, St. Thomas’ Hospital, London, UK 14.4: Hypertension in pregnancy Brian W. McCrindle University of Toronto, Toronto, Canada; The Hospital for Sick Children, Toronto, ON, Canada 19.11.12: Kawasaki disease Theresa A. McDonagh King’s College Hospital, Denmark Hill, London, UK 16.5.1: Epidemiology and general pathophysiological classification of heart failure A.D. McGavigan Flinders University,
SA, Australia 16.2.2: Syncope and palpitation; 16.4: Cardiac arrhythmias Fiona McGill Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections John A. McGrath Genetic Skin Disease Group, St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, UK 23.1: Structure and function of skin Alastair McGregor Department of Tropical Medicine and Infectious Diseases, London Northwest Hospitals NHS Trust, London, UK; Department of Medicine, Imperial College London, London, UK 8.11.4: Intestinal trematode infections Jane McGregor Clinical Senior Lecturer and Honorary Consultant Dermatologist, Blizard Institute, Barts and the London School Medicine and Dentistry, London, UK 23.9: Photosensitivity Iain B. McInnes University of Glasgow, Glasgow, UK 3.3: Cytokines C.J. McKay Consultant Pancreaticobiliary Surgeon, West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK 15.26.1: Acute pancreatitis William J. McKenna The Heart Hospital, University College London, London, UK 16.7.2: The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular Curtis McKnight Dignity Health Medical Group;
St. Joseph’s Hospital and Medical Center; Creighton University School of Medicine,
Phoenix, AZ, USA 26.5.3: Organic psychoses Alison McMillan East and North Hertfordshire NHS Trust, Stevenage, UK 18.5.2: Sleep-​related breathing disorders Martin A. McNally The Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford University Hospitals, Oxford, UK 20.3: Osteomyelitis Regina McQuillan St Francis Hospice and Beaumont Hospital, Dublin, Ireland 7.3: Symptoms other than pain Simon Mead MRC Prion Unit, University College London, Institute of Prion Diseases; NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, Queen Square, London, UK 24.11.5: Human prion diseases Jill Meara Hyperbaric Medicine Unit, St Richard’s Hospital, Chichester, UK 10.3.7: Radiation Wajahat Z. Mehal Section of Digestive Diseases Yale University, New Haven, CT, USA 15.21: Pathobiology of chronic liver disease Tobias F. Menne Consultant Haematologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia David K. Menon Division of Anaesthesia, University of Cambridge, UK; Neurosciences Critical Care Unit, Royal College of Anaesthetists, London, UK; Queens’ College, Cambridge, UK; National Institute for Health Research, UK 17.7: Management of raised intracranial pressure Andrew Menzies-​Gow Royal Brompton Hospital, London, UK 18.7: Asthma Catherine H. Mercer Professor of Sexual
Health Science, Centre for Population Research in Sexual Health and HIV, Institute for Global Health, University College London, London, UK 9.2: Sexual behaviour Vinod K. Metta Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Jan H. ter Meulen Philipps University Marburg, 35043 Marburg, Germany 8.5.17: Arenaviruses; 8.5.18: Filoviruses Wayne M. Meyers Department of Environmental and Infectious Disease Sciences, Armed
Forces Institute of Pathology, Washington DC, USA 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection Paul K. Middleton Clinical Research Fellow, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Stephen J. Middleton Consultant Gastroenterologist, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge; Consultant Gastroenterologist (Hon.) St Mark’s Hospital, Harrow, London; Associate Professor (Hon.) Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Mark E. Mikkelsen Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 17.12: Persistent problems and recovery after critical illness Michael A. Miles Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.8.12: Chagas disease Robert F. Miller University College London, London, UK 8.7.5: Pneumocystis jirovecii Dawn S. Milliner Emeritus Professor of Medicine and Pediatrics at the Mayo Clinic Alix School of Medicine, Rochester, MN, USA 12.10 Hereditary disorders of oxalate metabolism: The primary hyperoxalurias K.R. Mills King’s College London, London, UK 24.3.4: Investigation of central motor pathways: Magnetic brain stimulation Philip Minor National Institute for Biological Standards and Control (NIBSC), Ridge, UK 8.5.8: Enterovirus infections Fraz A. Mir Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 16.17.3: Secondary hypertension Pramod K. Mistry Professor of Pediatrics and Medicine, Chief, Pediatric Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA 12.7.2 Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Andrew R.J. Mitchell Jersey General Hospital, Jersey, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Oriol Mitjà Barcelona Institute for Global Health, University of Barcelona, Spain; Lihir Medical Centre, InternationalSOS, Lihir Island, Papua New Guinea 8.6.36: Non-​venereal endemic treponematoses: Yaws, endemic syphilis (bejel), and pinta Aarthi R. Mohan Obstetrics and Maternal Medicine, University Hospitals Bristol NHS Foundation Trust, Bristol, UK 14.21: Contraception for women with medical diseases Fiachra Moloney Consultant Radiologist, Department of Radiology, Cork University Hospital, Cork, Ireland 15.3.3: Radiology of the gastrointestinal tract P.L. Molyneaux Royal Brompton and Harefield NHS Trust, London, UK 18.11.2: Idiopathic pulmonary fibrosis

Contributors lix Andrew J. Molyneux The Manor Hospital, Oxford, UK 24.3.3: Imaging in neurological diseases Peter D. Mooney Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Anthony V. Moorman Professor of Genetic Epidemiology, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK 22.4.2: Acute lymphoblastic leukaemia Pilar Morata Department of Biochemistry and Molecular Biology, School of Medicine, University of Málaga, Málaga, Spain 8.6.22: Brucellosis Marina S. Morgan Royal Devon and Exeter NHS Foundation Trust, Exeter, UK 8.6.19: Pasteurella Michael L. Moritz Professor of Pediatrics, University of Pittsburgh School of Medicine, Clinical Director, Division of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA 21.2.1: Disorders of water and sodium homeostasis Pedro L. Moro Immunization Safety Office, Division of Healthcare Quality Promotion, NCEZID, Centers for Disease Control and Prevention, Atlanta, GA, USA 8.10.2: Cystic hydatid disease (Echinococcus granulosus) Mary J. Morrell Imperial College London, London, UK 18.5.2: Sleep-​related breathing disorders Nicholas W. Morrell British Heart Foundation Professor of Cardiopulmonary Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK 16.15.1: Structure and function of the pulmonary circulation; 16.15.2: Pulmonary hypertension Emma C. Morris Professor, Division of Infection and Immunity, UCL Institute of Immunity and Transplantation, Royal Free Campus, Royal Free Hospital, London, UK and Honorary Consultant, University College London Medical School, London, UK 22.8.2: Haemopoietic stem cell transplantation Neil J.McC. Mortensen Professor of Colorectal Surgery, Nuffield Department of Surgery, University of Oxford; Honorary Consultant Colorectal Surgeon, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 15.14: Colonic diverticular disease Peter S. Mortimer St George’s University of London; St George’s Hospital, London; Royal Marsden Hospital, London, UK 16.18: Chronic peripheral oedema and lymphoedema; 23.12: Blood and lymphatic vessel disorders Ghulam J. Mufti King’s College Hospital/​King’s College London, London, UK 22.5.2: Acquired aplastic anaemia and pure red cell aplasia Victoria Mulcahy Norwich Medical School, University of East Anglia, Norwich, UK 15.10.1: Differential diagnosis and investigation of malabsorption David R. Murdoch Professor and Head of Pathology, University of Otago, Christchurch, New Zealand 10.3.6: Diseases of high terrestrial altitudes Paul Murphy NHS Blood and Transplant, Bristol, UK 17.11: Diagnosis of death and organ donation Christopher Murray University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Jean B. Nachega Departments of Epidemiology,
Infectious Diseases and Microbiology,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA USA; Department of Medicine, Centre for Infectious Diseases,
Stellenbosch University, Tygerberg, Cape Town, South Africa 8.6.26: Tuberculosis Robert B. Nadelman Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, NY, USA 8.6.33: Lyme borreliosis Alexandra Nanzer-​Kelly Guys and St Thomas’ Hospital, London, UK 18.7: Asthma Nikolai V. Naoumov Novartis Pharma, Basel, Switzerland 8.5.21: Hepatitis viruses (excluding hepatitis C virus) Kikkeri N. Naresh Department of Histopathology, Imperial College Healthcare NHS Trust and Imperial College, London, UK 15.10.4: Gastrointestinal lymphomas Kate Nash University Hospital Southampton NHS Foundation Trust, Southampton, UK 15.23.1: Hepatitis A to E N. Navani University College Hospital,
London, UK 18.19.1: Lung cancer Catherine Nelson-​Piercy Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Randolph M. Nesse Center for Evolution and Medicine, Arizona State University, AZ, USA 2.2: Evolution: Medicine’s most basic science Peter J. Nestor German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany 24.4.1: Disturbances of higher cerebral function Stefan Neubauer Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT James Neuberger Hon Consultant Physician, Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 15.24.5: The liver in systemic disease James D. Newton Oxford University Hospitals NHS Trust, Oxford, UK 16.3.2: Echocardiography; 16.14.1: Acute aortic syndromes Paul N. Newton Lao-​Oxford-​Mahosot Hospital-​ Wellcome Trust Research Unit (LOMWRU), Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR; Nuffield Department of Medicine, University of Oxford, Oxford; Infectious Diseases Data Observatory (IDDO), University of Oxford, Oxford, UK 2.10: Medicine quality, physicians,
and patients Wan-​Fai Ng Newcastle University and NIHR Newcastle Biomedical, Research Centre for
Ageing and Chronic Diseases, Newcastle upon Tyne, UK 19.11.4: Sjögren’s syndrome A.G. Nicholson Royal Brompton and Harefield NHS Trust; Professor of Respiratory Pathology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK 18.11.2: Idiopathic pulmonary fibrosis Jerry P. Nolan Warwick Medical School, Coventry; Royal United Hospital, Bath, UK 17.2: Cardiac arrest John Nowakowski New York Medical College,
NY, USA 8.6.33: Lyme borreliosis Paul Nyirjesy Drexel University College of Medicine, Philadelphia, PA, USA 9.4: Vaginal discharge Sarah O’Brien Modelling, Evidence and Policy
Group, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK 15.18: Gastrointestinal infections Amy O’Donnell Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 26.6.1: Brief interventions for excessive alcohol consumption Nigel O’Farrell Ealing Hospital, London North West University Healthcare NHS Trust, London, UK 8.6.14: Haemophilus ducreyi and chancroid John G. O’Grady Institute of Liver Studies, King’s College Hospital, London, UK 15.22.6: Liver transplantation Denis O’Mahony Department of Medicine, University College Cork and Department of Geriatric Medicine, Cork University Hospital, Cork, Ireland 6.7: Drugs and prescribing in the older patient E.E. Ooi Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore 8.5.12: Alphaviruses Susie Orme Barnsley Hospital NHS Foundation Trust, Barnsley, UK 6.9: Bladder and bowels Kevin O’Shaughnessy Division of Experimental Medicine and Immunotherapeutics,
Department of Medicine, University of Cambridge, Cambridge, UK 2.6: Principles of clinical pharmacology and drug therapy

Contributors lx Edel O’Toole Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry; and Department of Dermatology, Barts and the London NHS Trust, London, UK 23.14: Tumours of the skin Petra C.F. Oyston Biomedical Sciences, DSTL Porton Down, Salisbury, UK 8.6.20: Francisella tularensis infection Jacqueline Palace Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.18: Disorders of the neuromuscular junction Thomas Pap Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany 19.1: Joints and connective tissue—​structure and function Jayan Parameshwar Consultant Cardiologist, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Daniel H. Paris University of Oxford, Oxford, UK; Rickettsial Research (Oxford Tropical Network); Mahidol-​Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.6.41: Scrub typhus Sarah Parish Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Mike Parker Ethox Centre, Oxford, UK 1.5: Medical ethics Miles Parkes Consultant Gastroenterologist, Cambridge University Hospitals,
Cambridge, UK 15.11: Crohn’s disease Philippe Parola University Hospital Institute Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses Christopher M. Parry Clinical Sciences, Liverpool School of Tropical Medicine, and Institute of Infection and Global Health, University of Liverpool, UK; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 8.6.9: Typhoid and paratyphoid fevers Judith Partridge Guys and St Thomas’ Hospitals London, UK 6.6: Supporting older peoples’ care in surgical and oncological services Sant-​Rayn Pasricha MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK 22.6.5: Anaemia of inflammation Harnish Patel Academic Geriatric Medicine, University of Southampton, Southampton, UK 6.2: Frailty and sarcopenia Raj Patel Solent NHS Trust, Southampton, UK 9.6: Genital ulceration Sejal Patel Oxford Childrens Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 13.7.2: Normal puberty and its disorders John Paul SE region, National Infection Service, Public Health England, UK 8.6.47: A checklist of bacteria associated with infection in humans; 8.12: Non​venomous arthropods Jason Payne-​James Specialist in Forensic and Legal Medicine and Consultant Forensic Physician; Lead Medical Examiner, Norfolk and Norwich University Hospital, Norfolk, UK; Honorary Clinical Professor, William Harvey Research Institute, Queen Mary University of London, UK; Consultant Editor-​in-​Chief, Journal of Forensic and Legal Medicine; Director, Forensic Healthcare Services Ltd, Southminster, UK 27.1: Forensic and legal medicine Sharon J. Peacock University of Cambridge, Cambridge, UK 8.6.8: Pseudomonas aeruginosa; 8.6.16: Melioidosis and glanders Fiona Pearce Clinical Lecturer, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham City Hospital, Nottingham, UK 19.2: Clinical presentation and diagnosis of rheumatological disorders Rupert Pearse Queen Mary University of London, London, UK 17.4: Assessing and preparing patients with medical conditions for major surgery Malik Peiris School of Public Health, The University of Hong Kong, Hong Kong, Special Administrative Region of China 8.5.1: Respiratory tract viruses Neil Pendleton School of Biological Sciences, Faculty Biology Medicine and Health and Manchester Institute for Collaborative Research in Ageing, University of Manchester, Manchester, UK 6.1: Ageing and clinical medicine Hugh Pennington University of Aberdeen, Aberdeen, UK 8.6.7: Enterobacteria and bacterial food poisoning Mark B. Pepys Director, Wolfson Drug Discovery Unit, and Honorary Consultant Physician, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, University College London, London, UK 12.12.1 The acute phase response and C-​reactive protein; 12.12.3 Amyloidosis Stephen P. Pereira Professor of Hepatology and Gastroenterology, Institute for Liver and Digestive Health, University College London; Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.16: Cancers of the gastrointestinal tract; 15.26.3: Tumours of the pancreas Gavin D. Perkins Warwick Medical School, Coventry; Intensive Care Unit, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 17.2: Cardiac arrest David J. Perry Previously Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK 14.17: Blood disorders in pregnancy Hans Persson Swedish Poisons Centre, Stockholm, Sweden 10.4.3: Poisonous fungi; 10.4.4: Poisonous plants Eskild Petersen Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital Skejby, Aarhus, Denmark 8.8.4: Toxoplasmosis L.R. Petersen Director, Division of Vector-borne Infectious Diseases, Centers for Disease
Control and Prevention, Fort Collins,
Colorado, USA 8.5.12: Alphaviruses Trevor N. Petney Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP),
Faculty of Medicine, Khon Kaen University,
Khon Kaen, Thailand; Department of Paleontology and Evolution, Organization/​ University State Museum of Natural History, Karlsruhe, Germany 8.11.2: Liver fluke infections Philippa Peto Consultant in Renal and Acute Medicine, Queen Elizabeth Hospital, Lewisham and Greenwich NHS Trust, London, UK 1.6: Clinical decision-​making Richard Peto Nuffield Department of Population Health, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials
and meta-​analyses of trials; 5.1: Epidemiology of cancer Timothy E.A. Peto Nuffield Department of Clinical Medicine, University of Oxford; John Radcliffe Hospital, Oxford, UK 1.6: Clinical decision-​making; 8.5.23: HIV/​AIDS John D. Pickard University of Cambridge, Cambridge, UK 24.5.6: Brainstem death and prolonged disorders of consciousness Matthew C. Pickering Imperial College London, London, UK 4.2: The complement system Massimiliano di Pietro Senior Clinical Investigator Scientist and Consultant Gastroenterologist,
MRC Cancer Unit, University of Cambridge, Hutchison/​MRC Research Centre,
Cambridge, UK 15.7: Diseases of the oesophagus Michael R. Pinsky Professor Critical Care Medicine, Bio­engineering, Cardiovascular Disease and Anesthesiology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 17.6: Circulation and circulatory support in the critically ill Julia Platts University of Cardiff, Cardiff, UK 13.9.1: Diabetes Raymond J. Playford, Professor of Medicine, University of Plymouth, Plymouth, UK; Vice President Research Strategy, Pantheryx Inc., Boulder, CO, USA 15.10.2: Bacterial overgrowth of the small intestine; 15.10.7: Effects of massive bowel resection Michael I. Polkey Royal Brompton and Harefield NHS Trust, London, UK 18.15: Chronic respiratory failure; 18.18 Disorders of the thoracic cage and diaphragm

Contributors lxi Eleanor S. Pollak Associate Professor of Pathology and Laboratory Medicine (retired), Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA 22.7.4: Genetic disorders of coagulation Andrew J. Pollard Professor of Paediatric Infection and Immunity at the University of Oxford,
Director of the Oxford Vaccine Group, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital,
Oxford, UK 10.3.6: Diseases of high terrestrial altitudes Aaron Polliack Emeritus Professor, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel 22.4.5: Chronic lymphocytic leukaemia Allyson M. Pollock Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Cristina Ponte Department of Rheumatology, Hospital de Santa Maria -​ CHLN, Lisbon Academic Medical Centre, Lisbon, Portugal; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK 19.11.6: Large vessel vasculitis Kyle J. Popovich Rush University, Chicago,
IL, USA 8.6.4: Staphylococci Françoise Portaels Institute of Tropical Medicine, Antwerp, Belgium 8.6.29: Buruli ulcer: Mycobacterium ulcerans infection John B. Porter Professor of Haematology and Consultant Haematologist, University College London Hospitals, London, UK 22.6.4: Iron metabolism and its disorders Stephen Potts Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.5.5: Substance misuse William G. Powderly Division of Infectious Diseases and Institute for Public Health, Washington University in St. Louis, MO, USA 8.7.2: Cryptococcosis Janet Powell Department of Surgery and Cancer, Imperial College, London, UK 16.14.2: Peripheral arterial disease Amy Powers Associate Professor of Pathology, John A Burns School of Medicine, University of Hawaii, Department of Pathology, Honolulu, HI, USA 22.6.12: Acquired haemolytic anaemia Ann M. Powers Centers for Disease Control and Prevention, Atlanta, GA, USA 8.5.12: Alphaviruses Anton Pozniak Department of HIV and GUM, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK 18.4.5: Pulmonary complications of
HIV infection Bernard D. Prendergast John Radcliffe Hospital, Oxford, UK 16.9.2: Endocarditis Michael Prentice School of Microbiology, University College Cork, Cork, Ireland 8.6.17: Plague: Yersinia pestis; 8.6.18: Other Yersinia infections: Yersiniosis David Price Queen Mary University of London, London, UK 2.15: How much should rich countries’ governments spend on healthcare? Christopher Pugh Nuffield Department of Medicine, University of Oxford, Oxford, UK 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis Meredith Pugh Division of Pulmonary and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA 14.8: Chest diseases in pregnancy Graham Raftery South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK 19.7: Infection and arthritis Kazem Rahimi The George Institute for Global Health, University of Oxford,
Oxford, UK 16.13.2: Coronary heart disease: Epidemiology and prevention Anisur Rahman Centre for Rheumatology, University College London, London, UK 19.11.2: Systemic lupus erythematosus and related disorders Tim Raine IBD Lead and Consultant Gastroenterologist, Cambridge University Hospital, Cambridge, UK 15.11: Crohn’s disease K. Rajappan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 16.2.2: Syncope and palpitation S. Vincent Rajkumar Edward W. and Betty Knight Scripps Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA 22.4.6: Plasma cell myeloma and related monoclonal gammopathies Mary Ramsay Health Protection Agency,
London, UK 8.3: Immunization A.C. Rankin Glasgow Royal Infirmary, Glasgow, UK 16.2.2: Syncope and palpitation Didier Raoult University Hospital Institute  Méditerranée Infection, Marseille, France 8.6.40: Rickettsioses; 15.10.6: Whipple’s disease Michael Rawlins Medicines and Healthcare Products Regulatory Agency, London, UK 2.19: Regulation versus innovation in medicine Phillip Read University of New South Wales, Kensington, NSW, Australia 8.6.37: Syphilis Michael C. Reade Burns, Trauma and Critical Care Research Centre, Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Qld, Australia; Joint Health Command, Australian Defence Force, Canberra, ACT, Australia 17.8: Sedation and analgesia in the ICU Paul J. Reading Department of Sleep Medicine, The James Cook University Hospital, Middlesbrough, UK 24.5.3: Sleep disorders Jeremy Rees National Hospital for Neurology and Neurosurgery, London, UK; UCL Institute of Neurology, London, UK 24.23: Paraneoplastic neurological syndromes; 24.10.4: Intracranial tumours P.T. Reid Respiratory Unit, Western General Hospital, Edinburgh, UK 18.13: Pneumoconioses Shelley Renowden North Bristol NHS Trust, Bristol, UK 24.3.3: Imaging in neurological diseases John Richens Research Department of Infection and Population Health, University College London, London, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) Alan B. Rickinson Institute for Cancer Studies, University of Birmingham, Birmingham, UK 8.5.3: Epstein–​Barr virus B.K. Rima Wellcome-​Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK 8.5.5: Mumps: Epidemic parotitis David J. Roberts Radcliffe Department of Medicine, University of Oxford; Department of
Haematology, Oxford University Hospitals
NHS Trust and NHS Blood and Transplant,
Oxford, UK 22.6.3: Anaemia as a challenge to world health Harold R. Roberts Sarah Graham Kenan Professor of Medicine, Division of Hematology-​Oncology, University of North Carolina, Chapel Hill, NC, USA 22.7.1: The biology of haemostasis and thrombosis Irene Roberts Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 22.5.1: Inherited bone marrow failure syndromes Douglas Robertson Senior Lecturer and Honorary Consultant in Restorative Dentistry, University of Glasgow, Glasgow, UK 15.6: The mouth and salivary glands Marcus Robertson Gastroenterologist and Hepatologist, Monash Health, Vic, Australia; Monash University Department of Medicine,
Vic, Australia 15.22.3: Portal hypertension and variceal
bleeding Esther Robinson Public Health England, Birmingham, UK 8.6.13: Haemophilus influenzae T.A. Rockall Professor of Colorectal Surgery, University of Surrey; Consultant Colorectal Surgeon, Royal Surrey County Hospital Guildford, UK 15.4.2: Gastrointestinal bleeding Edward Roddy Keele University, Keele, UK 19.10: Crystal-​related arthropathies Simon D. Roger Renal Physician, Conjoint Professor, School of Medicine and Public Health, University of Newcastle, Newcastle; Director, Department of Renal Medicine, Central Coast Local Health District, Gosford, NSW, Australia 21.9.1: Acute interstitial nephritis

Contributors lxii Jean-​Marc Rolain IHU Méditerranée Infection, Marseille, France 8.6.43: Bartonellas excluding B. bacilliformis Pierre Ronco Professor of Renal Medicine, University Pierre et Marie Curie, and Inserm Unit UMR_​S1155, Tenon Hospital, Paris, France 21.10.5: Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Antony Rosen Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 4.6: Autoimmunity Jonathan D.C. Ross University Hospitals Birmingham NHS Trust, Birmingham, UK 9.8: Pelvic inflammatory disease Shannan Lee Rossi Department of Pathology, Center for Biodefense and Emerging Infectious Diseases; Member, Center for Tropical Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Peter M. Rothwell Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 24.10.1 Stroke: Cerebrovascular disease Simon M. Rushbrook Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK 15.24.6: Primary and secondary liver tumours Nigel Russell Professor of Haematology, Nottingham University, Nottingham, UK 22.3.3: Acute myeloid leukaemia Fiona Ryan Oxford Childrens Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK 13.7.2: Normal puberty and its disorders Nikant Sabharwal Department of Cardiology, John Radcliffe Hospital, Oxford, UK 16.3.3: Cardiac investigations: Nuclear, MRI, and CT Alan D. Salama University College London, London, UK 21.8.5: Proliferative glomerulonephritis Moin Saleem Professor of Paediatric Renal Medicine, University of Bristol Children’s Renal Unit, Bristol Royal Hospital for Children, Bristol, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Hesham A. Saleh Charing Cross Hospital and Royal Brompton Hospital, London; Imperial College London, London, UK 18.6: Allergic rhinitis Susan Salt Trinity Hospice, Blackpool, UK 7.1: Introduction to palliative care Nilesh J. Samani Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 16.17.4: Mendelian disorders causing hypertension Luis G. Sambo University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health David S. Sanders Royal Hallamshire Hospital and University of Sheffield, Sheffield, UK 15.10.3: Coeliac disease Jeremy Sanderson Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 15.12: Ulcerative colitis Vijay G. Sankaran Associate Professor of Pediatrics, Harvard Medical School, Division of Hematology/​Oncology, Boston Children’s Hospital, Dana-​Farber/​Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA 22.6.1: Erythropoiesis Swati Sathe Rutgers New Jersey Medical School, Newark, NJ, USA 24.17: Inherited neurodegenerative diseases Brian P. Saunders Consultant Gastroenterologist, St Mark’s Hospital, North West London Hospitals Trust; Adjunct Professor of Endoscopy, Imperial College London, London, UK 15.3.1: Colonoscopy and flexible sigmoidoscopy Kate E.A. Saunders University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.3.2: Self-​harm; 26.5.7: Bipolar disorder Rana Sayeed Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery John A. Sayer Institute Of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, UK 21.15: The renal tubular acidoses Claire Scampion Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK 6.11: Promotion of dignity in the life and death of older patients Matthew Scarborough Oxford University Hospitals NHS Foundation Trust, Oxford, UK; University of Oxford, Oxford, UK 8.2.3: Nosocomial infections Klaus P. Schaal Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany 8.6.30: Actinomycoses Michael L. Schilsky Associate Professor of Medicine, Medical Director, Adult Liver Transplant, Yale-​New Haven Transplantation Center, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA 12.7.2: Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease Jonathan M. Schott Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK 24.4.2: Alzheimer’s disease and other dementias Heinz-​Peter Schultheiss Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany 16.7.1: Myocarditis Jane Schwebke University of Alabama at Birmingham, AL, USA 8.8.14: Trichomoniasis Neil Scolding University of Bristol Institute of Clinical Neurosciences, Southmead Hospital, Bristol, UK 24.21: Acquired metabolic disorders and the nervous system; 24.22: Neurological complications of systemic disease Anthony Scott KEMRI-​Wellcome Trust Research Programme, Kilifi, Kenya; London School of Hygiene and Tropical Medicine,
London, UK 8.6.3: Pneumococcal infections James Scott Imperial College London, London, UK 12.6: Lipid disorders Rebecca Scott Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK 15.9.1: Hormones and the gastrointestinal tract Mårten Segelmark Professor of Nephrology, Department of Clinical Sciences, Lund
University and Department of Nephrology
Skane University Hospital, Lund, Sweden 21.8.7: Antiglomerular basement membrane disease Julian Seifter Associate Professor of Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA 12.11: A physiological approach to acid–base disorders: The roles of ion transport and body fluid compartments Bhuvaneish T. Selvaraj University of Edinburgh, Edinburgh, UK 3.7: Stem cells and regenerative medicine Amartya Sen Harvard University, Cambridge, MA, USA 2.20: Human disasters Arjune Sen Oxford Epilepsy Research Group, NIHR Oxford Biomedical Research Centre,
John Radcliffe Hospital, Oxford, UK 24.5.1: Epilepsy in later childhood and adulthood Debasish Sen Occupational Medicine, University of Manchester, UK 10.2.1: Occupational and environmental health Nicholas J. Severs National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, London, UK 16.1.2: Cardiac physiology Pallav L. Shah Imperial College London, London, UK 18.1.1: The upper respiratory tract; 18.1.2: Airways and alveoli; 18.3.3: Bronchoscopy, thoracoscopy, and tissue biopsy Muddassir Shaikh James Cook University Hospital, Middlesbrough, UK 19.7: Infection and arthritis Alena Shantsila University of Liverpool, Liverpool, UK 16.17.5: Hypertensive urgencies and
emergencies Susie Shapiro Consultant Haematologist,
Oxford University Hospitals NHS Foundation Trust, Oxford Haemophilia and
Thrombosis Centre, Churchill Hospital,
Oxford, UK 22.7.3: Thrombocytopenia and disorders of platelet function Claire C. Sharpe Professor of Renal Medicine, Faculty of Life Sciences and Medicine, King’s College London, London, UK 21.10.7: Sickle cell disease and the kidney

