Immunosuppression In Renal Transplant Recipients Research Articles

Sirolimus in Renal Transplantation: Analysis of Safety and Efficacy in a Nonprotocol Conversion Group

BackgroundConversion to sirolimus (SRL)-based immunosuppression in renal transplant recipients is an alternative for chronic allograft dysfunction (CAD), cancer and viral infections. We sought to analyze the indications for and safety and efficacy of conversion to SRL among renal transplant patients. Methods/MaterialsWe examined a retrospective cohort, using medical records of renal transplant recipients >18 years old who had their immunosuppressive regimen converted to a SRL-based treatment. Data analysis included the indication for conversion, time posttransplant, as well as urine protein and serum creatinine at conversion and 6 months thereafter. The end points included death, graft loss and/or discontinuation of SRL. ResultsWe included 112 patients in this series who had indications for conversion: fungal, polyomavirus, or cytomegalovirus infection (n = 32), CAD (n = 30), cancer (n = 21), immunologic (n = 3), and other reasons (n = 26). Changes in immunosuppression were performed at 41 ± 57 months posttransplant or later in cancer patients. SRL was discontinued in 9 patients owing to adverse events such as edema, proteinuria, mucositis, or pneumonitis. Graft loss was observed in 19 patients, and death in 6. In 87 patients with functioning grafts, protein/creatinine ratios increased from 0.28 ± 0.03 (conversion) to 0.63 ± 0.09 (after 6 months; P < .001). Serum creatinine decreased from 2.24 ± 0.13 (conversion) to 1.89 ± 0.75 mg/dL (after 6 months; P < .001). Graft survival was 88% at 1 and 80% at 3 years after conversion. ConclusionIn, SRL was well tolerated; conversion to SRL improved graft function with a slight increase in proteinuria.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.

Full Dose Cyclosporine Versus Low Dose Takrolimus as Maintenance Immunosuppression in Renal Transplant Recipients with Posttransplant Diabetes Mellitus

Full Dose Cyclosporine Versus Low Dose Takrolimus as Maintenance Immunosuppression in Renal Transplant Recipients with Posttransplant Diabetes Mellitus

Belatacept Post Kidney Transplantation

Objective: To review the use of belatacept as an alternative to calcineurin inhibitor-based regimens for maintenance immunosuppression in renal transplant recipients. Data Sources: To provide an extensive overview of the pharmacology, pharmacokinetics, efficacy, and safety of belatacept, a MEDLINE/PubMed search (1980–December 2011) was performed for all articles evaluating belatacept's properties and patient outcomes, as well as abstracts from recent meetings, using key words belatacept, pharmacology, efficacy, pharmacokinetics, and safety. Study Selection/Data Extraction: Phase 2 and 3 studies in humans describing use, adverse reactions, pharmacology, pharmacokinetics, efficacy, and safety of belatacept were identified and reviewed. Other articles were identified through PubMed. Data Synthesis: Belatacept, a costimulation blocker, is a biologic recombinant fusion protein that has been shown to prevent acute cellular rejection in kidney transplant recipients and preserve renal function. It was recently approved by the FDA as an antirejection immunosuppressant agent for use in kidney transplant recipients. It is the first biologic agent used for maintenance immunosuppression. It acts as an antagonist to CD80 and CD86 receptors located on the surface of antigen presenting cells, thereby blocking CD28 T-cell activation and, thus, preventing acute rejection. In comparison with patients receiving other current therapies, patients on belatacept have demonstrated superior renal function with comparable outcomes in patient and graft survival. Conclusions: Belatacept has potential for use as an alternative to current maintenance immunosuppression regimens, with potentially fewer adverse effects.

Belatacept-versus Cyclosporine-Based Immunosuppression in Renal Transplant Recipients with Pre-existing Diabetes

Renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. To assess the effect of belatacept in this high-risk group, we evaluated outcomes of the subpopulation with PD from previously published BENEFIT and BENEFIT-EXT trials. A post hoc analysis evaluated pooled data from BENEFIT (living donors or standard criteria donors) and BENEFIT-EXT (extended criteria donors). Patients were randomized to receive cyclosporine or a more intensive (MI) or less intensive (LI) belatacept regimen. Of 1209 intent-to-treat patients, 336 had PD. At 12 months, the belatacept LI arm demonstrated a numerically higher rate of patients surviving with a functioning graft (90.4% MI [103 of 114], 92.8% LI [90 of 97], and 80.8% cyclosporine [101 of 125]), and fewer serious adverse events than cyclosporine or MI patients. Three cases of posttransplant lymphoproliferative disorder were reported in LI patients, one involving the central nervous system. Higher rates (% [95% confidence interval]: 22.8% MI [15.1 to 30.5]; 20.6% LI [12.6 to 28.7]; 14.4% cyclosporine (8.2 to 20.6]) and grades of acute rejection were observed with belatacept. Measured GFR (ml/min per 1.73 m(2), 59.8 MI; 62.5 LI; 45.4 cyclosporine), and cardiovascular risk profile were better for belatacept versus cyclosporine. In post hoc analysis of patients with PD, patient/graft survival and renal function at 12 months were numerically higher with belatacept versus cyclosporine, but not statistically significant. Further study is necessary to confirm the benefits belatacept may provide in these patients.

Single Time Point Immune Function Assay (ImmuKnowTM) Testing Does Not Aid in the Prediction of Future Opportunistic Infections or Acute Rejection

Current assays and tests that are used to determine the degree of immunosuppression in renal transplant recipients are suboptimal. The ImmuKnow assay (Cylex), a measure of intracellular CD4+ T cell ATP release proposed as a means to quantify cell-mediated immunity in transplant recipients, could be considered as a potential tool to identify patients at risk for opportunistic infections (OI) or acute rejection (AR). We retrospectively analyzed 1330 ImmuKnow assay values in 583 renal transplant recipients at a single center from 2004 to 2009 and correlated these values with episodes of OI and AR in the subsequent 90 days. Assay values were compared with a control population matched for age, gender, and time post-transplantation. In patients with OI (n=94), there were no differences in prior mean assay values compared with matched controls (386 versus 417 ng/ml, P=0.24). In 47 patients with AR, again no differences were detected in prior assay results (390 versus 432 ng/ml, P=0.25) when compared with controls. "Low" values (≤225 ng/ml) lacked sensitivity and specificity as a predictive test for subsequent OI, as did "strong" (≥525 ng/ml) values as a predictive test for subsequent AR. Our results fail to show an association between single time point ImmuKnow assay values and the subsequent development of an adverse event in the subsequent 90 days. The optimal use of the ImmuKnow assay in kidney transplantation has yet to be determined.

Switch to a Sirolimus‐Based Immunosuppression in Long‐Term Renal Transplant Recipients: Reduced Rate of (Pre‐)Malignancies and Nonmelanoma Skin Cancer in a Prospective, Randomized, Assessor‐Blinded, Controlled Clinical Trial

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Gene Expression of P-glycoprotein and Cytochrome P450 3A4 in Peripheral Blood Mononuclear Cells and Correlation With Expression in Liver

Long-term immunosuppression in renal transplant recipients generally includes calcineurin inhibitors (CNIs), which demonstrate marked interindividual diversity and a narrow therapeutic range. In the clinical setting, it is important to reach therapeutic drug concentrations to prevent allograft rejection. The same immunosuppressant dosage leads to different drug concentrations. Therefore, we investigated factors that influence the metabolism of immunosuppressant agents. The CNIs are substrates of cytochrome P450 (CYP450) and P-glycoprotein. The CYP450 3A genotype significantly influences CNI concentration. Differences in expression of these proteins may explain interindividual pharmacokinetic variations. However, it is risky and impractical to obtain specimens from the liver in renal transplant recipients. Therefore, we investigated the correlation of gene expression between peripheral blood mononuclear cells (PBMCs) and liver parenchyma. We observed that the correlation of relative P-glycoprotein gene expression between PBMCs and liver is not significant (r2 = 0.03; P = .65). In addition, the correlation of CYP450 3A4 gene expression between PBMCs and liver is not strong (r2 = 0.23; P = .42). The expression level of CYP450 3A5 is too low to be detected in the sample from PBMCs.

