Other viruses \200 \200 \200 \200 Adenovirus. Hepatitis C. Hepatitis B. HIV. Bacterial infections These account for 80% of all infections. Urinary tract infections This is the most common primary site of infection associ- ated wit h secondary bacteremia. Patients with anatomically or functionally abnormal blad- ders or d iabetes are particularly at risk. A poor outcome is associated with: \200 \200 \200 Gram-negative bacteria; multiresistant organisms; Candida spp. Infection with Corynebacterium urealyticum is associated with encrustation and urinary trac t obstruction and can be dif \201 cult to isolate with routine culture methods. CHAPTER 14.6 Long-term medical complications of renal transplantation 567 Problem bacteria These may present as pneumonia, meningitis, cellulitis, osteomyelitis or g eneralized sepsis and include: \200 allograft recipients who developed 8724 de novo cancers. The great majority (6821) are kidn ey allograft recipients and there is a facility for nephrologists from around the world to enter their own data into the registry. Listeria monocytogenes (from unpasteurized dairy prod- ucts); Legionella spp.; Nocardia spp .; Mycobacterium tuberculosis (especially in high risk patients from developing countries); Nontuberculous mycobacteria; Vancomycin-resistant enterococcus (VRE); Methicillin-resistan t Staphylococcus aureus (MRSA). Post-transplant lymphoproliferative disease Incidence: 1 \200\2232%. Immunophenotypically i t is a CD20+ B-cell lymphoma. Associated with EBV infection. Seronegative recipients of an organ from a seropositive donor are at highest risk. EBV transforms B-lymphocytes when immu ne surveillance is inadequate and may promote uncontrolled polyclonal/ monoclonal prolifera tion. There is an increased risk with the use of lymphocyte- depleting antibodies (ATG, OKT 3, Campath-1H). PTLD usually presents with lymphadenopathy but extran- odal involvement is common (CNS, kidney, GI tract, liver, lungs) and multiple sites are often involved. Renal t ransplant involvement may mimic severe rejection. May respond to: \200 \200 \200 \200 \200 Fungal infections Pneumocystis jiroveci infection usually occurs in the \201 rst 6 months of transplantation but may occasionally occur later, particularly during periods of increa sed immunosup- pression. Cryptococcus neoformans can cause pneumonia and menin- goencephali tis. Aspergillus spp. Histoplasmosis, coccidioidomycosis, and rarely blastomy- cosis (geogr aphic or endemic fungal infections). signi \201 cant reduction or withdrawal of immunosuppres- sion (especially polyclonal dise ase); anti-CD20 humanized monoclonal antibody (rituximab); or may require conventional chem o- and radiotherapy Parasitic infections Strongyloides \200\223 there is a risk of hyperinfection syndrome in patients from endemic regions. Toxoplasma gondi is associated with CNS disease and cho- rio retinitis. \200 Antiviral agents are of no value. PTLD carries a high mortality. Poor prognostic factors in clude: \200 \200 \200 \200 Malignancy This is a major cause of death in kidney transplant recipi- ents (26% in the ALE RT study). There is an increased risk of most malignancies compared with: \200 \200 increasing age; raised LDH levels; multiple organ involvement; constitutional symptoms. Skin cancer 5 \200\22322% prevalence in UK. an age-matched general population; patients with ESRD on the transplant waiting list. Squamous cell carcinoma More common than basal cell carcinoma (BCC) in trans- plant recipie nts, in contrast to the general population where BCC is more common. Occur early, grow rapi dly and are often multiple and metastasize. Causative factors in the transplant recipient i nclude: \200 \200 \200 \200 Risk factors include: \200 \200 \200 \200 age; immunosuppression; chronic viral infections; smoking. The relative risk of malignancy ranges from a 2 \200\2233-fold increase for common malignan cies (lung, prostate, breast, colon) to a 100-fold increase for nonmelanomatous skin cancer s, PTLD and Kaposi \200\231s sarcoma. An annual surveillance examination, especially of the skin, should be performed. Otherwise age-appropriate screening as for the general populati on is indicated (e.g. mammography, cervical smears). Reduction or modification of the immun osuppressive regimen should be considered when a malignancy occurs and the potential for gr aft loss balanced against the natural history and staging of the malignancy. Sirolimus use has been associated with a reduced incidence of cancer (including skin cancer) in the \201 rst 2 years post transplantation but the bene \201 t of switching to this form of imm unosuppression in patients who develop malignancy has yet to be proved. The Israel Penn Tra nsplant Tumor Registry is a world- wide tumor database that has information on 8191 organ immunosuppression; UV light