Contributors lxiii Michael Sharpe Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.1: General introduction; 26.2: The psychiatric assessment of the medical patient; 26.3.3: Medically unexplained symptoms; 26.4.2: Psychological treatments; 26.5.12: Somatic symptom and related disorders; 26.7: Psychiatry, liaison psychiatry, and psychological medicine Pamela J. Shaw Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK 24.15: The motor neuron diseases Debbie L. Shawcross Professor of Hepatology and Chronic Liver Failure, Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, UK 15.22.4: Hepatic encephalopathy Bart Sheehan Oxford University Hospitals NHS Foundation Trust, Oxford, UK 26.3.1: Confusion; 26.5.1: Delirium; 26.5.2: Dementia Neil Sheerin Professor of Nephrology, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 21.13: Urinary tract infection Mark Sherlock General Medicine and Emergency Medicine, NHS, UK; Médecins Sans Frontières (MSF), Paris, France 13.5.1: Disorders of the adrenal cortex Jackie Sherrard Wycombe General Hospital, High Wycombe, UK 8.6.6: Neisseria gonorrhoeae; 9.3: Sexual history and examination M.A. Shikanai-​Yasuda Faculdade Medicina, University of São Paulo (FMUSP), Brazil 8.7.4: Paracoccidioidomycosis Brian Shine Oxford University Hospitals NHS Foundation Trust, Oxford, UK 29.1: The use of biochemical analysis for diagnosis and management John M. Shneerson Papworth Hospital, Papworth Everard, UK 18.18: Disorders of the thoracic cage and diaphragm Volha Shpadaruk Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK 23.7: Cutaneous vasculitis, connective tissue diseases, and urticaria Joachim Sieper Free University, Berlin, Germany 19.6: Spondyloarthritis and related conditions Udomsak Silachamroon Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Leslie Silberstein Director, Transfusion Medicine, Boston Children’s Hospital, Boston, MA, USA 22.6.12: Acquired haemolytic anaemia Jorge Simões University Nova de Lisboa, Lisbon, Portugal 2.16: Financing healthcare in low-​income developing countries: A challenge for equity in health Alexandra Sinclair Institute of Metabolism and Systems Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The Medical School, University of Birmingham, Birmingham, UK 24.10.5: Idiopathic intracranial hypertension Rod Sinclair Department of Dermatology, University of Melbourne, Melbourne, Vic, Australia; Epworth Healthcare, Sinclair Dermatology Investigational Research, Education and Clinical Trials, East Melbourne, Vic, Australia 23.17: Management of skin disease Joseph Sinning Regional Cancer Care Associates, Hartford, CT, USA 22.3.1: Granulocytes in health and disease Thira Sirisanthana Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection J.G.P. Sissons† University of Cambridge School of Clinical Medicine, Cambridge, UK 8.5.2: Herpesviruses (excluding Epstein–​Barr virus) Paiboon Sithithaworn Professor, Cholangiocarcinoma Research Institute (CARI), Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University, Thailand; Professor Parasitology, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand 8.11.2: Liver fluke infections James R.A. Skipworth Consultant HPB and General Surgeon, Bristol Royal Infirmary, University Hospitals Bristol NHS Trust, Bristol, UK 15.26.3: Tumours of the pancreas Geoffrey L. Smith University of Cambridge, Cambridge, UK 8.5.4: Poxviruses Roger Smyth Department of Psychological Medicine, Edinburgh Royal Infirmary, Edinburgh, UK 26.2: The psychiatric assessment of the medical patient Rosamund Snow† BMJ, Tavistock Square, London, UK 1.3: What patients wish you understood E.L. Snyder Professor, Laboratory Medicine, Yale University Medical School; Director, Transfusion/​ Apheresis/​Tissue/​Cell Processing Services,
Yale-​New Haven Hospital, New Haven, CT, USA 22.8.1: Blood transfusion Jasmeet Soar Intensive Care Unit, Southmead Hospital, North Bristol NHS Trust, Bristol, UK 17.2: Cardiac arrest May Ching Soh Silver Star Unit, Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK 14.14: Autoimmune rheumatic disorders and vasculitis in pregnancy Elisaveta Sokolov Kings College Hospital, London, UK 24.7.2: Parkinsonism and other extrapyramidal diseases Tom Solomon Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 24.11.2: Viral infections Krishna Somers Royal Perth Hospital, Perth, WA, Australia 16.9.4: Cardiovascular syphilis Danielle Southerst NYU Langone Health, New York, NY, USA 19.4: Back pain and regional disorders Cathy Speed Consultant in Rheumatology, Sport and Exercise Medicine, Senior Physician, English Institute of Sport, Cambridge Centre for Health and Performance, Cambridge, UK 28.1: Sport and exercise medicine Des Spence Barclay Medical Centre, Maryhill Health Centre, Glasgow, UK 1.4: Why do patients attend and what do they want from the consultation? G.P. Spickett Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK 18.14.1: Diffuse alveolar haemorrhage; 18.14.2: Eosinophilic pneumonia; 18.14.4: Hypersensitivity pneumonitis S.G. Spiro University College Hospital,
London, UK 18.19.1: Lung cancer; 18.19.2: Pulmonary metastases David P. Steensma Institute Physician, Division of Hematologic Malignancies, Department of Medical Oncology, Dana-​Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA 22.3.2: Myelodysplastic syndromes Jerry L. Spivak Hematology Division,
Johns Hopkins University School of Medicine, Baltimore, MD, USA 22.3.7: Primary myelofibrosis Charles L. Sprung Department of Anesthesiology, Critical Care Medicine and Pain Medicine, Hadassah Medical Center, Hebrew
University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 17.10: Palliative and end-​of-​life care in the ICU Paweł Stankiewicz Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA 3.2: The genomic basis of medicine Natalie Staplin Clinical Trial Service Unit, University of Oxford, Oxford, UK 2.4: Large-​scale randomized evidence: Trials and meta-​analyses of trials Paul D. Stein Professor, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA 16.16.1: Deep venous thrombosis and pulmonary embolism Chris Stenton Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 18.14.11: Toxic gases and aerosols Dennis L. Stevens Infectious Diseases Section, VA Medical Center, Boise, ID, USA 8.6.2: Streptococci and enterococci; 8.6.25: Botulism, gas gangrene, and clostridial gastrointestinal infections Claire Steves King’s College London, London, UK 6.1: Ageing and clinical medicine † It is with great regret that we report that J.G.P. Sissons died on 25 September, 2016 and Rosamund Snow died on 2 February, 2017.

Contributors lxiv Carmel B. Stober University of Cambridge, Cambridge, UK 19.8: Reactive arthritis Nicole Stoesser Nuffield Department of Medicine Medical Sciences Division, University of Oxford, Oxford, UK 8.6.10: Intracellular klebsiella infections (donovanosis and rhinoscleroma) John R. Stradling Oxford Centre for Respiratory Medicine, John Radcliffe Hospital, Oxford, UK 18.1.1: The upper respiratory tract Michael A. Stroud Department of Medicine, University of Southampton, Southampton, UK 10.3.2: Heat; 10.3.3: Cold Michael Strupp Ludwig Maximilians University, Munich, Germany 24.6.2: Eye movements and balance Matthew J. Stuckey School of Veterinary Medicine, University of California, CA, USA 8.6.43: Bartonellas excluding B. bacilliformis Peter H. Sugden National Heart and Lung Institute (NHLI) Division, Faculty of Medicine, Imperial College London, UK 16.1.2: Cardiac physiology Mehrunisha Suleman Ethox Centre,
Oxford, UK 1.5: Medical ethics Joseph Sung Professor of Medicine, lately President and Vice Chancellor, The Chinese University of Hong Kong, Shatin, Hong Kong, China 15.8: Peptic ulcer disease Khuanchai Supparatpinyo Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand 8.7.6: Talaromyces (Penicillium) marneffei infection Erik R. Swenson VA Puget Sound Health Care System, Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA 10.3.6: Diseases of high terrestrial altitudes Anthony Swerdlow The Institute of Cancer Research, University of London, London, UK 5.1: Epidemiology of cancer David Taggart University of Oxford, Oxford, UK 16.13.6: Coronary artery bypass and valve surgery Kathy Taghipour The Whittington Health NHS Trust, London, UK 23.4: Autoimmune bullous diseases Penelope Talelli Homerton University Hospitals NHS Trust, UK 24.7.1: Subcortical structures: The cerebellum, basal ganglia, and thalamus Paolo Tammaro Associate Professor, Department of Pharmacology, University of Oxford, Oxford, UK 3.4: Ion channels and disease C.T. Tan University of Malaya, Kuala Lumpur, Malaysia 8.5.7: Nipah and Hendra virus encephalitides Chen Sabrina Tan Harvard Medical School, Boston, MA, USA 8.5.19: Papillomaviruses and polyomaviruses T.M. Tan Consultant in Diabetes, Endocrinology, and Metabolic Medicine, Imperial College London, London, UK 13.8: Pancreatic endocrine disorders and multiple endocrine neoplasia; 15.9.1: Hormones and the gastrointestinal tract; 15.9.2: Carcinoid syndrome David Taylor-​Robinson Section of Retrovirology and GU Medicine, Department of Infectious Diseases, Wright-​Fleming Institute, Faculty of Medicine, Imperial College London, London, UK 8.6.45: Chlamydial infections; 8.6.46: Mycoplasmas F. Teo National University Hospital, National University Health System, Singapore, China 18.11.1: Diffuse parenchymal lung disease: An introduction R.V. Thakker Academic Endocrine Unit, University of Oxford, OCDEM, Churchill Hospital, Oxford, UK 13.4: Parathyroid disorders and diseases altering calcium metabolism Nishanthi Thalayasingam Faculty of Medical Sciences, Newcastle University and Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2.7: Biological therapies for immune, inflammatory, and allergic diseases Richard J. Thompson Professor of Molecular Hepatology, Institute of Liver Studies, King’s College London, London, UK 15.24.7: Liver and biliary diseases in infancy and childhood S.A. Thorne University Hospital, Birmingham, UK 16.12: Congenital heart disease in the adult Guy E. Thwaites Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam 24.11.1: Bacterial infections C. Louise Thwaites Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.6.23: Tetanus Adam D. Timmis Barts Heart Centre, Queen Mary University London, London, UK 16.13.3: Management of stable angina Stephen M. Tollman University of the Witwatersrand, Johannesburg, South Africa; MRC/​Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences; INDEPTH Network (International Network for the Demographic Evaluation of Populations and Their Health), Accra, Ghana, South Africa; Centre for Global Health Research, Umeå University, Sweden 2.18: Fostering medical and health research in resource-​constrained countries Maciej Tomaszewski Division of Cardiovascular Sciences, University of Manchester, Manchester, UK 16.17.4: Mendelian disorders causing hypertension Charles Tomson Consultant Nephrologist,
Freeman Hospital, Newcastle upon
Tyne, UK 21.13: Urinary tract infection Pat Tookey Honorary Associate Professor, Population, Policy and Practice Research
and Teaching Department, University College London Institute of Child Health,
London, UK 8.5.13: Rubella Peter Topham Consultant Nephrologist,
John Walls Renal Unit, University Hospitals
of Leicester NHS Trust, Leicester, UK 21.8.2: Thin membrane nephropathy Nicholas Torpey Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.7.3: Renal transplantation Thomas A. Traill Division of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA 16.10: Tumours of the heart; 16.11: Cardiac involvement in genetic disease A.S. Truswell University of Sydney, Sydney, NSW, Australia 11.5: Diseases of affluent societies and the need for dietary change Steven Tsui Consultant Cardiac Surgeon, Royal Papworth Hospital, Cambridge, UK 16.5.5: Cardiac transplantation and mechanical circulatory support Youyou Tu Professor, Department of Chemistry, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 2.8: Traditional medicine exemplified by traditional Chinese medicine D.M. Turnbull Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK 24.19.5: Mitochondrial disease A. Neil Turner Professor of Nephrology,
University of Edinburgh, Queen’s Medical Research Institute (CIR), Edinburgh, UK 21.10.8: Infection-​associated nephropathies; 21.10.9: Malignancy-​associated renal disease Tabitha Turner-​Stokes MRC Clinical Research Fellow, Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK 21.8.6: Membranoproliferative glomerulonephritis Holm H. Uhlig Translational Gastroenterology Unit and Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK 15.15: Congenital abnormalities of the gastrointestinal tract Magnus Unemo WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden 8.6.6: Neisseria gonorrhoeae; 8.6.45 Chlamydial infections Robert Unwin Department of Renal Medicine, University College London, London, UK 21.1: Structure and function of the kidney

Contributors lxv John A. Vale National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit; City Hospital, Birmingham; School of Biosciences, University of Birmingham, Birmingham, UK 10.4.1: Poisoning by drugs and chemicals Patrick Vallance GlaxoSmithKline, London, UK 16.1.1: Blood vessels and the endothelium Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University, B-​3000 Leuven, Belgium 17.9: Metabolic and endocrine changes in acute and chronic critical illness Steven Vanderschueren Leuven Research Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, Clinical Department of General Internal Medicine, University Hospital Leuven, B-​3000 Leuven, Belgium 8.2.2: Fever of unknown origin Sirivan Vanijanonta Department of Clinical
Tropical Medicine, Faculty of Tropical
Medicine, Mahidol University,
Bangkok, Thailand 8.11.3: Lung flukes (paragonimiasis) Anita Vas-​Falcao London School of Hygiene and Tropical Medicine, London, UK 9.1: Epidemiology of sexually transmitted infections Nikos Vasilakis Department of Pathology,
Center for Biodefense and Emerging Infectious Diseases, Center for Tropical Diseases,
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 8.5.14: Flaviviruses excluding dengue Diana Vassallo Specialist Registrar, Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, UK 21.10.10: Atherosclerotic renovascular disease Birgitte Vennervald Section for Parasitology and Aquatic Diseases, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 8.11.1: Schistosomiasis Vanessa Venning Department of Dermatology, Churchill Hospital, Oxford, UK 23.2: Clinical approach to the diagnosis of skin disease Anilrudh A. Venugopal Los Angeles, CA, USA 8.6.11: Anaerobic bacteria Kristien Verdonck Institute of Tropical Medicine, Antwerp, Belgium 8.5.25: HTLV-​1, HTLV-​2, and associated
diseases Christopher M. Verity Addenbrookes Hospital, Cambridge, UK 24.20: Developmental abnormalities of the central nervous system Benjamin A. Vervaet Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium 21.9.2: Chronic tubulointerstitial nephritis Diego Viasus Division of Health Sciences, Faculty of Medicine, Universidad del Norte, Barranquilla, Colombia 8.6.39: Legionellosis and Legionnaires’ disease Angela Vincent Hon Cons Immunology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK 24.24: Autoimmune encephalitis and Morvan’s syndrome Raphael P. Viscidi Johns Hopkins Medical Institution, Baltimore, MD, USA 8.5.19: Papillomaviruses and polyomaviruses H. Josef Vormoor Clinical Director,
Department of Hemato-​oncology, Princess Máxima Center for Pediatric Oncology,
Utrecht, the Netherlands 22.4.2: Acute lymphoblastic leukaemia Theo Vos University of Washington, WA, USA 2.3: The Global Burden of Disease: Measuring the health of populations Henry J.C. de Vries Academic Medical Centre,
University of Amsterdam, Amsterdam, the Netherlands 9.7: Anogenital lumps and bumps Paresh Vyas Professor of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe
Department of Medicine, University of Oxford; Consultant Haematologist, Department of
Haematology, Cancer and Haematology
Centre, Churchill Hospital, Oxford
University Hospitals NHS Foundation Trust,
Oxford, UK 22.2.1: Cellular and molecular basis of haematopoiesis Peter D. Wagner Division of Physiology at the Department of Medicine, University of California San Diego, CA, USA 18.1.2: Airways and alveoli Nicholas Wald Institute of Health Informatics, University College London, London; Population Health Research Institute, St George’s University of London, London; Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Rhode Island, USA 2.12: Medical screening Herman Waldmann Sir William Dunn School of Pathology, University of Oxford, Oxford, UK 3.8: The evolution of therapeutic antibodies Jane Walker Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK 26.2: The psychiatric assessment of the medical patient; 26.3.4: Low mood Matthew C. Walker National Hospital of Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London, UK 24.5.2: Narcolepsy Elizabeth Wallin Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Sarah Walsh King’s College Hospital,
London, UK 23.16: Cutaneous reactions to drugs T.E. Warkentin Professor, Department of Pathology and Molecular Medicine and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada 22.7.5: Acquired coagulation disorders David A. Warrell Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses; 8.5.27: Orf and Milker’s nodule; 8.5.28: Molluscum contagiosum; 8.6.34: Relapsing fevers; 8.13: Pentastomiasis (porocephalosis, linguatulosis/​linguatuliasis, or tongue worm infection); 10.4.2: Injuries, envenoming, poisoning, and allergic reactions caused by animals; 10.4.3: Poisonous fungi; 24.11.2: Viral infections Mary J. Warrell Oxford Vaccine Group, University of Oxford, Oxford, UK 8.5.10: Rhabdoviruses: Rabies and rabies-​related lyssaviruses; 8.5.11: Colorado tick fever and other arthropod-​borne reoviruses John A.H. Wass University of Oxford, Oxford, UK 13.2.1: Disorders of the anterior pituitary gland; 13.2.2: Disorders of the posterior pituitary gland; 13.10: Hormonal manifestations of non-​endocrine disease Lawrence Waterman Loughborough University, Loughborough, UK; Park Health and Safety Partnership, Aylesbury, UK 10.2.2: Occupational safety Laurence Watkins The National Hospital for Neurology and Neurosurgery, London, UK 24.10.3: Traumatic brain injury Peter Watkinson Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Richard A. Watts Department of Rheumatology, Ipswich Hospital, Ipswich; Norwich Medical School, University of East Anglia, Norwich, UK 19.11.9: Small vessel vasculitis Richard W.E. Watts† Division of Inherited Metabolic Diseases, Northwick Park Hospital, London, UK 12.1: The inborn errors of metabolism: general aspects; 12.4: Disorders of purine and pyrimidine metabolism David J. Weatherall† Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK 22.6.2: Anaemia: Pathophysiology, classification, and clinical features; 22.6.3: Anaemia as a challenge to world health; 22.6.7: Disorders of the synthesis or function of haemoglobin G.J. Webb Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK 15.23.2: Autoimmune hepatitis Lisa J. Webber St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK 13.6.1: Ovarian disorders George J. Webster Consultant Hepatologist and Gastroenterologist, University College Hospital and Royal Free Hospital, London, UK 15.3.2: Upper gastrointestinal endoscopy † It is with great regret that we report that Richard W.E. Watts died on 11 February, 2018 and David J. Weatherall died on 8 December, 2018.

Contributors lxvi Anthony P. Weetman University of Sheffield, Sheffield, UK 13.3.1: The thyroid gland and disorders of thyroid function; 13.3.2: Thyroid cancer Robert A. Weinstein Rush University, Chicago, IL, USA 8.6.4: Staphylococci Louis M. Weiss Department of Pathology, Division of Parasitology and Tropical Medicine; Department of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, NY, USA 8.7.7: Microsporidiosis; 8.8.7: Cystoisosporiasis Robin A. Weiss University College London, London, UK 8.5.26: Viruses and cancer Peter F. Weller William Bosworth Castle Professor of Medicine, Harvard Medical School, Boston; Chief of the Infectious Diseases and the Allergy and Inflammation Divisions, Beth Israel Deaconess Medical Center, Boston, MD, USA 22.3.8: Eosinophilia A.U. Wells Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK 18.11.1: Diffuse parenchymal lung disease: An introduction; 18.11.2: Idiopathic pulmonary fibrosis; 18.11.3: Bronchiolitis obliterans and cryptogenic organizing pneumonia; 18.11.4: The lung in autoimmune rheumatic disorders; 18.11.5: The lung in vasculitis Simon Wessely Department of Psychological Medicine, King’s College London, London, UK 26.4.2: Psychological treatments Gilbert C. White, II Aster Chair for Medical Research, Executive Vice President for Research, Director, Blood Research Institute, Versiti; Professor of Medicine, Biochemistry, and Pharmacology, Associate Dean for Research, Medical College of Wisconsin, Milwaukee, WI, USA 22.7.1: The biology of haemostasis and thrombosis Nicholas J. White Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK 8.8.2: Malaria Hilton C. Whittle Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 8.5.6: Measles Anthony S. Wierzbicki Department of Metabolic Medicine/​Chemical Pathology, Guy’s and St Thomas’ Hospitals, London, UK 12.9: Disorders of peroxisomal metabolism in adults Mark H. Wilcox Professor of Medical Microbiology, Microbiology, Old Medical School, Leeds General Infirmary, and University of Leeds, Leeds, UK 8.6.24: Clostridium difficile Kate Wiles Department of Women and Children’s Health, King’s College London, London, UK 14.5: Renal disease in pregnancy James S. Wiley Principal Research Fellow, Florey Institute of Neuroscience, and Mental Health Honorary Professor, University of Melbourne, Melbourne, Vic, Australia 22.6.8: Anaemias resulting from defective maturation of red cells R.G. Will Professor of Clinical Neurology, Department of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK 24.11.5: Human prion diseases Lisa Willcocks Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK 21.8.3: Minimal change nephropathy and focal segmental glomerulosclerosis Bryan Williams University College London, London, UK 16.17.1: Essential hypertension: Definition, epidemiology, and pathophysiology; 16.17.2: Essential hypertension: Diagnosis, assessment, and treatment David J. Williams Obstetric Physician, Institute for Women’s Health, University College London Hospital, London, UK 14.1: Physiological changes of normal pregnancy; 14.2: Nutrition in pregnancy; 14.3: Medical management of normal pregnancy Catherine Williamson Professor of Women’s Health, King’s College London and Honorary Consultant in Obstetric Medicine, St Thomas’ and King’s College Hospitals, London, UK 14.9: Liver and gastrointestinal diseases of pregnancy Bridget Wills Centre for Tropical Medicine
and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.5.15: Dengue; 24.11.2: Viral infections R. Wilson Royal Brompton and Harefield NHS Trust, London, UK 18.9: Bronchiectasis Greg Winter MRC Laboratory of Molecular Biology, Cambridge, UK 3.8: The evolution of therapeutic antibodies Miles Witham AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UK 6.7: Drugs and prescribing in the older patient Fenella Wojnarowska Nuffield Department of Medicine, University of Oxford, Oxford, UK 14.13: The skin in pregnancy; 23.4: Autoimmune bullous diseases Edwin K.S. Wong Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 21.10.6: Haemolytic uraemic syndrome James L.N. Wood University of Cambridge, Cambridge, UK 8.1.1: Biology of pathogenic microorganisms Jonathan Wood Substance Misuse Psychiatry, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK 26.5.4: Alcohol misuse Kathryn J. Wood Transplant Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK 4.7: Principles of transplantation immunology Nicholas Wood University College London, London, UK 24.7.4: Ataxic disorders Andrew F. Woodhouse Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, UK 8.6.32: Rat bite fevers (Streptobacillus moniliformis and Spirillum minus infection) Jeremy Woodward Cambridge Intestinal Failure and Transplant Unit, Addenbrooke’s Hospital, Cambridge, UK 11.7: Artificial nutrition support; 15.2: Symptoms of gastrointestinal disease Elaine M. Worcester Professor of Medicine, Nephrology Section, Department of Medicine, University of Chicago, Chicago, USA 21.14: Disorders of renal calcium handling, urinary stones, and nephrocalcinosis B. Paul Wordsworth Emeritus Professor of Clinical Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK 20.1: Skeletal disorders—​general approach and clinical conditions Gary P. Wormser New York Medical College, NY, USA 8.6.33: Lyme borreliosis Mark Wright Consultant Gastroenterologist, University Hospital Southampton, Southampton, UK 15.25: Diseases of the gallbladder and biliary tree Channa Jayasumana Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka 21.9.2: Chronic tubulointerstitial nephritis Muhammad M. Yaqoob Barts Health NHS Trust, Renal Unit, Royal London Hospital, London, UK 21.17: Urinary tract obstruction Hasan Yazici Department of Medicine (Rheumatology), Academic Hospital, Istanbul, Turkey 19.11.10: Behçet’s syndrome Lam Minh Yen Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 8.6.23: Tetanus Duncan Young Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 8.1.2: Clinical features and general management of patients with severe infections Katherine Younger School of Biological and Health Sciences, Technological University Dublin, Dublin, Ireland 11.3: Minerals and trace elements Sebahattin Yurdakul Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey 19.11.10: Behçet’s syndrome Alberto Zanella Oncohematology Unit—​ Pathophysiology of Anemias Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore, Milan, Italy 22.6.10: Erythrocyte enzymopathies Adam Zeman Professor of Cognitive and Behavioural Neurology, University of Exeter Medical School, Exeter, UK 24.2: Mind and brain: Building bridges between neurology, psychiatry, and psychology Clive S. Zent University of Rochester Medical Center, Rochester, NY, USA 22.4.5: Chronic lymphocytic leukaemia

SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay 22.1 Introduction to haematology  5169 Chris Hatton 22.2 Haemopoiesis  5172 22.2.1 Cellular and molecular basis of haematopoiesis  5172 Paresh Vyas and N. Asger Jakobsen 22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181 Wendy N. Erber 22.3 Myeloid disease  5189 22.3.1 Granulocytes in health and disease  5189 Joseph Sinning and Nancy Berliner 22.3.2 Myelodysplastic syndromes  5197 Charlotte K. Brierley and David P. Steensma 22.3.3 Acute myeloid leukaemia  5205 Nigel Russell and Alan Burnett 22.3.4 Chronic myeloid leukaemia  5213 Mhairi Copland and Tessa L. Holyoake 22.3.5 The polycythaemias  5227 Daniel Aruch and Ronald Hoffman 22.3.6 Thrombocytosis and essential thrombocythaemia  5239 Daniel Aruch and Ronald Hoffman 22.3.7 Primary myelofibrosis  5247 Evan M. Braunstein and Jerry L. Spivak 22.3.8 Eosinophilia  5254 Peter F. Weller 22.3.9 Histiocytosis  5259 Chris Hatton 22.4 Lymphoid disease  5263 22.4.1 Introduction to lymphopoiesis  5263 Caron A. Jacobson and Nancy Berliner 22.4.2 Acute lymphoblastic leukaemia  5269 H. Josef Vormoor, Tobias F. Menne, and
Anthony V. Moorman 22.4.3 Hodgkin lymphoma  5280 Vijaya Raj Bhatt and James O. Armitage 22.4.4 Non-​Hodgkin lymphoma  5288 Vijaya Raj Bhatt and James O. Armitage 22.4.5 Chronic lymphocytic leukaemia  5302 Clive S. Zent and Aaron Polliack 22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310 S. Vincent Rajkumar and Robert A. Kyle 22.5 Bone marrow failure  5325 22.5.1 Inherited bone marrow failure
syndromes  5325 Irene Roberts and Inderjeet S. Dokal 22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336 Judith C.W. Marsh, Shreyans Gandhi, and
Ghulam J. Mufti 22.5.3 Paroxysmal nocturnal haemoglobinuria  5348 Lucio Luzzatto 22.6 Erythroid disorders  5354 22.6.1 Erythropoiesis  5354 Vijay G. Sankaran 22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359 David J. Weatherall and Chris Hatton 22.6.3 Anaemia as a challenge to world health  5366 David J. Roberts and David J. Weatherall 22.6.4 Iron metabolism and its disorders  5371 Timothy M. Cox and John B. Porter 22.6.5 Anaemia of inflammation  5402 Sant-​Rayn Pasricha and Hal Drakesmith 22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407 A.V. Hoffbrand 22.6.7 Disorders of the synthesis or function of haemoglobin  5426 Deborah Hay and David J. Weatherall 22.6.8 Anaemias resulting from defective maturation
of red cells  5450 Stephen J. Fuller and James S. Wiley

22.6.9 Disorders of the red cell membrane  5456 Patrick G. Gallagher 22.6.10 Erythrocyte enzymopathies  5463 Alberto Zanella and Paola Bianchi 22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472 Lucio Luzzatto 22.6.12 Acquired haemolytic anaemia  5479 Amy Powers and Leslie Silberstein 22.7 Haemostasis  5490 22.7.1 The biology of haemostasis and thrombosis  5490 Gilbert C. White, II, Harold R. Roberts,
and Nigel S. Key 22.7.2 Evaluation of the patient with a bleeding tendency  5509 Trevor Baglin 22.7.3 Thrombocytopenia and disorders of platelet function  5520 Nicola Curry and Susie Shapiro 22.7.4 Genetic disorders of coagulation  5532 Eleanor S. Pollak and Katherine A. High 22.7.5 Acquired coagulation disorders  5546 T.E. Warkentin 22.8 Transfusion and transplantation  5563 22.8.1 Blood transfusion  5563 D.S. Giovanniello and E.L. Snyder 22.8.2 Haemopoietic stem cell transplantation  5579 E.C. Gordon-​Smith and Emma C. Morris     SECTION 22  Haematological disorders

Malignant diseases of the urinary tract 5136 Tim E

Malignant diseases of the urinary tract 5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart

Mechanical and structural factors

Mechanical and structural factors

21.10.1  Diabetes mellitus and the kidney 4977 type 1 diabetes, although this distinction is not absolute. What is certain is that progression of nephropathy is much faster in patients with higher systemic blood pressure. Haemodynamic factors The glomerular filtration rate (GFR) is increased in newly diagnosed type 1 and type 2 diabetic patients. This phenomenon has been termed hyperfiltration and is thought to be due to a relative vasodila- tation of the afferent glomerular arteriole, which leads to an increase in intraglomerular capillary pressure (Fig. 21.10.1.1) and thereby glomerulosclerosis. Hyperfiltration and raised intraglomerular ca- pillary pressure are thought to be caused in part by activation of the local renin–​angiotensin system, leading to an excess production of angiotensin II and thereby relative vasoconstriction of the efferent glomerular arteriole. The evidence for a causative role of hyperfiltration for nephrop- athy in humans is conflicting and not helped by differing definitions of an abnormally high GFR and the difficulty of obtaining an esti- mate of intraglomerular capillary pressure. It appears that the rate of decline of GFR in hyperfiltering type 1 patients with a normal UAER is greater than that seen in age-​matched and duration-​ matched controls. A meta-​analysis has demonstrated a link between hyperfiltration and subsequent development of moderately in- creased albuminuria in type 1 diabetes but could not exclude a con- founding effect of hyperglycaemia. Recent data suggest that there is a link between hyperfiltration and later development of moderately increased albuminuria in adolescents, and a positive relationship between GFR and glomerular basement membrane thickening in younger adults. Pima Indians show an increase in GFR at or shortly after the development of type 2 diabetes, but their baseline values are not linked to the subsequent development of nephropathy. Growth factors In experimental animals, an initial increase in kidney size ob- served in diabetes is preceded by an increase in renal production of insulin-​like growth factor 1, and there are reports of increased circulating and urinary levels in people with diabetes. Other growth factors listed in Box 21.10.1.1 have been linked to matrix accumulation and development of proteinuria in experimental diabetes. Increased whole kidney volume is also a feature of newly diag- nosed type 1 diabetes in humans, but there is no conclusive link to subsequent development of nephropathy. Several of the growth factors listed in Box 21.10.1.1 have been found to have an in- creased production or gene expression in biopsies from patients with diabetes compared to those from nondiabetic patients. It is unclear whether these changes are causative. There are recent data linking the serum concentration of circulating tumour ne- crosis factor receptors 1 and 2 and fibroblast growth factor to subsequent development of nephropathy, but these results re- quire confirmation and there are problems with standardizing the assays. Mechanical and structural factors Along with whole kidney volume, glomerular size is also increased at diagnosis of type 1 diabetes and is a feature of established clinical proteinuria in both type 1 and type 2 diabetes. These changes may be secondary to haemodynamic alterations in early nephropathy or represent an adaptive response to loss of filtration surface in estab- lished glomerulopathy. A link between glomerular size and subse- quent progression to sclerosis has been described in patients with minimal-​change nephropathy, but the connection in diabetes is not proven. Reductions of heparan sulphate proteoglycan in the extracellular matrix of diabetic patients and the glomerular basement membrane of those with moderately and severely increased albuminuria have been reported. This finding has formed the basis of the so-​called Steno hypothesis, which proposes that these alterations underpin the pathophysiology of nephropathy. More recently there has been a focus on changes in the composition of the endothelial glycocalyx as an explanation of increasing albuminuria in diabetes, and it may be that changes in heparan sulphate proteoglycan in this struc- ture, rather than the GBM, are more important in terms of protein permselectivity. In vitro studies of mechanical stretch on cultured human mesangial cells and podocytes have demonstrated increased pro- duction of cytokines and growth factors associated with extracellular matrix accumulation. These studies provide a plausible mechanism whereby changes in intraglomerular capillary pressure may lead to glomerulosclerosis. The discovery of glomerular epithelial cells (podocytes) in the urine of patients with proteinuria has led to extensive research into their possible role in progressive nephropathies, including diabetes. Reduced numbers of podocytes have been found in human diabetic glomeruli from patients with diabetic nephrop- athy, but it remains unclear whether these changes precede or result from developing glomerulopathy. There is a significant negative relationship between the numbers of podocytes per glomerulus and increasing albuminuria in patients with estab- lished diabetic nephropathy. Glomerulus: Glomerular capillaries Glomerular filtrate Proximal tubule Bowman’s capsule Afferent arteriole Efferent arteriole Mesangium Fig. 21.10.1.1  Schematic of a glomerulus. In diabetes, there is relative afferent arteriolar dilatation and angiotensin II-​induced efferent arteriolar constriction. This leads to increased glomerular capillary flow and pressure resulting in elevated GFR (hyperfiltration) and increased albumin filtration. Blockade of the renin–​angiotensin system dilates the efferent arteriole and reduces GFR and capillary pressure.

