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Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

The medical needs of the transgender population are increasingly recognized within the US health care system. Hormone therapy and gender-affirming surgery present distinct anatomic, hormonal, infectious, and psychosocial issues among transgender kidney transplant donors and recipients. We present the first reported experience with kidney transplantation and donation in transgender patients. A single-center case series (January 2014-December 2018) comprising 4 transgender kidney transplant recipients and 2 transgender living donors was constructed and analyzed. Experts in transplant surgery, transplant psychiatry, transplant infectious disease, pharmacy, and endocrinology were consulted to discuss aspects of care for these patients. Four transgender patients identified as male-to-female and 2 as female-to-male. Three of 6 had gender-affirming surgeries prior to transplant surgery, 1 of whom had further procedures posttransplant. Additionally, 4 patients were on hormone therapy. All 6 had psychiatric comorbidities. The 4 grafts have done well, with an average serum creatinine of 1.45 mg/dL at 2 years (range 1.01-1.85 mg/dL). However, patients encountered various postoperative complications, 1 of which was attributable to modified anatomy. Thus, transgender kidney transplant patients can present novel challenges in regard to surgical considerations as well as pre- and posttransplant care. Dedicated expertise is needed to optimize outcomes for this population.

Background Organs from hepatitis C virus (HCV)-infected deceased donors are often discarded. Preliminary data from 2 small trials, including THINKER-1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), suggested that HCV-infected kidneys could be safely transplanted into HCV-negative patients. However, intermediate-term data on quality of life and renal function are needed to counsel patients about risk. Objective To describe 12-month HCV treatment outcomes, estimated glomerular filtration rate (eGFR), and quality of life for the 10 kidney recipients in THINKER-1 and 6-month data on 10 additional recipients. Design Open-label, nonrandomized trial. (ClinicalTrials.gov: NCT02743897). Setting Single center. Participants 20 HCV-negative transplant candidates. Intervention Participants underwent transplant with kidneys infected with genotype 1 HCV and received elbasvir-grazoprevir on posttransplant day 3. Measurements The primary outcome was HCV cure. Exploratory outcomes included 1) RAND-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) quality-of-life scores at enrollment and after transplant, and 2) posttransplant renal function, which was compared in a 1:5 matched sample with recipients of HCV-negative kidneys. Results The mean age of THINKER participants was 56.3 years (SD, 6.7), 70% were male, and 40% were black. All 20 participants achieved HCV cure. Hepatic and renal complications were transient or were successfully managed. Mean PCS and MCS quality-of-life scores decreased at 4 weeks; PCS scores then increased above pretransplant values, whereas MCS scores returned to baseline values. Estimated GFRs were similar between THINKER participants and matched recipients of HCV-negative kidneys at 6 months (median, 67.5 vs. 66.2 mL/min/1.73 m2; 95% CI for between-group difference, -4.2 to 7.5 mL/min/1.73 m2) and 12 months (median, 72.8 vs. 67.2 mL/min/1.73 m2; CI for between-group difference, -7.2 to 9.8 mL/min/1.73 m2). Limitation Small trial. Conclusion Twenty HCV-negative recipients of HCV-infected kidneys experienced HCV cure, good quality of life, and excellent renal function. Kidneys from HCV-infected donors may be a valuable transplant resource. Primary funding source Merck.

Dietary supplement use is high among US adults, with the intention by users to promote overall health and wellness. Kidney donors, who are selected based on their overall good health and wellness, can have high utilization rates of dietary supplements. We provide a framework for the evaluation of living kidney donors and use of dietary supplements. In this review, dietary supplements will include any orally administered dietary or complementary nutritional products, but excluding micronutrients (vitamins and minerals), food, and cannabis. Use of dietary supplements can influence metabolic parameters that mask future risk for chronic illness such as diabetes and hypertension. Dietary supplements can also alter bleeding risk, anesthesia and analgesic efficacy, and safety in a perioperative period. Finally, postdonation monitoring of kidney function and risk for supplement-related nephrotoxicity should be part of a kidney donor educational process. For practitioners evaluating a potential kidney donor, we provide a list of the most commonly used herbal supplements and the effects on evaluation in a predonation, perioperative donation, and postoperative donation phase. Finally, we provide recommendations for best practices for integration into a comprehensive care plan for kidney donors during all stages of evaluation. We recommend avoidance of dietary supplements in a kidney donor population, although there is a paucity of data that identifies true harm. Rather, associations, known mechanisms of action, and common sense suggest that we avoid use in this population.

Pre-existing anti-HLA allo-antibodies (allo-Abs) are a major barrier to successful kidney transplantation, resulting in an elevated risk for antibody-mediated rejection (AMR) and eventual graft loss. The cytokine B lymphocyte stimulator (BLyS) promotes B cell maturation and plasma cell survival; consequently, anti-BLyS therapy represents a potential therapeutic opportunity in diminishing pre-existing allo-Abs. Here we report that in our 1-year pilot trial, BLyS neutralization failed to reduce total anti-HLA allo-Ab levels in highly sensitized candidates awaiting kidney transplant in a clinically meaningful way. Additionally, we performed a post hoc analysis using sera from trial candidates which revealed selective depletion of anti-HLA class I and class II Abs in response to belimumab treatment, restricted to certain allele specificities and IgG subclasses. Altogether, we observed that BLyS blockade only results in selective depletion of anti-HLA Abs recognizing a few discrete HLA allele specificities.

Supplemental Digital Content is available in the text., Background. The clinical impact of weakly reactive pretransplant donor-specific antibody (DSA) in kidney transplantation is controversial. While some evidence suggests that weakly reactive DSA can lead to rejection, it is unclear which patients are at risk for rejection and whether posttransplant changes in weakly reactive DSA are clinically meaningful. Methods. We retrospectively studied 80 kidney transplant recipients with weakly reactive pretransplant DSA between 2007 and 2014. We performed a multivariate Cox regression analysis to identify immunologic factors most associated with risk of biopsy-proven rejection. Results. Biopsy-proven rejection occurred in 13 of 80 (16%) patients. The presence of both class I and II DSA before transplant (hazards ratio 17.4, P < 0.01) and any posttransplant increase in DSA reactivity above a mean fluorescence intensity of 3000 (hazards ratio 7.8, P < 0.01) were each significantly associated with an increased risk of rejection, which primarily occurred within the first 18 months. Conclusions. Pretransplant DSA class and DSA kinetics after transplantation are useful prognostic indicators in patients with weak DSA reactivity. These results identify a small, high-risk patient group that warrants aggressive posttransplant DSA monitoring and may benefit from alternative donor selection.