exposure; HPV (human papilloma viruses); genetic predisposition . Risk factors include: \200 \200 \200 \200 \200 \200 presence of actinic keratosis; age at transplantation; male gender; history of smoking; inc reased UV light exposure; duration of immunosuppression. Treatment depends on the size, site and number of lesions but includes: \200 \200 \200 cryotherapy or surgical excision; radiotherapy; 5- \202 uorouracil; C. DUDLEY 568 \200 \200 photodynamic therapy; immunosuppressive dose reduction. infection (e.g. CMV); smoking. Prevention includes photoprotection (avoid sun exposure, sun block creams). Retinoids have been used as secondary prevention in patients with multiple recurrent lesions. Chronic calcineurin inhibitor nephrotoxicity A paradox of modern transplantation is that CN Is, the agents that provide the cornerstone to most immunosup- pressive regimes, are nephro toxic. This may account for the fact that despite a dramatic reduction in the rate of early acute rejection with a con- comitant signi \201 cant improvement in 1 year renal allograf t survival after the introduction of ciclosporin (CsA) in the 1980s, there has been little improvement in graft half-life. Long-term studies of protocol biopsies have demonstrated th e natural history of CAN and emphasized that 90% of patients have evidence of chronic CNI n ephrotoxicity 5 years after renal (mostly SPK) transplantation. This is also emphasized by registry data documenting a CKD incidence of 16.5% in recipients 36 months after nonrenal s olid organ transplantation. In patients with a progressive decline in allograft function du e to CAN, substitution of CNI with mycophenolate mofetil (MMF) may be effective in improvin g allograft function without risking acute rejection. Substitution of CNI with sirolimus ma y also be effective in patients with suboptimal graft function. CNI dose minimization with MMF introduction may also be an effective strategy. Kaposi \200\231s sarcoma Uncommon. \200 \200 60% are cutaneous; 40% are disseminated (GI, pulmonary, lymph nodes). Associated with HHV 8 infection. Immunosuppression dose reduction, retinoids and conven- ti onal chemotherapy have been used. Regression with switching immunosuppression to sirolimus has been reported. Chronic allograft dysfunction Causes of chronic allograft dysfunction (CAD) include: \200 \200 \200 chronic allograft nephropathy (CAN); BK virus nephropathy; transplant renal artery stenosis or pseudorenal artery stenosis; recurrent glomerular disease; de novo glomerular disease. \200 Chronic allograft nephropathy CAN is the commonest cause of late allograft loss together wi th death with a functioning graft. It is a histological diagnosis characterized by: \200 \200 BK virus nephropathy BKV is a ubiquitous polyoma virus (60 \200\22380% of adults are seropo sitive). BKV causes latent infection of the kidney with reactivation during immunosuppressi on. Rates of infection range from 10 to 60%. BKV infection was originally described as caus ing ureteral stenosis or stricture, but now is more commonly associ- ated with a tubulointe rstitial nephritis with associated allograft dysfunction. The incidence of allograft failur e in affected patients ranges from 15 to 50%. The diagnosis requires a renal biopsy demonst rating: \200 \200 tubulointerstitial \201 brosis and tubular atrophy; \201 brointimal proliferation and t hickening of arteries with luminal narrowing; glomerular sclerosis. It re \202 ects cumulative and incremental damage from time- dependent immunological and n onimmunological causes. It has been suggested by histopathologists that in most cases they are able to identify histologically the predomi- nant lesion causing CAD. Therefore they ha ve proposed that the term CAN should be replaced by \200\230chronic allograft injury \200 \231. However, because of the cumulative and multifactorial elements that result in chronic allograft damage, this claim seems exaggerated. Immunological causes of CAN (alloantigen-d ependent risk factors): \200 \200 \200 \200 viral inclusion bodies in renal tubular cells; positive immunostains for SV40 T antigen. Polymerase chain reaction (PCR) of serum for BKV DNA and viral load may be useful as a diag nostic and monitoring test. Identi \201 cation of characteristic cytological changes in tu bu- lar cells shed in the urine ( \200\230decoy cells \200\231) may be used for screening. Speci \201 c antiviral therapy for BKV nephropathy does not exist. Management involves a r eduction in immunosuppression with close monitoring for rejection. Low dose cidofovir or le \202 unomide may be effective in some patients. clinical and subclinical acute rejection; degree of HLA mismatch; prior sensitization; subo ptimal immunosuppression and medication non- concordance; chronic antibody-associated rejec tion (peritubular C4d deposition