http://www.a-s-t.org/ American Society of Transplant Surgeons: http://www.asts.org/ See also Transplant surgery and surgical complications, p. 552 Immunosuppression for renal transplantation, p. 560 Recurrent disease and de novo disease post renal trans- plantation, p. 566 Drug-induced nephropathies, p. XXX Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in acute kidney injury, p. 328 Kauffmann HM. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transplant Int 2006; 19: 607 \200\223620. Kotton CN, Fishman JA. Viral infection in the renal transplant recip- ient. J Am Soc Nephrol 2005; 16: 1758 \200\2231774. Margreiter R; European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Ef \201 cacy and safety of tac- rolimus compared with ciclosporin microemulsion in renal trans- plantation: a randomized multicentre study. Lancet 2002; 359(9308): 741 \200 \223746. Singer J, Gritsh HA, Rosenthal KR. The transplant operation and its surgical complications. In: Danovitch G.M (ed.), Handbook of kidney transplantation, 4th edn. Philadelphia: Lippin cott Willliams & Wilkins; 2005. pp. 193 \200\223211. This page intentionally left blank C. DUDLEY 560 Immunosuppression for renal transplantation Introduction The number of immunosuppressive agents available for use in renal transplantat ion has increased in the last 20 years. In September 2004, the National Institute for Healt h and Clinical Excellence (NICE) published its guidance on the use of immunosuppressive the rapy in adults following renal transplantation (NICE Technology Appraisal 85). Randomized c ontrolled trials (RCTs) comparing different agents have nearly all been funded by pharmaceu tical com- panies with commercial interests and have had a number of shortcomings. These ha ve included: \200 \200 \200 minimized by giving IV methylprednisolone and an antihis- tamine 30 min before use. Thrombo cytopenia and leukopenia are common. Although \201 xed daily dosing regimens may be used, many clinicians dose according to total lymphocyte or CD3 count to avoid over-immunosuppre ssion. CMV and Pneumocystis jiroveci (carinii) prophylaxis should be considered mandatory, because of the increased risk of infections. The use of ATG is associated with an increased incidence of post-transplant lymphoproliferative disease (PTLD). OKT3 (Muromonab \200\223CD3) OKT3 is a mouse monoclonal IgG2a antibody that reacts with the T-cell receptor \200\223CD3 complex chain of the T-lymphocyte on the surface of circulatin g human T-cells. Deactivation of the CD3 complex causes the T-cell receptor to undergo endo cytosis and the ineffectual T-cell is cleared by the reticuloendothelial system. In the UK, OKT3 use tends to be restricted to the treat- ment of steroid-resistant rejection when ATG has failed or is contraindicated. In the USA it has been used as induction therapy. Potent ially life-threatening side-effects including noncar- diogenic pulmonary edema may occur du ring the \201 rst few days of treatment due to release of T-cell-derived cytokines (cytok ine release syndrome). Its use therefore, is contrain- dicated in volume-overloaded patient s. A sensible precau- tion is to dialyze/ultra \201 lter all patients to their target weig ht (or below) before its use. Intravenous methylprednisolone, an antihistamine and oral par acetamol are given 15 \200\22360 min before the \201 rst and sec- ond doses. Nearly all p atients develop fever and rigors which usually abate after the third dose and can be treate d with oral paracetamol. Neurological side-effects are also common and self-limiting and ra nge in severity from a mild headache to aseptic meningitis and encephalopathy. Once again, CMV and Pneumocystis jiroveci (carinii) prophy- laxis should be considered mandatory. The u se of OKT3 is associated with an increased incidence of post-transplant lymphoproliferative disease (PTLD). With repeated use, antimouse antibodies may develop. For this reason, when a second course of OKT3 is used, monitoring of CD3+ cells is recommended to ensure that ad equate depletion is being achieved. use of licensed rather than real-life dosing regimens; short-term follow-up only; inadequat e power to detect statistical differences in patient and graft survival; until recently the use of acute rejection rates as the primary endpoint rather than allograft function. Immunosuppressive regimens therefore have evolved within transplant centers based on local experience and need. Although there is no