The direct-acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end-stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon-free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy-proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon-based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment-related side effects.

BACKGROUND Leukopenia is a frequent complication following kidney transplantation. Granulocyte colony-stimulating factor (G-CSF) has been used to accelerate white blood cell (WBC) count recovery; however, published experience in kidney transplantation is limited. METHODS We retrospectively reviewed our kidney transplant recipients from January 2012 to September 2016 with a G-CSF order to evaluate leukopenia management (defined as WBC

BK virus nephropathy is a serious complication of kidney transplantation. Although 10%–30% of kidney recipients have BK viremia, nephropathy occurs in approximately 2% ([1][1]). Nephropathy is most common early after transplant when immunosuppression is at its peak. Patients are often asymptomatic

Background Kidney transplant induction therapy often includes inpatient administration of rabbit antithymocyte globulin (rATG) over multiple days. To reduce hospital length of stay (LOS) and drug expenditures, the rATG induction course was completed in the outpatient setting via peripheral intravenous administration. The present study assesses early readmission trends ascribable to an outpatient rATG administration protocol to ensure initial reduction in hospital LOS is sustained early after discharge. Methods This was a retrospective study of kidney recipient outcomes for patients transplanted between January 1, 2008, and February 29, 2016, immediately following implementation of an outpatient rATG protocol. Readmission data within 7 days of outpatient rATG administration were collected. The relatedness of rATG administration to an adverse drug reaction resulting in readmission was determined by the World Health Organization-Uppsala Monitoring Centre Causality Assessment Scale and the Naranjo Adverse Drug Reaction Probability Scale. Results A total of 1104 patients received outpatient doses of rATG and were included. An upward trend in kidney transplant volume and outpatient rATG administrations per year was found from 2008-2015. Following protocol implementation, the percentage of overall readmissions ranged from 9% to just over 12% from 2008-2014 and remained less than 10% for 2014 through 2016. The percentage of outpatient rATG infusions that potentially led to rATG-related readmissions was less than 4% per year over the study period. A total of 1124 hospital days were saved, 125 days per year on average. Conclusions Outpatient administration of rATG is feasible, safe, and did not increase readmissions in the period directly following administration. The findings of this analysis support our continued use of the outpatient rATG protocol at our institution.

Purpose Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. Summary The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient’s mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme–mediated drug interactions, (3) mental health–related medication use, (4) chronic pain–related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. Conclusion Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented.

There are limited data regarding intermediate-term outcomes in patients with persistent BK viremia. Other viral infections have been implicated in the development of allosensitization through heterologous immunity, but the relationship between BK viremia and donor-specific antibodies (DSAs) is unexplored. In 2008, we initiated routine post-transplant BK viremia and DSA screening at our center; 785 kidney or kidney–pancreas transplant recipients were included in our study. Of these recipients, 132 (17%) recipients developed BK viremia during the study period. The median duration of BK viremia was 140 days (interquartile range=40–393 days), and persistent BK viremia was defined as lasting ≥140 days. Kaplan–Meier curves were generated to assess differences in patient and allograft survival on the basis of BK viremia status; survival was modeled using Cox proportional hazard regression. After a median follow-up of 3 years, there was no significant difference in terms of patient (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.28 to 2.49) or allograft survival (HR, 0.80; 95% CI, 0.37 to 1.73) between patients with and without BK viremia, which was confirmed in a time-varying analysis. In our logistic regression model, persistent BK viremia was strongly associated with the development of class II (HR, 2.55; 95% CI, 1.30 to 4.98) but not class I (HR, 1.13; 95% CI, 0.46 to 2.77) DSAs. These data suggest that persistent BK viremia does not negatively affect intermediate-term patient or allograft survival but is associated with increased risk for de novo DSA, although the exact mechanism is unclear.

Kidney transplant recipients often receive antibody induction. Previous studies of induction therapy were often limited by short follow-up and/or absence of information about complications. After linking Organ Procurement and Transplantation Network data with Medicare claims, we compared outcomes between three induction therapies for kidney recipients. Using novel matching techniques developed on the basis of 15 clinical and demographic characteristics, we generated 1:1 pairs of alemtuzumab-rabbit antithymocyte globulin (rATG) (5330 pairs) and basiliximab-rATG (9378 pairs) recipients. We used paired Cox regression to analyze the primary outcomes of death and death or allograft failure. Secondary outcomes included death or sepsis, death or lymphoma, death or melanoma, and healthcare resource utilization within 1 year. Compared with rATG recipients, alemtuzumab recipients had higher risk of death (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 1.03 to 1.26; P

For more than 40 years, polyomaviruses (BK virus and JC virus) have been known to cause disease in human beings. Recently, 11 new polyomaviruses were discovered. However, the majority of these viruses are rare in renal transplant recipients and BK and JC viruses remain the most important polyomaviruses to impact this population. BK virus presents as BK virus nephropathy and has, in rare instances, been associated with hemorrhagic cystitis or ureteral strictures. JC virus can cause progressive multifocal leukoencephalopathy or nephropathy in this population as well, but is uncommon. Antiviral prophylactic and therapeutic interventions for these diseases are lacking to date, although reduction of immunosuppression has been associated with success in treating both BK virus nephropathy and JC virus-induced disease. Risk factors are not well defined and vary across studies. However, the cumulative degree of immunosuppression is regarded universally as an important contributor to BK virus replication. For these reasons, it is recommended to screen all renal transplant recipients prospectively for BK virus infection. Multicenter trials using standardized BK and JC virus screening methods are necessary to define risk factors better, and to determine the effect of prophylaxis and treatments for these polyomaviruses affecting renal transplant recipients.

In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody-conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.