Nonrenal outcomes

Nonrenal outcomes

Other aspects

Other aspects

section 21  Disorders of the kidney and urinary tract 4984 Criteria for diagnosis Diabetic nephropathy is a clinical diagnosis based upon the finding of albuminuria in a patient with diabetes and in whom there is no evidence of urinary infection. The definitions of mod- erate and severe elevations are shown in Table 21.10.1.1. Current United Kingdom guidelines suggest confirming the diagnosis with one or two repeat tests over the subsequent 1 to 6 months (Fig. 21.10.1.3). Although timed urine collections remain the gold standard for diagnosis, they are cumbersome to use in routine clinical prac- tice and most definitions depend on a spot urine sample and thus a test of albumin concentration. Levels above 50 mg/​litre or above 300 mg/​litre define moderately and severely elevated albuminuria, respectively. Sensitivity and specificity can be im- proved by using an early morning, first-​voided specimen and correcting the urinary albumin level for creatinine concentration (an albumin:creatinine ratio (ACR)). Defining levels are shown in Table 21.10.1.1. The latest modification of the classification of CKD has divided stage 3 into 3a and 3b (eGFR 45–​60 and 30–​45 ml/​min per 1.73 m2 respectively). It also incorporates an assessment of albumin- uria as it is now acknowledged that increased urine excretion of albumin represents an independent risk factor for cardiovascular disease. This goes some way to aligning the historical classification of diabetic and CKD (Table 21.10.1.4). eGFR estimated from the MDRD equation consistently underestimates measured GFR in large diabetic cohorts, and it is not very accurate at values above 90 ml/​min. The newer CKD-​EPI equation has improved accuracy at higher values. However, as many newly diagnosed type 1 and type 2 patients have an elevated GFR, significant reductions over time may pass undetected. Treatment Glycaemic control and blood pressure The roles of glycaemic control and blood pressure management have been discussed earlier in this chapter. Current target HbA1c levels from the National Institute for Health and Care Excellence guidelines in the United Kingdom are less than 48 mmol/​mol (6.5%) for type 1 and type 2 patients. The American Diabetes Association target is 53  mmol/​mol (<7.0%) for most patients of both types. Blood pressure targets are below 130/​80 mmHg for patients with elevated albuminuria. Recent analyses suggest that values lower than this are of no benefit and may cause harm. Due to the piv- otal role that angiotensin II is thought to play in diabetic nephrop- athy development, all guidelines suggest using renin–​angiotensin system blocking agents as first-​line treatment. However, the UKPDS has shown that most type 2 patients will require two or more agents in order to achieve the target. Following publication of the OnTARGET and ALTITUDE trials, multiple blockade of the renin–​angiotensin system with the combination of an ACEi and an ARB is not recommended. Meta-​analysis has shown that although dual blockade appears to be more effective at reducing albuminuria, it is also associated with more adverse events, notably hyperkalaemia and acute kidney injury. Achieving blood pressure targets is difficult, particularly in pa- tients with type 2 diabetes and systolic hypertension. Although the UKPDS showed a linear relationship between glycaemia and blood pressure and microvascular risk, implying the lower the better, the ACCORD glycaemia and blood pressure studies failed to show benefit of reduction of HbA1c to below 48 mmol/​mol (≤6.5%) and of blood pressure to less than 120/​80 mmHg, suggesting that there is no benefit for patients by reducing current targets. Other aspects Low-​protein diets have been shown by meta-​analysis to slow the rate of decline of GFR in diabetic patients, and a study from Denmark has also shown benefit on mortality. Current dietary recommenda- tions are for an intake of between 0.7 and 0.9 g protein/​kg body weight per day. Aspirin in a dose of 325 mg/​day reduced myocardial infarction (relative risk 0.72; 99% confidence interval 0.55–​0.95) in 3711 type 1 and 2 patients with retinopathy. Although nephropathy status was not determined in this study, the use of low-​dose aspirin should be considered for all patients with an increased UAER (unless contra- indicated) because of their high risk for cardiovascular disease. Lipid-​lowering therapy should also be commenced for all diabetic patients with CKD. Observational studies suggest that patients with better glycaemic control have a better overall survival on haemodialysis. Active foot Annual dipstick urinalysis for protein Positive (>300 mg/L) Previously positive on 2 or more occasions over previous 6 months Positive ACR>2.5 mg/mmol (men) ACR>3.5 mg/mmol (women) Positive No No Yes No Yes No Yes Severely increased albuminuria Moderately increased albuminuria Negative Test for moderately increased albuminuria Retest over next 1–6 months Retest over next 1–6 months Positive Fig. 21.10.1.3  Flowchart for diagnosis of moderately and severely elevated albuminuria. NB: assumes sterile urine throughout. Exclude infection when proteinuria first detected and at any time thereafter if a history of urinary tract infection.

Oxford Textbook of Medicine- Volume 4, 6e (May 6,

Oxford Textbook of Medicine- Volume 4, 6e (May 6, 2020)(0198746695)(Oxford University Press)

Pathology and pathogenesis

Pathology and pathogenesis

Pathology

Pathology

Perface

Perface

Preface Changes in medicine The Oxford Textbook of Medicine is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is nat- ural and proper to reflect on what has changed in medicine—​and what has not—​in recent years. In the context of burgeoning social changes and inequality across the world, we have cause to weigh and consider exactly what modern medicine has to offer patients and their doctors. Here we reflect on aspects of Medicine that are chan- ging rapidly and set out a vision for this in the sixth edition of the Oxford Textbook of Medicine. Demand, capacity, magic solutions, and the need for perspective Within all healthcare systems, in rich and poor nations alike, most physicians feel the inexorable rise in demand and are strug- gling to provide adequate ‘capacity’—​the term commonly applied by healthcare managers charged with the impossible task of con- straining expenditure while serving political masters who, almost without exception, promise more and more and blame inefficiency and ‘unwarranted variation’ for the failure to deliver. In response to the difficulties, claims are made that some new technological advance, be it sequencing of patients’ genomes, healthcare apps, the application of artificial intelligence or ‘Quality Improvement’ methodology, will provide the solutions. In the Oxford Textbook of Medicine, we do not shy away from these aspects and have several new chapters that consider how rich and ‘resource-​poor’ countries might best invest their revenues on health. It is often very hard for practising physicians, who care for patients as individuals, to maintain their bearings within the unfamiliar and depersonalized world of modern healthcare management. Many are left wondering whether those who organize health services ‘live on this planet’, or ‘did any working doctor check out that latest directive from above?’. When clinical outcomes that really matter are diffi- cult to quantify, doctors find themselves and their services judged by spurious measures of ‘productivity’ in the process of healthcare ‘de- livery’. Unrealistic and often clinically irrelevant targets might drive the thinking of the insurers, managers, and politicians, but who can determine the human and clinical value of the care provided? Timeliness of care is important and sometimes crucial for salutary outcomes, but disaster strikes when clock-​driven targets are blindly pursued for all patients irrespective of clinical urgency and to the ex- clusion of all else, including patients with greater clinical need. In the morass created by financial constraints and zealous pol- itical control of health services exercised by those without clinical responsibility, it is rare for doctors be able to stand back and perceive genuine improvements. However, it is certainly true that today we have greater potential to prevent and treat disease and to maintain health than ever before. It is our hope that the Oxford Textbook of Medicine will inform doctors about these changes and provide good guidance as to how they can be translated into clinical practice. Advances in biomedical sciences We seek to embody advances in understanding and practice that have arisen through scientific research. In the ten years since publication of the last edition of this book there has been spec- tacular progress in the application of science in medicine, espe- cially the understanding of genomics and molecular cell biology. These include: in diagnostics, non-​invasive prenatal diagnosis of chromosome abnormalities and monogenic disease by sampling maternal plasma for cell-​free fetal DNA, a technique which also holds promise for screening and monitoring of cancers; in meta- bolic disease, the introduction of molecular therapies that address the defective chloride transport in cystic fibrosis; in oncology, in- creased understanding of cancer immunity leading to the develop- ment of immunotherapies for cancers. Our authors include the very best in their fields. The founding editor and author in this edition, the late David Weatherall, was a recipient of the Lasker-​Koshland Special Achievement Award in Medical Science. Two new authors have received the Nobel Prize recently—​Professor Tu Youyou the 2015 prize for Medicine or Physiology, and Sir Greg Winter the 2018 prize for Chemistry. Another new author, Professor Y.M. Dennis Lo, was one of two winners of China’s inaugural Future Science Prize in 2016. Beyond scientific development, the introduction of new technolo- gies into practice typically leads to a sequence of events including initial ‘hype’ from many in the field, with extravagant claims of po- tential benefit. After an interval, these claims are followed by a more realistic assessment of what the technology can—​and cannot—​ provide. Frequently, this familiar pattern is driven by powerful com- mercial influences which can corrupt thinking in a manner that generates a climate in which those with views contrary to the big battalions are inevitably marginalized. In this edition of the Oxford Textbook of Medicine we have strived to bring an authentic perspec- tive and realism to recommendations for treatment. We sense, for in- stance, that the excitement generated by the sequencing of patients’ genomes continues to increase, but that this trajectory is flattening and expectations becoming more realistic. For patients very likely to have genetic disorders, diagnoses can be made for a proportion that was unimaginable until recently, but for most patients with the degenerative and/​or polygenic diseases that are the greatest burden

Preface viii to health, evidence of clinical benefit from genome sequencing re- mains elusive. Beyond the progress in genomics and cell biology there has been immense interest in bioinformatics and, especially with the enthu- siasm of major biomedical charities such as The Wellcome Trust, for ‘big data’, and the opportunities that these bring to the practice of medicine. However, while there are plentiful examples of gen- omics and cell biology having been translated productively from the bench to the bedside, with enormous benefit to patients, examples of transforming clinical impact from big data and bioinformatics are sparse. But examples there are, such as in the analysis of out- breaks of the scourges Clostridium difficile and methicillin-​resistant Staphylococcus aureus (MRSA). These discoveries give hope for the future as we learn which problems are tractable with this type of approach and which are not. Clinical skill Until recently, it would have been, to paraphrase Thomas Jefferson, regarded as self-​evident that the key requirements of a good phys- ician are the ability and will to obtain an informative history, carry out a thorough physical examination, formulate a relevant differ- ential diagnosis, instigate appropriate investigations, advise and administer correct treatment, including best efforts to relieve symp- toms in all cases. These skills, and the commitment to use them, are often forgotten when healthcare is described in the commercial terms of demand and capacity. While advances in biomedical sciences have dramatically im- proved the outcome for some diseases, and Paul Erhlich’s century-​ old magische Kugel (magic bullet) has whetted our appetite for wonder, it is prudent to recall Thomas Szasz: ‘Formerly, when reli- gion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medi- cine for magic’. The term ‘personalized’ medicine imputes remark- able and as yet unproven powers, excepting in a very few cases, to gene sequencing and molecular therapies, while the patient wants to be treated as a person. It is also alarming to us that some medical curricula increasingly focus on process, ‘behaviours’, and ‘communi- cation skills’, to the detriment of medical content or mature guidance and attitudes to lifelong learning. There is a tendency to forget the very essence of being, and how to become, a physician in the time-​ honoured understanding of the role. In the Oxford Textbook of Medicine we unashamedly emphasize the primacy of history, examination, differential diagnosis, investi- gation, and treatment. Without a firm grasp of these essentials the doctor cannot provide good care for patients, and nor can anyone else. Furthermore, having a firm understanding of clinical context and a well-​informed clinical perspective is an essential prerequisite for driving biomedical research into avenues that really matter. The broader context of health and disease The world has become a smaller place. We are now in an era when many regard not having a smartphone as an index of deprivation. An event that has happened on a different continent can, as a re- sult of social media, become known to millions of people within hours—​the term ‘viral’ has been rightfully translated from commu- nicable illness to global phenomenon. Narratives transmitted in this way often concern disasters, wars, and disease, and they are typically handled by the media in a sensationalized and superficial manner. One hundred and fifty years ago, Darwin’s 1859 masterpiece on evolution was entitled ‘On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life’. The ‘less favoured’ undoubtedly have poorer health outcomes, due largely to the persistent social ill of inequality, in poor as well as ostensibly rich countries. Continuing the tradition of previous edi- tions, we have contributions that discuss the impact of social deter- minants of health, also thoughtful chapters on human disasters (by another Nobel laureate, Prof Amartya Sen), and the practical and critically important aspects of humanitarian medicine. In addition, the modern problems of pollution and climate change are exam- ined. We contend that all doctors would benefit from reading these chapters. Patients and their expectations There are continuing changes in patients’ expectations, particularly those of articulate patients suffering from long-​term conditions and residing in countries with a rich provision of healthcare. A paternal- istic medical approach is no longer acceptable, and several patients have contributed greatly to the book by taking the opportunity to tell us how they think doctors should behave towards them and care for them. However, we are very aware that one size does not fit all, and that many patients want a doctor who will give them clear recom- mendations and not keep repeating a bewildering (to the patient) variety of options and ask them to choose. The mature and able physician will be alert and sensitive to those patients who want this and will provide them with clear advice, and we have endeavoured to ensure that the Oxford Textbook of Medicine will assist. Access to medical knowledge The ever-​expanding world of the smartphone and tablet device gives patients, families, doctors, and other healthcare professionals ready access to more information about medicine than all but a very few would have thought possible a decade ago. This has many benefits but often leaves users of the internet thoroughly perplexed, and some desperate people vulnerable to online quackery. Those wanting de- tails of particular studies will naturally refer to the original literature. Those wanting in-​depth reviews of particular subjects can refer to diverse resources: these are typically good at apprising the reader of plentiful options for investigation, diagnosis, or management, but often leave them uncertain of what a clinically experienced expert in the field would actually recommend. In the sections that form the bulk of the Oxford Textbook of Medicine, we have selected experts with specific clinical experience and given them this task, and we contend that they have met the challenge. Acknowledgements The Oxford Textbook of Medicine is a large undertaking: this edition, the most substantial so far, comprises 647 chapters and covers 6654 printed pages, and its production has required an extraordinary co- ordination of effort from many quarters. In darker moments the edi- tors feared that the process would never end, but as we have read and edited the chapters along the way, we have experienced the joy of learning a huge amount of medicine, often in fields far removed from our own. For this we are very grateful to our contributors, including those whose submissions were delayed!

Preface ix We wish to make particular acknowledgement of our friend and senior colleague, David Warrell, an editor from the first edition of this textbook, senior editor of the fourth and fifth editions, and au- thor in this edition. We and our readers, notably those seeking in- formation on tropical diseases and especially any who have been bitten by snakes, about which his knowledge is truly prodigious, owe him a great debt. We thank Helen Liepman, with whom we remain good friends: she has overseen and directed matters at Oxford University Press and coped in a steadfastly pleasant and professional way with expres- sions of editorial frustration caused by our failure to understand a publishing process that at times seemed to be Byzantine in its com- plexity, as might perhaps be expected in an ancient university. We also thank Anna Kirton, Jamie Oates, and Jess White at Oxford University Press for their considerable efforts on behalf of the book. Finally, we record that the editors’ personal lives have remained calm, and we are very grateful to Helen, Jenny, and Sue for their in- dulgence of our bizarre editorial pursuit. John D. Firth Christopher P. Conlon Timothy M. Cox

Section editors Jon G. Ayres  Emeritus Professor of Environmental
and Respiratory Medicine, University of Birmingham, Birmingham, UK Section 10: Environmental medicine, occupational medicine, and poisoning Christopher P. Conlon  Professor of Infectious Diseases, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 8: Infectious diseases; Section 25: Disorders of the eye; Section 29: Biochemistry in medicine Cyrus Cooper  MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK Section 20: Disorders of the skeleton Timothy M. Cox  Professor of Medicine Emeritus, Director of Research, University of Cambridge; Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 12: Metabolic disorders Jeremy Dwight  Previously John Radcliffe Hospital, Oxford, UK Section 16: Cardiovascular disorders Simon Finfer  Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, and The George Institute for Global Health, University of New South Wales, Sydney, Australia Section 17: Critical care medicine John D. Firth  Consultant Physician and Nephrologist, Cambridge University Hospitals, Cambridge, UK Section 1: Patients and their treatment; Section 2: Background to medicine; Section 3: Cell biology; Section 4: Immunological mechanisms; Section 5: Principles of clinical oncology; Section 21: Disorders of the kidney and urinary tract; Section 27: Forensic medicine; Section 28: Sport and exercise medicine; Section 30: Acute medicine Mark Gurnell  University of Cambridge Medical School, Cambridge, UK Section 13: Endocrine disorders Chris Hatton  Cancer and Haematology Centre, Churchill Hospital, Oxford, UK Section 22: Haematological disorders Deborah Hay  Honorary Consultant Haematologist, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 22: Haematological disorders Roderick J. Hay  King’s College London, London, UK Section 23: Disorders of the skin Christopher Kennard  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Section 24: Neurological disorders Finbarr C. Martin  Population Health Sciences, King’s College London, London, UK Section 6: Old age medicine Catherine Nelson-Piercy  Obstetric Medicine, Women’s Health Academic Centre, King’s Health Partners, King’s College London, London, UK Section 14: Medical disorders in pregnancy Jack Satsangi  Oxford Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK Section 15: Gastroenterological disorders Pallav L. Shah  Imperial College London, London, UK Section 18: Respiratory disorders Michael Sharpe  Psychological Medicine Research, University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK Section 26: Psychiatric and drug-related disorders Jackie Sherrard  Wycombe General Hospital, High Wycombe, Bucks, UK Section 9: Sexually transmitted diseases Richard A. Watts  Department of Rheumatology, Ipswich Hospital, Ipswich, UK; Norwich Medical School, University of East Anglia, Norwich, UK Section 19: Rheumatological disorders Bee Wee  Associate Professor of Palliative Care, University of Oxford, Oxford, UK Section 7: Pain and palliative care Katherine Younger  School of Biological and Health Sciences, Technological University Dublin, Ireland Section 11: Nutrition

Polyarteritis nodosa

Polyarteritis nodosa

Prevention

Prevention

Prevention—

Prevention—

CONTENTS 21.10.1 Diabetes mellitus and the kidney  4975 Rudolf Bilous 21.10.2 The kidney in systemic vasculitis  4988 David Jayne 21.10.3 The kidney in rheumatological disorders  5001 Liz Lightstone and Hannah Beckwith 21.10.4 The kidney in sarcoidosis  5012 Ingeborg Hilderson and Jan Donck 21.10.5 Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard 21.10.6 Haemolytic uraemic syndrome  5027 Edwin K.S. Wong and David Kavanagh 21.10.7 Sickle cell disease and the kidney  5032 Claire C. Sharpe 21.10.8 Infection-​associated nephropathies  5034 A. Neil Turner 21.10.9 Malignancy-​associated renal disease  5041 A. Neil Turner 21.10.10  Atherosclerotic renovascular disease  5044 Philip A. Kalra and Diana Vassallo 21.10.1  Diabetes mellitus and the kidney Rudolf Bilous ESSENTIALS Diabetic nephropathy is the commonest cause of endstage renal dis- ease in the developed world, causing 38% of prevalent cases and 47% of incident cases requiring renal replacement therapy in the United States of America in 2016, and 18% of prevalent cases and 29% of in- cident cases in the United Kingdom in 2017. Most patients have type 2 diabetes, and in most countries the proportion with endstage renal disease who have type 1 diabetes is falling. Aetiology and pathology—​causation is related to glycaemic control (e.g. glycation of proteins, oxidative stress, sorbitol overproduction, and alteration in growth factors), hypertension, inflammation, gen- etic factors, and dietary and other environmental factors. Pathological hallmarks in the glomerulus are thickening of the glomerular base- ment membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix. Many patients have a varying severity of tubulointerstitial inflamma- tion and fibrosis. Staging and natural history—​is classically described in terms of urinary albumin excretion rate (UAER):  (1) normoalbuminuria—​ UAER less than 20 µg/​min, albumin:creatinine ratio (ACR) less than 2.5 mg/​mmol (men), less than 3.5 mg/​mmol (women); (2) microalbuminuria (also called incipient nephropathy, but now termed moderately increased albuminuria)—​UAER 20 to 200 µg/​ min, ACR 2.5 to 30 mg/​mmol (men), 3.5 to 30 mg/​mmol (women); and (3) clinical proteinuria (sometimes called clinical nephropathy or overt nephropathy, but now termed severely increased albu- minuria)—​UAER greater than 200 µg/​min, ACR greater than 30 mg/​ mmol. This staging maps better to the latest classification of chronic kidney disease based upon estimated glomerular filtration rate. Clinical features—​most patients (>60%) will have a normal UAER throughout their diabetic life, but 1 to 2% of the remainder develop persistent moderately increased albuminuria each year. Once UAER exceeds 200 µg/​min, there tends to be a relentless increase in pro- teinuria and glomerular filtration rate declines progressively at a rate that largely depends upon blood pressure control. Prevention—​in both type 1 and type 2 diabetes, tight glycaemic control can prevent moderately increased albuminuria. Whether in- tensive blood pressure control using angiotensin-​converting enzyme (ACE) inhibitors can also prevent this remains controversial. In both type 1 and type 2 diabetes, intensive blood pressure control using ACE inhibitors or angiotensin II receptor blockers (ARBs) slows pro- gression from moderately to severely increased albuminuria and also slows the rate of decline in glomerular filtration rate in those with severely increased albuminuria. Management—​aims for (1) control of glycaemia—typical recom- mendations are for a glycated haemoglobin level <48 mmol/​mol 21.10 The kidney in systemic disease

Prognosis

Prognosis

Renal diseases in the tropics 5049 Vivekanand Jha

Renal diseases in the tropics 5049 Vivekanand Jha

Renal involvement in genetic disease 5065 D. Joly

Renal involvement in genetic disease 5065 D. Joly and J.P. Grünfeld

Renal involvement in plasma cell dyscrasias, immun

Renal involvement in plasma cell dyscrasias, immunoglobulin- based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias 5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

section 21  Disorders of the kidney and urinary tract 5016 21.10.5  Renal involvement in
plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias Pierre Ronco, Frank Bridoux, and Arnaud Jaccard ESSENTIALS Plasma cell disorders are characterized by uncontrolled proliferation of a single clone of B cells which is responsible for the secretion of a monoclonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. They can cause a wide range of renal diseases. Light-​chain amyloidosis—​renal presentation is usually with protein- uria, often progressing to nephrotic syndrome. A progressive decline in renal function may occur, leading finally to endstage renal failure. Diagnosis is made by the detection of monoclonal gammopathy and free light-​chain excess in the serum (90% of cases), in combination with biopsy evidence of amyloid-​forming light-​chain deposits. Treatment is based on chemotherapy with oral melphalan plus dexamethasone, or bortezomib-​based regimens in patients with heart involvement. High dose melphalan followed by autologous stem cell transplant- ation can be considered in highly selected patients. Treatment efficacy should be evaluated by estimation of light-​chain response. Myeloma—​renal failure is found at presentation in 20% of pa- tients, occurs in 50% at some time, and is most commonly caused by cast nephropathy, diagnosis of which relies on the detection of proteinuria mostly composed of monoclonal light chains, with renal biopsy typically showing ‘fractured’ casts. Chemotherapy should be introduced promptly (e.g. high-​dose dexamethasone, combined with bortezomib, and/​or alkylating agents, and/​or thal- idomide or another immunomodulatory agent). Light-​chain, light-​ and heavy-​chain, and heavy-​chain depos- ition disease—​collectively known as monoclonal Ig deposition dis- eases, present with proteinuria and renal failure. Diagnosis is by renal biopsy which reveals nodular glomerulosclerosis, monotypic light-​ and/​or heavy-​chain deposits along glomerular and tubular basement membranes (by immunofluorescence), and nonfibrillar linear electron-​dense deposits (by electron microscopy). Treatment strategy is based on chemotherapy (bortezomib-​based regimens) followed by autologous stem cell transplantation in selected cases. Fibrillary glomerulonephritis and immunotactoid glomerulopathy—
​usual presentation is with nephrotic syndrome, microscopic haema- turia, and hypertension. Diagnosis is by renal biopsy when electron microscopy reveals (respectively) fibrils (solid, diameter 12–​22 nm, randomly arranged) or microtubules (hollow, diameter 10–​60 nm, in parallel arrays). Immunotactoid glomerulopathy, often associated with chronic lymphocytic leukaemia or lymphoma, usually responds to chemotherapy. Cryoglobulinaemia—​type II (‘essential mixed’), which involves a monoclonal IgM with rheumatoid factor activity and a polyclonal IgG, may present with proteinuria, haematuria, hypertension, and gradually declining renal function, or with an acute nephritic picture. It should be suspected in the presence of an IgM rheumatoid factor and low complement C4, and confirmed by the finding of a cryo- globulin. It is often associated with hepatitis C. Renal biopsy typic- ally reveals membranoproliferative glomerulonephritis with massive subendothelial deposits. Treatment involves antiviral agents and/​or immunosuppression. Tumour lysis syndrome—​a life-​threatening metabolic emergency that occurs in patients with haemopathies with high cell turnover (e.g. Burkitt’s lymphoma and acute leukaemia), mostly at the onset of chemotherapy. Prevention is by vigorous hydration with 0.9% saline before treatment with the addition of allopurinol (in low-​risk cases) or the recombinant modified urate oxidase rasburicase (in high-​risk cases). Treatment is based on saline diuresis (if possible), rasburicase, and haemodialysis (if required). Introduction Plasma cell disorders are characterized by uncontrolled pro- liferation of a single clone of B cells, usually with plasma cell differentiation, which is responsible for the secretion of a mono- clonal immunoglobulin (Ig) or Ig subunit that can deposit in tissues. The range of renal diseases secondary to deposition or precipitation of Ig-​related material has expanded dramatically in recent years. These conditions can be classified into two categories on the basis of their ultrastructural appearances (Table 21.10.5.1). Those with organized deposits include diseases with crystal formation, mainly Fanconi’s syndrome and myeloma cast nephropathy; diseases with fibril formation, mainly light-​chain amyloidosis; and diseases with microtubule formation, including cryoglobulinaemia kidney and immunotactoid/​microtubular glomerulonephritis (also called glomerulonephritis with organized microtubular monoclonal Ig de- posits (GOMMID)). A second category of diseases is characterized by the presence of nonorganized granular electron-​dense deposits made of light and/​or heavy chains along the basement membranes of many tissues, most importantly the kidney. First described by Randall and associates, these are referred to as monoclonal Ig de- position diseases (MIDD). More recently, glomerular diseases with amorphous monoclonal Ig deposits distinct from Randall-​type MIDD and referred to as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) have been de- scribed. It is now established that the spectrum of plasma cell dys- crasia-​related renal complications is due to intrinsic properties of the monoclonal component. Except for myeloma cast nephropathy, diagnosis relies on careful analysis of a biopsy specimen taken from the kidney, which should systematically include immunohistochemical studies with specific antibodies and also electron microscopy in all ambiguous cases. Since most of these patients will develop renal failure, it is essen- tial to identify the underlying plasma cell clone because appropriate treatment may halt the extension of visceral deposits, and even in- duce their regression. Except in patients with myeloma cast neph- ropathy, who usually present with a high-​mass myeloma, most renal disorders related to monoclonal Ig deposition occur in the context of an indolent B-​cell disorder that manifests as isolated monoclonal