consensus on the best regimen to use, the general principles are: \200 to match the amount of immunosuppression with the perceived immunological risk; to use high doses in the early part of transplantation (induction) with phased reduction and even with drawal of some agents thereafter (maintenance); to \200\230tailor \200\231 the type of age nt with the patient \200\231s speci \201 c needs, e.g. cosmetic considerations. All regimens are still based around the use of calcineurin inhibitors. Individual drugs can be considered under two broad headings: \200 \200\230Biological \200\231 agents: monoclonal or polyclonal antibodies used as induction therapy or to treat severe acute rejection. Agents used for maintenance immunosuppression: \200 \200 \200 calcineurin inhibitors (CNIs); anti-proliferative agents; corticosteroids. Biological agents Antithymocyte globulin (ATG) A polyclonal antibody derived from rabbits w ith activity against human lymphocytes, particularly a number of T-cell markers. Administra tion results in depletion of peripheral blood lymphocytes that are either lysed or cleared by the reticu- loendothelial system. In most UK centers its use is reserved for the treatme nt of steroid-resistant acute rejection although in the USA it is also used as induction th erapy at the time of transplanta- tion to prevent rejection. It should be administered into a central vein (or fast- \202 owing vein such as an AVF) to avoid thrombophlebitis. Side- effects relate largely to allergic reactions including chills, fevers, arthralgia and rarel y anaphylaxis. These can be Humanized anti-CD25 monoclonal antibodies Basiliximab (Simulect) Daclizumab (Zenapax) These monoclonal antibodies are directed against the A chain (CD25) of the IL-2 receptor on acti vated T-cells. As such they are used together with CNIs to prevent (but not treat) acute re jection. Although derived from mouse, both monoclonal antibodies have been genetically engi neered such that a large proportion of the antibody is replaced by human IgG. CHAPTER 14.5 Immunosuppression for renal transplantation 561 Strictly speaking, basiliximab is a chimeric (xi) antibody (75% human, 25% mouse) whereas b aclizumab is a human- ized (zu) antibody (90% human, 10% mouse). Both are of low immunogeni city and do not induce a significant human antimouse antibody response when administered. T herefore \201 rst-dose reactions are rare and both have long half-lives. Because basilixi mab has a greater af \201 nity for the IL-2 recep- tor, a less intense dosing regimen is r equired compared with daclizumab. Despite increasing the early immunosuppressive burden, an increased incidence of opportunistic infections or PTLD over the control groups was not ob served in the phase 3 studies which led to their clinical introduction. Short-term phase 2 studies have shown that belatacept when used in combination with basilix imab, mycopheno- late mofetil (MMF) and corticosteroids, allows CNI avoid- ance with improv ed renal function when compared with ciclosporin-treated patients, although the incidence o f acute rejection, graft and patient survival was similar between groups. Histological feat ures of chronic allograft nephropathy were less common. Agents used for maintenance immunosuppression Calcineurin inhibitors Ciclosporin A (CsA) an d tacrolimus are the two major CNIs that have provided the cornerstone of maintenance immun osuppressive regimens in the modern era of solid organ transplantation. Engagement of the T -cell receptor results in activation of calcineurin, a phosphatase that dephosphorylates a number of nuclear regulatory proteins including NFAT (nuclear factor of activated T-cells) thereby facilitating their movement into the nucleus where they upregulate the transcriptio n of a number of important cytokines genes including IL-2, IL-4, interferon-G (IFN-G) and t umor necrosis factor-A. The CNIs bind to their cytoplasmic receptor proteins (cyclophilin f or CsA and FK-binding protein for tacrolimus). The resulting complex binds to calcineurin, inhibiting its action thereby preventing T-cell activation and proliferation. CsA is a smal l cyclic polypeptide (MW 1203) consisting of 11 amino acids derived from the fungus Tolypoc ladium in \202 atum. The most widely used preparation is a microemul- sion formulation kno wn as Neoral. Tacrolimus is a macrolide antibiotic compound isolated from Streptomyces tsuk ubaensis (Tsukuba macrolide immunosuppressant). Both drugs have