Immunosuppression nonadherence increases the risk for kidney transplant loss after transplantation. Wireless-enabled pill bottles have created the opportunity to monitor medication adherence in real time. Reminders may help patients with poor memory or organization. Provision of adherence data to providers may motivate patients to improve adherence and help providers identify adherence barriers.Randomized controlled trial.Kidney transplant recipients (n=120) at a single center.Participants were provided wireless pill bottles to store tacrolimus and record bottle openings. Participants were randomly assigned 1:1:1 to adherence monitoring with customized reminders (including alarms, texts, telephone calls, and/or e-mails), monitoring with customized reminders plus provider notification (every 2 weeks, providers received notification if adherence decreased to 90% during that period), or wireless pill bottle use alone (control).The main outcome was bottle-measured tacrolimus adherence during the last 90 days of the 180-day trial. A secondary outcome was tacrolimus whole-blood concentrations at routine clinical visits.Adherence for the primary outcome was assessed via wireless pill bottle openings.Mean participant age was 50 years; 60% were men, and 40% were black. Mean adherence was 78%, 88%, and 55% in the reminders, reminders-plus-notification, and control arms (P0.001 for comparison of each intervention to control). Mean tacrolimus levels were not significantly different between groups.The study did not assess clinical end points. Participants and study coordinators were not blinded to intervention arm.Provider notification and customized reminders appear promising in helping patients achieve better medication adherence, but these strategies require evaluation in trials powered to detect differences in clinical outcomes.

The calcineurin inhibitors (CNIs)6 tacrolimus (TAC) and cyclosporine A (CsA) are effective immunosuppressive agents for renal transplantation but require careful management to avoid toxicity. Routine therapeutic monitoring guides dosing, but uncertainty surrounds different monitoring methods and time points. Additionally, the effectiveness of strategies to reduce CNI exposure is unclear. A recent report commissioned by the Agency for Healthcare Research and Quality (AHRQ) based on research conducted by the ECRI Institute–Penn Medicine Evidence-based Practice Center to address these questions is now available (https://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports). The systematic review evaluates the evidence for 3 questions. The first question compared immunoassay analysis with liquid chromatographic or mass spectrometric analytical techniques for therapeutic monitoring of CNIs. The second question examined CsA monitoring time points, and the third question evaluated alternatives to full-dose CNI regimens. The review included 105 studies. Eleven studies addressing the analytic validity of monitoring …

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.

An open-label pilot trial involving 10 patients shows that hepatitis C virus genotype 1–infected kidneys transplanted into HCV-negative recipients, followed by direct-acting antiviral therapy, can result in excellent allograft function with cure of HCV infection.

BK virus-associated nephropathy (BKVN) occurs in up to 5% of kidney transplants and is a significant cause of graft loss. Four major subtypes of BKV have been described, with the vast majority of individuals persistently infected with BKV Type I (>80% of the population). Sequencing of BKV isolates subcloned from BKVN patients revealed a high percentage of variants in the urine (40%) in the VP1 subtyping region. In vitro analysis of several viral variants revealed that all variants recovered from the urine of BKVN patients produced infectious viral particles and were replication competent in cell culture while some of the variants induced cytopathic changes in infected cells when compared to the major BKV subtype, VP1 Type I. These results suggest that rare BKV VP1 variants are more frequently associated with disease and that some variants could be more cytopathic than others in renal transplant recipients.

Background: Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Methods: Data are presented on six subjects who participated in this trial – four were on dialysis and two were renal transplant recipients. Dialysis-dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4-mg doses of tacrolimus and two 1000-mg doses of mycophenolate mofetil (MMF) over the 24-h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (Tmax) and the area under the plasma concentration vs. time curve (AUC0–12 and AUC0–∞ where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Results: Significant inter-patient variability in the Cmax, Tmax and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non-bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. Conclusions: When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non-bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non-bypass patient.

To define and discuss the pathogenesis, clinical presentation, diagnosis, risk factors, and current preventive and treatment strategies of posttransplant lymphoproliferative disorder (PTLD).MEDLINE was searched for articles published from January 1966 to July 2007. Search terms used include posttransplant lymphoproliferative disease, posttransplant malignancy, antiviral agents, interferon-alfa, rituximab, immunosuppression, chemotherapy, radiation, and surgery. Additional articles were identified by a hand search of references.Studies in English of pediatric and adult solid organ transplantation populations published were selected and analyzed. Data from these studies and information from review articles were included in this review.PTLD occurs in 1-20% of organ recipients following solid organ transplantation. PTLD risk factors include recipient pretransplant Epstein-Barr virus (EBV) negative serostatus, type of transplant, intensity of immunosuppression, and age. The PTLD presentation is variable. Some patients present asymptomatically; in others, early symptoms can be nonspecific. To prevent PTLD, minimizing immunosuppression burden and using antiviral agents active against EBV are useful strategies. PTLD treatment may require reduction of immunosuppression, radiation, surgical excision, monoclonal antibodies, interferon-alfa, and chemotherapy.Screening for patients at risk and balancing the intensity of immunosuppressive regimens against the risk of rejection can substantially reduce the risk of developing PTLD. If PTLD occurs, an individualized treatment plan including decreased immunosuppression and other agents should be chosen based on the severity and extent of disease.

Over the last decade, polyomavirus-associated nephropathy (PVAN) has occurred with increasing frequency after renal transplantation, leading to significant renal dysfunction and graft loss. More than 95% of all cases are caused by the human polyomavirus type 1 called the BK virus. The primary treatment for PVAN is immunosuppression reduction, which must be carefully balanced against increased risks of rejection. Although no validated protocols exist, a first step commonly involves reduction of calcineurin inhibitors with antiproliferative agents by more than one-third, e.g., reaching trough levels of tacrolimus

Summary Steroids and calcineurin inhibitors (CNI) have been mainstays of immunosuppression but both have numerous side effects that are associated with substantial morbidity and mortality. This study was carried out to determine if steroids can be eliminated with early discontinuation of cyclosporine A (CsA) and later discontinuation of mycophenolate mofetil (MMF). Ninety-six patients with kidney transplants were entered into four subgroups of two pilot studies. All patients received Thymoglobulin® induction, rapamycin (RAPA), and the immunonutrients arginine and an oil containing ω-3 fatty acids. Mycophenolate mofetil was started in standard doses and discontinued by 2 years. CsA was given in reduced doses for either 4, 6, or 12 months. Follow-up was 12–36 months. Thirteen first rejection episodes occurred during the first year (14%). Combining all patients, 86% were rejection-free at 1 year, 80% at 2 years and 79% at 3 years. No kidney has been lost to acute rejection. Ninety percent of the 84 patients at risk at the end of the study were steroid-free and 87% were off CNI. Fifty-seven percent of 54 patients with a functioning kidney at 3 years were receiving monotherapy with RAPA. We conclude that this therapeutic strategy is worthy of a prospective multi-center clinical trial.