Posttransplantation Hypomagnesemia and Its Relation with Immunosuppression as Predictors of New-Onset Diabetes after Transplantation

New-onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients. We conducted a retrospective single-center analysis (2002-2008) in order to assess NODAT the first year posttransplantation as defined by American Diabetes Association criteria. Serum magnesium (Mg) levels were defined as the median of all Mg levels registered during the first month posttransplantation. Patients with NODAT (N = 75; 29.5%) versus non-NODAT had lower Mg levels (p < 0.001). Patients with an Mg level < versus > or = 1.9 mg/dL showed a faster development of NODAT (log-rank p < 0.001). Mg levels were lower in patients on calcineurin inhibitors (CNI) versus no CNI patients (p < 0.001). Mg levels, albumin, BMI, triglycerides, posttransplantation hyperglycemia, tacrolimus levels and the use of sirolimus were predictors of NODAT in the multivariate analysis. Hypomagnesemia was an independent predictor of NODAT in renal transplant recipients. We confirm that the use of CNI is associated with NODAT, but, to a large extent, this effect seems attributable to the induction of hypomagnesemia. After adjustment for Mg, sirolimus was also associated with NODAT.

Influence of genetic polymorphisms in GSTM1, GSTM3, GSTT1 and GSTP1 on allograft outcome in renal transplant recipients

Glutathione S-transferases (GSTs) are important in protection against xenobiotic compounds and toxicity caused by immunosuppressants in renal transplant recipients. In the present study we hypothesize that genetic variability in GSTM1, GSTM3, GSTP1 and GSTT1 genes may be associated with allograft outcome. The study included 223 controls and 273 transplant recipients categorized into 184 stable graft function (SGF), 57 rejection episodes (RE) and 32 delayed graft function (DGF). The polymorphism was studied using multiplex PCR and PCR-RFLP. GSTM1 null genotype showed a 3.35-fold higher risk for rejection in SGF vs. RE category [95% confidence interval (CI) 1.27-8.84, p = 0.014]. Mutant (G) allele of GSTP1 was associated with a 5.52-fold risk for DGF (95% CI 1.37-22.17, p = 0.016). Kaplan-Meier analysis revealed significantly lower mean time to first RE in null genotype as compared with GSTM1 present patients (Log p = 0.002). The dose adjusted C(2) levels in null genotype was higher as compared with GSTM1 present patients at one (p = 0.007) and three months (p = 0.027) post transplantation. Patients with variant genotype of GSTM1 and GSTP1 were at higher risk for rejection and delayed functioning of the allograft, respectively, supporting the hypothesis for involvement of GST isoform variants in allograft outcome in renal transplant recipients.

Skin lesions in renal transplant recipients: A single center analysis

The chronic use of immunosuppressants in renal transplant recipients (RTRs) predisposes them to a variety of skin manifestations. Studies on skin lesions in RTRs from India have been limited. To study the prevalence and clinical spectrum of skin diseases in RTR in patients attending the Nephrology clinic of a tertiary care hospital in South India. Between October 2002 and June 2003, 365 RTRs were evaluated for skin lesions, including 280 examined after renal transplant (group A) and 85 examined once before and then monthly after transplant for a period of 6 months (group B). A total of 1163 skin lesions were examined in 346 RTRs (94.7%) including lesions of aesthetic interest (LAI) [62.3%] followed by infections [27.3%]. All LAI were drug-related manifestations, making it the most common skin lesion, while fungal (58.7%) and viral (29.3%) infections constituted majority of lesions caused by infection. Lesions related to neoplasms were relatively uncommon (2.1%) and all lesions were benign. Miscellaneous lesions constituted 8.3% of skin lesions, which included vaccine-induced necrobiotic granulomas at the site of Hepatitis B vaccination and acquired perforating dermatoses. Skin lesions among RTRs from India consist predominantly of drug-related LAI and infections and are different from the West in view of the paucity of neoplastic lesions.

Ciclosporin A Tapering Monitored by NFAT-Regulated Gene Expression: A New Concept of Individual Immunosuppression

The impact of long-term immunosuppression in renal transplant recipients with respect to safety and efficacy remains undetermined. Pharmacodynamic monitoring of the relative reduction of T-cell-specific gene expression in renal transplant recipients treated with cyclosporine A (CsA) was applied in this study. During the study, 20 stable renal transplant recipients with tapered CsA dose and 20 patients with stable CsA dose (matched for age, gender, CsA dose, time after transplantation) were compared for a median period of 18 months (range 6-44). CsA dose was tapered in two stages of 15% each, and the expression of the nuclear factor of activated T cells (NFAT)-regulated genes was determined by reverse-transcription polymerase chain reaction method at CsA trough level and 2 hr after oral uptake. The initial residual gene expression at 2 hr after CsA intake increased from 6.31% (range 1.30-16.6) to 21.3% (range 6.58-31.8) in patients with CsA dosage reduction. In one patient, the residual gene expression increased more than 40% and resulted in a reversible Banff 1A rejection episode. Blood pressure was significantly lower after CsA dosage reduction (P<0.05). In the pair-matched control group NFAT-regulated gene expression was comparable before and after the follow-up period (7.45% [range 0.21-18.3] vs. 5.87% [range 0.66-13.2]; P=NS). Estimated glomerular filtration rate was significantly worse in the control group (P<0.05). Our observation suggests that the measurement of the relative gene expression in CsA-treated patients is a promising tool to monitor the CsA dosage reduction in long-term renal transplant patients. An increase in residual expression of NFAT-regulated gene expression may result in an acute rejection episode.