a narrow therapeutic index; too little results in under-immunosuppression and too much in side- effects the most impor tant of which is nephrotoxicity. Furthermore, there is large inter- and intrapatient variat ion in drug metabolism and for these reasons therapeutic drug monitoring (TDM) is required with measurement of 12 h trough levels. For Neoral, there is evidence that its 2 h postdose peak concentration (C2 level) correlates better with drug expo- sure than the C12 level an d is used in preference in some centers. Both agents are metabolized in the gut and liver b y the cytochrome P450 IIIA system (CYP3A) found in the gastroin- testinal tract and liver a s well as by p-glycoprotein in gut. The heterogeneity in intestinal CYP3A gene expression m ay account for some of the wide interpatient variability in drug metabolism. Any drug that in \202 uences the CYP3A system in the gut or liver has a potential interaction with the C NIs and constant awareness is required. Well-recognized interactions that increase CNI leve ls result from: \200 \200 \200 Campath-1H (Alemtuzumab) Campath-1H is an anti-CD52 humanized monoclonal anti- body develop ed in the Cambridge Pathology Laborato- ries and licensed as a treatment for chronic lympho cytic leukemia. When used off-label in transplantation, it results in profound and long-las ting lymphocyte depletion that may take many months to return to pretransplant levels. It i s used most commonly as induction therapy as part of a steroid-free low-dose maintenance im munosuppression regimen. However, few long-term RCTs have been performed and its exact plac e as an immunosuppressive agent has yet to be determined. Rituximab Rituximab is a chimeric (mouse/human) monoclonal antibody directed against the CD 20 antigen expressed on B lymphocytes. Its use results in rapid and sustained depletion of both circulating and tissue-based B-cells. Originally developed for the treatment of non-Ho dgkin lymphoma, its use has been extended to a number of presumed B-cell-mediated autoimmun e conditions. In transplantation it has been used in a variety of ways, most notably in pla sma exchange/immunoadsorption regimens to remove and prevent resynthesis of preformed antib odies in HLA- or ABO-incompatible living donor transplantation. It has also been used to tr eat antibody-associated acute rejection as well as PTLD when CD20 is expressed. Belatacept (LEA29Y or CTLA-4-Ig) For an optimal and sustained T-cell response both antigen recognition by the T-cell receptor (signal 1) and costimula- tory signals (signal 2) delive red through accessory T-cell surface molecules are required. Experimental studies have sugg ested that interruption of costimulatory signals may lead to donor-speci \201 c graft tole rance. Belatacept is a selective costimulation blocker that binds surface costimulatory lig ands (CD80 and CD86) of antigen- presenting cells. It is a cytotoxic T-lymphocyte antigen ( CTLA)-4-Ig fusion protein homolog of CD28 which binds CD80 and CD86 with high af \201 nity and blocks the interaction with CD28, thereby preventing full T-cell activation. calcium channel blockers, particularly diltiazem; antifungal agents such as \202 uconazol e; macrolide antibiotics such as erythromycin or clarithro- mycin (but not azithromycin). C. DUDLEY 562 \200 \200 \200 \200 Interactions that reduce CNI concentration result from the use of: \200 \200 \200 delayed would healing and thin skin; glucose intolerance/NODAT; weight gain; cataracts; non targeted immunosuppression resulting in increased susceptibility to infection. rifampicin; phenytoin; carbamazepine. The CNIs may inhibit the metabolism of other drugs and important interactions occur with ce rtain statins when used in full dose which may result in rhabdomyolysis. Nephrotoxicity is the most important side-effect of both CNIs and appears to have two components. The \201 rst is a reversible functional decrease in renal blood \202 ow and GFR mediated by vasoco nstriction of the afferent arteriole. Long-term use is associated with chronic interstitial \201 bro- sis which is a universal \201 nding in longitudinal biopsy studies. Although \201 brosis may be \200\230striped \200\231 and associated with hya- line arteriolar le sions, these are not speci \201 c features and similar \201 ndings may arise in response to a number of renal insults. A thrombotic microangiopathy similar to HUS/TTP may rarely b e observed. Electrolyte abnormalities include