Polyomavirus-associated nephropathy (PVAN) is an emerging cause of kidney transplant failure affecting 1-10% of patients. As uncertainty exists regarding risk factors, diagnosis, and intervention, an independent panel of experts reviewed the currently available evidence and prepared this report. Most cases of PVAN are elicited by BK virus (BKV) in the context of intense immunosuppression. No specific immunosuppressive drug is exclusively associated with PVAN, but most cases reported to date arise while the patient is on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Immunologic control of polyomavirus replication can be achieved by reducing, switching, and/or discontinuing components of the immunosuppressive regimen, but the individual's risk of rejection should be considered. The success rate of this intervention is increased with earlier diagnosis. Therefore, it is recommended that all renal transplant recipients should be screened for BKV replication in the urine: 1) every three months during the first two years posttransplant; 2) when allograft dysfunction is noted; and 3) when allograft biopsy is performed. A positive screening result should be confirmed in

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.

Background. Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication that occurs in a small but significant minority of solid organ transplant recipients. Published experiences with PTLD in cardiac transplant recipients are limited to relatively small single-center reports. Methods. This report presents experience with 274 cases of PTLD in cardiac transplant recipients reported to the Israel Penn International Transplant Tumor Registry (IPITTR). Results. PTLD carried an ominous prognosis: Kaplan Meier survival after PTLD diagnosis was 45%, 33%, 30%, and 13%, respectively, at 1, 3, 5, and 10 years. Common causes of death included: PTLD, cardiovascular collapse, and infection; all occurred at a median of less than 6 months. Risk of death from cardiovascular collapse secondary to immunosuppression withdrawal was substantial (28%), indicating that a fine balance exists between death from PTLD and from sudden cardiac death due to acute rejection. PTLD therapy in the majority of patients consisted of combination therapy (49%). Survival in patients receiving immunosuppression minimization (ISM) alone was 32%, with ISM plus other therapy was 27%, and with other therapies not containing ISM was 11% (P Conclusion. PTLD in cardiac transplant recipients is associated with low long-term survival rates. Analysis of PTLD therapies and outcomes suggest that immunosuppression minimization, when applied, improves survival. However, risk of sudden death may mitigate the positive effect of ISM. This observation has important implications for ISM in PTLD therapy in cardiac transplant recipients. Carefully designed prospective studies are needed to evaluate the positive and negative effects of ISM in cardiac transplant recipients with PTLD.

Immunosuppression used in transplantation is associated with an increased incidence of various cancers. Although the incidence of colorectal cancer in transplant patients seems to be equal to nontransplant population, the effects of immunosuppression on patients who develop colorectal cancer are not well defined. The purpose of this study was to define the characteristics and survival patterns of transplant patients developing de novo colorectal cancer.The Israel Penn International Transplant Tumor Registry was queried for patients with colorectal cancer. Analysis included patient demographics, age at transplantation and colorectal cancer diagnosis, tumor stage, and survival. Age and survival rates were compared to United States population-based colorectal cancer statistics using the National Cancer Institute Surveillance Epidemiology and End Results database.A total of 150 transplant patients with de novo colorectal cancer were identified: 93 kidney, 29 heart, 27 liver, and 1 lung. Mean age at transplantation was 53 years. Age at transplantation and colorectal cancer diagnosis was not significant for gender, race, or stage of disease. Compared to National Cancer Institute Surveillance Epidemiology and End Results database, transplantation patients had a younger mean age at colorectal cancer diagnosis (58 vs. 70 years; P0.001), and a worse five-year survival (overall, 44 vs. 62 percent, P0.001; Dukes A and B, 74 vs. 90 percent, P0.001; Dukes C, 20 vs. 66 percent, P0.001; and Dukes D, 0 vs. 9 percent, P = 0.08).Transplant patients develop colorectal cancer at a younger age and exhibit worse five-year survival rates than the general population. These data suggest that chronic immunosuppression results in a more aggressive tumor biology. Frequent posttransplantation colorectal cancer screening program may be warranted.

This study defines the incidence and recurrence risk of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) after organ transplant. Patients from the United States with a history of HD or NHL before organ transplantation reported to the Israel Penn International Transplant Tumor Registry from 1968 to 2001 were analyzed. A total of 91 patients underwent organ transplantation with a lymphoma history: HD (38 patients) and NHL (53 patients). Median disease-free interval pretransplant was 99 (range 0-459.1) months, and median follow-up posttransplant was 25.7 (0.4-131.1) months. Ten patients were excluded from further analysis because of lack of follow-up information (n=9) or they never achieved remission (n=1). Recurrence incidence was 8 of 81 patients (10%) (HD=3/34 [9%] vs. NHL=5/47 [11%]). Gender, race, allograft type and source, age at lymphoma diagnosis, and immunosuppression did not influence recurrence. Patients with less than a 2-year period between diagnosis and transplant seem to be at increased risk of relapse. Median disease-free interval before transplant was longer for patients without recurrence (115 vs. 30.2 months, P=0.24), but was not statistically significant. Median time to recurrence posttransplant was 18.7 (range 1.9-82.2) months (HD=3.7 vs. NHL 23.6 months, P=0.10). Survival after recurrence was poor (HD [1/3] and NHL [1/5], median survival 6.8 [range 0-22.1] months). There is no difference in recurrence rates for HD and NHL. The outcome for recurrent lymphoma is poor. The low risk of recurrence (10%) indicates that preexisting HD and NHL need not be an absolute contraindication to transplantation.