21.10.5  Renal involvement in plasma cell dyscrasias 5017 gammopathy. To individualize this condition, the term monoclonal gammopathy of renal significance (MGRS) was recently introduced to highlight the association of a small B-​cell clone and renal disease related to the nephrotoxic property of the secreted monoclonal Ig, and the importance of chemotherapy to prevent consequences of renal and sometimes widespread organ deposition. Renal involvement in Ig light-​chain amyloidosis Definition and epidemiology Amyloidosis is a general term for a family of diseases defined by mor- phological criteria and characterized by deposition in extracellular spaces of a proteinaceous material that stains with Congo red and is metachromatic. Amyloid deposits are composed of a felt-​like array of 10-​nm-​wide, rigid, linear aggregated fibrils of indefinite length with a β-​pleated sheet configuration. They occur in a variety of con- ditions including Alzheimer’s disease and other neurodegenerative disorders, tumoural and inflammatory diseases, and plasma cell disorders. The various types of amyloidosis differ essentially by the nature of the precursor protein that yields the main component of fibrils, and are classified accordingly (see Chapter 12.12.3 for further discussion). Light-​chain (AL) amyloidosis is the most frequent form of sys- temic amyloidosis with renal involvement in Western countries. AL amyloidosis most commonly occurs in patients with isolated monoclonal gammopathy or smouldering myeloma, with only 20% of patients having evidence of a symptomatic plasma cell or B-​cell disorder at diagnosis. Clinical presentation Systemic AL amyloidosis can infiltrate almost any organ and thus be responsible for a wide variety of clinical manifestations. The main presenting symptoms are fatigue and dyspnoea. Renal disease is the most common manifestation of systemic AL amyloidosis. Proteinuria, composed mainly of albumin, is the usual symptom, detected in approximately 70% of patients at presentation and often progressing to a severe nephrotic syndrome, which can be complicated by renal vein thrombosis. Haematuria is uncommon, and when present should prompt examination for a bleeding lesion of the urinary tract. Progressive decline in renal function leading finally to endstage renal failure may occur, particularly in patients with baseline proteinuria greater than 5 g/​24 h and an estimated glomerular filtration rate less than 50 ml/​min per 1.73 m2. In those rare patients in whom renal tubulointerstitial deposits predom- inate, renal failure may progress without a nephrotic stage, and renal tubular dysfunction may be the presenting problem. Hypertension is uncommon but may develop concomitantly with renal failure. The kidneys may be of normal size or large, even when renal function is impaired. Systemic organ involvement is common, particularly cardiac dis- ease, diagnosed in 60% of patients and strongly impacting survival. Deposits commonly also affect the liver, peripheral nervous system, carpal tunnel, gastrointestinal tract, skin, and tongue. Purpuric macules in the periorbital region are very typical of AL amyloidosis. Diagnosis AL amyloidosis should be suspected when the clinical manifestations previously described are associated with a monoclonal component in the serum or urine. AL amyloidosis is always the result of the prolif- eration of a small plasma cell clone: most patients have an increased number of plasma cells in the bone marrow, but only 15% have true myeloma. By immunofixation, a monoclonal Ig is found in the serum and/​or the urine in nearly 80% of patients. The recent development of a sensitive nephelometric immunoassay for circulating free Ig light chains has been an important advance in the management of AL amyloidosis, allowing detection of abnormal serum free light-​chain levels in 98% of patients, the λ isotype being involved twice as fre- quent as the κ isotype, with an over-​representation of the Vλ6 sub- group found in AL amyloidosis with renal involvement. Monitoring of serum free light chains at diagnosis and throughout follow-​up is mandatory to evaluate the response to chemotherapy. It is important to recognize that detection of monoclonal gammopathy is insufficient for the diagnosis of AL amyloidosis, which should be established in all cases by taking a biopsy specimen from a superficial organ (salivary glands), or by aspiration biopsy of abdom- inal fat. These biopsies should be performed before biopsies of rectal mucosa and/​or of kidney, because of the risk of bleeding complica- tions due to factor X deficiency, fibrinolysis, or amyloid infiltration of vascular walls. After Congo red staining, amyloid deposits appear faintly red and show characteristic apple-​green birefringence under polarized light. Congo red staining may be falsely negative if tissue sections are less than 5 µm in thickness. In the kidney, the earliest le- sions are located in the mesangium, along the glomerular basement membrane, and in the blood vessels (Fig. 21.10.5.1). Because there are specific diagnostic and therapeutic strategies depending on the type of protein deposited within tissues, immunofluorescence with specific antisera including anti-​κ and anti-​λ light chains should be performed routinely. When pathological confirmation of AL type cannot be obtained, genetic studies should be performed to exclude systemic hereditary amyloidosis caused by mutations in the genes encoding leucocyte chemotactic factor 2, fibrinogen A  α-​chain, Table 21.10.5.1  Pathological classification of diseases with tissue deposition or precipitation of monoclonal Ig-​related material Organized Nonorganized (granular) Crystals Fibrillar Microtubular MIDD (Randall-​type) Other Myeloma cast nephropathy Light-​chain amyloidosis Cryoglobulinaemia kidney LCDD Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) Fanconi’s syndrome Nonamyloid fibrillary GN Immunotactoid GN/​GOMMID LHCDD Waldenström’s macroglobulinaemia Other HCDD GN, glomerulonephritis; GOMMID, glomerulonephritis with organized microtubular monoclonal Ig deposits; LCDD, LHCDD, HCDD, light-​chain, light-​ and heavy-​chain, heavy-​chain deposition disease; MIDD, monoclonal immunoglobulin deposition disease.

section 21  Disorders of the kidney and urinary tract 5018 lysozyme, or apolipoprotein A-​I or A-​II, all of which are frequently associated with renal involvement. New techniques, which combine specific sampling by laser microdissection followed by tandem mass spectrometry-​based proteomic analysis, may help to identify the na- ture of amyloid deposits in paraffin-​embedded tissue biopsy samples, with a great sensitivity and specificity. Assessment of organ involvement is crucial in AL amyloidosis. Detection of cardiac involvement is particularly important, and this should be sought using measurements of sensitive cardiac markers (troponin, B-​type natriuretic peptide (BNP), N-​terminal (NT)-​proBNP), doppler echocardiography and magnetic reson- ance imaging. A prognostic score (Mayo Clinic staging) has been established based on serum levels of troponin and NT-​proBNP (Table 21.10.5.2). Treatment AL amyloidosis is a wasting disease with a mean survival of only 12  months in untreated patients. Cardiac involvement is a main prognostic factor, accounting for 30% of deaths, with a median survival of less than 6 months in patients with severe (Mayo Clinic stage 3) amyloid heart disease. The aim of treatment is to suppress production of amyloidogenic free light chains with acceptable tox- icity. Low-​dose chemotherapy (oral melphalan and prednisone) Table 21.10.5.2  Diagnostic and response criteria in AL
amyloidosis Definition of renal involvement 24-​h urine protein ≥0.5 g/​day, predominantly albumin Mayo Clinic
staging for
heart involvement Stage 1: hs-​cTnTa ≤77 ng/​litre and NT-​proBNP ≤332 ng/​ litre Stage 2: hs-​cTnT >77 ng/​litre or NT-​proBNP >332 ng/​litre Stage 3: hs-​cTnT >77 ng/​litre and NT-​proBNP >332 ng/​ litre Definition of renal response 2005 criteria: 50% decrease (at least 0.5 g/​day) of 24-​h urine protein (urine protein must be >0.5 g/​day pretreatment) in the absence of a reduction in eGFR ≥25% or an increase in serum creatinine ≥0.5 mg/​dl 2014 revised criteria: ≥30% decrease in proteinuria or drop of proteinuria below 0.5 g/​24 h in the absence of renal progression (as defined by ≥25% decrease in eGFR) Definition of haematological response CR: negative serum and urine IFE, normal kappa/​ lambda ratio VGPR: dFLC <40 mg/​litre PR: dFLC <40 mg/​litre NR: other situations CR, complete response; Dflc, difference between the involved and uninvolved serum free light chain; eGFR, estimated glomerular filtration rate; hs-​cTnT, high sensitivity cardiac troponin T; IFE, mmunofixation electrophoresis; NT-​proBNP, N-​terminal natriuretic peptide type B; NR, no response; PR, partial response; VGPR, very good partial response. a When cTnT is used, the threshold value is: 0.035 µg/​litre. Data sources: Gertz MA, Merlini G (2010). Definition of organ involvement and response to treatment in AL amyloidosis: an updated consensus opinion. Amyloid, 17 Suppl 1, 48–​9. Dispenzieri A, Gertz MA, Kyle RA (2004). Serum cardiac troponins and N-​terminal pro-​brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol, 22, 3751–​7. Palladini G, et al. (2010). The combination of high-​sensitivity cardiac troponin T (hs-​cTnT) at presentation and changes in N-​ terminal natriuretic peptide type B (NT-​proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood, 116, 3426–​30. Palladini G, et al. (2014) A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood, 124, 2325–​32. (a) (b) (c) Fig. 21.10.5.1  Light-​chain amyloidosis. (a) Amyloid deposits in a renal glomerulus (Masson’s trichrome stain, magnification ×312). (b) Apple-​green/​yellow dichroism under polarized light (Congo red stain, magnification ×312). (c) Immunofluorescence with anti-​λ antibody. Note glomerular and arteriolar deposits (magnification ×312). From Béatrice Mougenot’s personal collection.

21.10.5  Renal involvement in plasma cell dyscrasias 5019 was extensively used in the 1990s with a modest increase in median survival (up to 18 months). Improved results have been obtained with high-​dose dexamethasone-​based regimens, such as oral melphalan plus dexamethasone. These regimens, which induce rapid and higher rates of haematological response, have been shown to in- crease median survival to 40 to 50 months, with limited treatment-​ related mortality. Intensive therapy (i.e. high-​dose intravenous melphalan followed by autologous stem cell transplantation) has been extensively used, resulting in complete clonal response in up to 40% of cases and median survival of more than 5 years. However, such intensive therapy is associated with significant morbidity and treatment-​related mortality, ranging from 5 to 10% in experienced centres to more than 40% in multicentre series. It is therefore limited to carefully selected patients, usually on the basis of the following criteria: aged under 70 years, one or two organs involved, glom- erular filtration rate above 50 ml/​min per 1.73 m2, and absence of advanced amyloid cardiopathy. In a randomized controlled trial that enrolled 100 patients with systemic AL amyloidosis, oral melphalan plus dexamethasone resulted in improved overall survival compared to high-​dose chemotherapy followed by autologous stem cell trans- plantation. Recently, regimens based on novel antimyeloma agents, thalidomide, lenalidomide and (particularly) bortezomib, in associ- ation with high-​dose dexamethasone, with or without an alkylating agent, were shown to induce high haematological (>70%) and organ response rates. They should be considered as first-​line treatment in patients with heart involvement (Mayo Clinic stage 2 or 3). Results of chemotherapy in amyloidosis are difficult to document because the organ response is often delayed and there is no easy way to measure the amount of amyloid present. Scintigraphy after the injec- tion of 123I-​labelled serum amyloid P may be helpful for monitoring the extent of systemic amyloidosis, but it is available only in a limited number of centres (see Chapter 12.12.3). The effects of chemotherapy are better evaluated by serial nephelometric measurements of serum free light chains. When at least a very good partial hematological re- sponse (defined by the achievement of a difference between the con- centration of the involved and uninvolved serum free light chain of less than 40 mg/litre), organ response rates and overall survival are significantly increased. Serum levels of NT-​proBNP and troponin T, which are sensitive markers of myocardial dysfunction and predict survival in AL amyloidosis, should be routinely monitored. Amyloid nephropathy requires supportive therapy of renal failure and of the nephrotic syndrome, which can persist even in patients with endstage renal disease. Depending on the burden of their extrarenal disease, patients in endstage renal disease are candidates for regular dialysis and/​or kidney transplantation. Their prognosis is comprom- ised by the risks of extension of extrarenal deposition, especially to the heart, and by recurrence of amyloidosis in the graft if suppression of the plasma cell disorder has not been obtained with appropriate treatment. Renal involvement in myeloma Definition and epidemiology Renal failure is one of the main complications of myeloma, found at presentation in 20% of patients and occurring in 50% during the course of the disease. It is mostly due to cast nephropathy, although other forms of renal disease may occur, including AL amyloidosis (10% of myeloma patients), light-​chain deposition disease (5%), Fanconi’s syndrome, infiltration of renal interstitium by plasma cells, calcium precipitation, and renal infection. Myeloma cast neph- ropathy is due both to alterations in tubule cells induced by mas- sive reabsorption of light chains in proximal tubule cells, and to cast formation involving light chains and Tamm–​Horsfall protein in the distal tubule. The risk of developing renal failure is twice as high in patients with pure light-​chain myeloma, and five to six times greater in patients with light-​chain proteinuria of more than 2.0 g/​day com- pared with those with proteinuria of less than 0.05 g/​day. Clinical presentation Myeloma cast nephropathy usually presents as acute or subacute renal failure, often revealing myeloma with a high tumour burden (found in 70–​80% of myeloma patients with renal failure). Common triggering factors include hypercalcaemia, dehydration, infection, use of toxic compounds including radiocontrast media, nonsteroidal anti-​inflammatory drugs, diuretics, and angiotensin-​converting en- zyme inhibitors or angiotensin II receptor antagonists, all of which reduce renal perfusion, especially in those who are dehydrated. Renal failure induced by cast nephropathy is remarkably silent. The clinical and urinary syndrome is characterized by nonspecific signs including weakness, weight loss, bone pain, and signs of infec- tion, all due to myeloma, and by urinary excretion of a monoclonal light chain. It must be emphasized that urinary dipsticks do not de- tect the light chain, which is measured by quantitative tests of pro- teinuria. Light chain accounts for more than 90% of total proteinuria by urine electrophoresis. Tubular dysfunction is rarely a presenting symptom. Fanconi’s syndrome due to proximal tubule impairment may result from tox- icity of intratubular inclusions of κ light chains, usually organized into crystals. This can lead to osteomalacia and may precede the diagnosis of myeloma by several years. Diagnosis Diagnosis of myeloma cast nephropathy relies on the detection of a urinary monoclonal light chain with excess in serum free light chain level in patients with acute or subacute renal failure of apparently unknown origin. In those patients with pure light-​chain myeloma, diagnosis can be suspected before urinalysis on the basis of dramatic hypogammaglobulinaemia detected by serum electrophoresis. A renal biopsy should not be performed routinely in patients with a presumed diagnosis of myeloma cast nephropathy. It can, how- ever, be useful for several reasons: first, to analyse tubulointerstitial lesions and allow diagnosis and treatment of other potential causes of renal impairment in those with multiple possible precipitating factors (infection, drugs, etc.); second, to establish the diagnosis of Fanconi’s syndrome; third, to identify glomerular lesions in patients with albuminuria greater than 1 g/​day and no evidence of amyloid deposits in ‘peripheral’ biopsies; and fourth, to evaluate the extent of cast formation and the degree of tubulointerstitial fibrosis that may predict renal outcomes. Myeloma casts have unique characteristics, including a ‘fractured’ appearance due to crystal formation, poly- chromatism when stained with Masson’s trichrome, and the pres- ence of multinucleated giant cells. They are consistently associated with severe epithelial tubular lesions and interstitial inflammatory infiltrates.

section 21  Disorders of the kidney and urinary tract 5020 Treatment The first aim of treatment is to prevent or retard renal impairment in all patients with myeloma, most particularly those with light-​ chain myeloma, by prevention of dehydration, maintenance of a high urinary output and urine alkalinization, avoidance of nephrotoxic drugs, and control of hypercalcaemia (if present), which requires correction of salt and water deficit, steroids, and/​or bisphosphonates, which are potent inhibitors of osteoclast activity but must be used with caution as they can be associated with acute kidney injury. Renal failure of recent onset should be promptly and vigorously managed. Intravascular depletion must be rapidly corrected by intra- venous infusion of 0.9% saline, after which a high urinary output should be maintained whenever possible by continued saline and/​or forced alkaline diuresis (which may help to prevent intratubular light-​ chain precipitation). Plasma exchange has been advocated to remove light chains more rapidly, but its value is unproven. In patients with oli- guria, dialysis should be provided early. Recently, it has been suggested that an extended haemodialysis protocol, using a new-​generation dialyser with very high permeability to proteins, was highly efficient in removing circulating free light chains. In preliminary studies, this ap- proach combined with chemotherapy, resulted in dialysis withdrawal in more than 60% of patients with myeloma cast nephropathy and se- vere renal failure. However, two recent randomized controlled studies that compared highcutoff hemodialysis to conventional hemodialysis in patients with biopsy-proven myeloma cast nephropathy showed dis- cordant results, and further investigation is required to define whether this strategy may increase renal recovery. Most patients with overt myeloma cast nephropathy should be promptly given chemotherapy to reduce the production of mono- clonal light chains, which is justified because partial or complete recovery of renal function occurs in approximately one-​half of pa- tients. Only patients with refractory haematological disease should be given purely symptomatic treatment. However, median survival in those with progressive renal failure (about 2  years) remains shorter than that of patients without renal failure. The optimum use of chemotherapy in patients with multiple mye- loma and renal failure is uncertain due to the lack of randomized studies in myeloma patients with impaired renal function. Current strategies rely on the use of high-​dose oral dexamethasone, which induces rapid decrease in serum free monoclonal light chains, has potent anti-​inflammatory effects, and can be introduced immedi- ately after diagnosis. This is commonly used in combination with the proteasome inhibitor bortezomib, which is well tolerated in patients with severe renal failure. Thalidomide and cyclophosphamide, which do not require dose adaptation in patients with renal impairment, are also commonly used. However, safety and efficiency of these protocols remain to be evaluated in controlled trials. Monitoring of serum free light chains should be performed to optimize therapy. Prophylactic measures to prevent infectious complications are mandatory. In younger patients (those aged less than 60)  with multiple myeloma, high-​dose melphalan followed by autologous stem cell transplantation should be considered because substantially longer survival and renal response can be achieved. However, in those with persistent renal failure, high-​dose regimen should consist of melphalan 140 mg/​m2 to reduce toxicity and treatment-​related mor- tality. The indication for the procedure should be carefully evaluated if creatinine clearance is less than 30 ml/​min, and restricted to pa- tients with good performance status. In patients with irreversible renal failure and in those whose renal function deteriorates later, regular dialysis may be indicated if al- lowed by the patient’s general clinical condition. Light-​chain, light-​ and heavy-​chain, and heavy-​ chain deposition disease (Randall type) Definition and epidemiology It has been known since the late 1950s that nonamyloidotic forms of glomerular disease resembling the lesion of diabetic glomerulosclerosis could occur in multiple myeloma. Randall and associates recognized the presence of monoclonal light chains in these lesions in 1976, defining light-​chain deposition disease. Monoclonal heavy chains can also be found in association with light chains (defining light-​ and heavy-​chain deposition disease), or oc- casionally in the absence of light chains (heavy-​chain deposition disease). In clinical and pathological terms, light-​chain deposition disease, light-​ and heavy-​chain deposition disease, and heavy-​chain deposition disease are similar and hence are also collectively re- ferred to as (Randall-​type) MIDD. They differ from amyloidosis by the lack of affinity for Congo red and fibrillar organization. MIDD occurs in a wide range of ages (31–​79 years) with a slight male pre- ponderance. Myeloma accounts for 40% of cases, but, as in amyl- oidosis, a monoclonal plasma cell clone can be found in virtually all patients by immunofluorescence examination of the bone marrow. Clinical presentation Light-​chain deposition disease is a systemic disease with deposition of Ig light chains along basement membranes in most tissues. However, deposition in tissues other than the kidney is often (but not always) totally asymptomatic and renal involvement dominates clinical pres- entation, mainly in the form of proteinuria and renal failure. In 30 to 60% of patients with light-​chain deposition disease, albuminuria is associated with the nephrotic syndrome. In 25%, the urinary al- bumin output is less than 1 g/​day, and these patients mainly exhibit a tubulointerstitial syndrome. Haematuria is more frequent (60%) than one would expect for a nephropathy in which cell proliferation is usu- ally modest. Renal failure is remarkable for its high prevalence (90%), early appearance, and severity, irrespective of urinary albumin output. Hypertension occurs in approximately one-​half of patients. Diagnosis Diagnosis of MIDD relies on the association of the clinical features de- scribed earlier in this chapter with the finding of a monoclonal Ig com- ponent in the serum and/​or the urine. This component is detected by immunofixation in more than 80% of patients, and serum free light-​ chain excess is found in virtually all cases. The diagnosis of MIDD re- quires pathological confirmation, mostly by renal biopsy. In virtually all patients with this condition, tubular lesions are characterized by the deposition of periodic acid–​Schiff-​positive ribbon-​like material along the basement membrane. This is usually associated with a marked inter- stitial fibrosis and nodular glomerulosclerosis (found in two-​thirds of patients with light-​chain deposition disease and in all patients with heavy-​chain deposition disease reported so far). Nodules are composed of membrane-​like material with nuclei at the periphery (Fig. 21.10.5.2). A key step in the diagnosis of the various forms of Randall-​type MIDD is immunofluorescence examination of the biopsy specimen, revealing

21.10.5  Renal involvement in plasma cell dyscrasias 5021 evidence of monotypic linear light-​ and/​or heavy-​chain deposits along glomerular and tubular basement membranes in all cases. By contrast with AL amyloidosis, the κ isotype is two to three times more frequent than the λ isotype, with a predominance of the Vκ4 subgroup. In those patients with heavy-​chain deposition disease, a deletion of the first constant domain of the heavy chain can invariably be demonstrated by immunofluorescence analysis of the kidney specimen with specific antisera. Finally, granular powdery punctate electron-​dense deposits are visible by electron microscopy along tubular basement membranes and in glomerular lesions. Treatment The natural history of MIDD is more uncertain than that of light-​ chain amyloidosis because extrarenal deposits can be totally asymp- tomatic or cause severe organ damage, including severe heart failure, pulmonary disease, and occasionally hepatic insufficiency or portal hypertension. With conventional chemotherapy, mean patient survival of 90 months, with 40% of cases progressing to endstage renal disease (mean renal survival 64 months), has been reported. Patients with MIDD and myeloma should be treated with con- ventional chemotherapy if they are over 60 years of age, but inten- sive chemotherapy with autologous stem cell transplantation should be discussed in younger patients (see the treatment section in ‘Renal involvement in myeloma’). The correct treatment for those without myeloma is uncertain, the rarity of the disease meaning that there are no controlled trials. Deposited light chains have disappeared in iso- lated instances after intensive therapy. A pragmatic approach is to use chemotherapy in those with moderate but rapidly progressive renal insufficiency in an endeavour to prevent progression to endstage renal failure, but not to treat those with severe renal failure unless there are significant extrarenal complications, or if renal transplantation is planned. Recurrence of the disease after renal transplantation is to be expected if the underlying clone has not been suppressed beforehand. Recent data indicate that bortezomib-​based regimens are highly ef- ficient in MIDD, with high rates of haematological response that re- sult in prolonged renal and patient survival. Monitoring of the serum free light chain response appears to be useful to evaluate treatment efficacy. The achievement of a difference between the involved and uninvolved serum free light chain of less than 40 mg/​litre has been reported as a predictive factor of renal response. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) An increasing number of cases of proliferative glomerulonephritis with monoclonal Ig deposits that do not display the characteristic features of Randall-​type MIDD have been described. Almost all patients pre- sent initially with renal failure, proteinuria, and microscopic haema- turia, with nephrotic syndrome and hypertension found in more than 50% of patients. PGNMID is a renal-​limited disease. A serum and/​or urine monoclonal component is detected in only 30% of patients, and only 10% have evidence of an associated lymphoproliferative or plasma cell disorder. Activation of the classical or alternative complement pathway is present in 25% of cases. Endocapillary proliferative glom- erulonephritis or membranoproliferative glomerulonephritis are the most common patterns of glomerular lesions. Electron-​dense granular deposits of nondeleted monotypic IgG (most commonly IgG3), and less commonly IgM, IgA, or light chains, are located in mesangial and paramesangial areas, and in subendothelial and/​or subepithelial areas of glomerular basement membranes. These deposits do not show significant organization at the ultrastructural level. At variance with Randall-​type MIDD, deposits are not found around tubular basement membranes or in vascular walls around myocytes. Treatment is de- bated, but most cases appear to respond to chemotherapy targeting the underlying plasma cell/​B-​cell clone when identified. Recurrence on the renal allograft is frequent. Nonamyloid fibrillary and immunotactoid/​ microtubular glomerulopathies Definition and epidemiology Fibrillary glomerulonephritis and immunotactoid glomerulopathy are characterized (respectively) by fibrillar and microtubular (a) (b) Fig. 21.10.5.2  Monoclonal Ig deposition disease. (a) Typical nodular glomerulosclerosis. Note the membrane-​like material in the centre of the nodules and nuclei at the periphery. Some glomerular capillaries show double contours. Note also thickening of the basement membrane of atrophic tubules (Masson’s trichrome stain, magnification ×312). (b) Bright linear staining of tubular basement membranes and mesangial nodules and, to a lesser extent, of glomerular basement membrane with anti-​κ antibody in a case of κ light-​chain deposition disease (immunofluorescence, magnification ×312).

section 21  Disorders of the kidney and urinary tract 5022 deposits in the mesangium and the glomerular capillary loops. These deposits do not have a β-​pleated sheet organization and are readily distinguishable from amyloid by the larger thickness of fibrils and the lack of Congo red staining. It is now established that the distinction between the two diseases is of great clinical and pathophysiological interest in the context of plasma cell dyscrasias, because monotypic deposits are detected in 50 to 80% of immunotactoid/​microtubular glomerulopathies (sometimes referred to as GOMMID), while they are found in fewer than 20% of fibrillary glomerulopathies. The prevalence of glomerulopathy with nonamyloid deposition of fibrillary or tubular material in a nontransplant adult biopsy popu- lation is around 1%, but this is almost certainly an underestimate because insufficient attention is given to atypical reactions with histochemical stains for amyloid and also most specimens are not examined by electron microscopy. The age range extends from 10 to 80 years with a peak incidence between 40 and 60 years. Clinical presentation The usual presentation is with the nephrotic syndrome, microscopic haematuria, and hypertension. Extrarenal manifestations, including skin and peripheral nerve involvement, have been described, al- most exclusively in immunotactoid/​microtubular glomerulopathy, which—​at variance with fibrillary glomerulopathy—​often occurs in the setting of chronic lymphocytic leukaemia or B-​cell lymphoma. Diagnosis Diagnosis relies entirely on analysis of the renal biopsy specimen by immunofluorescence microscopy with anti-​light-​chain and anti-​IgG subclass antibodies, and by electron microscopy. In immunotactoid/​ microtubular glomerulopathy, this reveals either atypical membranous glomerulonephritis (often associated with segmental mesangial pro- liferation) or lobular membranoproliferative glomerulonephritis. Immunofluorescence shows coarse granular deposits of IgG and C3 along capillary basement membranes and in mesangial areas. Monotypic deposits composed of either IgG1, IgG2, or IgG3 (usually with a κ light chain) are common. Using sensitive techniques such as immunoblotting, a circulating monoclonal Ig is detected in approxi- mately 60% of patients. Electron microscopy shows immunotactoid/​ microtubular glomerulopathy to be remarkable for the presence of or- ganized deposits of thick-​walled microtubules with a central hollow core, 10 to 60 nm in diameter (usually >30 nm), at times arranged in parallel arrays (Fig. 21.10.5.3). When immunotactoid/​microtubular glomerulopathy occurs in the setting of chronic lymphocytic leu- kaemia or related B-​cell lymphoma, inclusions showing the same microtubular organization and containing the same IgG subclass and light-​chain type as the renal deposits are often detected in the cyto- plasm of leukaemic lymphocytes in the blood. Mesangial proliferation and membranoproliferative glomerulo- nephritis are the commonest lesions observed in nonamyloid fi- brillary glomerulonephritis. Immunofluorescence studies show predominant polyclonal IgG4, usually associated with IgG1 deposits. DNAJB9 was recently found as sensitive and specific biomarker for fibrillary glomerulonephritis. Positive glomerular staining for DNAJB9 by immunohistochemistry is a strong indicator of the diagnosis. Electron microscopy shows the fibrils, devoid of a central lumen, to be randomly arranged with a diameter varying between 12 and 22 nm. In almost all cases there is no evidence of associated lymphoproliferative disorder or monoclonal gammopathy. Infection with hepatitis C virus has sometimes been reported in patients with nonamyloid fibrillary glomerulonephritis and immunotactoid glomerulopathy. (a) (b) (c) Fig. 21.10.5.3  Immunotactoid/​microtubular glomerulopathy in a patient with chronic lymphocytic leukaemia. Atypical membranous glomerulonephritis showing exclusive staining of the deposits with (a) anti-​ γ (b) and anti-​κ antibodies (immunohistochemistry, alkaline phosphatase, magnification × 312). (c) Electron micrograph of glomerular basement membrane, showing the microtubular structure of the subepithelial deposits (uranyl acetate and lead citrate, magnification × 12 000). From Béatrice Mougenot’s personal collection.