hyperkalemia often asso- ciated with a hyperc hloremic acidosis as in type IV RTA. Hyperphosphaturia, hypermagnesuria and hypercalciura m ay all occur. Hypertension is common, as are hyperuricemia and gout. Cosmetic changes such as hypertrichosis and gum hyper- plasia may be observed with CsA, whereas hair loss may occ ur with tacrolimus. Glucose intolerance and new-onset diabetes after trans- plantation (NOD AT) is observed with both agents, although these are commoner with tacrolimus as are neu- r ological complications such as tremor. By contrast, hyperlipidemia is commoner with CsA. Antiproliferative drugs Azathioprine Azathioprine is a purine analog which inhibits the syn thesis of nucleotides for both DNA and RNA. It prevents cell replication and inhibits T-cel l proliferation. Although used for many years as combination therapy with CNIs and corticos teroids, it has been largely superseded by MMF. Its most important side-effect is generaliz ed marrow suppression and regular monitoring of the FBC is mandatory in the \201 rst few months of therapy. Patients with an inherited de \201 ciency of the enzyme thiopu- rine me thyltransferase (TPMT) metabolize azathioprine slowly. This results in rapid drug accumulat ion and pro- nounced marrow suppression with standard azathioprine doses. Measurement of TP MT levels is recommended with dose reduction in patients with low enzyme levels. Azathiopri ne is also metabolized by xanthine oxidase which is inhibited by concomitant use of allopur inol. This drug combination should therefore be avoided or used with great caution, i.e. az athioprine dose reduction to 25% of standard dose. Other side-effects include hepatitis and cholestasis. Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) These are respectively the ester and sodium salt prodrugs of the active compound mycophenolic acid (MPA), a prod- uct of se veral Penicillium spp. MPA is a reversible inhibitor of the enzyme inosine mono- phosphate dehydrogenase (IMPDH), a critical, rate-limiting enzyme in the de novo synthesis of purines . Because lymphocytes lack the salvage pathway for purine synthesis that is present in othe r cell types, they are dependent on the de novo pathway and are therefore sus- ceptible to its inhibition. The antiproliferative effect of MPA is thus relatively selec- tive for acti vated lymphocytes. MPA blocks the proliferation of T- and B-lymphocytes, inhibits antibody formation and the generation of cytotoxic T-cells. Mycophenolate mofetil and mycophenolate sodium are usually used in combination with CNIs and corticosteroids. Mycophenolate mofetil has been shown to be more effec- tive than azathioprine at preventing acute rejection when used in a triple therapy regimen. Gastrointestinal side-effects are the most troublesome a dverse effects, with diarrhea occurring in 30% of patients and esophagitis and gastritis i n 20%. Upper gastrointestinal hemorrhage has been observed. Bone marrow suppression also oc curs commonly and may necessitate a dose reduction. Corticosteroids Corticosteroids inhibit the transcription of a number of cytokine genes inc luding IL-1, IL-2, IL-3, IL-6, TNF-A and IFN-G. They act by inhibiting the translocation to the nucleus of nuclear factor- B (NF- B), an important transcription factor that regul ates the expression of a large number of cytokine genes. In addition, corticosteroids thems elves translocate to the nucleus via a steroid \200\223receptor complex which binds to gluc ocorticoid response elements (GREs) in the promoter region of several cytokine genes, preve nting their tran- scription. Corticosteroids also have nonspeci \201 c immunosuppressant a nd anti-in \202 ammatory actions including inhibition of chem- okines, vasodilators and bl ocking monocyte migration to sites of in \202 ammation. Although they have been part of mo st immunosuppressive regimens since the beginning of transplantation, their side- effects h ave led to new regimens that withdraw, minimize or avoid the use of these agents. The most troublesome side-effects include: \200 cosmetic changes and growth impairment, particularly in children and young adults; osteopor osis; CHAPTER 14.5 Immunosuppression for renal transplantation 563 The increased immunosuppression provided by MPA is associated with a slightly increased inc idence of opportun- istic infections and PTLD. Therapeutic drug monitoring is not usually n ecessary. There are few important drug interactions but MPA may increase