Rupture of an Infected Liver Cyst Into the Pericardium in a Kidney Transplant Recipient With Polycystic Kidney Disease

Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease. Hepatic cysts often are multiple, and in renal transplant recipients, occult infection with or without concurrent kidney cyst infection is a frequent cause of abdominal pain and fever and may require long-term antibiotic use and hospitalization. Rupture and bleeding of hepatic cysts into the peritoneum or viscera are infrequent complications that have been reported. Identification of a single culprit lesion that could be targeted for surgical intervention often is difficult because such imaging studies as computed tomographic scans, magnetic resonance images, or radionuclide-tagged white cell scans often show several inflamed cysts that can persist over several subsequent scans. Treatment may require surgical intervention. Eradication of infection and wound healing also is made difficult by concomitant immunosuppression in renal transplant recipients. We present the case of a renal transplant recipient with an infected dominant polycystic liver cyst that ruptured into the pericardium, leading to tamponade.

A Randomized, Prospective, Pharmacoeconomic Trial of Tacrolimus versus Cyclosporine in Combination with Thymoglobulin in Renal Transplant Recipients

To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA). When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.

Safety Analysis After Tacrolimus Immunosuppression in Renal Transplant Recipients in Japan: 5-Year Results in >1500 Patients

Tacrolimus was approved in Japan in April 1996 for the prevention of allograft rejection in patients receiving kidney transplants. There has been a concern that immunosuppressive therapy may be associated with cardiovascular and metabolic complications, including hyperlipidemia, hypertension, and posttransplant diabetes mellitus. A multicenter (59 institutions) study was conducted in Japan in patients who underwent renal transplantation and received tacrolimus immunosuppression. Patients were followed for >5 years, from April 1996 to December 2002. Of the 1569 patients enrolled, 1542 were evaluated. In this analysis, graft survival rate and medication usage patterns of antihyperlipidemics, antihypertensives, insulin, and oral hypoglycemics were observed for >5 years in patients receiving tacrolimus immunosuppression. The graft survival rates of patients requiring antihyperlipidemic therapy and experiencing acute rejection were significantly lower compared with all other patients ( P < .05). The risk of graft rejection was significantly greater in patients with cardiovascular complications requiring antihyperlipidemics or antihypertensives. Graft survival was significantly lower in patients with acute rejection and antihyperlipidemic therapy than in other patients.

Steroid Withdrawal or Steroid Avoidance in Renal Transplant Recipients: Focus on Tacrolimus-Based Immunosuppressive Regimens

Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.

Tuberculosis in renal transplant recipients on various immunosuppressive regimens

Mycophenolate mofetil (MMF) and tacrolimus (TAC) are more potent than conventional immunosuppressive drugs, i.e. azathioprine, cyclosporin and prednisolone, and may be associated with an increase in the incidence of infections in the post-transplantation (post-tx) period. The aim of this study was to determine if the use of either or both of MMF and TAC for immunosuppression in renal transplant recipients increases the prevalence or modifies the clinical presentation of tuberculosis (TB), when compared with conventional therapy. The medical records of 443 adult patients who received a kidney transplant between 1994 and 2002 were reviewed retrospectively. Comparisons were made between patients who had conventional immunosuppressive treatments (cyclosporin, azathioprine and prednisolone) or an alternative regimen (including MMF, TAC or both). We found 20 patients (4.5%) to have post-tx TB. There were 13 cases of TB (age 38.9+/-10.6 years) among 328 patients who received conventional immunosuppressants (group I) (4.0%) and seven cases (age 24.2+/-7.4 years) among 115 (6.1%) who received an alternative immunosuppressive regimen (group II) (P>0.05). The patients in group II were younger than the patients in group I (P = 0.002). A significantly higher number of patients in group II developed TB within the first 6 months post-tx (P = 0.042). However, there was no significant difference between the two groups regarding clinical and radiographic presentations or outcomes. Immunosuppression with TAC or MMF is associated with the development of TB earlier in the post-tx period and in younger patients.