21.10.5  Renal involvement in plasma cell dyscrasias 5023 Treatment In patients with GOMMID, especially in those with chronic lymphocytic leukaemia, chemotherapy is associated with partial or complete remission of the nephrotic syndrome, parallel with im- provement of the haematological condition. More variable results are obtained with cytotoxic treatments in patients with fibrillary glomerulonephritis, although rituximab produced improvement in renal parameters in few patients. Recurrence of these diseases has been reported in patients receiving a renal allograft. Renal involvement in cryoglobulinaemia Definition and epidemiology Cryoglobulinaemia is a pathological condition in which the blood contains Igs that precipitate on cooling (4°C) and resolubilize on warming (37°C). According to Brouet’s classification, there are three types of cryoglobulinaemia defined by their composition. Renal involvement is observed mainly in patients with mixed type II cryoglobulinaemia involving a monoclonal IgM (most often including a κ light chain) with rheumatoid factor activity and a polyclonal IgG. Type II cryoglobulinaemia can be associated with overt lymphoproliferative disorders of the B-​cell lineage, although in many cases no underlying haematological disorder is found such that this type of cryoglobulinaemia has long been referred to as es- sential mixed cryoglobulinaemia. Glomerular disease may also occur in type I  cryoglobulinaemia, composed of a single mono- clonal Ig (mostly IgM or IgG), usually in the context of underlying lymphoproliferative or plasma cell disorder (see later). Viral infections may trigger the formation of cryoglobulin. Whereas hepatitis B and Epstein–​Barr virus infections have been implicated in the past, the role of hepatitis C virus infection is now recognized to be an important factor in the pathogenesis of type II cryoglobulinaemia. Antibodies to hepatitis C virus and hepa- titis C virus RNA are found in the sera of most patients with type II cryoglobulinaemia, probably explaining the uneven geographical distribution of mixed cryoglobulinaemias, which predominate in southern Europe where hepatitis C infection is more prevalent. The condition is commonest in adults in the fifth and the sixth decades of life, with a slight female predominance. Clinical presentation Renal disease most often occurs in patients with a long history of cryoglobulinaemia-​related vasculitic symptoms, including palpable purpura (70%), arthralgias (50%), fatigue, Raynaud’s phenomenon, peripheral neuropathy (22%), and hepatic involvement. The renal disease may present as an acute nephritic syndrome (in 20 to 30% of patients) with gross haematuria, heavy proteinuria, hypertension, and renal failure of sudden onset, sometimes with oliguria (5% of patients). The pathological finding in these patients is membranoproliferative glomerulonephritis with the presence of numerous intraluminal thrombi and/​or necrotic vasculitic lesions. Remission may occur spontaneously or during therapy, with re- lapses following in up to 20% of cases. Most patients with mixed cryoglobulinaemia (55%) have an in- dolent and protracted renal course, presenting with proteinuria, haematuria, and hypertension. The usual renal lesion in this context is membranoproliferative glomerulonephritis, with some of the pe- culiarities described earlier. Nephrotic syndrome affects another 20% of patients. Arterial hyper- tension is observed in more than 80% of patients at the time of onset of renal disease. Endstage renal disease develops in fewer than 10% of pa- tients. It should be stressed that the overall risk of non-​Hodgkin B-​cell lymphomas is 35 times higher in patients with hepatitis C virus-​related cryoglobulinaemia compared to the general population. Diagnosis Mixed type II cryoglobulinaemia should be suspected in patients with the clinical picture described previously, an IgM rheumatoid factor, and a very low serum C4 fraction and total haemolytic ac- tivity of complement. In this context, a careful search for the pres- ence of cryoglobulin must be made, requiring that a blood sample from a fasting patient should be placed in warm water and taken promptly to the laboratory, which needs to be forewarned that such a sample will arrive. Cryoglobulinaemia-​related membranoproliferative glomeruloneph- ritis usually shows several distinctive histological features, including massive subendothelial deposits filling the capillary lumen and forming so-​called thrombi, and dramatic infiltration by leucocytes, mainly monocytes (Fig. 21.10.5.4). The thrombi are brightly stained with anti-​ μ and anti-​κ antibodies and present a microtubular crystalline structure similar to that of the cryoprecipitate. These glomerular changes may be associated with acute vasculitis of the small and medium-​sized ar- teries (33%) and lymphocytic infiltrates in the interstitium. Crescentic extracapillary proliferation is rare and always limited. Treatment The best treatment of mixed cryoglobulinaemia is not firmly estab- lished because the course of the disease is unpredictable and acute exacerbations may remit spontaneously. In patients with moderate renal and extrarenal manifestations, immunosuppressive agents are not indicated. In those with hepatitis C virus infection, sustained viral response is generally associated with improvement in clinical mani- festations of cryoglobulinaemia. Combined pegylated interferon and ribavirin for at least 1 year was until recently the treatment of choice. The use of novel direct-acting antihepatitis C agents is more efficient in eradicating hepatitis C virus, and with less side effects, will likely result in improved outcomes in type II cryoglobulinaemia. In more severe cases, particularly those with signs of systemic vasculitis, high-​dose steroids, plasma exchange, and cytotoxic drugs are indicated. Among these, the monoclonal anti-​CD20 antibody (rituximab), which is usu- ally well tolerated, is recommended, as it also appears to be as efficient as cyclophosphamide. Hypertension needs to be carefully controlled because cardiovascular complications are the major causes of death. In patients with severe symptomatic type I  or type II cryoglobulinaemia secondary to B-​cell proliferative disorder, treatment relies on chemotherapy adapted to the nature of the underlying clone. Renal involvement in Waldenström’s macroglobulinaemia A glomerulonephritis with intracapillary thrombi of monoclonal IgM is rare, but is almost specific for Waldenström’s macroglobulinaemia. It is characterized by periodic acid–​Schiff-​positive, noncongophilic

section 21  Disorders of the kidney and urinary tract 5024 endomembranous deposits in capillary loops, which sometimes oc- clude the capillary lumen either partially or completely, thus forming thrombi. These lesions, which occurred in patients with advanced disease and high serum IgM levels, usually with hyperviscosity syndrome and detectable cryoglobulinaemia, have decreased over time. AL amyloidosis currently represents the most frequent glom- erular disease, but other types have been described, including membranoproliferative glomerulonephritis with nonorganized monoclonal IgM deposits, type I  and type II cryoglobulinaemic glomerulonephritis, and Randall-​type MIDD. Neoplastic infiltra- tion of the renal interstitium by malignant B cells is common and may be observed alone or associated with glomerular or tubular disorders. Tubular lesions, secondary to monoclonal light chain precipitation, are less frequent, but cases of Fanconi’s syndrome and cast nephropathy have been reported. Management relies on chemotherapy (see Chapter 22.4.6) with rituximab-​based regimens. Plasmapheresis should be considered in patients with acute kidney injury and symptoms of hyperviscosity. C3 glomerulopathy and monoclonal gammopathy Isolated glomerular deposition of C3 is a rare condition in adults that results from dysregulation of the complement alternative pathway. It manifests histologically with mesangial proliferative or membranoproliferative glomerulonephritis, with diffuse, bright de- position of C3 in the mesangium and capillary walls by immunofluores- cence, and no significant immunoglobulin deposit. Ultrastructurally, two different patterns may be observed: dense deposit disease char- acterized by diffuse intramembranous electron-​dense deposits with a typical ‘sausage-​like’ appearance, and C3 glomerulonephritis with less intense granular mesangial, subendothelial, or subepithelial de- posits. A high prevalence of monoclonal gammopathy (>60%) was recently identified in patients with C3 glomerulopathy aged over 50 years. Clinical presentation is with hypertension, chronic renal failure, nonvisible haematuria, and proteinuria, with nephrotic syn- drome in half of cases. Most patients have an indolent plasma cell proliferation, consistent with MGRS, and one-​third have decreased C3 levels at diagnosis. Control of the underlying plasma cell clone with appropriate chemotherapy may result in significant improve- ment in renal parameters, before severe renal impairment develops. Although the pathophysiology remains unclear, local or systemic ac- tivation of the complement alternative pathway by the monoclonal immunoglobulin is likely to be involved, through autoantibody ac- tivity of the monoclonal Ig against a complement alternative pathway regulator protein, or other mechanisms, including direct activation of the complement alternative pathway by the monoclonal immuno- globulin itself. See Chapter 21.8.6 for further discussion. Renal involvement in lymphomas and leukaemias Renal complications of lymphomas and leukaemias are summar- ized in Box 21.10.5.1. All patients with unexplained renal failure should undergo ultrasound examination of the kidney, which should be arranged as a matter of urgency, to identify either enlarged kid- neys due to tumour infiltration or hydronephrosis. The presence of heavy albuminuria in this setting is suggestive of paraneoplastic glomerulopathy. (a) (b) (c) Fig. 21.10.5.4  Cryoglobulinaemic glomerulonephritis. (a) The glomerulus shows a marked endocapillary hypercellularity with massive infiltration of mononuclear leucocytes (Masson’s trichrome stain, magnification × 500). (b) Frequent double-​contour aspect and intraluminal thrombi (periodic acid–​Schiff stain, magnification × 312).
(c) Thrombi and segments of glomerular basement membrane are brightly stained with anti-​IgM antibody (immunofluorescence, magnification × 312). From Béatrice Mougenot’s personal collection.

21.10.5  Renal involvement in plasma cell dyscrasias 5025 Hodgkin’s disease and non-​Hodgkin’s lymphoma Glomerulonephritis is a rare complication of lymphoma, most often described in patients with Hodgkin’s disease, of whom 0.4% have minimal-​change disease and 0.1% have amyloid A amyloidosis. This low incidence of amyloidosis in patients with Hodgkin’s disease is most likely attributable to modern treatment protocols that induce rapid remission. Hodgkin’s lymphoma-​related minimal-​change disease shows features of a paraneoplastic glomerulopathy. The nephrotic syndrome usually ap- pears early, revealing the haemopathy in about one-​half of the cases; it rapidly disappears after effective treatment of the underlying condition; and it usually relapses simultaneously with the haemopathy. Cases of crescentic glomerulonephritis with rapidly progressive renal failure due to antiglomerular basement antibodies have also been reported. Glomerulonephritis may also occur in patients with non-​Hodgkin’s lymphoma, including both T-​ and B-​cell proliferations. In these con- ditions, unlike in Hodgkin’s lymphoma, minimal-​change disease is uncommon, and membranoproliferative glomerulonephritis and necrotizing crescentic glomerulonephritis with or without vasculitis are the most frequent lesions. Some cases are associated with type I cryoglobulinaemia or GOMMID. In other cases, the association between non-​Hodgkin’s lymphoma and renal disease may be coin- cidental. Presenting renal symptoms are nephrotic syndrome and/​or renal impairment. Full remission of these symptoms can be achieved in some patients by aggressive therapy of the lymphoma. Chronic lymphocytic leukaemia and low-​grade B-​cell lymphoma These haemopathies, particularly chronic lymphocytic leukaemia, have been reported in association with glomerular disease in about 50 cases. Most commonly, the nephropathy, usually manifesting as nephrotic syndrome with impaired renal function, and the leu- kaemia are detected simultaneously. The most frequent glomerular disease is membranoproliferative glomerulonephritis with or without cryoglobulinaemia (mostly type I). In type I cryoglobulinaemic glom- erulonephritis, glomerular monoclonal Ig deposits often display an ultrastructural organization into microtubules, and less frequently into crystals. In the absence of cryoglobulinaemia, a molecular link can be established between the haemopathy and the glomerulopathy when monotypic Ig deposits are found in the glomerulus, which can occur even in the absence of detectable circulating M component. As discussed previously, some of these patients present with typical immunotactoid/​ microtubular glomerulopathy or MIDD. Improvement of the neph- ropathy after chemotherapy for the leukaemia is well described. Acute leukaemias Disseminated intravascular coagulation has been associated with acute progranulocytic leukaemia. Other renal complications are commonly due to treatment, most particularly the tumour lysis syn- drome (see ‘Tumour lysis syndrome’). POEMS syndrome POEMS syndrome is a rare condition defined by the presence of per- ipheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder (IgA, IgG, IgM, or LC only the LC being almost always of the lambda isotype), and skin changes. The association of POEMS syndrome with osteosclerotic myeloma or Castleman’s dis- ease is common. Although the pathophysiology of the disease is un- known, POEMS syndrome is characterized by a very high serum level of vascular endothelial growth factor, which seems to be respon- sible for most symptoms present in this disease. Renal disease may occur, which usually manifests as proteinuria, haematuria, and renal failure that may progress to endstage renal failure. Kidney biopsy re- veals lesions resembling thrombotic microangiopathy, with glom- erular enlargement, cellular proliferation, and mesangiolysis with marked swelling of endothelial and mesangial cells, associated with endarteritis-​like lesions in the small renal arteries. The monoclonal component is usually not deposited in kidney. Tumour lysis syndrome Tumour lysis syndrome is a life-​threatening metabolic emergency. It occurs in patients with haemopathies involving a high cell turnover, such as Burkitt’s lymphoma or acute leukaemia, mostly at the onset of chemotherapy and/​or on radiation therapy. The ensuing massive cy- tolysis generates high levels of uric acid, phosphate, potassium, and xanthine (especially in patients treated with allopurinol), with a con- comitant decrease in serum calcium concentration. Oliguric or anuric acute kidney injury may occur, especially in those who are dehydrated or have pre-​existing impairment of kidney function. This acute kidney injury is mostly the consequence of acute precipitation of urate crystals in the tubular lumen, but in those with a moderate increase in uric acid concentration, the role of severe hyperphosphataemia causing precipi- tation of calcium/​phosphate complexes in renal interstitium and the tubular system has been assumed. Prevention is better than cure, and intensive monitoring is man- datory to prevent the development and the consequences of this syndrome. Patients at risk of the tumour lysis syndrome should be vigorously hydrated with 0.9% saline (assuming normal or near-​ normal baseline renal function, and with care taken to avoid inducing pulmonary oedema) before receiving chemotherapy or radiotherapy. Urinary alkalinization should be used with caution because it may induce phosphate precipitation. Reduction of urate production with allopurinol, which increases the risk of formation of xanthine neph- ropathy/​stones due to accumulation of xanthine, should be reserved for patients at low risk for developing tumour lysis syndrome. In high-​ risk patients (high tumour burden, aggressive chemotherapy, hypo- volaemia) with hyperuricaemia, recombinant modified urate oxidase (rasburicase) should be preferred, which rapidly reduces the uric acid pool, prevents accumulation of xanthine and hypoxanthine, and does Box 21.10.5.1  Renal complications of lymphomas and leukaemias • Mechanical complications: —​  Infiltration of renal parenchyma —​ Obstructive uropathy (retroperitoneal fibrosis) —​ Compression of renal artery or vein • Electrolyte disturbances and disseminated intravascular coagulation • Glomerulopathies (including amyloidosis) • Treatment-​induced complications: —​ Tumour lysis syndrome —​ Lithiasis and urate nephropathy —​ Radiation nephropathy —​ Drug-​induced toxic nephropathy —​ Thrombotic microangiopathy and mesangiolysis

section 21  Disorders of the kidney and urinary tract 5026 not require alkalinization for effect. Rasburicase is also indicated in the treatment of established tumour lysis syndrome, associated with vigorous hydration with 0.9% saline to encourage urinary output in patients passing urine, with close clinical monitoring to prevent iatro- genic fluid overload. Patients with severe acute kidney injury should be treated with haemodialysis, which allows recovery of renal func- tion following the reduction of serum phosphate and serum uric acid concentrations. FURTHER READING Bridoux F, et  al. (2015). Diagnosis of monoclonal gammopathy of renal significance. Kidney Int, 87, 698–​711. Leung N, et  al. (2012). Monoclonal gammopathy of renal signifi- cance:  when MGUS is no longer undetermined or insignificant. Blood, 120, 4292–​5. Leung N, et al. (2019). The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol, 15, 45–59. Renal involvement in Ig light-​chain amyloidosis Dispenzieri A, et al. (2004). Serum cardiac troponins and N-​terminal pro-​brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol, 22, 3751–​7. Gertz MA, Merlini G (2010). Definition of organ involvement and response to treatment in AL amyloidosis:  an updated consensus opinion. Amyloid, 17 Suppl 1, 48–​9. Jaccard A, et al. (2007). High-​dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med, 357, 1083–​93. Kyle RA, Gertz MA (1995). Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol, 32, 45–​59. Palladini G, et al. (2010). The combination of high-​sensitivity cardiac troponin T (hs-​cTnT) at presentation and changes in N-​terminal natriuretic peptide type B (NT-​proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood, 116, 3426–​30. Palladini G, et al. (2014). A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis. Blood, 124, 2325–​32. Ronco PM, Aucouturier P, Moulin B (eds) (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin depos- ition. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Vrana JA, et  al. (2009). Classification of amyloidosis by laser microdissection and mass spectrometry-​based proteomic analysis in clinical biopsy specimens. Blood, 114, 4957–​9. Wechalekar AD, et al. (2015). Guidelines on the management of AL amyloidosis. Br J Haematol, 168, 186–​206. Renal involvement in myeloma Bridoux F, et al. (2017). Effect of high-cutoff hemodialysis vs conven- tional hemodialysis on hemodialysis independence among patients with myeloma cast nephropathy: a randomized clinical trial. JAMA, 318, 2099–110. Dimopoulos MA, et al. (2010). Renal impairment in patients with mul- tiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol, 28, 4976–​84. Ecotière L, et al. (2016). Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant, 31, 64–​72. Hutchison CA, et al. (2007). Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies. J Am Soc Nephrol, 18, 886–​95. Hutchison CA, et al. (2019). High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib- based chemotherapy (EuLITE): a phase 2 randomised controlled trial. Lancet Haematol, 6, e217–e228. Leung N, Behrens J (2012). Current approach to diagnosis and man- agement of acute renal failure in myeloma patients. Adv Chronic Kidney Dis, 19, 297–​302. Light-​chain, light-​ and heavy-​chain, and heavy-​chain deposition disease Cohen C, et  al. (2015). Bortezomib produces high haematological response rates with prolonged survival in monoclonal immuno- globulin deposition disease. Kidney Int, 88, 1135–​43. Joly F, et al. (2019). Randall-type monoclonal immunoglobulin depos- ition disease: novel insights from a nationwide cohort study. Blood, 133, 576–87. Ronco PM, Aucouturier P, Moulin B (2010). Renal amyloidosis and glomerular diseases with monoclonal immunoglobulin de- position. In: Floege J, Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 4th edition, pp. 322–​34. Saunders Elsevier, London. Royer B, et al. (2004). High dose chemotherapy in light chain or light and heavy chain deposition disease. Kidney Int, 65, 642–​8. Non-​Randall-​type MIDD Gumber R, et al. (2018). A clone-directed approach may improve diag- nosis and treatment of proliferative glomerulonephritis with mono- clonal immunoglobulin deposits. Kidney Int, 94, 199–205. Nasr SH, et al. (2009). Proliferative glomerulonephritis with mono- clonal IgG deposits. J Am Soc Nephrol, 20, 2055–​64. Touchard G (2003). Ultrastructural pattern and classification of renal monoclonal immunoglobulin deposits. In: Touchard G, et al. (eds) Monoclonal gammopathies and the kidney, pp. 95–​117. Kluwer, Dordrecht. Nonamyloid fibrillary and immunotactoid glomerulopathies Bridoux F, et al. (2002). Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immuno- logic features. Kidney Int, 62, 1764–​75. Javaugue V, et al. (2013). Long-​term kidney disease outcomes in fibril- lary glomerulonephritis: a case series of 27 patients. Am J Kidney Dis, 62, 679–​90. Nasr SH, et al. (2011). Fibrillary glomerulonephritis: a report of 66 cases from a single institution. Clin J Am Soc Nephrol, 6, 775–​84. Nasr SH, et al. (2017). DNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis. Kidney Int Rep, 3, 56–64. Rosenstock JL, et al. (2003). Fibrillary and immunotactoid glomerulo- nephritis: distinct entities with different clinical and pathologic fea- tures. Kidney Int, 63, 1450–​61. Renal involvement in cryoglobulinaemia Brouet JC, et  al. (1974). Biologic and clinical significance of cryo- globulins. A report of 86 cases. Am J Med, 57, 775–​88. Cacoub P, Terrier B, Saadoun D (2014). Hepatitis C virus-​induced vas- culitis: therapeutic options. Ann Rheum Dis, 73, 24–​30.

Role of infection

Role of infection

Serology

Serology

21.10.2  The kidney in systemic vasculitis 4993 Investigation There are no diagnostic criteria for vasculitis syndromes and diag- nosis depends on recognition of the pattern of clinical features, supported by serology, histology, and imaging, and the exclu- sion of secondary causes and mimics of vasculitis. Patients with suspected renal vasculitis require systematic review of all organ systems for the detection of other foci of vasculitis and the identi- fication of comorbidities likely to influence treatment choice and prognosis. Serology ANCA positivity (Fig. 21.10.2.3) has historically required a positive cytoplasmic ANCA (C-​ANCA) or perinuclear ANCA (P-​ANCA) by indirect immunofluorescence, confirmed by a positive PR3-​ ANCA or MPO-​ANCA, but improvements in the quality and speci- ficity of PR3 and MPO-​ANCA assays have reduced the value of the indirect immunofluorescence assay. The clinical utility of ANCA assays depends on the clinical context, but in suspected nephritis a positive PR3 or MPO-​ANCA has a 95% specificity for vasculitis. However, 5 to 10% of patients with a pauci-​immune necrotizing crescentic glomerulonephritis are ANCA negative, and ANCA will be negative in some early or limited forms of AAV, and after treat- ment. Immune-​complex-​mediated vasculitis syndromes, such as IgA vasculitis and large-​vessel vasculitis, are ANCA negative. Complement C3 and C4 and immunoglobulin levels are normal in AAV and anti-​GBM disease; rarely, they are reduced in IgA vas- culitis. A positive rheumatoid factor, paraprotein (usually IgM), and low C3 and C4 is the typical pattern in cryoglobulinaemia. A  low-​titre positive rheumatoid factor and atypical pattern antinuclear antibody can be seen in AAV, where they appear to be of no significance. Urine analysis The presence of haematuria, occasionally visible, is universal in renal vasculitis and is accompanied by proteinuria. In AAV and anti-​GBM disease, proteinuria is non-​nephrotic and averages 1 g/​24 h, although an increase in proteinuria can be seen in the recovery phase due to glomerular remodelling. Phase contrast microscopy reveals dys- morphic red cells of glomerular origin, and the presence of red cell casts is almost diagnostic of a crescentic nephritis (Fig 21.10.2.4). Nephrotic-​range proteinuria may be found in vasculitis associated with immune complexes, such as cryoglobulinaemia or IgA vascu- litis, but other causes of the nephrotic syndrome are more likely if this is the initial presentation, especially if the serum creatinine is normal. Histology Renal histology enables the most secure diagnosis to be made. The typical renal biopsy features in AAV are a pauci-​immune necrotizing glomerulonephritis with crescent formation (Fig. 21.10.2.1). MPA is associated with more severe biopsy changes, with greater evidence of chronicity and scarring. In GPA, acute tubular changes are more frequent, scarring is less apparent, and the prognosis is better. Histological severity is classified according to the Berden system into focal, crescentic, mixed, and sclerotic subgroups, which associate with renal prognosis (Table 21.10.2.3). The presence of severe scarring does not exclude the possibility of a good renal outcome and this system is not used to guide induc- tion therapy. Extensive tubulointerstitial inflammation or damage, extraglomerular arterial disease, and MPO-​ANCA are further negative predictive factors for renal outcomes. Occasionally, a dual pathology is identified, such as anti-​GBM disease or IgA nephropathy. (a) (b) Fig. 21.10.2.3  Indirect immunofluorescence assay for ANCA. (a) Typical staining pattern of cytoplasmic ANCA that is usually due to antibodies to proteinase 3. (b) Typical staining pattern of perinuclear ANCA that is usually due to antibodies to myeloperoxidase. (a) (b) Fig. 21.10.2.4  (a) Dysmorphic urinary red blood cells. (b) A red blood cell cast.

Staging and natural history—

Staging and natural history—

Structure and function of the kidney 4717 Steve Ha

Structure and function of the kidney 4717 Steve Harper and Robert Unwin

ESSENTIALS The kidneys are the archetypal organs of homeostasis. Their pri- mary function is filtration and segregation. Through these processes they rebalance the continual electrolyte and chemical disturbances that derive from physiological and pathological metabolic pro- cesses. Electrolytes, hydrogen (H+) ions from metabolic acids, amino acids, fatty acids, plasma proteins, immunoglobulins, and metabolic products are either retained, reabsorbed, and recycled; or they are filtered, secreted, concentrated, and excreted. These processes con- vert approximately 120 ml/​min of primary glomerular filtrate into
1 ml/​min of urine. In addition, the kidneys play crucial roles in bone mineralization, the maintenance of cardiovascular tone, systemic blood pressure, and bone marrow synthetic function via their contri- bution to vitamin D production, the renin–​angiotensin system, and erythropoiesis. Introduction The kidneys control the milieu intérieur by rebalancing the con- tinual electrolyte and chemical disturbances that derive from physiological and pathological metabolic processes. Their mech- anism of action involves the conversion of about 120 ml/​min of plasma filtrate into 1 ml/​min of urine, with incredible precision in the control of excretion of an enormous variety of substances. Electrolytes, hydrogen (H+) ions from metabolic acids, amino acids, fatty acids, plasma proteins, immunoglobulins, and meta- bolic products are either retained, reabsorbed, and recycled, or they are filtered, secreted, concentrated, and excreted. To illustrate the vital homeostatic role of the kidney, we need to look no further than sodium, which with its main anions chloride and bicarbonate constitutes the major osmotically active solute in the extracellular fluid (ECF), and hence Na+ concentration is the chief determinant of ECF osmolality and fluid shifts between the ECF and intracellular fluid compartments. If the Na+ concentration changes, osmoreceptors in the hypothalamus detect the change and affect the sensation of thirst and modulate the release of vasopressin. In this way, the volume of the ECF, which is intimately related to blood pressure, is determined largely by its Na+ content, which in turn is controlled by renal Na+ excretion. The kidney is therefore inevitably involved in any condition where blood pressure or ECF volume is abnormal. The concept of effective circulating volume relates to the body’s perception of the ‘fullness’ of the vascular tree. Changes in effective circu- lating volume are detected by both high-​pressure baroreceptors in the aortic arch and carotid sinus, and low-​pressure recep- tors in the cardiac atria. Their stimulation produces corrective changes in Na+ excretion by the kidneys, mediated by appropriate changes in activity of the renin–​angiotensin–​aldosterone system, renal sympathetic nerves, and natriuretic peptides. In congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome, the effective circulating volume is reduced even though the ECF volume is not, resulting in enhanced renal Na+ (and water) reten- tion causing oedema. The kidneys play a crucial role in the homeostasis of electrolytes other than sodium, as evidenced by the dangers of hyperkalaemia in renal failure. They also have critical actions in regard to bone mineralization and bone marrow synthetic function via their con- tribution to vitamin D production and erythropoiesis. This chapter describes how the structure and function of the kidney enables it to perform such remarkable feats. Ultrastructure The functional unit linking ‘blood in’ to ‘urine out’ is the nephron (Fig. 21.1.1). The blood supply to the nephron is eventually arrived at after sequential division of the renal arteries and subsequent vessels to reach specialized portal exchange microvascular beds. These are the glomerular capillaries, which occur in grape-​like clusters in the outer cortex of the kidneys and, in total, constitute 19 km of capillary filtra- tion area. The structure of the nephron is that the glomerulus, including the postfiltration barrier Bowman’s space (which in life is a potential space like the pleural and pericardial spaces), leads on to the proximal convoluted tubule (PCT), loop of Henle, and distal convoluted tubule (DCT) before reaching the collecting duct. The mammalian nephron has evolved to include systems for dynamic feedback from distal to proximal parts of the nephron (tubuloglomerular feedback) in that the 21.1 Structure and function of the kidney Steve Harper and Robert Unwin

SECTION 21 Disorder s of the ki dne y and u rinary trac 4718 (b) (c) (d) AVC AVC AVC Afferent Arteriole Conduit Conduit Efferent Arteriole Conduit (a) Fig. 21.1.2  Collagen supported Glomerular Vascular Chambers identified in human kidneys perfusion fixed under physiological hydrostatic and osmotic pressures. (a) Scale diagram of the Afferent (Red) and Efferent (Blue) ends of the glomerular vasculature within the glomerular stalk. Diagram shows size and branch relationships between arterioles, vascular chambers and 1st order conduit vessels (few branches); mesangium close to vascular pole—(grey). Scale bar 100 µm. (b) & (c) Still images from 3D-video reconstruction of physiologically fixed human glomerulus demonstrating elongated afferent vascular chamber (AVC) (red network) and right angle approach of incident arteriole. (d) Collapsed Vascular chambers are occasionally visible on human renal biopsy tissue. Source data from Neal, C., Arkill, K., Bell, J., et al., Novel hemodynamic structures in the human glomerulus, Renal Physiology, American Journal of Physiology, Volume 315 Issue 5, November 2018, Pages F1370–F1384. Copyright © 2018 the American Physiological Society. tubular structures, after descending into the medulla, wend their way back to the renal cortex so that the DCT lies adjacent to its own glom- erular stalk (the juxtaglomerular apparatus) (Fig. 21.1.1). Glomerulus The microvascular ultrastructure The glomerular capillary bed is composed of five to seven glomerular lobules fed by conduit capillaries that diverge from the afferent ar- teriole in the glomerular stalk. These initial lobular capillaries have few branches until they reach the periphery of the glomerular tuft, at which point multiple division results in approximately twice the number of efferent lobular vessels converging on the efferent arteriole. The efferent arterioles subsequently diverge again into the peritubular and medullary capillary plexi, which finally converge to the renal venous system via the returning medullary vasa recta. The glomerular capillaries are lined by a nondiaphragmatic highly fenestrated endo- thelium, with each fenestration being 15 times the diameter of an al- bumin molecule. The afferent arteriole enters the glomerular tuft at an acute right angle (Fig. 21.1.2). This, in conjunction with a subsequent vascular dilatation immediately within the glomerular stalk (the Afferent Vascular Chamber – AVC), is predicted to result in complex, even rotational flow, to promote a more even distribution of blood into the conduit vessels of the glomerular lobules which originate from the AVC at a variety of disparate positions, orientations and angles (Fig. 21.1.2). Both afferent and efferent arterioles are vasoactive, responding to—​among other agents—​prostaglandins (afferent vessel AA JG MD www.people.upei.ca Glomerulus Afferent arteriole Loop of Henle Distal convoluted tubule (DCT) Straight collecting tubule Urine Proximal convoluted tubule (PCT) Efferent arteriole Fig. 21.1.1  The nephron. Specialized cells of the thick ascending limb of the DCT (macula densa (MD)) approximate to the juxtaglomerular cells (JG) and afferent arteriole (AA) of its own glomerulus. This facilitates fine and rapid modification of SNGFR and Na+, water, and blood pressure homeostasis via the renin–​angiotensin and other systems.