and demonstration of donor-speci \201 c antibodies). Nonimmunological causes of CAN (alloantigen-independent risk factors): \200 \200 \200 \200 \200 Transplant artery stenosis or pseudoartery stenosis Incidence: 1 \200\2233%. Typically occu rs 2 months to 2 years after transplantation either from atherosclerosis of the donor vesse ls, clamp/ cannulation injury or poor surgical technique. donor factors (age, donor type); prolonged cold ischemic time; calcineurin inhibitor (CNI) nephrotoxicity; hypertension; hyperlipidemia; CHAPTER 14.6 Long-term medical complications of renal transplantation 569 \200 \200 \200 Immunological injury has also been proposed but is unproven. May present as: \200 \200 \200 hepatitis C infection; rejection episodes; Black race; high BMI. graft dysfunction (especially with ACEI/ARB use); dif \201 cult-to-control hypertension; d iuretic-resistant salt and water retention (peripheral edema); erythrocytosis. Treatment is aimed at weight loss, diet and exercise, oral hypoglycemics as monotherapy or in combination with insulin to achieve tight glycemic control. Post-transplant erythrocytosis Occurs in up to 20% of patients, most commonly during the \201 rst 2 years after transplantation. The mechanism responsible is uncertain but it may r esult from either overproduction of erythropoetin or of insulin- like growth factor-1 (IGF- 1). IGF-1 may increase the sensitivity of erythroid precursors to erythropoetin. It require s treatment if the hematocrit is >52% to avoid the risk of increased viscosity and thrombos is (cardiovascular event). ACEIs or ARBs are effective in most patients. Theophylline may b e used as an alternative. Phlebotomy may be required in resistant cases. There may be an associated bruit over the transplanted kidney. Diagnosis may be con \201 r med by: \200 color \202 ow Doppler examination (but this is operator dependent and interpretation may be dif \201 cult); CT angiography; conventional angiography. \200 Given concerns over gadolinium-associated nephrogenic fibrosing dermopathy, MR angiography is no longer a favored method of investigation. Treatment is with angioplasty and endovascu lar stenting or in recurrent cases operative revascularization. Pseudorenal artery stenosis occurs if an atherosclerotic plaque in the recipient \200\231s iliac vessels impairs blood \202 ow to the transplant renal artery. An iliac artery stenosis may also arise from int raoperative clamp damage. Chronic kidney disease The prevalence of CKD in renal transplant recipients from a UK regis try study in 2007 showed that: \200 \200 \200 \200 Cardiovascular disease This is the commonest cause of death after renal trans- plantation ( 34% of all deaths in the ALERT study). The incidence of cardiovascular disease (CVD) is inc reased compared with a matched general population but it is not as high as in dialysis pati ents. Both traditional and nontraditional risk factors contribute to CVD mortality and morb idity. Nontraditional factors include CKD-associated LVH and myocardial \201 brosis leadi ng to arrhythmias and death. An association with CMV infection (in heart transplant recipi- ents) has been observed but causality remains unproven. Modi \201 able risk factors shoul d be treated including: \200 \200 \200 \200 21.6% had CKD stage 2T; 57.5% had CKD stage 3T; 15.7% had CKD stage 4T; 3.1% had CKD stage 5T. Complications of CKD are frequently observed and are either inadequately treated or resista nt to treatment. Many patients in stage 4T \200\2235T have CKD-related complica- tions but registry data would suggest that these complica- tions are often less well-managed than in nontransplanted CKD stage 4 \200\2235 patients. Anemia The prevalence of anemia (Hb <11 g/d L) increases across CKD stages, reaching 51.5% in stage 5T. Contributing factors in additio n to CKD include: \200 \200 \200 diabetes; hypertension; hypercholesterolemia; smoking. drugs (azathioprine, MMF, sirolimus, ACEI/ARB); chronic in \202 ammatory state; infections (e.g. parvovirus). The American Society of Transplantation and European Best Practice Guidelines (EBPG) recomm end a target BP of: \200 \200 Intravenous/oral iron and erythropoiesis-stimulating agents (ESA) should be used according to the same criteria applied to nontransplant patients. <135/85 mmHg; <125/75 in high risk patients or with proteinuria >1 g/day. The metabolism of some statins (those metabolized via CYP3A) may be inhibited by CNIs and when used in high dose may rarely cause rhabdomyolysis. Hydrophilic statins such as pravastatin may be prefer red. Bone disease and metabolic acidosis Hypocalcemia, hyperphosphatemia, hyperparathyroidism an d metabolic acidosis should be managed as in nontrans- plant patients with CKD using phosph ate-binders, calcitriol and sodium bicarbonate. New-onset diabetes mellitus after