Modifiable risk factors for non-adherence to immunosuppressants in renal transplant recipients: a cross-sectional study.

Non-adherence to immunosuppressants is a major cause of renal transplant failure. Interventions to improve adherence need to target modifiable risk factors. Adherence was measured using the 'gold standard' measure of electronic monitoring in 58 adult renal transplant recipients from a UK transplant unit. Subjects were identified from a stratified random sample of 153 recipients recruited to a larger cross-sectional study comparing different measures of adherence. Inclusion criteria included age over 18 years and a functioning renal transplant, transplanted 6-63 months previously. Exclusion criteria included residence outside the region served by the unit and inability to give informed consent. Health beliefs, depression and functional status were measured using standardized questionnaires (Beliefs about Medicines Questionnaire, Illness Perception Questionnaire, Revised Clinical Interview Schedule and SF-36) and semi-structured interview. Transplant and demographic details were collected from the notes. Seven [12%, 95% confidence interval (CI) 4-20%] subjects missed at least 20% of days medication and 15 (26%, 15-37%) missed at least 10% of days. Lower belief in the need for medication and having a transplant from a live donor were the major factors associated with non-adherence. Depression was common, although not strongly associated with non-adherence. Beliefs about medication are a promising target for interventions designed to improve adherence. The lower adherence in recipients of transplants from live donors needs confirming but may be clinically important in light of the drive to increase live donation.

Risk of malignancy with long-term immunosuppression in renal transplant recipients

Improvements in immunosuppressive regimens have significantly enhanced patient and graft survival in renal transplant recipients. However, susceptibility to neoplastic disorders is increased as a consequence of prolonged immunosuppression. Available data pertaining to cancer risks in renal transplant recipients have been inconsistent, and much of it is derived from international studies, which may not be truly representative of the United States population. We studied a total of 1979 transplants performed in 1739 patients from a single center in the United States with a mean follow-up of 6.1 years, and a total of 9852 person-years' follow-up. The mean age at the time of diagnosis of cancer was 50 years, and the mean interval between transplant and diagnosis of cancer was 95 months. Older patients receiving a transplant had a significantly higher risk for developing cancer as opposed to younger patients (RR 6.2 for >60 years compared with <40 years). When compared with the general population using data from the Surveillance, Epidemiology and End Results (SEER) registry, the overall risk for nonskin malignancies was modestly increased in our transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P= 0.01). When stratified by age groups, younger age at transplant (<40 years) had the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10 years had an SIR of 2.4 (P < 0.001). We believe that this study is representative of the United States' renal transplant population, and highlights the need for reduced immunosuppression in the long-term and increased vigilance for cancers in younger patients receiving renal transplantation.