21.1  Structure and function of the kidney 4719 dilatation) and angiotensin (predominant efferent vessel constriction). This allows dynamic manipulation of flow through the glomerular capillary network, influencing intraglomerular pressure, ultrafiltra- tion, and single-​nephron glomerular filtration rate (SNGFR). Even modest alterations in vessel diameter can have a profound influence on vessel function since flow is proportional to the fourth power of the vessel radius—​hence the clinically relevant change in glomerular filtration rate (GFR) that can result from the use of prostaglandin and angiotensin-​converting enzyme (ACE) inhibitors. The barrier The glomerular filtration barrier (GFB) is a complex, integrated, multilayered structure that behaves in many ways like a simple an- ionic sieve. It appears to segregate primarily according to size, but molecular charge, shape, orientation, and solubility all contribute to the tendency for a molecule to be retained (or not) within the vas- cular lumen. The resulting differential restriction ensures poor per- meability to large, lipid insoluble or anionic molecules, for example, only 1 in 1600 albumin molecules traverse the barrier (Fig. 21.1.3). In contrast, the GFB is highly permeable to water and small water-​ soluble molecules (Fig. 21.1.4). In sequential order, from the glomerular capillary lumen out- wards, the fused layers of the barrier include the endothelial glycocalyx, the fenestrated endothelium, the glomerular basement membrane (GBM), the 40-​nm podocyte foot process/​slit diaphragm (between interdigitating foot processes of adjacent podocytes—​the slit diaphragms are composed of molecules that appear to have signalling as well as structural functions), the glycocalyx of the (b) (a) Fig. 21.1.3  (a) Isolated rabbit glomerulus, cannulated and perfused with 60-​kDa rhodamine-​labelled dextran. Dilute solution in afferent arteriole (AA) gives a signal comparable to background. Free water is ultrafiltrated out, [rhodamine-​dextran] rises to reveal intense fluorescence in the efferent arteriole (EA). (b) Mouse glomerulus. Red fluorescence = mouse albumin (atto-​565 labelled). Glomerular albumin sieving coefficient (Θalb): Urinary space [albuminatto565]/​glomerular capillary [albuminatto565] = 0.0006
(i.e. approximately 1 in 1600 albumin molecules penetrates the GFB). (a) Reproduced with permission from Salmon A, et al. (2009). New aspects of glomerular filtration barrier structure and function: five layers (at least) not three. Current Opinion in Nephrology and Hypertension, 18(3), 197–​205. Copyright © 2009 Lippincott Williams. (a) (b) Fig. 21.1.4  Two stills from a video showing the glomerular filtration barrier is highly permeable to water and small water-​soluble molecules (here Lucifer yellow). In this in vivo preparation, the time difference of the fluorescence intensity peak of glomerular filtrate at two regions of interest (ROI) can be used to visualize and investigate the SNGFR. G, glomerulus; PT, proximal tubule. Scale = 50 μm. http://​ ajprenal.physiology.org/​content/​ajprenal/​suppl/​2006/​04/​12/​00521.2005.DC1/​40XSNGFR_​short.avi. Reproduced with permission from Kang et al. Am J Physiol Renal Physiol 2006;291: F495–​F502. Copyright © 2006 the American Physiological Society.

SECTION 21 Disorder s of the ki dne y and u rinary trac 4720 podocyte, and the space under the podocyte (the sub-​podocyte space) (Fig. 21.1.5). It has been shown in in vivo models, and in clin- ical disease, that faults in any one of these layers can lead to a failure of normal permselectivity (Fig. 21.1.5). The wide acceptance of the pore theory of permeability (see ‘Theories of permeability’) and the high density of fenestrations both initially lent credence to the view of the GFB as a glorified sieve (i.e. a continuous barrier with pores of regular size and spacing). However, the GFB is now regarded as a dynamic structure, with all cellular and acellular (matrix or space) components subject to dynamic modifi- cation: for example, the hydraulic resistance of the GBM increases as hydrostatic pressure rises; the cell surface layers (glycocalyx) can present formidable barriers to protein flux in their own right and can be altered by permeability modifying growth factors such as vascular endothelial growth factor and angiopoietin I (produced by podocytes); and even podocytes themselves appear to be able to con- tract and migrate. Barrier permeability The permeability of a capillary barrier is defined as the volume of fluid traversing the barrier per unit area, per unit time, per unit driving force (units: m.s−1.pascal−1). The factors governing this phenomenon were first described by Starling in 1896. Hence the Starling equation: Flow Area Driving Force (ΔP − Δπ) Permeability (to water) A Jv = Lp[(Pc−Pi)−σ(πp−πi)] Pod GCL 2 5 3 4ii 4i 1 Glomerular Capillary Lumen (GCL) 6. Sub-podocyte space 6. Sub-pod ocyte space (a) (b) Fig. 21.1.5  (a) A two-​photon in vivo image of the subpodocyte space between podocyte and glomerular endothelial cell. (b) Transmission electron microscopy of a perfusion fixed human glomerulus with addition of Lanthanum Dysprosium GlycosaminoGlycan Adhesion (or LaDy GAGa) stain (section 80 nm thick) which highlights the multilayered GFB including glycocalyx. Scale = 200 nm. http://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3922634/​bin/​1471-​2369-​15-​24-​ S15.mov .Acquired or genetic abnormalities in multiple layers of the GFB can result in abnormal glomerular permselectivity and/​or glomerular disease: 1. Endothelial glycocalyx: thickness reduced by enzymatic degradation or pathological hyperglycaemia (causes proteinuria). Restored experimentally by angiopoietin I or VEGF165b with a reduction in protein leak. 2. Fenestrated endothelium: fenestration density modified by podocyte-​derived pro-​ and antipermeability isoforms of vascular endothelial growth factor. .3. GBM: target for Goodpasture’s antibody; mutations of GBM components cause proteinuria (e.g. Alport’s syndrome). Increased GBM thickness and altered GBM composition seen in diabetic nephropathy. 4. Podocyte: slit
diaphragm proteins—​mutations cause steroid-​resistant (e.g. Finnish) nephrotic syndrome.
Nonslit diaphragm podocyte gene mutations cause proteinuria and glomerular injury, for example, WT1 (Denys–​Drash syndrome). 5. Glycocalyx of the podocyte (yet to be investigated). 6. The subpodocyte space: endows as much resistance as GBM itself. Alters in foot process effacement and as podocytes migrate.

21.1  Structure and function of the kidney 4721 where ΔP is the hydrostatic pressure gradient, Δπ is the functional oncotic pressure, and σ is the reflection coefficient. The tendency of a barrier to resist macromolecular flux: if, for example, 50% of the macromolecular solute penetrated the barrier, then Δπ would be functionally only 50% of that measured. Effectively flow depends on the balance of two opposing forces: driving force and resistance (permeability−1), thus the scenario is very similar to Ohm’s law governing the flow of current around an electrical circuit which is dependent on voltage (driving force) and electrical resistance (conductance−1). Theories of permeability How the observed structure of the barrier (or that of any capillary) equates to its function has long been debated. Early work suggested endothelia possessed ‘size-​limiting structures’ to the movement of solutes and water, leading to the pore theory of permeability. However, structural pores of the correct size and number could not be identified. The subsequent identification of the molecular mesh or network structure of the glycocalyx and basement membrane as well as the podocyte glycocalyx and glomerular slit diaphragm led to the ‘fibre-​matrix junction-​break’ theory of permeability, which pos- tulates that the complex molecular network of the above-​mentioned structures behave functionally as one might expect pores to func- tion, but there are no discrete ‘holes’, that is, there are pathways through endothelial barriers, not pores. Glomerular filtration rate Total GFR is the sum of all SNGFRs. From Starling’s formula this would therefore be ( ) [ ( ) ] SNGFR Lp P A ∑ ∑

− × ∆ ∆π . Permeability and filtration area can be influenced by glomerular cell function, and glom- erular structure and number (and adversely by damage and sclerosis). The predominant cause of loss of GFR as we age, for example, is numer- ical loss (6500 glomeruli per year) reducing the available ‘A’. Reduced hydraulic permeability has been implicated in declining GFR of early pre-​ eclampsia and in some forms of glomerular disease (e.g. membranous nephropathy) in which a fall in both area and Lp has been cited. Although SNGFR does increase with falling Δπ, increased capillary flow and in- creased afferent arteriolar pressure, the predominant factor influencing the driving force is intraglomerular pressure. This in turn is determined by the balance of afferent and efferent arteriolar tone, which are influenced by many molecules including prostaglandins, angiotensin II, and natri- uretic peptides (atrial and brain). These changes can happen rapidly, sup- porting the argument that the glomerulus is dynamic and responsive (Figs. 21.1.6 and 21.1.7). Tubuloglomerular feedback The proximity of the DCT to the afferent arteriole of its own glom- erulus facilitates a unique fine tuning of single nephron function (GFR and sodium handing) via mechanisms controlled by the juxta- glomerular apparatus. This involves some specialized cells of the DCT that sense NaCl delivery to the distal nephron, unique cells at the glomerular stalk, and renin-​producing granular cells of the af- ferent arteriole (sometimes called juxtaglomerular cells). A decrease in DCT NaCl content is interpreted as a decrease in GFR or systemic blood pressure. This induces the release of renin from preformed granules prompting the indirect production of angiotensin II, re- sulting in systemic vasoconstriction and preferential efferent glom- erular arteriolar vasoconstriction, raised intraglomerular pressure, and maintained or increased GFR. Conversely, an increase in DCT NaCl content prompts a parallel system which leads to adenosine-​ mediated afferent arteriolar vasoconstriction and reduced GFR (Figs. 21.1.6 and 21.1.7). Clinical relevance Glomerular selectivity dysfunction and glomerular disease Derangement of the differential permeability of the glomeruli is a characteristic sign of the various types of glomerulonephritis (GN), as well as other glomerular diseases of which the most prevalent is diabetic nephropathy. The glomerulonephritides are a spectrum of conditions associated with abnormal glomerular cell number, injury, type, or morphology, with or without the deposition of immune-​ or nonimmune-​related proteins, resulting in injury and destruction of (a) (b) Fig. 21.1.6  Dynamic SNGFR and tubuloglomerular feedback. Rapid changes in glomerular physiology, SNGFR, and downstream nephron flow are a normal feature in health. (a) and (b) show a rapid in vivo degranulation of renin stores (green quinacrine stain) in the glomerulus (G) and afferent arteriole (AA) (R18, red) from juxtaglomerular cell (JG) apparatus in an isolated rabbit kidney, in this instance in response to hyperglycaemia with resultant AA dilatation:
http://​www.jci.org/​articles/​view/​33293/​sd/​2. Reproduced with permission from Toma I, Kang JJ, Sipos A, Vargas S, Bansal E, Hanner F, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest 118:2526–​2534 (2008). Copyright © 2018 American Society for Clinical Investigation.

SECTION 21 Disorder s of the ki dne y and u rinary trac 4722 the filtering mechanism and subsequent glomerulosclerosis. A clin- ical hallmark of GN is proteinuria due to loss of the usual molecular segregation of glomerular filtration. The abnormalities provoking these conditions can be inherent to the host, with some types of GN recurring after kidney transplantation. The search for circulating causative factors and underlying immune abnormalities continues in different patterns of GN, but with variable success. Clinically GN is a wide spectrum of disease. At one end of the morphological spectrum of injury is minimal change disease, char- acterized by morphological changes only in the podocytes (foot process effacement or flattening), and only observable on electron microscopy, yet provoking such marked proteinuria that nephrotic syndrome is the clinical presentation. At the other extreme are se- vere, destructive inflammatory lesions causing necrosis and forma- tion of extracapillary crescents, typically presenting with rapidly progressive renal failure and seen, for example, in renal vasculitis, Goodpasture’s disease, and systemic lupus. Other common patterns of GN of intermediate morphological and functional severity include IgA nephropathy, membranous nephropathy, mesangiocapillary GN, and focal segmental glomerulosclerosis. Diabetic nephrop- athy is a particularly complex form of glomerular injury involving every facet of glomerular physiology, from resistance, pressure, and glomerular flow rate to endothelial, GBM, and podocyte defects, as well as altered communication between layers and between nephron segments. Proteinuria, as well as being a marker of glomerular injury, is also an independent risk factor for cardiovascular and all-​cause mor- tality in people with kidney disease. The explanation is unknown, but abnormalities in the glycocalyx have been implicated since these are consistent features despite the ultrastructural changes in capil- laries and macrovessels being widely different. Abnormal flattening of the glycocalyx (Fig. 21.1.8) in the endothelial cells of the glom- erular capillary is a feature of diabetic nephropathy, and emerging data suggest that similar abnormalities are simultaneously present in systemic vessels. Furthermore sodium and hyperaldosteronism have also been associated with a reduction in glycocalyx thickness in in vivo models. Tubule Figure 21.1.1 is a reasonably natural representation of the nephron, with the tubule folding back on itself, but it is easier to consider renal tubular function along its course by representing the nephron diagram- matically in a linearized ‘opened up’ form (Fig. 21.1.9). However, both Figs. 21.1.1 and 21.1.9 are oversimplified: in particular they do not illus- trate that the nephron is up to 1000 times as long (3–​5 cm) as it is wide (50–​60 µm). A mathematically similar garden hose would be 20 m long.   0 50 100 150 Time (s) CCD PT Glom Fluorescence intensity 200 250 300 Fig. 21.1.7  An in vivo rat kidney perfused with rhodamine-​labelled dextran. Modest amounts of dextran can be detected in filtrate and downstream flow detected in distal parts of the nephron PCT and cortical collecting duct (CCD). The apparent oscillations in flow are rapid and affected by multiple parameters including those of tubuloglomerular feedback. (a) (b) (c) (d) (e) Fig. 21.1.8  Confocal images. Glycocalyx (GLX) disruption is associated with increased glomerular permeability and proteinuria. This can be reproduced experimentally by enzymatic disruption, for example, with neuraminidase (a, b). Glomerular endothelial cells (EC) of rats stained green (Lucifer yellow), GLX coloured red (Alexa-​594-​wheat germ agglutinin (WGA) lectin). GCL, glomerular capillary lumen. (c–​e) GLX disruption seen in diabetes. Rat kidneys perfused in vivo with cell membrane labelled (R18, red) and glycocalyx labelled (alexa-​ 488-​WGA lectin; green) then imaged with confocal microscopy. In (c) to (e), the GCL is on the right of each panel and the EC to the left. The healthy control in (c) has normal GLX depth (solid arrows). (d) Absent glomerular endothelial GLX lining the luminal surface of EC in a diabetic proteinuric animal. (e) GLX restored after VEGF-​A165b treatment with reduction of proteinuria.

21.1  Structure and function of the kidney 4723 Proximal convoluted tubule The PCT, extending from Bowman’s space, is divided in func- tional terms, and to a lesser extent histologically, into three parts (Fig. 21.1.9). As we have shown previously, the passage of water and solutes across the GFB is primarily dependent on Starling’s forces, and has been regarded as a passive process. The proximal tubular epithelium is highly permeable (of low resistance—​often termed ‘leaky’), meaning that water (fluid) and some solutes can pass with relative ease between cells (a paracellular pathway as determined by Starling’s forces—​Fig. 21.1.10), and that a small osmotic (δπ) and/​or hydrostatic pressure gradient (δP) between blood (in the peritubular capillaries; Fig. 21.1.1) and tubular fluid (glomerular filtrate) can have a big effect on fluid reabsorption. The phenomenon of glomerulotubular balance reflects this, and is another way in which glomerular filtrate delivery to the tubule and tubular reabsorption are normally kept in balance. In addition, however, and in contrast to mechanisms at the GFB, in the tubule, water and solutes can be transported transcellularly (often against concentration gradients) by three active transport mechanisms involving (1)  molecule-​specific channels (acting via electrochemical gradients), (2)  cotransporters, or (3)  exchange ‘pumps’. Both cotransporters and exchange pumps are described as secondarily active in that they are driven by the ATP-​generated low intracellular Na+ concentration resulting from action of the sodium–​ potassium ATPase (Na+,K+-​ATPase) pump sited in the basolateral membrane (Fig. 21.1.10). The movement of solutes transcellularly is driven in all tubular cells by this sodium pump which keeps the Na+ concentration inside the cell low (20–​30 mM), creating a fa- vourable concentration gradient for Na+ entry from the tubular fluid on the apical (luminal) side, where its concentration (at the start) is similar to plasma (140–​145 mM). Other solutes are reabsorbed by a coupling or exchange mechanism that can operate in parallel (cotransport), as for glucose, phosphate, and amino acids, or in ex- change (counter-​transport), as with protons (H+) for bicarbonate re- absorption, and for ammonium (NH4+) secretion. In addition to its reabsorptive function, the PCT has a metabolic role in converting 25-​OH vitamin D to active 1,25-​(OH)2 vitamin D, and also an enzyme that can inactivate vitamin D (24-​hydroxylase). The proximal tubule also synthesizes glucose (and ammonium), as well as several paracrine factors such as angiotensin II and prostaglandins. The PCT is where the bulk (about 65%) of filtered sodium and water is reabsorbed, but unlike in the collecting duct (see ‘Late distal convoluted tubule and collecting duct’), the amount reabsorbed is relatively fixed (obligate) (Fig. 21.1.11). Table 21.1.1 lists the main transport functions of the PCT. Early proximal convoluted tubule (S1) S1 reabsorbs several selected filtered solutes, including glucose and amino acids, and significant amounts of phosphate and bicar- bonate, and—​importantly—​small or low molecular weight proteins (LMWPs), including any filtered albumin (Figs. 21.1.12 and 21.1.13). Reabsorption Filtration Excretion ~150 litres/day ~20,000 mmol Na+/day S3 S2 S1 Thick ascending Loop of Henle CD DCT Secretion PCT ~1.5 litres/day ~150 mmol Na+/day Reabsorption when solute clearance < creatinine clearance Secretion when solute clearance > creatinine clearance descTL ascTL Fig. 21.1.9  Linearized representation of the nephron contrasting input load to output excretion. DCT, distal convoluted tubule; PCT, proximal convoluted tubule. Cotransporters Exchangers Channels Low [Na+] Tight junctions (variable claudin content) Na+ Na+ Na+ Na+ X K+ K+ Basolateral membrane ∆π and ∆P gradients affect paracellular net transport Apical membrane Y+ Lumen Interstitium Sodium pump Fig. 21.1.10  A prototypical polarized renal tubular cell membrane. The intracell [Na+] is kept actively low (20–​30 mM) by the Na+,K+-​ATPase pump in the basolateral membrane (red fill). Three types of transporter reside in apical membrane: (1) channels; these (Na+ entry and K+ exit) are electrochemical gradient dependent (for Na+, both concentration and voltage favour entry; for K+, concentration favours exit, limited by voltage). (2) Cotransporters; X = for example, glucose, PO4 3-​, and amino acids. (3) Exchangers; Y = H+ or NH4 +. Tight junctions vary in composition (different claudins being a key component) along the tubule. High permeability (leaky) in the PCT and low permeability (tight) in the TALH and beyond, which is why a transepithelial potential difference can be established across the distal nephron. Sodium and Water reabsorption <1% excreted 19% 25% 15% 50% 50% 5% ~0 15% 15% ~0

4% 1% excreted Fig. 21.1.11  Sites of relative reabsorption of Na+ and water along the nephron.

SECTION 21 Disorder s of the ki dne y and u rinary trac 4724 The mechanism for LMWP reabsorption is highly specialized, involving receptor-​mediated endocytosis and internalization, with eventual protein degradation in lysosomes. The apical surface re- ceptors responsible for binding LMWPs are megalin and cubilin (Fig. 21.1.14). Late proximal convoluted tubule (S2) The S2 segment reabsorbs more than 50% of the filtered Na+ and K+ ions, in addition to Cl− and residual glucose and amino acids (Fig. 21.1.15). Bicarbonate is reabsorbed as a result of H+ ion se- cretion generated by intracellular carbonic anhydrase inside (type II) and at their apical membranes (type IV) by conversion of bicarbonate to CO2 for rapid cell entry to form bicarbonate for basolateral extrusion. Carbonic anhydrase inhibitors (still used orally for treating glaucoma) prevent bicarbonate reabsorption, increasing urinary bicarbonate (and potassium) excretion and causing a form of proximal renal tubular acidosis. This mimics the carbonic anhydrase (type II) mutations of osteopetrosis. Secretory transport mechanisms handle endogenous (dietary) organic anions and cations, also xenobiotics, drug metabolites, and drugs (e.g. diuretics) that require secretion for their action. Urate is secreted and reabsorbed, the overall effect being that around 10% of filtered urate is excreted. Increased urate reabsorption occurs when the ΔP across the PCT favours paracellular reabsorption (see ‘Proximal convoluted tubule’), for example, with hypovolaemia or diuretic therapy. In chronic kidney or liver disease, weak organic acids (e.g. uric and lactic acids) and conjugates of glucuronic acid increase and interfere with the secretion (and excretion) of drugs such as chlorothiazide, penicillin, and probenecid (and vice versa). Potassium reabsorption is mainly paracellular, driven by the small concentration (and electrical) gradients and reabsorption of water (convection—​solvent drag). Chloride reabsorption is both paracellular, depending on electrical (S1) and concentration (S2) gradients and convection, and transcellular via specialized car- riers (S2). S2 also reabsorbs (paracellularly) some calcium and magnesium. Straight proximal tubule (S3) This segment forms the beginning of the descending limb of the loop of Henle and will be discussed in this context later. Its proper- ties and function are similar to S2. Clinical relevance PCT abnormalities can be acquired (usually drugs, e.g. amino­ glycosides and cytotoxics) or genetic. Chronic damage from drugs (e.g. ifosfamide), myeloma, and amyloidosis can cause a renal Fanconi’s syndrome with urinary glucose, phosphate, and bicar- bonate wasting, and tubular (LMWP) proteinuria. Genetic forms of renal Fanconi’s syndrome include Dent’s disease (CLCN5) and Lowe’s syndrome (OCRL) (both X-​linked). Selective genetic trans- port defects include renal glycosuria (SGLT2; SCL5A2) and a Table 21.1.1  Key transport functions of the proximal tubule Reabsorption Secretion • c.65% of filtered Na+, H2O, K+, and Cl− • Organic anions (e.g. salicylate and furosemide) • All filtered glucose and amino acids • Organic cations (e.g. creatinine, histamine, cimetidine,a and amiloride) • All filtered LMWPs (megalin/​ cubilin receptor dependent) • H+ • Most filtered bicarbonate (coupled to H+ secretion) • NH4 + • Most filtered phosphate (inhibited by parathyroid hormone) • Most filtered urate a Cimetidine can be used to reduce creatinine secretion, which increases in chronic kidney disease, and to estimate GFR more accurately from creatinine clearance. Lumen S1 Na+ Cotransporter Cotransporter Cotransporter Exchanger Na+ Na+ Na+ H+ H2O AQP1 AQP1 K+ K+ Na+ Interstitium glucose Low molecular weight proteins (LWMP - RBP/albumin) → amino acids phosphate Fig. 21.1.12  S1 contains AQP1 diffusive water channels, so there is some transcellular diffusive water movement driven osmotically.

21.1  Structure and function of the kidney 4725 form of isolated proximal renal tubular acidosis (SLC4A4). See Chapter 21.16 for further discussion. Loop of Henle The loop of Henle is defined as the segment between S2 and the DCT and includes S3, the thin descending (present in deep, long-​ looped juxtamedullary nephrons) and ascending limbs, and the thick ascending limb of Henle (TALH). The loop reabsorbs 40% of Na+ and 30% of filtered water. In the thin descending limb, water is reabsorbed osmotically into the hypertonic medullary interstitium. In contrast, the thin and thick ascending limbs are impermeable to water, although significant quantities of Na+ are reabsorbed passively in the thin ascending limb and actively in the TALH (Fig. 21.1.16). Na+ reabsorption in the water-​impermeable ascending limb, to- gether with osmotic equilibration in the descending limb, and coun- tercurrent flow (due to its U shape) generates an osmotic gradient (from cortex to medulla) in the medullary interstitium, which can reach approximately 1200 mOsm/​kg in the papillae (countercurrent multiplication). This gradient ensures concentrated urine in the col- lecting ducts. Countercurrent multiplication is driven by active trans- port of Na+ along the TALH. Na+ enters via the triple cotransporter (Na+,K+,2Cl−; NKCC2), which is the target of ‘loop diuretics’ such 2.0 1.5 1.0 0.5 0 25 20 % of proximal tubular length HCO3- Na+ CI- Inulin TF/P ratio Amino acids Glucose 75 10 0 Fig. 21.1.13  Relative concentration of molecules along the PCT. Results based on micropuncture data using the nonreabsorbed, but freely filtered, marker inulin. As water is reabsorbed along the proximal tubule, the inulin concentration in tubular fluid relative to plasma (TF/​P) rises, but that for Na+ stays the same (TF/​P = 1), because water is reabsorbed in proportion to Na+. Phosphate and bicarbonate decrease, since they are reabsorbed; chloride (Cl−) increases slightly, because reabsorption is delayed and slower. LMW proteins Albumin PTH DBP - 25(OH)D3 Lumen RBP/albumin Megalin/ cubilin Recycling endosome Early endosome Late endosome Lysosome Ligand receptor Proximal tubule cell Coated vesicle Fig. 21.1.14  The mechanism for low molecular weight (LMW) protein reabsorption involving receptor-​mediated endocytosis and internalization, with eventual protein degradation in lysosomes. Albumin and LMW proteins, including parathyroid hormone (PTH) and vitamin D-​binding protein (DBP) with 25(OH)D3, are filtered into the primary urine and endocytosed by PT cells via the megalin-​ cubilin receptor pathway. Following internalization in coated vesicles, the receptor-​ligand complexes progress along the endocytic pathway. The endosomes undergo a progressive, ATP-​dependent acidification that results in the dissociation of the receptor–​ligand complexes, with megalin and cubilin being recycled in the apical membrane, whereas the ligand is directed to lysosomes for degradation. In the case of 25(OH)D3-​DBP, DBP is degraded in lysosomes, whereas 25(OH)D3 is released in the cytosol and metabolized to active 1,25(OH)2D3 in mitochondria before being released into the circulation. Adapted with permission from Devuyst O and Pirson Y (2007). Genetics of hypercalciuric stone forming diseases. Kidney International, 72(9), 1065–​72. Copyright © 2007 International Society of Nephrology.