transplantation (NODAT) A US registry study reported a cu mulative incidence of 24% for developing NODAT at 3 years post transplantation. NODAT signi \201 cantly reduces patient and graft survival. Risk factors for NODAT include: \200 \200 \200 Preparation for dialysis Patients need to be prepared for a return to dialysis or retranspl antation in a timely manner when appropriate (e.g. AVF formation, relisting). Bone disease Renal bone disease Almost all transplant recipients have some degree of renal osteodystrophy that persists after kidney transplantation. use of CNIs (tacrolimus greater risk than CsA); use of corticosteroids; age; C. DUDLEY 570 EBPG recommend that patients with tertiary hyperpar- athyroidism (HPTH) should be observed for 1 year after transplantation to allow for spontaneous involution. After the \201 rst year, tertiary HPTH may be treated by surgi- cal parathyroidectomy although the procedure m ay be associated with a decline in renal allograft function through poorly de \201 ned mec hanisms. The calcimimetic agent cinacalcet may provide an alterna- tive to surgical parathy roidectomy but its safety and cost- effectiveness needs to be established in transplantatio n. Serum levels of calcium, phosphate and intact PTH (iPTH) should be maintained within the range for nontransplant CKD patients. Davidson J, Wilkinson A, et al. New-onset diabetes after transplan- tation: International c onsensus guidelines. Transplantation 2003;75:SS3 \200\22324. Dudley C, Pohanka E, et al. Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic pro- gressive allograft dysfunction: the \200\234creepi ng creatinine \200\235 study. Transplantation 2005; 79: 466 \200\223475. European Best Practice Guidelines for Renal Transplantation (Part 2). Nephrol Dial Transplant 2000; 17(Suppl 4): 1 \200\22367. Frimat L, Cassuto-Viguier E, et al. Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The \200\230reference \200\231 study. Am J Transp lant 2006; 6: 2725 \200\2232734. Holdaas H, Fellstr m B, et al. Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators. Long-term cardiac outcomes in renal transplant recipients receiving \202 uvastatin: the ALERT extension study. Am J Transplant 2005; 5: 2929 \200\2232936. Osteoporosis Osteoporosis (bone mineral density 2.5 SD below the young adult mean value or T-score) is common after trans- plantation. There is a fracture rate of 7 \200\22311% (high er in diabetic patients receiving combined kidney pancreas transplants). Maximum bone loss occurs during the \201 rst 6 \200\22312 months of transplantation and continues at a lowe r rate or stabilizes thereafter. Risk factors include: \200 corticosteroid use; \200 CN I use; \200 previous renal bone disease; \200 persistent HPTH; \200 hypogonadism; \200 metabolic acidosis; \200 smoking. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the Un ited States. Am J Transplant 2004; 4: 905 \200\223913. Nankivell BJ, Borrows RJ, et al. The natural history of chronic allo- graft nephropathy. N Engl J Med 2003; 349: 2326 \200\2232333. Ojo AO, Hold PJ, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349: 931 \200\223940. Solez K, Colvin RB, et al. Banff \200\23005 Meeting Report: differential diag- nosis of ch ronic allograft injury and elimination of chronic allo- graft nephropathy ( \200\230CAN \200\231). Am J Transplant 2007; 7: 518 \200\223526. Watson CJ, Firth J, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppres- sion following renal transplantation. Am J Transplant 200 5; 5: 2496 \200\2232503. Internet resources British Transplantation Society Guidelines: http://www.bts.org.uk/standards.htm CTS \200\223 Collaborative Transplant Study: Treatment strategies to prevent osteoporosis include: \200 \200 \200 \200 \200 www.ctstransplant.org/ European Best Practice Guidelines: corticosteroid minimization or avoidance; oral calcium and vitamin D supplementation; testo sterone/estrogen replacement if appropriate; correction of metabolic acidosis; use of oral or IV biphosphonates. http://www.ndt-educational.org/ Eurotransplant: http://www.transplant.org/ Australia and New Zealand Dialysis and Transplant Registry: However, effect of treatment on fracture rate is unproven. There is concern over the use of biphosphonates in patients with low bone turnover. Assessment of bone density with dual en ergy X-ray absorptiometry (DEXA) scan at intervals may be indicated in patients in whom it will change practice. www.anzdata.org.au/ Israel Penn Transplant Tumor Registry: http://www.ipittr.uc.edu/Home.cfm United States Renal Data System (USRDS): Avascular necrosis or osteonecrosis This is associated with corticosteroid use although the pathogenesis is poorly understood. The femoral head is affected in 90% of cases. Avascular necrosis typically presents as hip or groin pain exacerbated by weight bearing. MRI is