Polyomavirus nephropathy has become an important complication in kidney transplantation, with a prevalence of 1% to 8%. Unfortunately, the risk factors for polyomavirus nephropathy and renal allograft loss are not well defined. The definitive diagnosis is made through assessment of a kidney transplant biopsy. Recently, noninvasive urine and serum markers have been used to assist in polyomavirus nephropathy diagnosis and monitoring. Primary treatment is immunosuppression reduction, but must be balanced with the risks of rejection. No antiviral treatments for polyomavirus nephropathy have been approved by the Food and Drug Administration. Although cidofovir has shown in vitro activity against murine polyomaviruses, and has been effective in some patients, it is associated with significant nephrotoxicity. Graft loss due to polyomavirus nephropathy should not be a contraindication to retransplantation; however, experience is limited. This review presents potential risk factors, screening, diagnostic and monitoring methods, therapeutic management, and retransplantation experience for polyomavirus nephropathy.

Background. In an era of organ shortage, the use of expanded or marginal donors has been attempted to increase transplantation rates and diminish waiting list mortality. One strategy is the use of organs from patients with a history of or active central nervous system (CNS) tumor. Methods. Sixty-two recipients were identified as the recipients of organs from donors with a history of or active CNS malignancy. Patient demographics, donor tumor management, incidence of tumor transmission, and patient survival were examined. Results. Of the organs recovered and transplanted from donors with astrocytoma, 14 were associated with at least one risk factor including high-grade tumor (n=4), prior surgery (n=5), radiation therapy (n=4), and systemic chemotherapy (n=4). One tumor transmission was identified at 20 months posttransplant with the patient expiring from metastatic disease. Twenty-six organs were transplanted from glioblastoma patients with 15 demonstrating risk factors including high-grade tumor (n=9) and prior surgery (n=10). Eight transmissions were identified with a range of 2 to 15 months posttransplant, with seven patients dying as the result of metastatic disease. Seven organs were used from donors with a medulloblastoma. Three transmissions were identified at a range of 5 to 7 months, all associated with ventriculoperitoneal shunts. Two medulloblastoma recipients died as the result of metastatic disease, whereas the third is alive with diffuse disease. The rate of donor tumor transmission, in the absence of risk factors, was 7%, whereas in the presence of one or more risk factor this rate dramatically rose to 53% (P Conclusions. Organs from donors with CNS tumors can be used with a low risk of donor tumor transmission in the absence of the following risk factors: high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy, and systemic chemotherapy.

Purpose. To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney–pancreas transplant (KPTX) recipients. Methods. Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999. Results. Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6–48) months after KTX and 17 (range 9–31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus. Conclusions. Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.

Purpose: To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil. Methods: Retrospective, single centre analysis of 45 patients transplanted between 1995 and 2000 who received 54 courses of thymoglobulin, including 36 courses in 29 solitary pancreas transplant recipients (16 pancreas alone, 13 pancreas after kidney transplants) and 18 courses in 16 simultaneous kidney-pancreas transplant patients. Thirty-two patients (71%) were primary pancreas transplants, 10 (22%) were second transplants and three (7%) were third transplants. Of the 54 treatment courses, 19 (35%) were for induction, 27 (50%) were for primary rejection and eight (15%) were rescue therapy for rejection. All rejection episodes were biopsy-proven in at least one organ. Results: The median thymoglobulin dose was 1.5 mg/kg/d with a mean of six doses (range 3-10). Dose reduction or interruption was required in 28 courses (52%), most often due to leukopenia (n = 24), fever (n = 2) and thrombocytopenia (n = 2). Thymoglobulin was d in all but three patients, two with persistent fever and one with infection. Infectious complications (n = 25) occurred in 17 patients (38%) within 30 days and included bacterial (n = 16), cytomegalovirus (n = 4), polyoma (n = 1), fungal (Candida albicans, n = 1), toxoplasmosis (n = 1) and ehrlichiosis (n = 2). Post-transplant lymphoproliferative disease occurred in two patients (4%) at a mean of 70 d post-thymoglobulin treatment. In the 19 patients that received thymoglobulin induction, one simultaneous kidney-pancreas transplant, two pancreas alone and four pancreas after kidney transplant recipients developed rejection (37% incidence), while all remaining patients followed by surveillance protocol biopsies were rejection-free. In the 35 patients that received thymoglobulin for rejection, reversal occurred in 26 of the patients (74%). Rejection recurred within 30 d in five patients and post-treatment biopsies revealed persistent rejection in three of 20 pancreas and two of eight renal biopsies. After a mean follow-up of 6 months, the actual patient and pancreas graft survival rates were 93% and 71%, respectively. Conclusion: Thymoglobulin was effective as induction therapy in high-risk pancreas transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population.