SECTION 21 Disorder s of the ki dne y and u rinary trac 4726 as furosemide, and is transported across the basolateral membrane by the sodium pump (Na+,K+-​ATPase) (Fig. 21.1.16). There is also a small contribution from Na+/​H+ exchanger as in the PCT. TALH ion transport produces a lumen-​positive transepithelial potential differ- ence (10–​15 mV) that drives cation reabsorption (Ca2+ and Mg2+; and some Na+ and K+) through a selective paracellular (paracellin/​ claudin) pathway. By blocking the triple cotransporter in the TALH, loop diuretics dissipate the medullary osmotic gradient and positive transepithelial potential difference, leading to natriuresis and diur- esis, and increased K+, Ca2+, and Mg2+ excretion. At the ‘top’ of the TALH are the specialized macula densa cells that ‘sense’ NaCl delivery and can adjust the rate of NaCl delivery to match the reabsorptive capacity of the TALH through the mech- anism of tubular glomerular feedback (mentioned previously), which vasoactively (via local release of angiotensin II and adeno- sine) reduces glomerular filtration. Loop diuretics block the sensing mechanism and can inhibit tubular glomerular feedback, thus aug- menting their natriuretic and diuretic effect. Clinical relevance The autosomal recessive Bartter’s syndrome has a phenotype similar to chronic loop diuretic administration, and its various clinical sub- types are the result of mutations in transporters involved in Na+ re- absorption along the TALH (Fig. 21.1.16): Bartter type 1, NKCC2 (apical Na+ entry; SLC12A2); Bartter type 2, K+ channel (apical K+ recycling; ROMK/​KCNJ1); Bartter type 3, Cl− channel (basolateral Cl− exit; CLCNKB); and Bartter type 4, Cl− channel regulatory sub- unit (basolateral Cl− exit; BSND). These are examples of ‘loss-​of-​ function’ mutations; however, there is also a type 5 variant due to an activating mutation of a basolateral calcium sensing receptor (CASR) that inhibits TALH Na+ reabsorption. See Chapter 21.16 for further discussion. Early distal convoluted tubule The early DCT (Fig. 21.1.17) is part of the so-​called diluting seg- ment because it is still relatively impermeable to water. Sodium reabsorption is via the thiazide-​sensitive Na+-​Cl− cotransporter (NCC). Unlike loop diuretics, thiazides reduce Ca2+ excretion, in part as a result of a lower intracellular Na+ concentration, leading to an increase in Na+/​Ca2+ exchange and basolateral Ca2+ extrusion (Fig. 21.1.17), as well as a mild degree of diuretic-​induced hypovol- aemia increasing proximal reabsorption (see earlier). Clinical relevance Thiazides are used to reduce hypercalciuria in renal stone formers, and are modest antihypertensive drugs with few side effects, apart from hypokalaemia and hyponatraemia that are especially prevalent in elderly women. The autosomal recessive Gitelman’s Lumen Urate Na+ Citrate2- CI- Na+ Na+ H+ K+ K+ Na+ NaDC-1 URAT1 ABCG2, NPT1,4 S2 K+ H2O AQP1 AQP1 CA-II CA-IV Interstitium Fig. 21.1.15  Late proximal convoluted tubule. Lumen Interstitium Loop diuretics work here K+ K+ K+ K+ CI- CI- Ca2+ CaSR CIC-Ka CIC-Kb Barttin regulatory subunits CLDN16/19 TALH (Paracellin) 10–15 mV lumen positive potential difference Encourages reabsorption K+ Ca2+ Mg2+ 2CI- Na+ Na+ Na+ δ+ δ– * Fig. 21.1.16  Thick ascending limb of Henle.

21.1  Structure and function of the kidney 4727 syndrome has a similar phenotype to chronic thiazide diuretic use and is due to mutations in the gene encoding NCC (SLC12A3). See Chapter 21.16 for further discussion. Late distal convoluted tubule and collecting duct The DCT epithelial permeability is low, hence almost all transepithelial transport across the DCT is active and transcellular. DCT and collecting duct cells are of two main types: principal cells (most numerous) that reabsorb Na+ and water and secrete K+ (Fig. 21.1.18), and intercalated cells that secrete H+ (α-​cells) or bicarbonate (β-​cells) ions (Fig. 21.1.19), α-​cells outnumber β-​intercalated cells. Potassium-​sparing diuretics (e.g. amiloride) block the apical Na+ channel (ENaC) and decrease the transepithelial voltage, reducing K+ secretion and potentiating hyperkalaemia, especially in combin- ation with nonsteroidal anti-​inflammatory drugs or ACE inhibitors, and occasionally with trimethoprim. Principal cells respond to two key hormones:  aldosterone (Fig. 21.1.18) and vasopressin (anti- diuretic hormone), which activates adenylate cyclase via basolateral membrane V2-​receptors, increasing aquaporin water channel in- sertion into apical membrane. Collecting duct fluid then becomes osmotically equilibrated with the surrounding interstitial fluid, iso- tonic in the cortex but increasingly hypertonic in the medulla such that the osmolality of maximally concentrated urine can be approxi- mately 1200 mOsmol/​kg. In the absence of antidiuretic hormone, the TALH hypotonic fluid remains hypotonic and the urine dilute. Clinical relevance DCT and collecting duct defects in water handling lead to polyuria. Lithium interferes with vasopressin signalling causing a nephrogenic diabetes insipidus. Genetic mutations in the vasopressin V2 (AVPR2) receptor cause an X-​linked form of nephrogenic diabetes insipidus, and mutations in the gene encoding aquaporin 2 (AQP2) cause both reces- sive and dominant forms. A rare activating mutation of V2 receptor can be a cause of hyponatraemia. See Chapter 21.2.1 for further discussion. Mutations in ENaC can cause a form of pseudohypoaldosteronism (type IA), as can mutations of the mineralocorticoid receptor (type IB) (recessive). A gain-​of-​function mutation in ENaC is the cause of Gordon’s syndrome (dominant) with the expected clinical features of hypertension and hypokalaemia. Genetic mutations in the acid–​base transporters of the α-​intercalated cells cause distal renal tubular acidosis, which can be recessive (apical H+ secretion; ATP6V1B1, ATP6V0A4) or dominant and recessive (basolateral Cl−/​bicarbonate exchanger; SLC4A1). See Chapters 16.17.4 and 21.15 for further discussion. Interstitium The interstitium comprises the intertubular, extraglomerular, and extravascular space of the kidney, limited by the tubular and vas- cular basement membranes, and containing extracellular matrix and interstitial fluid as well as lymphatics. It also contains immune cells (dendritic cells, macrophages, and lymphocytes) and fibroblasts. The interstitium is not only a source of hormonal and paracrine fac- tors produced locally and secreted from other renal cells, including renin (from juxtamedullary cells), adenosine (transforming growth Na+ Na+ Lumen DT Interstitium Thiazide diuretics work here K+ K+ CI– CI– Ca2+ Ca2+ Ca2+ Mg2+ Na+ Fig. 21.1.17  Early DCT. Amiloride works here 20–25 mV lumen negative potential difference ENaC Na+ K+ K+ K+ Na+ H2O ADH AQP2 AQP3 or AQP4 Late DT and CD ROMK δ+ δ– + ++ Aldosterone enhances all three pathways Spironolactone acts here Fig. 21.1.18  The principal cell of DCT. Na+ enters via the apical epithelial Na+ channel (ENaC) and exits by the usual sodium pump. This process generates a lumen negative transepithelial potential difference (cf. TALH) that favours K+ secretion via apical K+ channels (ROMK). Aldosterone increases Na+ reabsorption and K+ secretion by stimulating the basolateral sodium pump and enhancing activity of the apical Na+ (ENaC) and K+ (ROMK) channels. ADH inserts AQP2 into the apical membrane. Spironolactone acts by competing with nuclear mineralocorticoid receptors in epithelial cell nuclei. Atrial and brain natriuretic peptides decrease sodium reabsorption in the DCT and cortical collecting duct via 3ʹ,5ʹ-​cyclic guanosine monophosphate (cGMP)-​dependent phosphorylation of ENaC. Lumen H+ H+ HCO3

H2O + CO2 Late DCT and CD β (beta) α (alpha) CA-II HCO3

HCO3

CI- CI- H+ CI- CI- Interstitiun Fig. 21.1.19  α-​Intercalated cells actively secrete H+ across their apical membrane via an H+-​ATPase pump (cf. the sodium pump) and with the help of carbonic anhydrase (type II—​cf. the proximal tubule), bicarbonate exits across the basolateral membrane via an exchanger with Cl−, similar to the one present in red blood cells. CD, collecting duct.

SECTION 21 Disorder s of the ki dne y and u rinary trac 4728 factor), and endothelin, but it also has a major role in the pathogen- esis of interstitial fibrosis, a key factor in the progression of chronic kidney disease. The renal fibroblast is the key cell with a complex lineage and several functions, including synthesis of extracellular matrix, and it is also the source of erythropoietin that is reduced in chronic kidney disease, resulting in anaemia. Some authorities have also speculated that the renin-​secreting juxtaglomerular cells may be fibroblast precursors, linking the two hormonal systems. ACE inhibitors and angiotensin receptor blockers are known to reduce the haematocrit, decrease postrenal transplant erythrocytosis, and to increase the clinical requirement for recombinant erythropoietin in chronic kidney disease. Acknowledgement In memoriam: the authors are grateful for the slides and teaching materials of the late Professor David Shirley on which Figs. 21.1.9 to 21.1.19 are based. The authors also wish to thank Miss Nia Harper for further de- tailed artwork. FURTHER READING Burford JL, et al. (2017). Combined use of electron microscopy and intravital imaging captures morphological and functional features of podocyte detachment. Pflugers Arch, 469(7–8), 965–74. Butler MJ, et al. (2019). Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx. Kidney Int, 95(1), 94–107. Gyarmati G, et al. (2018). Advances in Renal Cell Imaging. Semin Nephrol, 38(1), 52–62. Mount DB (2014). Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol, 9, 1974–​86. Neal CR, et al. (2018). Novel hemodynamic structures in the human glomerulus. Am J Physiol Renal Physiol, 315(5), F1370–F1384. https://www.ncbi.nlm.nih.gov/pubmed/30388047. Palmer LG, Schnermann J (2015). Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol, 10, 676–​87. Subramanya AR, Ellison DH (2014). Distal convoluted tubule. Clin J Am Soc Nephrol, 9, 2147–​63. Other material The following articles obtain videos that are very useful on this subject: http://​ajprenal.physiology.org/​content/​ajprenal/​suppl/​2006/​04/​12/​ 00521.2005.DC1/​40XSNGFR_​short.avi http://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3922634/​bin/​1471-​ 2369-​15-​24-​S15.mov http://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3884556/​bin/​ NIHMS530039-​supplement-​3.mov http://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3884556/​bin/​ NIHMS530039-​supplement-​4.mov http://​www.jci.org/​articles/​view/​33293/​sd/​2

Table 21.10.1.1 Levels of proteinuria, albuminuria

Table 21.10.1.1 Levels of proteinuria, albuminuria, and albumin:creatinine ratio (ACR) that define normal, moderately increased(microalbuminuria), and severely increased albuminuria (clinical proteinuria). Borderline results should be repeated on early morningsamples or confirmed by a timed collection

Table 21.10.1.2 Natural history of nephropathy in

Table 21.10.1.2 Natural history of nephropathy in type 1 diabetesa

section 21  Disorders of the kidney and urinary tract 4980 Prevention Glycaemic control The association of glycaemia and development of nephropathy has led to numerous studies exploring the potential of glycaemic control in the prevention of increases in UAER. The two landmark studies were the Diabetes Control and Complications Trial (DCCT) in type 1 and the UKPDS in type 2 (Table 21.10.1.3). Both compared the intensive management of hyperglycaemia using multiple injections of insulin in type 1, and early use of insulin in type 2, against more conventional control. Those in the intensively treated groups also had more frequent contact with healthcare professionals. The DCCT co- hort was invited to continue surveillance for a further 8 years as part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Both DCCT and UKPDS demonstrated a significant reduc- tion in numbers developing moderately increased albuminuria, although there was still a substantial incidence of 15 and 19.2%, respectively, in the intensively treated cohorts (Table 21.10.1.3). Interestingly, the benefit of intensive treatment continued in the EDIC follow-​up, despite a deterioration in glycated haemoglobin (HbA1c) to levels close to those seen in the conventional group at 66 mmol/​mol (8.2%). Thus a prolonged period of good glycaemic control appears to confer benefit in terms of prevention of compli- cations in the kidney (and the retina) for many years. Moreover, the intensive cohort who were normotensive at the beginning of the EDIC study showed a 32% reduction in the risk of developing hypertension (blood pressure >140/​90 mmHg) compared to the conventional group. By contrast, the ACCORD Study of intensive glycaemic control in patients with type 2 diabetes at high cardio- vascular risk failed to demonstrate a benefit in terms of prevention Table 21.10.1.2  Natural history of nephropathy in type 1 diabetesa Normal ↔ Moderately increased albuminuria → Severely increased albuminuria UAER <20 µg/​min 1–​2% p.a. progress to moderately increased albuminuria 20–​200 µg/​min (increasing by 20% p.a.) (up to 25% type 1 revert to normal) 1–​4% p.a. progress to severely increased albuminuria

200 µg/​min GFR Stable: declines at 1 ml/​min per year from over 40 years of age Age-​related changes until UAER approaches 200 µg/​ min or if blood pressure increases Declines at 10 ml/​min per year (hypertensive), 4 ml/​min per year (normotensive) Blood pressure Stable: significantly higher in those progressing to microalbuminuria Initially stable, but higher than normal controls. Tends to increase with increasing UAER Most patients hypertensive (>140/​90 mmHg) Increases with declining GFR Pathology Large kidneys Tubular hypertrophy/​ hyperplasia Glomerular enlargement—​ normal ultrastructure, but glomerular basement membrane thickening 20 nm p.a. Kidneys can remain large Glomerular basement membrane thickening 54 nm p.a. Mesangial expansion 4% p.a. Kidneys tend to shrink Glomerular basement membrane 2–​3 times normal thickness, but stable Nodule formation Global glomerulosclerosis Mesangial expansion c.7% p.a. GFR, glomerular filtration rate; p.a., per annum; UAER, urinary albumin excretion rate. a Fewer data in type 2 patients, many of whom are hypertensive at diagnosis. Table 21.10.1.1  Levels of proteinuria, albuminuria, and albumin:creatinine ratio (ACR) that define normal, moderately increased (microalbuminuria), and severely increased albuminuria (clinical proteinuria). Borderline results should be repeated on early morning samples or confirmed by a timed collection 24-​h urine Timed overnight ‘Spot’ samplea, b Total protein
(g/​day) Albumin
(mg/​day) Albumin
(µg/​min) Albumin concentration (mg/​litre) ACR
(mg/​mmol) ACR
(mg/​g) Normal <0.15 <30 <20 <20 <2.5 male <3.5 female <20 male <40 female Moderately increased albuminuria (microalbuminuria) 30–​300 20–​200 50–​300 2.5–​30 male 3.5–​30 female 20–​300 male 40–​300 femalec Severely increased albuminuria (clinical proteinuria) 0.5 300 200 300 30 300 a False-​positive results with diurnal variation, exercise, urine infection, other renal disease, haematuria, or heart failure. b False-​negative results with dilution or diuresis. c American Diabetes Association uses a definition of 30–​300 mg/​g for both males and females.

Table 21.10.1.3 Comparison of intensive versus con

Table 21.10.1.3 Comparison of intensive versus conventional therapy in the prevention of moderately increased albuminuria in type 1(DCCT + EDIC) and newly diagnosed type 2 (UKPDS) patients

Table 21.10.1.4 Cross- tabulation of latest classi

Table 21.10.1.4 Cross- tabulation of latest classification of chronic kidney disease and historical definition of diabetic kidney disease

Table 21.10.2.1 The classification of primary syst

Table 21.10.2.1 The classification of primary systemic vasculitis, updated in the 2012 Chapel Hill Consensus statement

Table 21.10.2.2 Classification of rapidly progress

Table 21.10.2.2 Classification of rapidly progressiveglomerulonephritis according to renal immunofluorescence andcirculating immune reactants

21.10.2  The kidney in systemic vasculitis 4991 are present in granulomata and at sites of vasculitic injury. They have specificity for ANCA autoantigens and demonstrate features of af- finity maturation. Autoantibodies to endothelial antigens are found in over 50% of patients with vasculitis, but their targets have not been defined and their contribution to pathogenesis is unclear. Role of infection The involvement of the respiratory tract in GPA has led to interest in the interaction between respiratory tract infection and a dysregulated immune response in the epithelium. Colonization with Staphylococcus aureus is associated with a higher relapse rate, and bacterial strains ex- pressing toxic shock staphylococcal toxin are implicated. Damage to the respiratory tract resulting from vasculitic inflammation impairs its ability to eradicate microbial infection and a cycle of vasculitis and recurrent infection develops. Cytokine-​induced up-​regulation of endothelial adhesion molecules promotes leucocyte adhesion and in- jury, providing an additional mechanism by which inflammation sec- ondary to infection can stimulate vasculitis. Epidemiology The incidence of AAV is 15 to 20/​million population per year, with prevalence rates of 200 to 250/​million. The incidence is similar between Europe and Japan, but there is phenotypic variation with a predomin- ance of MPA with MPO-​ANCA in Japan and China and an even distri- bution of GPA and MPA with PR3 and MPO-​ANCA in Europe. There is a paucity of epidemiological data from Southern Asia or black people of African descent. A latitudinal gradient with GPA predominating in colder, temperate climates has been reported in both hemispheres. Both GPA and MPA are very rare in children and have an increasing incidence with age, with a mean age at diagnosis of GPA of 55 years, and MPA at 10 years older. Renal involvement is very common in MPA, occurring in 90%, and in 70% of GPA and 15% of EGPA cases. Renal function at diagnosis is worse in older patients, indicating that not only is renal involvement more frequent, but also more aggressive. Renal vasculitis is less frequent in Takayasu’s arteritis at 0.2/​million per year, with polyarteritis nodosa and anti-​GBM disease at 1/​million per year each. IgA vasculitis is much more common in children, but when it occurs in adults, renal disease is frequent and the outcomes more severe. Cryoglobulinaemia is typically associated with hepatitis C infection, but idiopathic forms with renal involvement are fewer than 1/​million per year. Clinical features Patients with primary systemic vasculitis vary in their prodromal features, in the pattern and severity of organ involvement, in their response to therapy, and in their subsequent disease course and prognosis. A high index of suspicion is required to make the diag- nosis in any scenario where there is suspected nephritis or un- explained chronic inflammation (Box 21.10.2.1). Clinical and laboratory evaluation confirms the extent and severity of organ involvement, which is used to guide therapy (Table 21.10.2.2). Treatment aims to recover renal function and to obtain and sustain disease remission, but relapses are common and refractory disease or chronic, persisting low disease activity states are therapeutic challenges. Box 21.10.2.1  Clinical features that should raise suspicion of vasculitis Features of nephritis • Haematuria with proteinuria, with or without impaired renal function Features of chronic inflammation, otherwise unexplained • Constitutional disturbance: —​  Polymyalgia, polyarthralgia, flitting polyarthritis —​ Fatigue, malaise, weight loss, fevers, night sweats • Ear, nose, and throat: —​ Nasal obstruction and epistaxis —​ Recurrent sinusitis —​ Deafness —​ Facial pain • Eye: —​ Episcleritis/​scleritis —​ Corneal ulcer —​ Retinal vein thrombosis —​ Visual loss • Lung: —​ Haemoptysis —​ ‘Maturity-​onset’ asthma, chronic breathlessness —​ ‘Antibiotic-​resistant pneumonia’ —​ Respiratory failure —​ Subglottic or endobronchial stenosis • Heart: —​ Pericarditis —​ Aortic valve disease, aortitis • Skin: —​ Nailfold infarction (splinter haemorrhages) —​ Purpura —​ Nonhealing ulcer • Nervous system: —​ Cranial or peripheral neuropathy (sensory or motor) —​ Cerebral mass lesion(s) —​ Myelitis Table 21.10.2.2  Classification of rapidly progressive glomerulonephritis according to renal immunofluorescence and circulating immune reactants Type Renal immunofluorescence Compatible serology Diagnosis I Linear IgG Anti-​GBM antibodies Anti-​GBM disease II Granular IgG/​IgA/​IgM ANA/​anti-​dsDNA/​low C3/​4 Systemic lupus erythematosus Granular IgG/​IgA/​IgM Low C3/​4 Postinfectious glomerulonephritis Granular IgG/​IgA/​IgM Low C3/​4 Mesangiocapillary glomerulonephritis Granular IgG/​IgA/​IgM Low C3/​4, cryoglobulins Cryoglobulinaemia Granular IgA None IgA vasculitis (Henoch–​Schönlein purpura) III Pauci-​immune (absent or scanty deposits) ANCA ANCA-​associated vasculitis (GPA, MPA, or EGPA) ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasm autoantibodies; dsDNA, double-​stranded DNA; GBM, glomerular basement membrane.

Takayasu’s arteritis

Takayasu’s arteritis

Tertiary prevention

Tertiary prevention

Title

Title

1 Oxford Textbook of Medicine SIXTH EDITION Volume 4: Sections 22–30 EDITED BY John D. Firth Christopher P. Conlon Timothy M. Cox

Treatment

Treatment

section 21  Disorders of the kidney and urinary tract 4994 The haemorrhagic risks of renal biopsy are increased by ur- aemia, anticoagulation, and clotting factor deficiency after plasma exchange. Renal biopsy should not be considered essential when ANCA is positive, and treatment should not be delayed while waiting for a biopsy or biopsy result. By contrast, biopsy is strongly recommended when PR3-​ANCA and MPO-​ANCA are negative. Imaging In small-​vessel vasculitis, ultrasonography reveals normal-​sized kidneys that may have increased cortical echogenicity if the disease is severe. The diagnosis of polyarteritis nodosa is usually made by angiographic demonstration of vascular irregularity, patchy areas of hypoperfusion, and aneurysms of medium-​sized muscular arteries. Mesenteric, including hepatic, splenic, and renal, studies have the best diagnostic yield (Fig 21.10.2.5a). Biopsy of affected tissue reveals fibrinoid necrosis of involved vessels, accompanied by a marked in- flammatory response. Destruction of the internal elastic lamina and aneurisms may be seen (Fig. 21.10.2.5b). Acute-​phase reactants are raised, but ANCA and other autoantibodies are negative. Differential diagnosis Secondary causes of vasculitis and diseases mimicking vascu- litis need to be excluded before a diagnosis of primary systemic vasculitis can be made (Box 21.10.2.2). Chronic inflammatory dis- orders such as bacterial endocarditis or rheumatoid arthritis can mimic vasculitis (e.g. with constitutional symptoms and renal im- pairment) or induce a systemic vasculitis syndrome such as an AAV. Chronic bacterial infection may be obvious, as in cystic fibrosis or bronchiectasis, but occult endocarditis or abdominal sepsis should be considered. Tuberculosis and other nonvasculitic causes of pul- monary cavities can mimic GPA. When suspected, bronchoscopy and bronchoalveolar lavage are indicated. Lung biopsy is now rarely performed to confirm a vasculitic diagnosis, but may be required if the serology is unhelpful and there is little extrapulmonary disease. Hepatitis C is the most common cause of cryoglobulinaemic vascu- litis and has also been linked to other forms of vasculitis. For those presenting with deteriorating renal function, other causes of rapidly progressive glomerulonephritis, myeloma kidney, atheroembolic renal disease, and other causes of acute kidney injury need to be considered. Treatment Without therapy, renal vasculitis will usually progress to endstage renal disease. Treatment aims to recover renal function, protect against further episodes of renal vasculitis, and address extrarenal features of disease activity. In patients with systemic disease, other organ involvement may dominate the therapeutic course, espe- cially if renal function is preserved. Disease state definitions have been established and treatment is adapted to the disease state (Table 21.10.2.4). Treatment protocols developed for AAV include an induction phase of 3 to 6 months to control active features of vasculitis and then a maintenance or remission phase of 1 to 4 years to consolidate disease control and prevent relapse. Treatment is then slowly withdrawn, but indefinite follow-​up is required for the early detection of late relapse, and the management of irrevers- ible damage caused by the disease and its treatment. A summary of current treatment recommendations for ANCA vasculitis is shown in Fig. 21.10.2.6. Table 21.10.2.3  The Berden classification of renal histology in ANCA-​associated vasculitis Subgrouping Definition Endstage renal failure risk at 5 years Focal ≥50% normal glomeruli 0% Crescentic ≥50% cellular crescents 25% Mixed <50% normal with a mixture of cellular
crescents and global sclerosis 50% Sclerotic ≥50% of glomeruli with global sclerosis 70% (a) (b) Fig. 21.10.2.5  (a) A renal arteriogram from a patient with polyarteritis nodosa demonstrating multiple aneurysms. The elastic lamina has been destroyed and the artery has become aneurysmal. (b) A histological cross-​section in polyarteritis nodosa from a renal artery. The elastic lamina has been destroyed and the artery has become aneurysmal.

21.10.2  The kidney in systemic vasculitis 4995 Box 21.10.2.2  Secondary causes and mimics of renal vasculitis Secondary causes • Infections: —​ Tuberculosis —​ Hepatitis B and C, HIV —​ Chronic bacterial infections • Malignancy • Drugs: —​ Penicillamine —​ Hydralazine —​ Cocaine/​levamisole • Other inflammatory autoimmune disorders: —​ Rheumatoid arthritis —​ Systemic lupus erythematosus —​ Sjögren’s syndrome —​ IgG4-​related disease —​ Behçet’s disease Mimics of renal vasculitis • Atheroembolic disease • Antiphospholipid syndrome • Left ventricular failure • Infections: —​ Atypical pneumonia —​ Hantavirus • Myeloma Table 21.10.2.4  Definitions of disease state in primary systemic vasculitis according to a European League against Rheumatism/​ European Vasculitis Society consensus statement Activity state Definition Remission Absence of disease activity attributable to active disease, qualified by the need for ongoing stable maintenance immunosuppressive therapy. The term ‘active disease’ is not restricted to vasculitis only, but also includes other inflammatory features such as granulomatous inflammation in Wegener’s granulomatosis or tissue eosinophilia in the Churg–​Strauss syndrome Response A 50% reduction of disease activity score and absence of new manifestations Relapse Reoccurrence or new onset of disease attributable to
active vasculitis Major relapse Reoccurrence or new onset of potentially organ-​ or life-​ threatening disease Minor relapse Reoccurrence or new onset of disease which is neither potentially organ-​threatening nor life-​threatening Refractory
disease Unchanged or increased disease activity in acute AAV after 4 weeks of treatment with standard therapy with cyclophosphamide and corticosteroids Or Lack of response, defined as ≤50% reduction in the disease activity score after 6 weeks of treatment Or Chronic, persistent disease—​defined as the presence of at least one major or three minor items on the disease activity score list after ≥12 weeks of treatment Low activity
disease state Persistence of minor symptoms (e.g. arthralgia, myalgia) that respond to a modest increase in the corticosteroid dose and do not warrant an escalation of therapy beyond a modest dose increase of the current medication No organ threatening involvement CYC+ GC RTX + GC or or or or Disease control “on drug” remission “off drug” remission Maintenance Induction of Remission Diagnosis of AAV Disease assessment Switch to AZA or MTX Taper GC Taper AZA or MTX Stop RTX Continue RTX Taper GC add PLEX Vital organ/life threatening Creat>500µmol/L Consider MTX/MMF Fig. 21.10.2.6  British Society of Rheumatology recommendations for the management of ANCA-​ associated vasculitis (AAV). AZA, azathioprine; CYC, cyclophosphamide; GC, glucocorticoid; MMF, mycophenolate mofetil; MTX, methotrexate; PLEX, plasma exchange; RTC, rituximab. Reproduced with permission from Ntatsaki E, et al. (2014). BSR and BHPR guideline for the management of adults with ANCA-​associated vasculitis. Rheumatology (Oxford), 53(12), 2306–​9. Copyright © 2014 Oxford University Press.