the most sensitive imaging method for diagnosis. Core decompression before the femoral head co llapses may relieve pain but 60% of cases require total hip replacement. www.usrds.org/ UK Renal Registry: www.renalreg.com/ United States Transplant Registry: http://www.ustransplant.org See also Early management of transplant recipients, p. 556 Cardiovascular risk factors in C KD, p. 412 Hypertension in CKD, p. 406 Immunosuppression for renal transplantation, p. 560 Outcome of renal transplantation, p. 576 Further reading Ansell DA, Udayaraj UP, et al. Chronic renal failure in kidney trans- plant recipients. Do they receive optimum care?: Data from the UK Renal Registry. Am J Transplan t 2007;7:1167 \200\2231176. Bostom AD, Brown RS, et al. Prevention of post-transplant cardio- vascular disease \200 \223 report and recommendations of an ad hoc group. Am J Transplant 2002;2:491 \200\223500. This page intentionally left blank C. NEWSTEAD 572 Recurrent and de novo disease post renal transplantation Introduction The most common cause of post-transplantation proteinu- ria is chronic allogra ft nephropathy (60%), followed by recurrent (15%) and de novo (10%) glomerulonephritis. The most common diseases associated with allograft glomerulonephritis and their recurrence rat es post trans- plantation are: \200 \200 \200 In isolated renal transplantation the majority would argue for strict glycemic control with the early use of ACEIs, often in conjunction with ARBs to slow progression of glomerular r enal disease. De novo diabetic nephropathy Renal transplant recipients are at risk of new-onset diabe- te s, particularly because of treatment with corticosteroids, tacrolimus and ciclosporin. Ther e is good evidence that the disorder has a signi \201 cant impact on patient and graft sur vival. It is therefore appropriate to aim for good glycemic control and to use ACEIs libera lly if necessary in conjunc- tion with ARBs for renal protection, irrespective of any favor able impact this management would be expected to have on cardiovascular disease. Attention to other modi \201 - able risk factors such as physical activity, smoking and weight reduc tion are important. idiopathic focal glomerular sclerosis (25%); IgA nephropathy (25%); mesangiocapillary glome rulonephritis (type I, 25%, type II, 80%); membranous nephropathy (30%); hemolytic uremic s yndrome (classic 1%, atypical, 20% familial 80%). \200 Clinical features of recurrent disease In general, recurrence of disease affecting the rena l trans- plant mimics the features of the original disease. The discrimination between allo graft dysfunction due to recurrent disease and that due to acute or chronic rejec- tion, dr ug nephrotoxicity or pyelonephritis usually involves urine culture, measurement of proteinu ria, measurement of immunosuppressive drug concentrations and ultrasound imaging. If recurr ent renal disease is a likely diagnosis then a renal biopsy with full electron microscopy a nd immuno- histological processing of a renal biopsy will be necessary. Idiopathic focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is an especially important problem in pediatric practice. The absolute recurrence rate post tr ansplantation in children varies with different series; but is between 20% and 30%. Data fr om the North American Pediatric Renal Transplant Co-operative Study show that patients with FSGS have the highest overall graft failure rate. Risk of relapse is increased with: \200 \200 Antiglomerular basement membrane disease In patients with ESRD due to anti-GBM disease stan dard practice is to measure circulating anti-GBM antibodies periodically and most would adv ise waiting 12 months from when antibodies were negative before offering trans- plantation, whether from a cadaveric or a live donor source. Clinical disease is signi \201 cantly le ss common than histological recurrence and rarely leads to graft loss. age <15 years; aggressive clinical course of original disease with the interval from diagno sis to ESRD less than 3 years; diffuse mesangial proliferation on native biopsy. Given the high frequency of recurrent disease it is impor- tant to advise patients and fami lies about the relative mer- its of living verses cadaveric transplant donor sources. Despi te the high rate of graft loss, overall recipients of a living donor kidney have a better g raft survival than recipients of cadaveric renal transplants at 50 months. Many clinicians would avoid a living donor organ source as a primary transplant if the clinical course of t he original disease was <3 years or if the patient was aged <15 years, especially if the FS GS was accompanied with diffuse mesangial proliferation. If a primary transplant is lost to recurrent disease, a living related transplant should be avoided for subsequent graft- ing as the recurrence rate is