aciclovir/ganciclo vir levels by inhibiting renal tubular secretion. Unlike azathioprine it can be used safely with allopurinol and no dose reduction is necessary. The antiproliferative agent is usually MMF in place of azathioprine. Anti-CD25 antibody ind uction therapy may be included as a routine or reserved for patients at increased risk of a cute rejection or delayed graft function. Regimens that avoid, minimize or withdraw cortico steroids are becoming increasingly popular but carry risks. Calcineurin inhibitor avoidance regimens These are based around anti-CD25 induction, MMF an d sirolimus, and have been associated with a high incidence of acute rejection and side-eff ects as well as worse graft function at 1 year. CNI avoidance regimens based around belatac ept use are currently more promising. mTOR inhibitors; sirolimus and everolimus Sirolimus and everolimus are both inhibitors of t he mam- malian target of rapamycin, a key regulatory kinase that controls cell division. On ly sirolimus is licensed for use in the UK. It is derived from a macrolide antibiotic \201 rst identi \201 ed on Rapa Nui (Easter Island) and was originally called rapamycin. L ike tacrolimus, sirolimus binds to FKBP but the resultant complex inhibits mTOR blocking cy tokine (IL-2)-dependent cellular (lymphocyte) proliferation at the G1 \200\223S phase of th e cell cycle. It was originally developed as combination therapy with ciclosporin and corti costeroids but was shown to potenti- ate the nephrotoxicity of ciclosporin. This, together with other side-effects including delayed wound healing and lymphocele formation, has large ly precluded its use as initial immunosuppression after transplantation. Instead it has bee n used as switch therapy in place of a CNI after the \201 rst 3 months of transplantation . It has also been used in regimens of CNI withdrawal. It is metabolized mainly by the live r via both CYP3A and p-glycoprotein and therefore has a large number of drug interactions. Therapeutic drug monitoring using a 24 h trough level is required. In addition to lymphocel e formation and delayed graft function it has a number of other side-effects that have limi ted its use. These include: \200 \200 \200 \200 \200 \200 \200 Acute cellular rejection This is usually treated with high dose IV methylpred- nisolone on 3 consecutive days. Background immunosuppression may be increased, i.e. addition of MMF if not already part of the regimen. Steroid-resistant acute rejection This is usually treated with ATG (occasionally OKT3). Antibody-mediated acute rejection This may be treated by plasma exchange IV immuno- glob ulin. Rationale for antibody-based induction therapy It provides rapid and profound early immunos uppression when acute rejection is most common. In kidneys with a high risk of delayed graf t function (long cold ischemia time, nonheart-beating donors etc.) it allows a delay to the introduction of CNIs (or use of reduced dose) when avoiding nephrotoxicity is particularly desirable. Campath-1H may provide suf \201 cient additional immuno- suppression to permit corticosteroid minimization or avoidance. ATG induction or anti-CD25 induction? ATG induction has not been routinely adopted in UK co m- pared with extensive use in the USA. ATG use is associated with an increased incidence o f opportunistic infections and PTLD. Licensing studies of anti-CD25 induction showed a sign i \201 - cant reduction in acute rejection rates with no increase in opportunistic infecti ons or apparent adverse events com- pared with placebo. A RCT of ATG (n = 141) versus basil iximab (n = 137) induction in patients at high risk of acute rejection or delayed graft fun ction treated with CsA, MMF and pred- nisolone, showed a lower incidence of acute rejection in the ATG group (15.6% vs 25.5% P = 0.02). There was a similar incidence of delayed graft function as well as graft loss and death at 1 year. The incidence of serious adverse effec ts was similar between groups (3 PTLD in ATG vs 0 in basiliximab); there was a greater inci dence of infection with ATG but a lower incidence of CMV disease. prolongation of delayed graft function; painful mouth ulcers; hyperlipidemia; bone marrow s uppression; thrombotic microangiopathy; pneumonitis; rash. It also has antiangiogenic effects (inhibits VEGF) and has been used successfully in the ma nagement of Kaposi \200\231s sar- coma when substituted for a CNI. It may also inhibit othe r tumors. Clinical use of