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.