in the order of 80%. If the \201 rst graft was lost from rejec tion or another compli- cation with no evidence of recurrence there is much less risk of re currence in a subsequent graft. De novo anti-GBM nephritis Approximately 15% of patients with Alport \200\231s syndrome dev elop anti-GBM antibodies in response to what is for them the neoantigen of the chain of type IV collagen. A small fraction of this subgroup develops severe crescen- tic glomerulon ephritis with a poor outlook. However, given its rarity most authorities advise transplanta tion, whether from a live donor or a cadaveric source in Alport \200\231s syndrome. ANCA-associated vasculitis Patients are not listed for transplantation until they are in cl inical remission. The duration of pretransplant dialysis does not appear, albeit based on s mall numbers, to have any signi \201 cant in \202 uence on the risk of relapse. The pres- ence of a positive ANCA at the time of transplantation does not preclude transplantation a nd subsequent sero- logical monitoring would seem to be relatively unhelpful for predicting outcome. It is important to emphasize that patients, often adults, with the histology of focal and s egmental sclerosis where that is secondary to low renal mass, and who typically are not nep hrotic, are not at risk of recurrent glomerulonephritis. Diabetic nephropathy Histological recurrence of diabetic renal disease is seen in 100% of p atients within 4 years of transplantation. Although histological recurrence rate is very hi gh the frequency with which diabetic nephropathy is ascribed as a cause of graft loss is mu ch smaller and was only 1.8% in the largest series. Treatment of recurrent FSGS Treatment remains suboptimal with multiple case series of diffe rent strategies. Treatments have included: \200 \200 ACEIs; indomethacin; CHAPTER 14.7 Recurrent and de novo disease post renal transplantation 573 \200 \200 \200 \200 \200 Hemolytic uremic syndrome (HUS) It is critical to discriminate between: \200 \200 \200 immunoabsorption with protein A columns; IV immunoglobulin; high dose ciclosporin; cyclopho sphamide; plasmapheresis; double \201 ltration plasmapheresis. diarrhea-associated HUS; familial HUS; de novo HUS. In the more common diarrhea-associated HUS recurrence rate with graft loss is of the order of 1%. By contrast in the group with HUS with no diarrhea 20% subsequently lose grafts due to recurrence. In the subgroup with HUS associated with factor H de \201 - ciency, graft loss rates of the order of 80% are seen. Family history is particularly important and molec ular investigation of complement regulators as well as von Willebrand protease activity is advised; guidelines are available from the European Society of Pediatric Nephrology (ESPN). Live related donation should only occur after a careful pre- diction of the risks of prema ture graft loss. The clinical presentation may be gradual or relatively abrupt with marked thrombocytopenia, and hemolysis associated with progressive renal dysfunction. Therapeutic options are limited with little evidence that altering calcineurin inhibitors changes progn osis. In severe thrombocytopenia most practitioners would adopt treatment strategies simila r to that used in classic HUS with plasma fraction infusions and plasma exchange. In the ev ent of life-threatening thrombocytopenia or hemolysis, particularly in the presence of seve re allograft dysfunction, transplant nephrectomy may be required to restore stability. Plasmapheresis is the most widely used technique in the treatment of recurrent nephrotic sy ndrome post trans- plantation. This is usually in combination with other immunosuppressive treatments. It is important to decide whether treatment with plasma exchange needs to be augmented with cyclophosphamide, especially in children. The literature generally supports the early use of both plasma exchange and cyclophosphamide. Familial FSGS It is important to recognize familial FSGS, although rare, as it is a differe nt syndrome from idiopathic FSGS. Patients generally present in their 3rd or 4th decade and post-transplantation recurrent disease is rare with an overall 10 year graft survival of 6 2%. Mutations in genes coding for podocyte proteins have now been reasonably well-character ized in hereditary FSGS. In patients with two pathogenic NPHS2 mutations there is a very lo w risk of recurrent disease; in other situations the prognostic value of genotyping is less clear. Genetic testing is now available and can improve coun- seling before transplant. De novo FSGS in renal transplants This histological appearance is most commonly reported as sociated with other pathology, particularly chronic allo- graft nephropathy, or transplant glomerulopathy and occa- sionally ciclosporin toxicity or IgA disease. In contrast to FSGS affecting native