immunosuppressant agents Immunosuppressive regimens Conventional regimens T hese consist of: \200 \200 \200 Which calcineurin inhibitor? Trials of head-to-head comparisons have been confounded by ina dequate power and variable dosing regimens. A large meta-analysis of 30 trials demonstrated a signi \201 - cant reduction in graft loss at 6 months in tacrolimus- treated recipients that persisted up to 3 years. calcineurin inhibitor; corticosteroids; antiproliferative agent. C. DUDLEY 564 At 1 year, tacrolimus treated patients had: \200 \200 \200 late rejection (>1 year post transplant) in the Campath-1H group. less acute rejection (RR 0.69); less steroid-resistant rejection (RR 0.49); more insulin-de pendent diabetes mellitus (RR 1.86), tremor and headaches. Further reading Ahsan N, Hricik D, et al. Prednisone withdrawal in kidney transplant recipi ents on cyclosporine and mycophenolate mofetil \200\223 a pro- spective randomized study. Steroid Withdrawal Study Group. Transplantation 1999; 68: 1865 \200\2231874. Ciclosporin-treated patients had more cosmetic side- effects and constipation. There was no difference in incidence of infection or malignancy. In a recent large RCT (ELITE \200\223S ymphony Study n = 1645), low risk patients were randomized to one of four immunosup- pressi ve regimens. Patients receiving a low dose tacrolimus regimen (daclizumab induction, MMF an d corticosteroids) had a signi \201 cantly better 12 month calculated GFR than regimens ba sed on CsA (standard dose CsA, MMF and corti- costeroids or daclizumab induction, low dose CsA, MMF and corticosteroids). Choice of CNI should also be in \202 uenced by patient char ac- teristics: \200 Borrows R, Loucaidou M, et al. Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. Am J Transplant 2004; 4: 1845 \200\2231851. Brennan DC, Daller JA, et al. Rabbit antithymocyte globulin versus Basiliximab in renal tra nsplantation. N Engl J Med 2006; 355: 1967 \200\2231977. Ekberg HE, Tedesco-Siva H, et al. Reduced exposure to calcineurin inhibitors in renal trans plantation. N Engl J Med 2007; 357: 2562 \200\223 2575. Vanrenterghem Y, Lebranchu Y, et al. Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft reject ion. Transplantation 2000; 70: 1352 \200\2231359. Vincenti F, Larsen C, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353: 770 \200\223781. use tacrolimus in a dark-haired young female (avoid hypertrichosis and gum hyperplasia); us e CsA in overweight patients with glucose intolerance (attempt to prevent development of NO DAT). Vincenti F, Schena FP, et al. A randomized multicenter study of ster- oid avoidance, early steroid withdrawal, or standard steroid therapy in kidney transplant recipients. Am J Trans plant 2008; 8: 307 \200\223316. Watson CJ, Bradley JA, et al. Alemtuzumab (CAMPATH 1H) induc- tion therapy in cadaveric kid ney transplantation \200\223 ef \201 cacy and safety at \201 ve years. Am J Transplant 2005; 5: 1347 \200\2231353. Corticosteroid withdrawal, minimization and avoidance The side-effects and morbidity associ ated with cortico- steroid use has led to adoption of regimens that have avoided, minimized or withdrawn their use. In 2004, 23% of US patients were discharged on steroid- free maint enance regimens. Double-blind RCTs of corticosteroid withdrawal at 3 and 4 months in low ri sk patients maintained on CsA and MMF were discontinued because of an increased incidence o f acute rejection in the withdrawal group (30.8 vs 9.8% and 20% vs 5% respectively). An RCT of steroid avoidance, early steroid withdrawal (after day 7) or standard steroid therapy w ith basiliximab induction, CsA and MPS failed to demonstrate noninferi- ority in GFR at 12 months in the steroid avoidance or withdrawal groups compared with standard therapy. The in cidence of acute rejection at 12 months was 36%, 29.6% and 19.3% in the avoidance, withdraw al and standard groups respectively. Uncontrolled single center studies have demonstrated t hat steroid minimization regimens (used for \201 rst 7 days only) with tacrolimus and MMF are associated with excellent outcomes. However, in an ongoing unpublished double-blind st udy by the Astellas Steroid Withdrawal Group, steroid minimiza- tion (used for \201 rst 7 days only) was associated with more clinical rejection and a signi \201 cantly increased incidence of chronic allograft nephropathy at 4 years compared with maintenance therapy. Ba seline immunosuppression was with ATG/anti-CD25 