Nonimmunologic complications of kidney transplantation

•Lymphoceles may be more common in patients treated with target of rapamycin (TOR) inhibitors •Urine leaks (1% to 3% incidence)•Ureteral obstruction (strictures, ureteral rejection, BK polyoma infection) •Bleeding•Thrombosis (1% to 2% incidence)•Mycotic aneurysms•Late arterial stenosis •Caused by surgery or trauma 1.Valente JF, Schulak JA: Surgical considerations in kidney transplantation, in Hricik DE (ed): Kidney Transplantation: State of the Art. London, UK, Remedica Publishing, 2003, pp 79–962.Langer RM, Kahan BD: Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 74:804–808, 2002 •Most common cause of mortality (40% to 50%) after kidney transplantation •Hypertension (≥60% prevalence)•Hyperlipidemia (≥60% prevalence, severity influenced by type of immunosuppression)•Diabetes mellitus/glucose intolerance ▪Worsening glycemic control in previous diabetics▪New-onset diabetes mellitus in 10% of patients (with wide variations depending on risk factors: advanced age, African-American or Hispanic ethnicity, type of immunosuppression)•Smoking•Obesity •Anemia•Role of impaired renal function•Proteinuria•Hyperhomocysteinemia 1.Kasiske BL: Epidemiology of cardiovascular disease after kidney transplantation. Transplantation 72:S5-S8, 2001 (suppl 6)2.Woodward RS, Schnitzler MA, Baty J, et al: Incidence and cost of new onset diabetes mellitus among U.S. waitlisted and transplanted renal allograft recipients. Am J Transplant 3:590–598, 20033.Meier-Kriesch HU, Arndorfer JA, Kaplan B: The impact of body mass index on renal transplant outcomes: A significant independent risk factor for graft failure and patient death. Transplantation 73:70–74, 20024.Djamali A, Becker YT, Simmons WD, Johnson CA, Premasathian N, Becker BN: Increasing hematocrit reduces early posttransplant cardiovascular risk in diabetic transplant recipients. Transplantation 76:816–820, 20035.Meier-Kriesch HU, Baliga R, Kaplan B: Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 75:1291–1295, 2003 •Herpes viruses: ▪Cytomegalovirus ○Prophylaxis and treatment regimens▪Herpes simplex ○Herpes zoster•Hepatitis B and C•Emerging viruses: ▪BK polyoma, Parvovirus, West Nile virus •Prophylaxis and treatment regimens 1.Rubin R: Temporal aspects of transplant infectious disease. Transpl Infect Dis 5:63–64, 20032.Fishman J: Prevention of CMV in transplant patients. Transpl Infect Dis 1:35–39, 1999 (suppl 1)3.Myonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman J: BK virus in solid organ transplantation: An emerging syndrome. Transplantation 72:1587–1592, 20014.Fishman J, Rubin RH, Koziel MJ, Periera BJ: Hepatitis C virus and organ transplantation. Transplantation 62:147–154, 1996 •Incidence varies widely from center to center•Immune and nonimmune mechanisms •Immune causes (cellular versus humoral acute rejection)•Nonimmune causes: ▪Prerenal azotemia▪Calcineurin inhibitor nephrotoxicity▪Obstructive uropathy▪Hemolytic uremic syndrome (secondary to calcineurin inhibitors)▪Vascular obstruction •Chronic allograft nephropathy ▪Immune mechanisms (role of humoral immunity and indirect allopeptide recognition)▪Nonimmune mechanisms (drug nephrotoxicity, effects of hypertension and hyperlipidemia, ischemia-reperfusion injury, viral infection)•Recurrence of native kidney disease•De novo kidney disease (eg, membranous nephropathy, diabetic nephropathy) 1.Burdmann EA, Andoh TF, Yu L, Bennett WM: Cyclosporine nephrotoxicity. Semin Nephrol 23:465–476, 20032.Waaga AM, Gasser M, Laskowski I, Tilney NL: Mechanisms of chronic rejection. Curr Opin Immunol 12:517–521, 20003.Ramos EL, Tisher CC: Recurrent diseases in the kidney transplant. Am J Kidney Dis 24:142–154, 1994 Neoplastic disorders occurring with higher frequency than in the general population •Role of Epstein-Barr virus •Increased incidence with time posttransplantation•Relatively high ratio of squamous to basal cell carcinoma •Cervical and vulvar carcinoma•Kaposi’s sarcoma Influence of Immunosuppressive Drugs on the Metastatic Potential of Solid Tumors 1.Penn I: Cancers in renal transplant recipients. Adv Ren Replace Ther 7:147–156, 20002.Dampanich E, Kasiske BL: Risk factors for cancer in renal transplant recipients. Transplantation 68:1859–1864, 1999 •High fracture incidence after transplantation ▪Underlying renal osteodystrophy▪Persistent hyperparathyroidism▪Hypogonadism▪Drug-induced osteopenia (corticosteroids, calcineurin inhibitors) Aseptic Necrosis 1.Shane E, Epstein S: Transplantation osteoporosis. Transplant Rev 15:11–32, 2001 •Pharmacokinetic or pharmacodynamic •Antiproliferative agents •Cushingoid features with corticosteroids, hirsutism and gingival hyperplasia with cyclosporine, alopecia with tacrolimus and antiproliferative agents •Corticosteroid-induced acne and ecchymoses •Corticosteroids, antiproliferative agents •Hyperkalemia, hypomagnesemia associated with calcineurin inhibitors; sodium retention associated with corticosteroids and calcineurin inhibitors •Calcineurin inhibitors 1.Danovitch GM: Immunosuppressive medications and protocols for kidney transplantation, in Danovitch GM (ed): Handbook of Kidney Transplantation. (ed 3). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 62–110