kidneys, only 24% of those with biopsy-proven glomerular disease have neph - rotic syndrome. This histological \201 nding is associated with poor graft sur- vival. The pathogenesis and whether this entity is separate from a chronic rejection process are u nclear. De novo HUS De novo HUS has been attributed to OKT3, tacrolimus, vascular rejection as well as ciclosporin post renal trans- plantation. This syndrome occurs most frequently within a month of transplantation and is associated with graft loss in 60% and patient death in 20 % of cases. Calcineurin dose minimization is usual as well as a treat- ment strategy simila r to that used in diarrhea-associated HUS. Henoch \200\223Sch nlein purpura Because of the very small numbers of patients reported it is very dif \201 cult to predict accurately recurrence of this condition. Overall the act uarial risk for renal recurrence and graft loss due to recurrence has been reported to be b etween 11% and 35% at 5 years after transplantation. Importantly, recurrence may occur desp ite a >12 month delay between disappearance of purpura and transplanta- tion. The common ad vice to delay for a year between disap- pearance of purpura and transplantation may therefo re not protect from recurrent disease. Hepatitis-B-associated glomerulonephritis Concomitant hepatitis B infection has an importan t impact on survival of renal transplant patients. Glomerulonephritis secondary to hepatiti s B post renal transplantation is rarely an important clinical problem. Membranous glomerul onephritis is the most common form of glomerular disease associated with hepatitis B. This has a far from benign prognosis, and a similar prognosis would be expected in renal transpl ant recipients who develop nephrotic syndrome. Antiviral treatment is the mainstay of manag ement. Hepatitis-C-associated glomerulonephritis Cryoglobulinemic nephritis with mesangiocapillary glomer- ulonephritis has been described after transplantation in patients infected with he patitis C virus. Although this has a poor prognosis in general it is liver failure that is responsible for most of the inferior graft and patient survival. IgA nephropathy At a mean follow-up of 5 years 13% of patients will have some recurrence-r elated renal graft dysfunction and 5% will lose the graft as a result of recurrence. C. NEWSTEAD 574 In the only series in which all patients were biopsied recurrence was found in 58%. Younger patients are at greater risk of recurrence, as are those with a shorter duration of diseas e in the native kidneys. At least one group has demonstrated clinically signi \201 cant po orer graft survival in patients presenting with native cresentic glomerulonephritis. Overal l, graft survival at 5 and 10 years appears to be the same as average. There is no establis hed treatment for preventing or treat- ing recurrent IgA nephropathy, but one group has rep orted a trend towards improved 5 and 10 year graft survival in those prescribed ACEI/ARB th erapy. The use of living related donors for recipients with IgA nephropathy has been the su bject of some controversy. A large registry series found an increased rate of IgA neph- rop athy-related graft loss among zero HLA-mismatched recipients of kidneys from a live donor s ource. This offset the advantage normally seen among zero HLA-mismatched recipients. These authors argued that as overall survival was similar there was no reason to avoid live donor -recipi- ent pairs with zero HLA mismatches. Mesangiocapillary glomerulonephritis type I Where the renal disease is thought to be mediat ed by glomerular deposition of immune complexes generated after exposure, for example to na tive DNA (SLE) or hepa- titis antigens, recurrence would be expected after trans- plantatio n as these antigens would be predicted to persist in the circulation post transplant. Publi shed experience suggests that type I MCGN recurs after renal transplantation in half the pa tients and that this frequency may be even greater in recipients of identical living relate d donor grafts. Recurrence in a second transplant after recurrence in the \201 rst graft is extremely common and once diagnosed has an important detrimental impact on graft surviva l. The risk of recurrence may be considerably less in Japanese patients with a rate of only 3% in one published series. It is not possible to give any evidence-based advice with rega rd to treatment. Antiviral therapy would be logical in patients with persistent hepatitis B antigenemia. Mesangiocapillary glomerulonephritis type II The most comprehensive recent analysis is from the North American Pediatiric database. Recurrent disease was seen in 67% and 5 year graft survival was 50%, compared to 74% on average. There was no correlation between severity of pre- transplantation presentation, pre- or post-transplantation C3 levels