Passive immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is important to prevent recurrence of hepatitis B virus (HBV) after orthotopic liver transplantation (OLT) for chronic HBV cirrhosis. With availability of lamivudine (3TC), the use of combination prophylaxis with long-term HBIG/3TC has been shown to prevent short-term HBV recurrence. This report compares HBV recurrence rates between groups receiving no/short-term HBIG, long-term HBIG alone, or HBIG/3TC prophylaxis, and describes HBIG requirements during the first 6 and 12 months in the latter two groups. This study involved patients undergoing OLT at the University of Tennessee-Memphis between May 1990 and July 2001. During this period, 388 liver transplants were performed at our center. All hepatitis B surface antigen (HBsAg)-positive recipients (n = 27) were included in this retrospective analysis. The groups were similar with regard to pre-transplant demographic characteristics such as age, gender, weight, and pre-transplant diagnosis. Owing to the retrospective study design, median follow-up was longer for the no-prophylaxis (5.6 years) and the HBIG-alone (6.0 years) groups compared to the HBIG/3TC group (4.2 years). Patient survival was 50% in the no-prophylaxis and 71% in the HBIG-alone groups compared to 100% in the HBIG/3TC group (P = 0.09). When censored for death with a functioning graft, graft survival was 50% in the no-prophylaxis and 86% in the HBIG-alone group compared to 100% in the HBIG/3TC group (P = 0.07). The overall incidence of HBV recurrence in the no-prophylaxis era was 100% and 21% in the HBIG-alone era compared to 0% in the HBIG/3TC era (P < 0.001), despite similar mean and median HBIG trough titers in the HBIG-alone and HBIG/3TC groups. The incidence of HBV recurrence in HBV DNA-positive recipients was 100% in the no-prophylaxis era, 30% in the HBIG-alone era, and 0% in the HBIG/3TC era (P < 0.001). Recipients in the HBIG-alone group had a nearly two-fold increase in HBIG requirement at 6 and 12 months in order to maintain similar HBIG trough titers post-transplant compared to recipients in the HBIG/3TC group despite similar pre-transplant HBV serology. This increased HBIG requirement in the HBIG-alone group resulted in a marked increase in the mean overall cost of HBV prophylaxis in this group ($47,367 US dollars at 6 months; $84,280 US dollars at 12 months) compared to the HBIG/3TC group ($25,931 US dollars at 6 months; $49,599 US dollars at 12 months). These data demonstrate an improvement in patient and graft survival rates in the group receiving combination HBIG/3TC prophylaxis compared to the HBIG-alone and no-prophylaxis groups. There was a significant reduction in HBV recurrence in the group receiving combination HBIG/3TC when compared to the groups receiving HBIG alone or no prophylaxis. Furthermore, we demonstrated that the addition of 3TC to the long-term HBIG regimen led to elimination of the disparity previously described in HBV recurrence rates between HBV DNA-positive and HBV DNA-negative recipients. Importantly, our data demonstrates a complete lack of HBV recurrence in the HBIG/3TC group at a median follow-up of 4.2 years. Additionally, the data show that the addition of 3TC to the post-operative prophylaxis regimen resulted in a reduction in the requirement of HBIG at 6 and 12 months, which markedly reduced the overall cost of post-transplant HBV prophylaxis.

We report the case of a pancreas-alone transplant recipient who developed Rhodococcus equi pneumonia after receiving multiple courses of antilymphocyte therapy for the treatment of recurrent acute pancreas allograft rejection. We also review and discuss the diagnosis, clinical course, and treatment of 18 cases of R. equi infection reported in solid organ transplant recipients. The lung is the most common primary site of infection, but R. equi infection is difficult to diagnose because of the pleomorphic, gram-positive, and partially acid-fast nature of the organism. Treatment usually involves a combination of antibiotics including rifampin, macrolides, vancomycin, and ciprofloxacin. The optimal duration of therapy is unknown, but relapse is common if the duration of treatment is less than 14 days. The duration of therapy should be guided by clinical recovery, culture results, and radiographic findings. Monitoring levels of immunosuppressive agents—such as tacrolimus and cyclosporine—is needed in order to avoid clinically significant drug interactions with rifampin or the macrolides when these agents are used in order to treat R. equi infection in the transplant population.

Human ehrlichioses are tick-borne infections caused by bacteria in the genus Ehrlichia of the family Rickettsiaceae. To date there have been three cases of ehrlichiosis reported in the transplant population, a human monocytic ehrlichiosis (HME) infection in a liver transplant recipient and two cases of human granulocytic ehrlichiosis (HGE) in kidney transplant recipients. We report three pancreas transplant patients who developed HGE in the last two years at a single southeastern center in the United States. All three patients had clinical, laboratory, and pathophysiologic findings on bone marrow biopsy and peripheral blood smears consistent with HGE, and responded to doxycycline therapy. In the setting of potent immunosuppression, ehrlichiosis should be considered in the differential diagnosis of transplant patients presenting with persistent fever, pancytopenia, and abnormal liver function. Patients with ehrlichiosis infection may be at risk for developing other opportunistic infections or lymphoproliferative disease.

Background: The impact of tacrolimus (TAC), mycophenolate mofetil (MMF) and steroid immunosuppression on cytomegalovirus (CMV) infection in combination with ganciclovir prophylaxis in simultaneous kidney-pancreas transplantation (SKPT) has not been well studied. Methods: A retrospective analysis was made of 75 SKPTs performed between 1 January 1996 and 7 January 1999. All patients received ganciclovir for 3 months, but CMV donor (D)+ / recipient (R)- patients received ganciclovir for 6 months. Results: 16/74 (22%) were CMV D+/R-, 25 (33%) D+/R+, 16 (22%) D-/R+, and 17 (23%) D-/R- (1 patient with unknown donor serology was excluded). The mean time to CMV infection was 198 days post-transplant. The incidence of either CMV infection or tissue invasive CMV disease was 16/74 (22%), including 9 (12%) with CMV infection and 7 (10%) CMV disease. The one-year patient, kidney, and pancreas graft survival rates were 91%, 89%, and 83%, respectively The mean follow-up was 29 months (minimum of 12 months). CMV infection was not associated with an increased incidence of graft failure or mortality. The D+/R- group had the highest incidence of CMV infection (44%) compared with the other serologic groups (17%, P=0.02). Concurrent CMV and rejection occurred more frequently in the D+/R- than the other serologic groups (25% vs. 7%, P= 0.03). The D-/R- group had the best outcomes, with no CMV infection, improved kidney graft survival at the end of follow-up (82% VS. 72%, P= 0.04) and the highest event-free survival (no CMV infection, rejection, or graft loss) when compared to the other groups (76% vs. 33%, P