induction, tacrolimus and MMF. In a 5 year follow-up study, low dose CsA monotherapy following Campath-1H induction demonstrated simil ar patient and graft survival and acute rejection rates as a retrospective contemporaneous group treated with CsA, azathioprine and prednisolone. More patients experienced Webster AC, Woodroffe RC, et al. Tacrolimus versus ciclosporin as primary imunnunosuppressi on for kidney transplant recipients; meta-analysis and meta-regression of randomized trial data. Br Med J 2005; 331: 810 \200\223820. Internet resources Renal transplantation \200\223 immunosuppressive regimens (adults). NIC E Technology Appraisal 85: http://www.nice.org.uk/guidance/index. jsp?action=byID&o=11544 Renal transplantation \200 \223 immunosuppressive regimens for children and adolescents. NICE Technology Appraisal 99: http://www.nice.org.uk/guidance/index. jsp?action=byID&o=11576 British Transplantation Soci ety Guidelines: http://www.bts.org.uk/standards.htm Eurotransplant: http://www.transplant.org/ ANZDATA Australia and New Zealand Dialysis and Transplant Regist ry: http://www.anzdata.org.au/ANZOD United States Transplant Registry: http://www.ustransplant.org See also Selection and preparation of recipients, p. 544 Long-term medical complications of renal transplantation, p. 566 Drug-induced nephropathies, p. 698 This page intentionally left blank C. DUDLEY 566 Long-term medical complications of renal transplantation Introduction For most patients, renal transplantation is the best form of renal replacement therapy. However, it does not provide a cure and is itself associated with a number of med ical complications. In this section, long-term medical compli- cations are those developing more than one year after transplantation. Long-term medical complications arise as a resul t of: Chronic drug therapy: \200 Viral infections Human herpes virus (HHV) HHV 1, herpes simplex virus 1 \200 cold sores. HHV 2, herpes simplex virus 2 \200 genital herpes. HHV 3, varicella zoster virus \200 \200 chicken pox; shingles. e.g. osteoporosis associated with corticosteroid use. HHV 4, Epstein \200\223Barr virus (EBV) \200 Nonspeci \201 c consequences of immunosuppression: \200 \200 \200 post-transplant lymphoproliferative disease (PTLD). opportunistic infections; conventional infections; malignancy. HHV 5, cytomegalovirus (CMV) \200 retinitis or colitis (late infections). HHV 8, Kaposi \200\231s sarcoma virus \200 Chronic kidney disease: \200 Kaposi \200\231s sarcoma. all renal transplant patients should be considered to have chronic kidney disease; the suf \201 x T should be appended to the CKD classi \201 cation (e.g. CKD stage 3T); CKD may be stable but associated with all the complica- tions of CKD (e.g. anemia, renal bone disease ); CKD can be progressive \200\223 chronic allograft dysfunction (CAD). Polyoma viruses BK virus \200 BK virus (BKV) nephropathy. JC virus \200 progressive multifocal leukoencephalopathy. Human papilloma virus (HPV) Squamous cell carcinoma of the: \200 \200 \200 \200 Accelerated cardiovascular disease. It is most convenient to consider long-term medical com plications under the following headings: \200 \200 \200 \200 \200 \200 skin; vulva; anus cervix. Infection Malignancy Chronic allograft dysfunction Cardiovascular disease Chronic kidney di sease Bone disease. Parvovirus B19 Anemia. HTLV 1 Tropical spastic paraparesis. T-cell leukemia/lymphoma. Infection This is an important cause of death in kidney transplant recipients (18% in the A ssessment of Lescol in Renal Transplant [ALERT] study, 2005). It is an inevitable consequen ce of nonspeci \201 c immunosup- pression. Specific infections occur at different time-poi nts after transplantation. Opportunistic infections are more likely in the early post- tran splant period because this is the time of greatest immu- nosuppression and the infection ma y be transmitted by the donor. Most patients in the late post-transplant period have stable graft function and are maintained on minimal immunosup- pressive therapy. The infections e xperienced by these patients are similar to those in the general population. However, some opportunistic infections may persist into the late transplant period or arise at any time t hat immunosuppression is increased, particularly in the absence of the chemoprophylaxis use d in the early post- transplant period (e.g. trimethoprim-sulfamethoxazole, antiviral agent s). 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 