section 21  Disorders of the kidney and urinary tract 4996 Induction therapy The combination of cyclophosphamide or rituximab with gluco- corticoids is the routine induction regimen for renal AAV vasculitis. Cyclophosphamide is equally effective as a daily oral or pulsed intra- venous preparation. The pulsed protocols expose the patient to a lower cumulative cyclophosphamide dose and permit bladder protection through rehydration and the use of mesna, and leucopenia—​an im- portant risk factor for severe infection and death—​is more common with daily oral treatment. The elimination of cyclophosphamide and its active metabolites are influenced by age and renal function, hence doses must be modified accordingly. Close monitoring of the full blood count is required for the early detection of cytopenias and ap- propriate dose adjustment. Cyclophosphamide is continued for 3 to 6 months, by which time vasculitis will have been controlled in 80 to 90% of patients. The rituximab regimen is 375 mg/​m2 per week for 4 weeks, although a simpler regimen of 1000 mg repeated after 2 weeks appears equally effective. Mycophenolate mofetil is an alternative in- duction agent for AAV for MPO-​ANCA-​positive patients. Improvement in renal vasculitis is recognized by improvement or stability of renal function, control of extrarenal vasculitis, and nor- malization of the C-​reactive protein. Persisting nonvisible haema- turia does not have clinical significance, but ongoing proteinuria reflects more severe glomerular damage and a worse renal prog- nosis. ANCA levels are not used to guide the duration or intensity of induction therapy. Initial treatment with intravenous methylprednisolone (total dose 1000–​3000 mg) is widely used for renal vasculitis without robust evi- dence, and may be commenced on suspicion of the diagnosis before ANCA testing or renal histology is available. Prednisolone is com- menced at high dose, 1 mg/​kg per day, and reduced in steps to 5 to 10 mg/​day by 6 months. Prophylaxis against Pneumocystis jirovecii pneumonia with low-​ dose sulfamethoxazole/​trimethoprim is recommended, regardless of induction agent, as is prophylaxis against fungal infections, peptic ulceration, and steroid-​induced bone disease. Plasma exchange improves the chances of renal recovery in those presenting in renal failure with serum creatinine levels over 500 μmol: it is also used for renal vasculitis with rapidly deteriorating renal function below 500 μmol, and in those with a poor response to induction drug therapy. The increasing evidence for the pathogen- icity of ANCA in renal vasculitis provides a rationale for its use, but removal of coagulation factors, cytokines, complement fragments, cell microparticles, and NETs may also be important. Plasma fil- tration or centrifugation appear equally effective, with a dose of 60 ml/​kg and a total of seven daily or alternate-​day exchanges recom- mended. The procedure requires central vascular access, and may be complicated by haemorrhage and thrombocytopenia. Progressive or refractory renal vasculitis following induction treatment should be treated with intravenous methylprednisolone and/​or plasma exchange, with rituximab added following cyclo- phosphamide induction and cyclophosphamide added if rituximab induction was used. Treatment intolerance and severe infection are additional causes of treatment failure in the induction phase. Maintenance therapy Disease relapse occurs in 75% of those with GPA and 35% of those with MPA by 5 years. The goal of maintenance therapy is to pre- vent disease relapse, but this is at risk of increasing cumulative drug toxicity. Cyclophosphamide is withdrawn and substituted by azathioprine, methotrexate, or mycophenolate mofetil, with metho- trexate avoided in the presence of renal insufficiency. Azathioprine allergy or intolerance occurs in 5 to 10%, and testing for thiopurine S-​methyltransferase activity identifies rare patients at risk of severe myelosuppression. Leflunomide is an alternative oral immunosup- pressive for this disease phase. Intermittent rituximab infusions, 500 to 1000 mg every 6 months, are more effective than azathioprine after cyclophosphamide induction. There is a controversy over the optimal relapse prevention agent after rituximab induction, where the relapse risk is high, with cur- rent data favouring further rituximab without concomitant oral im- munosuppressive. The use of prednisolone to prevent relapse varies between expert centres. Glucocorticoid withdrawal increases re- lapse risk when an oral immunosuppressive is used for maintenance, but if rituximab is used to prevent relapse then glucocorticoid with- drawal is usually successful and rituximab permits reduced gluco- corticoid exposure. Several factors are known to influence relapse risk (Table 21.10.2.5). Nasal colonization with Staphylococcus aureus has con- sistently been shown to increase relapse risk and long-​term treat- ment with sulfamethoxazole/​trimethoprim has reduced relapse rates. An alternative approach is topical mupirocin, but this has not been fully evaluated. ANCA levels are not closely related to dis- ease activity, but the persistence of ANCA at 6 months after induc- tion therapy, or a rising ANCA level, indicate relapse is more likely. This is particularly useful when treatment is withdrawn and after rituximab, relapse being almost inevitable if ANCA remains posi- tive or returns after becoming negative. There is no consensus on the optimal duration of maintenance therapy. In those at low risk, this may be limited to 6 to 12 months after diagnosis, while higher-​risk patients are typically treated for at least 2 to 4 years, and those with a history of relapse for longer. Relapse of vasculitis is classified as minor (nonsevere) or major (severe) depending on the threat to vital organ function, with the severity and consequences of relapse being dependent on how quickly relapse is detected. Relapse is usually associated with ANCA positivity and rises in erythrocyte sedimentation rate and C-​reactive protein. Infection may trigger relapse and can be diffi- cult to distinguish from relapse. In GPA, the two processes often occur together in the respiratory tract, hence if relapse is being considered, thorough microbiological assessment, including studies for tuberculosis, fungi, and viral infections, are required, and aggressive treatment of infection is necessary for vasculitis therapy to be effective. Minor relapses are treated by an increase in prednisolone and return of immunosuppression to full dosage if it has been reduced. However, minor relapses almost always Table 21.10.2.5  Factors predictive of relapse in ANCA-​associated vasculitis Clinical presentation Serology Treatment related GPA (Wegener’s) PR3-​ANCA Steroid withdrawal Ear, nose, or throat involvement ANCA + after induction Immunosuppression withdrawal Better renal function (creatinine < 200 μmol/​litre) Rise in ANCA Lower cyclophosphamide Exposure

21.10.2  The kidney in systemic vasculitis 4997 recur and multiple minor relapses require a trial of an alternative immunosuppressive or rituximab. Major relapse is treated by an increase in prednisolone, and rituximab is preferred to reintroduc- tion of cyclophosphamide. Adverse events of therapy The main early risk of treatment is sepsis, which is more likely with cyclophosphamide-​associated leucopenia, in the elderly, and those with impaired renal function. Cyclophosphamide dosing should avoid neutropenia and be adapted for age and renal function. All types of infection are seen and these are the major cause of early mortality in ANCA vasculitis, hence infection should be diagnosed and treated promptly. If vasculitic therapy is reduced or interrupted disease control may be lost. There is limited data that rituximab is preferable to cyclophosphamide when treating vasculitis in the pres- ence of infection. Glucocorticoid-​related side effects are very frequent and in- clude fluid retention, weight gain, hypertension, diabetes, and steroid-​induced bone disease. Glucocorticoids are now the major reversible cause of serious adverse events, long-term damage and chronic morbidity of vasculitis. The treatment of elderly patients with severe renal disease is a particular challenge due to their high risk of infection and treatment intolerance. Glucocorticoid tox- icity can be quantitated using the Glucocorticoid Toxicity Index, which is a composite score of 31 toxicities that has been shown to correlate well with expert opinion. Rituximab may permit more rapid tapering and withdrawal of glucocorticoids. Rituximab induces hypogammaglobulinaemia in some vasculitis patients. This appears to be an idiosyncratic effect not closely related to rituximab dose. A low IgG level before rituximab has been iden- tified as a risk factor. Falling IgG levels are associated with increased infective risk and such patients need to be monitored regularly, and given prophylactic antibiotics and replacement immunoglobulin when severe. Comorbidities Thromboembolic events, including pulmonary emboli, myo- cardial infarction, and stroke occur in 7 to 15% during the first year. Thromboprophylaxis may well have an important role in management, but this has not yet been determined. The occur- rence of thrombosis has been associated with antiplasminogen antibodies, but this awaits confirmation. The cardiovascular events, myocardial infarction and stroke, are common during the active phase of the disease and remain at increased risk during follow-​up. In addition to the contribution of classical risk fac- tors including age and renal function, MPO-​ANCA positivity and more extensive disease at diagnosis increase the risk of such events. A major concern of cyclophosphamide use has been the de- velopment of urothelial malignancy over the long term. This is a dose-​dependent phenomenon and is more common with oral cyclo- phosphamide, when total exposure is higher, and is particularly frequent in those who develop haemorrhagic cystitis. It is now re- commended that patients never exceed a lifetime exposure of 25 g cyclophosphamide, although this figure is not adjusted for age and the relative risk for malignancy is higher in the young. Rates of all malignancies are increased in vasculitis patients, with a notably increased risk of nonmelanoma skin cancer. It appears that malignancy rates are reducing as alternatives to cyclophosphamide have become available, but this long-​term risk needs to be borne in mind whenever immunosuppressive agents are being introduced or continued. Refractory vasculitis Refractory vasculitis is defined in Table 21.10.2.4. It occurs in around 20% of patients during the induction phase, but is more common later in the disease course, especially in PR3-​ANCA-​ associated disease, when it is manifested by multiple relapses or a chronic state of persistent disease activity. The availability and ef- ficacy of rituximab has been of major benefit to patients with re- fractory disease, both achieving disease control and avoiding the increased toxicity risks associated with further exposure to gluco- corticoids and cyclophosphamide. High-​dose intravenous immunoglobulin reduces levels of vas- culitic activity in persisting or relapsing vasculitis, reduces ANCA production, and is a useful short-​term additional agent permitting reduction in immunosuppressive or steroid dosing. This is desirable in the face of active infection, in patients at high risk of infection, such as on the intensive care unit, and in pregnancy. Blockade of TNFα with infliximab or etanercept has led to remission when used as an additional agent, but prolonged use is ineffective and may in- crease the risk of infection. Progressive disease may continue to deteriorate after rituximab and additional prednisolone, hence cyclophosphamide or plasma exchange may be required for 6 to 8 weeks until rituximab takes effect. A failure to deplete peripheral B cells is associated with a failure to respond to rituximab. This is rare in naive patients but is seen occasionally after previous rituximab due to the induction of antichimeric antibodies. Monitoring The goals of monitoring are to assess control of disease activity and detect early relapse, to minimize drug-​related toxicity, and manage disease-​related damage and comorbidities. Disease activity assess- ment has been standardized by using the Birmingham Vasculitis Activity Score. Changes in C-​reactive protein and the erythrocyte sedimentation rate are helpful but lack specificity. Treatment should not be adjusted according to ANCA levels, but these can be used to assess relapse risk. Concerning renal vasculitis, the return of haema- turia with proteinuria when they have disappeared might indicate renal relapse and a renal biopsy should be considered if the diagnosis of relapse is not supported by extrarenal disease activity. Persisting haematuria and proteinuria after diagnosis is not helpful in assessing renal activity, but persisting proteinuria is an adverse renal prog- nostic factor. Cyclophosphamide dosing requires regular white blood cell count assessment to avoid leucopenia, and monitoring for liver dysfunction, hypersensitivity, infection, and malignancy is re- quired. Patients receiving rituximab should be screened for tuber- culosis and hepatitis B and C infection, and immunoglobulin levels

section 21  Disorders of the kidney and urinary tract 4998 should be measured before treatment and after every 6  months. Hypogammaglobulinaemia and recurrent infection appears more frequent when rituximab is used in vasculitis than for other auto- immune indications. Routine B-​cell counts have been used to guide repeat rituximab dosing but are not necessary if a fixed-​interval rituximab dosing regimen in used. Endstage renal disease and transplantation In renal-​limited vasculitis, treatment with immunosuppression and prednisolone can be withdrawn once endstage renal disease is estab- lished. However, in GPA and MPA, continued therapy may be re- quired to control extrarenal vasculitic disease. Relapse rates of AAV are lower in patients with endstage renal disease, but relapse—​espe- cially of the respiratory tract—​may still occur. Patients with vascu- litis and endstage renal disease have a higher incidence of infection, which complicates therapy. The success of renal transplantation in AAV is similar to that for other nondiabetic causes of endstage renal disease. Transplantation reduces the risk of vasculitic relapse and can proceed in the face of a persistently positive ANCA. Previous cyclophosphamide and corticosteroid exposure places patients with a history of vasculitis at increased risk of opportunistic infection after transplantation. Over the long term, graft and patient survival is better for PR3-​ ANCA-​ than for MPO-​ANCA-​positive patients. Relapse of vascu- litis in the renal graft occurs in 2% and usually leads to irreversible loss of function. Management of other vasculitic syndromes involving the kidney IgA vasculitis (Henoch–​Schönlein purpura) Although nephritis is not prevented by prednisolone, this is com- monly used to treat active renal disease causing progressive deterioration in renal function, often in combination with an im- munosuppressive, typically cyclophosphamide or mycophenolate mofetil. Plasma exchange has the rationale of removing IgA and IgA-​containing immune complexes and may be considered when deterioration in renal function is refractory, and renal outcomes are better in severe acute kidney injury due to IgA vasculitis or IgA nephropathy after plasma exchange. Polyarteritis nodosa Treatment recommendations for polyarteritis nodosa reflect those for AAV with the exception of plasma exchange, which was inef- fective in one small trial, and rituximab, with which there has been little experience. Cryoglobulinaemic vasculitis When associated with hepatitis C, therapy is directed at controlling viral replication. Prednisolone may be required for initial therapy of inflammatory manifestations such as nephritis. Hepatitis C-​negative ‘essential’ cryoglobulinaemia with nephritis is treated with gluco- corticoids, with an immunosuppressive agent, and plasma exchange. Rituximab has led to remissions in refractory hepatitis C-​associated and essential cryoglobulinaemia. Takayasu’s arteritis Prednisolone and an immunosuppressive are used to arrest pro- gression of vascular disease, but renal artery involvement requires specific therapy if there is evidence of functional decline in the af- fected kidney. The stenoses are less amenable to angioplasty and stenting than in atheromatous renovascular disease, but this op- tion may still be effective. Renal autotransplantation appears to be a useful alternative. Prognosis Creatinine at presentation remains the strongest predictor of both patient and renal survival in renal vasculitis. Those presenting with a glomerular filtration rate below 50 ml/​min per 1.73 m2 have a poorer outcome, with 50% reaching the composite endpoint of death or endstage renal failure by 5 years (Fig 21.10.2.7a). Mortality of AAV 0 0.00 0.25 0.50 Proportion with Renal Survival 0.75 1.00 (a) 2 4 Time (years) 6 8 100 (b) 90 80 70 60 0 10 20 30 Time to death (months) Cumulative Survival (%) Survival and age 40 50 60 70 Fig. 21.10.2.7  (a) Renal and patient survival (composite endpoint) of patients presenting with ANCA-​associated vasculitis with glomerular filtration rate above (red line) or below (blue line) 50 ml/​min per 1.73 m2.
(b) Long-​term survival of patients with ANCA-​associated vasculitis according to age above (orange line) or below (green line) 60 years at diagnosis. (a) Data from the European Vasculitis Society.

21.10.2  The kidney in systemic vasculitis 4999 at 1 and 5 years is 10 and 25%, respectively; for those under 60 years of age, it is 5% at 1 year, rising to 23% for those over 60, and 44% for those over 70 (Fig. 21.10.2.7b). In part, this is due to more ad- vanced renal disease with more chronicity on renal biopsy in elderly patients, but intolerance of therapy and infections are significant contributors. If treatment of renal vasculitis is unsuccessful and the patient progresses to endstage renal failure, mortality is particularly high. Dual positive presentations of anti-​GBM disease and vasculitis are associated with particularly aggressive pulmonary and renal dis- ease and poor outcomes. Specific predictors of endstage renal disease include a lack of re- sponse to therapy, a high level of proteinuria during the recovery phase, and histological features with predominant glomerular scler- osis. A high level of disease activity at diagnosis, as measured by the Birmingham Vasculitis Activity Score, MPO-​ANCA positivity, and the early accrual of irreversible damage are independent mortality predictors. There is gradual improvement in renal function over the first year in those presenting with renal impairment who respond to therapy. Glomerular filtration rate may then remain stable for many years, even if recovery is to a glomerular filtration rate below 30 ml/​min per 1.73 m2. In this setting, vasculitis relapse with renal involvement carries a high risk of endstage renal disease. However, a few patients develop progressive glomerulosclerosis and lose renal function without reactivation of vasculitis; in these patients, blockade of the renin–​angiotensin system may improve renal outcome but requires further study. Over 50% of relapses are mild, with no consequences on vital organ function. However, a protracted relapsing–​remitting course, often seen in patients with ear, nose, and throat, or pulmonary dis- ease, does lead to progressive damage and a high cumulative drug burden. The risk of relapse declines with time, but follow-​up should remain lifelong because late relapse can still occur with potentially devastating consequences. Quality of life and health economic aspects The quality of life of patients with AAV is severely depressed when their disease is active, and physical activity remains reduced during follow-​up when features of active vasculitis are no longer present, with a plateau in recovery attained after 6 to 12 months. Respiratory function is often chronically impaired, and there are negative consequences on social and economic activity. First year direct health costs in uncomplicated ANCA vasculitis were $16 000 in a 2013 study from the United States of America, but rose sharply in those with a serious adverse event and to $62 000 in those with a disease relapse. The referral of patients to centres with experience in managing vasculitis is recommended, and in- tegrated multispecialty pathways for care are developing in larger vasculitis centres. Areas of uncertainty or controversy The diagnosis of vasculitis is often delayed due to a poor under- standing of many physicians as to when the possibility of a vasculitic illness should be considered, and a lack of diagnostic criteria both for vasculitis in general and for the specific vasculitic subgroups. The current phenotypic classification is likely to be replaced by one based on PR3 and MPO-​ANCA due to their genetic associations. Phenotypic overlaps between syndromes are common and EGPA sits with difficulty in an ANCA vasculitis subgroup due to the low inci- dence of ANCA. There is controversy as to how to classify patients with overlapping features of vasculitis syndromes, for example, those with both middle-​sized arterial involvement and microscopic vascu- litis. According to the Chapel Hill statement, they should be regarded as MPA, although features of polyarteritis nodosa are present. Renal biopsy is recommended for all patients with potential renal vasculitis, but in the presence of ANCA positivity (both C-​ANCA or P-​ANCA and PR3-​ANCA or MPO-​ANCA) over 95% of biopsies will show renal vasculitis, hence it has been argued that biopsy is unnecessary for these patients. The prognostic value of renal biopsy for endstage renal disease is useful, but is not sufficiently well deter- mined to influence treatment in a particular individual. Nonvisible haematuria persists for many months after the commencement of therapy for renal vasculitis despite normalization of the inflamma- tory markers C-​reactive protein and erythrocyte sedimentation rate. It is unclear how well haematuria correlates with histological activity and what the criteria for repeat biopsy should be. Although ANCA testing is widely used for the diagnosis of vas- culitis there is often confusion concerning the value of a negative result, this depending heavily on the clinical context, and in the in- terpretation of marginally positive results. In part, this is influenced by variable assay performance and differing referral practices. The role of ANCA in monitoring is more controversial, with the best evi- dence suggesting that ANCA positivity during the remission phase indicates a higher risk of subsequent relapse. The first consensus treatment guidelines published in 2007 were updated in 2016 and highlight areas where evidence is lacking and no clear direction can be given. The introduction of rituximab has been the major change, but uncertainty persists over rituximab dosing, dosing interval, and use of concomitant immunosuppres- sion. There is a paucity of quality evidence to guide glucocorticoid dosing, and clinical practice varies widely. The duration of main- tenance immunosuppression and glucocorticoid therapy also varies widely, between 6 months and over 4 years. The value and toxicity of prolonged therapy needs to be assessed. The short-​term benefit of plasma exchange on renal recovery has been demonstrated, but it is not known whether this intervention influences long-​term mor- tality or likelihood of endstage renal disease; there is also contro- versy over its role in other severe vasculitis presentations, such as in rapidly progressive glomerulonephritis without advanced renal failure and in lung haemorrhage with respiratory failure. Most clinical trials focus on AAV and there is less evidence sup- porting treatment in the less common vasculitis subgroups. IgA vasculitis in adults is a particular problem, with uncertainty as to the use of immunosuppressives, plasma exchange, and intravenous immunoglobulin. Likely developments in the near future Further genetic associations defining subgroups both for ANCA vasculitis and IgA vasculitis will be identified and their functional

section 21  Disorders of the kidney and urinary tract 5000 significance explored. This will influence the classification of vas- culitis. The development of computer-​based diagnostic algorithms and widespread ANCA testing will help early detection of vasculitis. Urinary biomarkers, such as CD163 and monocyte chemoattractant protein 1, may be validated to assist in the assessment of renal ac- tivity of vasculitis. A transcriptomic biomarker has been identified from peripheral mononuclear cells that predicts relapse risk. The importance of the alternative complement pathway in ANCA vasculitis and the development of complement C5 ant- agonists as therapies for vasculitis might improve the speed of induction therapy and reduce or avoid glucocorticoid exposure. Preventing relapse will remain a challenge, but the dosing of rituximab will be optimized. Other biologics that may enter the clinical arena are more potent B-​cell-​depleting antibodies, B-​cell cytokine antagonists, T-​cell costimulation inhibitors, and prote- asome antagonists. Further study of long-​term cohorts will more precisely define predictive biomarkers for the major comorbidities and advice on preventative strategies will develop. Improved organization of healthcare systems and delivery of current treatment recommenda- tions will be the largest benefit to patients in the near future. FURTHER READING Basu N, et al. (2010). EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis, 69, 1744–​50. Berden AE, et  al. (2010). Histopathologic classification of ANCA-​ associated glomerulonephritis. J Am Soc Nephrol, 21, 1628–​36. Coppo R, Amore A, Gianoglio B (1999). Clinical features of Henoch-​ Schönlein purpura. Italian Group of Renal Immunopathology. Ann Med Interne (Paris), 150, 143–​50. Damoiseaux J, et  al. (2017). Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-​specific immunoassays. Ann Rheum Dis, 17, 647–​53. de Groot K, Adu D, Savage CO (2001). The value of pulse cyclophos- phamide in ANCA-​associated vasculitis: meta-​analysis and critical review. Nephrol Dial Transplant, 16, 2018–​27. de Groot K, et  al. (2005). Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic anti-​neutrophil cytoplasmic antibody-​associated vasculitis. Arthritis Rheum, 52, 2461–​9. Fauci AS, Wolff SM, Johnson JS (1971). Effect of cyclophosphamide upon the immune response in Wegener’s granulomatosis. N Engl J Med, 285, 1493–​6. Ferrario F, Rastaldi MP (2005). Histopathological atlas of renal dis- eases: ANCA-​associated vasculitis (first part). J Nephrol, 18, 113–​16. Flossmann O, et  al. (2011). Long-​term patient survival in ANCA-​ associated vasculitis. Ann Rheum Dis, 70, 488–​94. Guerry MJ, et al. (2012). Recommendations for the use of rituximab in anti-​neutrophil cytoplasm antibody-​associated vasculitis. Rheumatology (Oxford), 51, 634–​43. Guillevin L, et  al. (1991). Longterm followup after treatment of polyarteritis nodosa and Churg-​Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa. J Rheumatol, 18, 567–​74. Heijl C, et al. (2011). Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-​associated vasculitis:  follow-​ up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis, 70, 1415–​21. Hellmich B, et al. (2007). EULAR recommendations for conducting clinical studies and/​or clinical trials in systemic vasculitis:  focus on anti-​neutrophil cytoplasm antibody-​associated vasculitis. Ann Rheum Dis, 66, 605–​17. Hiemstra TF, et al. (2010). Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-​ associated vasculitis:  a randomized controlled trial. JAMA, 304, 2381–​8. Hogan SL, et  al. (2007). Association of silica exposure with anti-​ neutrophil cytoplasmic autoantibody small-​vessel vasculitis:  a population-​based, case-​control study. Clin J Am Soc Nephrol, 2, 290–​9. Hruskova Z, et  al. (2015). Characteristics and outcomes of granulomatosis with polyangiitis (Wegener) and microscopic polyangiitis requiring renal replacement therapy: results from the European Renal Association-​European Dialysis and Transplant Association Registry. Am J Kidney Dis, 66, 613–​20. Jayne D, et  al. (2003). A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoanti- bodies. N Engl J Med, 349, 36–​44. Jayne DR, et al. (2007). Randomized trial of plasma exchange or high-​ dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol, 18, 2180–​8. Jennette J, et  al. (2013). 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum, 65, 1–​11. Jones RB, et al. (2010). Rituximab versus cyclophosphamide in ANCA-​ associated renal vasculitis. N Engl J Med, 363, 211–​20. Lane SE, Watts R, Scott DG (2005). Epidemiology of systemic vascu- litis. Curr Rheumatol Rep, 7, 270–​5. Lyons PA, et al. (2012). Genetically distinct subsets within ANCA-​ associated vasculitis. N Engl J Med, 367, 214–​23. Miloslavsky EM, et  al. (2017). Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. Ann Rheum Dis, 76, 543–​6. Specks U (2001). Diffuse alveolar hemorrhage syndromes. Curr Opin Rheumatol, 13, 12–​17. Stegeman CA, et  al. (1994). Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med, 120, 12–​17. Stone JH, et  al. (2010). Rituximab versus cyclophosphamide for ANCA-​associated vasculitis. N Engl J Med, 363, 221–​32. van der Woude FJ, et al. (1985). Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet, 1, 425–​9. Walton EW (1958). Giant-​cell granuloma of the respiratory tract (Wegener’s granulomatosis). BMJ, 2, 265–​70. Walsh M, et al. (2012). Risk factors for relapse of ANCA associated vasculitis. Arthritis Rheum, 64, 542–​8. Wegener F (1936). Uber generaliste, septische efaberkrankungen. Verh Dtsch Ges Pathol, 29, 202–​10. Watts RA, et al. (2008). Renal vasculitis in Japan and the UK—​are there differences in epidemiology and clinical phenotype? Nephrol Dial Transplant, 23, 3928–​31. Xiao H, et al. (2002). Antineutrophil cytoplasmic autoantibodies spe- cific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest, 110, 955–​63.

UAER

UAER

section 21  Disorders of the kidney and urinary tract 4982 increased albuminuria. Accurate data on GFR are not given in many of these studies, but in type 1 patients, long-​term ACE inhibitor therapy appears to stabilize renal function after an initial reduction. Interpretation of all these studies is complicated by the fact that the actively treated patients have nearly always had significantly lower blood pressures than the placebo groups. While statistical correc- tion for these differences has been applied, it is uncertain whether mathematical correction can completely allow for the biological consequences of blood pressure reduction. In addition, there are some data showing a return of albuminuria to pretreatment levels following withdrawal of therapy, calling into question the durability of effect. There are no conclusive long-​term data showing a posi- tive benefit on hard endpoints such as mortality or endstage renal disease. Tertiary prevention Studies in the early 1980s established that lowering blood pres- sure in hypertensive type 1 patients with severely elevated albu- minuria resulted in a more than 50% reduction in UAER and a significant slowing of the rate of decline of GFR from 10 to 3 ml/​ min per year. The Collaborative Study Group Trial in type 1 dia- betic patients who had a blood pressure below 140/​90 mmHg and severely elevated albuminuria showed that the addition of captopril 100 mg a day resulted in a significant reduction in the numbers of patients doubling baseline serum creatinine com- pared to placebo (35% vs 78%; P <0.001). This significance was confined to those with an entry serum creatinine concentration of more than 133 µmol/​litre (1.5 mg/​dl). There was a similar re- duction in the numbers reaching a combined endpoint of death or the need for renal replacement therapy in the captopril-​treated patients. In patients with type 2 diabetes, the results are complicated due to their increased cardiovascular comorbidity. Two large studies using angiotensin II receptor blockers in patients with clinical proteinuria have shown a reduction of 25 to 33% in the rate of doubling of serum creatinine after 2 to 3 years of treatment. This is considerably less than that seen in the captopril trial in type 1 patients, possibly be- cause the type 2 patients had more advanced diabetic nephropathy at entry. The ACCORD blood pressure trial investigated whether a systolic blood pressure of less than 120 mmHg versus less than 140  mmHg would be more renoprotective, but while there were fewer cases of severely elevated albuminuria there was no benefit in terms of GFR. Taken together, the studies in type 1 and 2 patients support the use of drugs which block the renin–​angiotensin system as first-​ line therapy in both moderately and severely elevated albuminuric patients, and are recommended in all national and international guidelines. Nonrenal outcomes Although there are many large studies of the effects of antihypertensive therapy on cardiovascular mortality and morbidity in patient groups that have included sizeable cohorts of diabetic pa- tients, their nephropathic status has rarely been specified. Most have shown that low blood pressure is associated with the reduction in overall mortality and stroke incidence, although the effect on myo- cardial infarction is inconsistent. Diabetic patients on the whole showed a greater benefit from active treatment. Clinical features Clinical progression is usually defined in terms of changes in UAER, GFR, and blood pressure. Much of our current understanding is based on cross-​sectional data, although more long-​term prospective studies of individual patients are being reported. Albuminuria is clearly a continuous variable and its separation into stages is arti- ficial, but the distinction between moderately and severely elevated albuminuria has proved to be clinically useful and has been incorp- orated into the latest classification of CKD. There is an increasing realization that an elevated UAER is not an invariable finding in pa- tients with diabetes and CKD. This is a particular feature of older people with type 2 diabetes, but has also been described in type 1. Because of this there has been a huge interest in exploring other biomarkers for diabetic kidney disease and there are promising data using proteomics and metabolomics suggesting improved predictive performance when combined with albuminuria. These methods are not yet available for routine clinical use. UAER UAER may be raised at diagnosis of type 1 diabetes and during acute hyperglycaemia, but usually returns to normal with glycaemic cor- rection. Thereafter most patients (>60%) will have a normal UAER throughout their diabetic life, but the remainder develop persistent mod- erately increased albuminuria at incident rates of between 1 and 2% per annum, usually preceded by intermittently positive tests. Interestingly, an inception cohort of Danish type 1 patients followed from diag- nosis showed that UAER was significantly higher (but well within the normal range) in those subsequently going on to develop moderately increased albuminuria after 15 to 20 years, compared to those who did not (11 vs 8 µg/​min; P  =  0.002). The rate of increase of UAER in patients with moderately increased albuminuria is historically around 20% per annum, but this is lower in those commencing antihypertensive therapy or intensified insulin regimens (Table 21.10.1.2). It is unusual to develop moderately increased albuminuria within the first 5 years of diabetes onset, but it can develop at any time thereafter, even after 40 years. Many patients with type 1 diabetes and moderately increased albuminuria will progress to severely ele- vated albuminuria unless treated; those with longer durations of diabetes before moderately increased albuminuria tend to progress more slowly. More recent prospective studies have shown that as many as 25% of type 1 moderately increased albuminuric patients may spontaneously regress to normoalbuminuria. Around 12.5% may oscillate between normoalbuminuria and moderately increased albuminuria for many years. The significance of these movements is unclear and is possibly the result of blood pressure-​lowering ther- apies and short-​term changes in glycaemic control. What seems clear, however, is that these patients are at lower risk of progressing to endstage renal disease. Once UAER exceeds 300 mg/​day, there tends to be a relentless increase, occasionally into the nephrotic range. The rate of change varies between patients and is very dependent on systemic blood pressure. Historically, the incidence of severely elevated albumin- uria peaked after 15 to 17 years’ duration of diabetes, but more re- cent studies are showing a delay to 25 years or more. As the onset of type 2 diabetes is more difficult to define, the pre- cise incidence of moderately increased albuminuria is harder to

Urinary tract obstruction 5124 Muhammad M. Yaqoob

Urinary tract obstruction 5124 Muhammad M. Yaqoob and Kieran McCafferty

Why does intensive glycaemic control fail to compl

Why does intensive glycaemic control fail to completelyprevent development of moderately increasedalbuminuria?

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AND NOT FOR EXPORT THEREFROM. NOT FOR SALE IN ANY OTHER COUNTRY IN THE WORLD SIXTH EDITION VOLUME 4 edited by John D. Firth Christopher P. Conlon Timothy M. Cox Oxford Textbook of Medicine INTERNATIONAL EDITION