We retrospectively reviewed long-term outcomes in simultaneous kidney-pancreas transplant (SKPT) recipients with portal-enteric (P-E) versus systemic-bladder (S-B) drainage. Forty-five patients were alive with functioning grafts 1 year after SKPT and were followed up for a minimum of 3 years (mean, 5.9 years), including 26 patients with P-E drainage and 19 patients with S-B drainage. Recipient demographic and transplant characteristics were similar between the two groups. In both groups, hospital admissions decreased significantly with increasing time after SKPT, although significantly fewer readmissions occurred in the first year in the P-E than the S-B group. The most common reason for readmission in both groups was infection, followed by miscellaneous, surgical, and immunologic morbidity. The incidence of readmission for dehydration was significantly less in the P-E group (P0.01). Mean systolic and diastolic blood pressures were similar between groups, although the number of antihypertensive medications was significantly less in the S-B group. Although fasting C-peptide levels were significantly greater in the S-B group, the two groups were similar with regard to carbohydrate (fasting serum glucose, hemoglobin A(1c)) and lipid (total cholesterol) metabolism. Renal and pancreas allograft functions were similar between the two groups. At 1 year post-SKPT, stabilization in most diabetic complications was reported. Four quality-of-life surveys that provided 29 scores were completed 6 to 24 months (mean, 18.5 months) after SKPT. Improved quality of life was reported in all but one of the scales, with many dimensions showing significant improvements. At 3 years after SKPT, no activity limitation was reported in 76% of patients with P-E drainage versus 53% with S-B drainage (P = 0.11). Five-year actual patient, kidney, and pancreas graft survival rates after P-E versus S-B drainage are 92% and 84%, 81% and 79%, and 88% and 74%, respectively (P = not significant). SKPT with P-E drainage is a safe and effective method to treat advanced diabetic nephropathy and is associated with decreasing morbidity, improving rehabilitation and quality of life, and stablizing metabolic function over time. The long-term prognosis after the first year is excellent and at least similar to the results achieved with S-B drainage.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of maribavir, a novel antiviral agent in the benzimidazole drug class. Data sources: Articles were identified through searches of MEDLINE (January 1998-July 2008). Abstracts from recent scientific meetings and the manufacturer were also included. Study Selection and Data Extraction: All English-language in vitro and in vivo studies and abstracts evaluating maribavir were reviewed and considered for inclusion. All human studies were included. Data Synthesis: Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses Unlike ganaclovir. which needs to be phosphorated by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase. UL 97 kinase is an early viral gene product involved in viral DNA elongation, DNA packaging and egress or shedding of capsids from viral nuclei. Maribavir has also been found to be effective against ganciclovir-resistant CMV strains. Maribavir differs from current CMV antiwal agents in its adverse event profile. Maribavir is not associated with nephrotoxicity or hematologic toxicities, but has been associated with taste disturbances. In February 2007, maribavir was granted Food and Drug Administration orphan drug status for prevention of CMV viremia and diseases in at-risk populations. Maribavir Phase 2 trials in stem-cell transplant recipients have been completed, and there are ongoing Phase 3 trials in stem-cell and organ transplant recipients. Conclusions: Maribavir may be an option for treatment of ganciclovir-resistant CMV infections. Its bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir. No differences in pharmacokinetics were seen in renally impaired patients, although dialysis-dependent patients were not evaluated. Maribavir is not associated with hematologic toxicities; however, the high prevalence of taste disturbances may limit its tolerability.

BK virus (BKV), which causes polyomavirus-associated nephropathy (PVN) in kidney transplant recipients (KTx), has 75% homology with JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML). The large T-antigen (T-ag) is the main regulatory protein of polyomaviruses that is expressed early in the viral cycle.To characterize epitopes of BKV and JCV T-ag recognized by CD8+ T-cells and explore the role of these cells in containing polyomavirus infection.We tested peripheral blood mononuclear cells of HLA A*0201+ BKV- and JCV-seropositive individuals, including patients with active BKV or JCV infection and healthy control subjects in a cross-sectional study.CD8+ T-cells that recognized the nonamer BKV Tp579, which is identical to JCV Tp578, were detected by tetramer staining in 10/13 (77%) healthy individuals, 3/10 (30%) KTx/PVN, and 4/9 (44%) patients with PML and/or HIV-infection. Conversely, BKV Tp398- and Tp410-specific CD8+ T cells were detected in 3/13 (23%) and 1/13 (8%) healthy individuals only.These data suggest that, as it is the case for the VP1 protein, the same population of CD8+ T-cells may recognize epitopes located on the BKV and JCV T protein. The overall cellular immune response against polyomavirus T-ag, however, is lower than against the VP1 protein and is more frequently detected in healthy individuals than in patients with active BKV or JCV infection.

Polyomaviruses [BK virus (BKV), JC virus (JCV) and simian virus 40 (SV40)] have been known to be associated with diseases in humans for over thirty years. BKV-associated nephropathy and JCV-induced progressive multifocal leukoencephalopathy (PML) were for many years rare diseases occurring only in patients with underlying severe impaired immunity. Over the past decade, the use of more potent immunosuppression (IS) in transplantation, and the Acquired Immune Deficiency Syndrome (AIDS) epidemic, have coincided with a significant increase in the prevalence of these viral complications. Prophylactic and therapeutic interventions for human polyomavirus diseases are limited by our current understanding of polyomaviral pathogenesis. Clinical trials are limited by small numbers of patients affected with clinically significant diseases, lack of defined risk factors and disease definitions, no proven effective treatment and the overall significant morbidity and mortality associated with these diseases. This chapter will focus on a review of the current and future research related to therapeutic targets and interventions for polyomavirus-associated diseases.

BK virus (BKV) is the etiologic agent of polyomavirus nephropathy (PVN), an infection of the kidney occurring in up to 8% of kidney transplant (KTx) recipients (38). BKV infects 90% of adults (20) but does not cause any disease in healthy individuals. Viral reactivation in renal transplant recipients occurs in the setting of pharmacologic immunosuppression. This reactivation leads to a lytic infection of renal tubular epithelial cells of the transplanted kidney, which was responsible for renal allograft loss in as high as 45 to 67% of cases in early experiences and is currently responsible for 10 to 30% of renal allograft losses (29, 35, 38). There is no specific antiviral treatment for PVN. Therefore, this disease is a growing medical problem as the population of KTx recipients continues to increase. The only currently available therapeutic option for PVN consists of reduction of chemical immunosuppression, which allows reconstitution of the immune system to clear the virus (4) but which may also be associated with an increased risk of transplant rejection. Hence, prognostic markers of disease evolution and a better understanding of the immune response against BKV are urgently needed for the appropriate management of patients with PVN. BKV has 75% homology with JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML). We have previously characterized two HLA-A*0201-restricted epitopes of JCV major capsid protein VP1 recognized by CD8+ cytotoxic T lymphocytes (CTL) and studied the role of these cells in PML patients and control subjects (12, 23). The presence of JCV-specific CTL was associated with a favorable outcome of PML (13), and these cells could be detected in the blood of 73% of healthy individuals (14), suggesting that the cellular immune response against the JCV VP1 protein may be important in the containment of JCV and the prevention of PML (10, 11, 13, 21, 23, 24). We therefore hypothesized that the BKV VP1 protein may play a similar role. Indeed, in parallel to our studies on the cellular immune response to BKV (5), Krymskaya et al. (26) also recently independently reported that the BKV VP1-specific epitope p108 (VP1p108) cross-reacted with JCV VP1p100 in healthy subjects and in two KTx recipients. In the present study, we have confirmed the cross-reactivity between BKV VP1p108 and JCV VP1p100 and identified an additional A*0201-restricted BKV VP1 CTL epitope p44, which cross-reacts with JCV VP1p36. Both the BKV VP1p44 and VP1p108 epitopes were naturally processed by cells infected with a recombinant vaccinia virus (rVV) expressing the entire BKV VP1 protein. We constructed tetrameric staining complexes with these peptides and the HLA-A*0201 molecule and used these reagents as a tool to detect BKV-specific CTL in healthy individuals and explore their role in KTx recipients with PVN. In addition, we compared the effects of the cellular and humoral immune responses on BKV viral load in the blood and urine samples of these patients. We found that these CTL play a critical role in control of BKV infection in KTx recipients with PVN and that a high degree of epitope cross-recognition exists between BKV and JCV-specific CTL.