and prognosis. Membranous nephropathy In adults the rate of recurrence is 30%. No speci \201 c risk fact or for recurrence has been clearly identi \201 ed. The outcome for graft survival is poor with a 52% graft loss at 10 years. The clinical syndrome seems to be similar to the disease in native kidneys with progressively more severe nephrotic syndrome. The management is usu ally based on extrapolation of data from management of native kidney disease and, similar t o that situation, spontaneous remission, failures of immuno- suppressive treatment as well as clinical response coinci- dent with change of treatment have all been reported. A recent case report of successful use of rituximab requires more experience and longer follow-up. No treatments are known to be effective: there are case reports describing successful use o f plasma exchange and immunosuppression. Systemic lupus erythematosus The rate of recurrent lupus nephritis is 1% at 5 years. Pre-t ransplantation serological parameters are unreliable predictors of the likelihood of recurr ence and also may not accurately re \202 ect disease activity in the post-transplanta- tio n interval. As would be expected given the small number of cases, there are no formal studi es of the management of recur- rent lupus nephritis. Most clinicians would opt for manageme nt that mirrored that of native disease. Anticoagulation during the early perioperative and early post-transplantation phase should be considered for patients with a history of throm bosis or those with the presence of lupus anticoagulant. De novo membranous nephropathy De novo membranous nephropathy is second only to trans- plan t glomerulopathy as a cause of nephrotic syndrome after renal transplantation. The mean tim e of diagnosis is at 5 years post transplanta- tion. The addition of pulsed steroid therap y to the baseline immunosuppression in heavily nephrotic patients makes no obvious impact o n outcome. Systemic sclerosis The evidence base in this condition is extremely small. Most clinicians would manage patients with systemic sclerosis in a similar way to patients with SLE and rec om- mend renal transplantation as a treatment option. The majority would use ACEIs for anti hypertensive control from the outset in patients who had ESRD secondary to scleroderma rena l crisis. Mesangiocapillary glomerulonephritis (MCGN) There are marked histological similarities betw een trans- plant glomerulopathy and MCGN, but immuno \202 uores- cence and electron micros copy can usually discriminate between the two diagnoses. A recent report analyzing the expe rience of a single coun- try (Ireland) concluded that younger age at initial diagnosis and the severity of the native glomerular histology inde- pendently predicted the risk of recur rence, and not the classi \201 cation of MCGN type, with the poorer reputation of type II disease explained by the more aggressive glomeru- lar changes seen in that condition. Further reading Bresin E, et al. Outcome of renal transplantation in patients with non-Shig a toxin-associated haemolytic uremic syndrome: prog- nostic signi \201 cance of genetic ba ckground. Clin J Am Soc Nephrol 2006; 1: 88 \200\22399. Couser W. Recurrent glomerulonephritis in the renal allograft: an update of selected areas. Exp Clin Transplant 2005;3:283 \200\223288. CHAPTER 14.7 Recurrent and de novo disease post renal transplantation 575 American Society of Transplantation: Floege J. Recurrent IgA nephropathy after renal transplantation. Semin Neprol 2004; 24: 287 \200\223291. http://www.a-s-t.org/ American Society of Transplant Surgeons: Gera M, et al. Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosuppression. Kidney Int 2007; 71: 1296 \200\2231301. http://www.asts.org/ European Society of Pediatric Nephrology (ESPN): Little MA, Dupont P, Campbell E, Dorman A, Walshe JJ. Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk. Kidney Int 2006; 69: 504 \200\223511. http://.espn.cardiff.ac.uk North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS): McDonald SP, Russ GR. Recurrence of IgA nephropathy among renal allograft recipients from l iving donors is greater among those with zero HLA mismatches. Transplantation 2006; 82: 759 \200\223762. https://web.emmes.com/study/ped/ See also Outcome of renal transplantation, p. 576 Early management of transplant recipients , p. 556 Long-term medical complications of renal transplantation, p. 566 Weber S. Tonshoff B. Recurrence of focal-segmental glomeruloscle- rosis in children after r enal transplantation: clinical and genetic aspects. Transplantation 2005; 80: S128 \200\223 S134. Internet resources British Transplantation Society: http://www.bts.org P. TOPHAM 576 Outcome of renal transplantation Renal transplant outcome can be measured in a number of different ways including: \200 \200 \200 \200 \200 \200 