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.