The purpose of this study was to define risk factors for acute rejection with early corticosteroid withdrawal (CSWD; within 7 days posttransplant) in renal transplantation. Data from prospective, IRB-approved early CSWD trials were analyzed. Overall acute rejection rate in 308 patients was 17.1%. Acute rejection rates and observed risks (OR) in patients with individual risk factors were: repeat transplants 38.6%; current PRA >25%; 29.4%; African Americans 23.5%; delayed graft function (DGF) 26.1%; HLA DR mismatches >0 17.9%; female gender 19.7%; Thymoglobulin induction 15.3%; type 1 diabetes 30.8%; type 2 diabetes 11.1%; deceased donor recipients 21%; and living donor recipients 14%. Logistic regression analysis provided the following risks (OR) for acute rejection: repeat transplant 2.51; current PRA > 25% 1.53; African Americans 1.47; DGF 1.58; HLA DR mismatches > 0 1.61; female gender 1.43; Thymoglobulin induction 0.61; type 1 diabetes 2.23, type 2 diabetes 0.5, deceased donor recipients 1.11, and living donor recipients 0.9. Risk factors for acute rejection under early corticosteroid withdrawal are similar to those previously defined under chronic corticosteroid therapy. These observations provide implications for future CSWD trials including: use of T cell depleting antibody induction therapy (thymoglobulin) to reduce acute rejection risk, 2) enrollment stratification for high risk groups, and 3) modified immunosuppression for high risk groups.

Introduction Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. Methods Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. Results Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 ± 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). Conclusions In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

A primary reason to eliminate corticosteroids from immunosuppressive regimens in solid organ transplant recipients is improved cardiovascular risk profiles. Although a number of studies have documented that corticosteroid withdrawal (CSWD) regimens reduce hypertension, hyperlipidemia, diabetes, and weight gain, global assessments of cardiovascular risk under CSWD have not been reported. The purpose of this study was to document cardiovascular risk under CSWD using a global risk assessment by Framingham risk assessment.Framingham global cardiovascular risk assessments were performed at baseline and 3, 6, and 12 months posttransplant on patients enrolled in prospective, IRB-approved early (7 days of corticosteroids) CSWD trials. Framingham score was based on age, sex, presence of diabetes, HDL and total cholesterol, and systolic blood pressure. All patients were nonsmokers. Left ventricular hypertrophy assessment by EKG criteria was not available at all time points and therefore were not included.One hundred eighty-three patients were included in the analysis. Fourteen percent of patients had evidence of coronary heart disease (prior MI, CABG, PTCA, or significant cardiovascular disease as evidenced by angiography) prior to transplant. Complete information was available for 160 patients at baseline, 132 at 1, 3, and 6 months, and 93 at 12 months posttransplant. Mean 10-year risk (expressed as percent) for developing coronary heart disease decreased over time: 8.03 at baseline, 8.31 at 3 months, 7.40 at 6 months, and 7.20 at 12 months, indicating that global cardiovascular risk fell at 1 year posttransplant by about 10% in renal transplant recipients undergoing early CSWD.Estimation of cardiovascular risk by Framingham risk factor assessment allows incorporation of several cardiovascular risk factors into a single estimate, thereby accounting for differential effects of each individual factor on global cardiovascular risk. This experience indicates that global cardiovascular risk decreases by approximately 10% at 1 year posttransplant in renal transplant recipients who undergo early corticosteroid withdrawal (CSWD).

Introduction The cost of misdiagnosis of central nervous system (CNS) tumors in donors has not been previously described. The purpose of this study was to examine the Israel Penn International Transplant Tumor Registry experience with these donors. Methods All cases where an error in diagnosis was made due to intracranial hemorrhage from undiagnosed CNS tumors and where CNS metastases were misdiagnosed as primary brain tumor were examined. Results Forty-two organ recipients with misdiagnosed primary brain deaths from 29 donors were examined. After transplantation these donors were identified with: melanoma (23%), renal cell carcinoma (19%), choriocarcinoma (12%), sarcoma (10%), Kaposi's sarcoma (7%), and variable tumors (22%). The majority of patients were renal allograft recipients (84%) followed by liver ( n = 4) and lung recipients ( n = 1). The most commonly diagnostic error was with intracranial hemorrhage (ICH) (62%). A donor-related transmission rate of 74% (31/42) was identified among those patients with a misdiagnosed brain death. The majority of donor-transmitted cancers were identified in the recipient allograft (71%). Sixty-four percent of recipients suffered diffuse metastatic disease. Overall survival was poor, with a 5-year survival rate of 32% (10/31). Explantation was performed in 17 patients with confirmed donor-transmitted cancer, and in these patients a survival benefit was noted (10/17, 59%, vs 0/14, 0%; P Conclusions Error in the diagnosis of donor brain death due to CNS tumors has significant and often fatal consequences. Allograft explantation for kidney recipients or retransplantation for extrarenal recipients may provide a survival benefit. Potential donors with unclear etiologies for brain death, particularly ICH, should be considered for a limited brain autopsy after donation.