Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients.

The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.

The effect of peri-transplant plasmapheresis in the prevention of recurrent FSGS.

Many pediatric centers utilize a variety of protocols including preemptive plasmapheresis to prevent the recurrence of FSGS post-transplant. But the effectiveness of this expensive, time-consuming process of plasmapheresis in the prevention of FSGS recurrence is still unclear. We retrospectively reviewed all pediatric cases of FSGS in our center that received a kidney transplant and compared the transplant and patient outcomes of those transplanted after 2006 who received pretransplant plasmapheresis to those prior to 2006 who did not. Of the 57 children with FSGS, 31 and 26 were transplanted before and after 2006, respectively. The cohorts differed significantly in keeping with the center immunosuppression protocol changes, and prior to 2006, the recipients were significantly younger. All children with FSGS transplanted after 2006 underwent three and one sessions of 1.0 plasma volume/exchange plasmapheresis with fresh frozen plasma replacement prior to the transplant in living and deceased donors, respectively, in addition to five sessions of every other day post-transplant pheresis. The incidence (27% vs 26%, P = 1.0) and time to recurrence of FSGS in the kidney allograft (P = .22) were not significantly different in patients that did and did not undergo prophylactic plasmapheresis. We need to re-evaluate the role of preemptive plasmapheresis in the prevention of FSGS recurrence in a prospective multicenter study.

Long-Term Non-End-Stage Renal Disease Risks After Living Kidney Donation.

Despite generally positive outcomes and high rates of satisfaction, living kidney donors are at risk for both medical and psychosocial problems. In this review, the authors summarize non-end-stage renal disease (ESRD) risks for donors and describe limitations to the data. We review the evidence of medical risks (e.g. increased cardiovascular disease and mortality, preeclampsia) and psychosocial risks (e.g. mood disturbance, financial burden). We then discuss the evidence of differential risks among subsets and the impact of postdonation events (e.g. development of diabetes). Collectively, available evidence indicates the following. (1) Recognizing the importance of non-ESRD risks has been overshadowed by analyses of the reported risk of ESRD. This imbalance should be remedied. (2) There is little quantification of the true contribution of donation to medical and psychosocial outcomes. (3) Most studies, to date, have been retrospective, with limited sample sizes and diversity and with less-than-ideal controls for comparison of outcomes. (4) Many postdonation events (diabetes and hypertension) can now be reasonably predicted, and their association with adverse outcomes can be quantified. (5) Mechanisms and systems need to be implemented to evaluate and care for donors who develop medical and/or psychosocial problems. (6) Costs to donors are a significant burden, and making donation financially neutral should be a priority.

Renal Consequences of Diabetes After Kidney Donation.

Whether diabetes after kidney donation is associated with an accelerated GFR decay in the remaining kidney has not been studied. We determined the incidence of diabetes in kidney donors, and compared GFR change over time in diabetic to nondiabetic donors, in addition to the effect of diabetes mellitus (DM) on the development of proteinuria, hypertension, and end-stage renal disease (ESRD). Of the 4014 donors, 309 (7.7%) developed diabetes at a median age of 56.0 years and after a median of 18 years after donation. The difference in annual estimated GFR (eGFR) change between diabetic and nondiabetic donors in the 7 years before the development of DM was -0.08 mL/min/year; p = 0.51. After DM development, the difference was -1.10 mL/min/year for diabetic donors with hypertension and proteinuria, p < 0.001; -0.19 for diabetic donors with hypertension but no proteinuria, p = 0.29; -0.75 mL/min/year for diabetic donors with proteinuria but no hypertension, p = 0.19; and -0.09 mL/min/year for diabetic donors without proteinuria or hypertension, p = 0.63. When DM was considered as a time-dependent covariate, it was associated with the development of proteinuria (hazard ratio [HR] 2.65, 95% confidence interval [CI] 1.89-3.70; p < 0.001) and hypertension (HR 2.19, 95% CI 1.74-2.75; p < 0.001). It was not, however, associated with ESRD. eGFR decline after DM development exceeds that of nondiabetic donors only in diabetic donors with concomitant proteinuria and hypertension.

Defining the Tipping Point in Surgical Performance for Laparoscopic Donor Nephrectomy Among Transplant Surgery Fellows: A Risk-Adjusted Cumulative Summation Learning Curve Analysis.

The United Network for Organ Sharing recommends that fellowship-trained surgeons participate in 15 laparoscopic donor nephrectomy (LDN) procedures to be considered proficient. The American Society of Transplant Surgeons (ASTS) mandates 12 LDNs during an abdominal transplant surgery fellowship. We performed a retrospective intraoperative case analysis to create a risk-adjusted cumulative summation (RACUSUM) model to assess the learning curve of novice transplant surgery fellows (TSFs). Between January 2000 and December 2014, 30 novice TSFs participated in the organ procurement rotation of our ASTS-approved abdominal transplant surgery fellowship. Measures of surgical performance included intraoperative time, estimated blood loss, and incidence of intraoperative complications. The performance of senior TSFs was used to benchmark novice TSF performance. Scores were tabulated in a learning curve model, adjusting for case complexity and prior TSF case volume. Rates of adverse surgical events were significantly higher for novice TSFs than for senior TSFs. In univariable analysis, multiple renal arteries, high BMI, prior abdominal surgery, male donor, and nephrolithiasis were correlated with higher incidence of adverse surgical events. Based on the RACUSUM model, high intraoperative time is mitigated after 28 procedures, incidence of intraoperative complications tends to diminish after 24 procedures, and improvement in estimated blood loss did not remain consistent. TSFs exhibit a tipping point in LDN performance by 24-28 cases and proficiency by 35-38 cases.

The Living Donor Collective: A Scientific Registry for Living Donors.

In the setting of an overall decline in living organ donation and new questions about long-term safety, a better understanding of outcomes after living donation has become imperative. Adequate information on outcomes important to donors may take many years to ascertain and may be evident only by comparing large numbers of donors with suitable controls. Previous studies have been unable to fully answer critical questions, primarily due to lack of appropriate controls, inadequate sample size, and/or follow-up duration that is too short to allow detection of important risks attributable to donation. The Organ Procurement and Transplantation Network does not follow donors long term and has no prospective control group with which to compare postdonation outcomes. There is a need to establish a national living donor registry and to prospectively follow donors over their lifetimes. In addition, there is a need to better understand the reasons many potential donors who volunteer to donate do not donate and whether the reasons are justified. Therefore, the US Health Resources and Services Administration asked the Scientific Registry of Transplant Recipients to establish a national registry to address these important questions. Here, we discuss the efforts, challenges, and opportunities inherent in establishing the Living Donor Collective.

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients.

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.

The impact of recipient BKV shedding before transplant on BKV viruria, DNAemia, and nephropathy post-transplant: A prospective study.

We previously demonstrated that detectable BKV replication in donor urine pretransplant was significantly associated with post-transplant recipient BKV viremia. In this 4-year prospective study, we assessed whether recipient BKV replication pretransplant was associated with post-transplant viremia/BKV nephropathy. We studied 220 primary adult and pediatric organ transplant recipients for 490 person-years and 2100 clinical visits. BKV viruria was detectable in 28 (16%), 26 adults and two children; and viremia in none pretransplant. Post-transplant viruria occurred in all recipients with pretransplant BKV viruria, significantly more than in recipients without pretransplant viruria on univariate (P<.005) and multivariate analysis including type of organ transplanted and immunosuppression type (P .008). Time to post-transplant viruria was significantly shorter in recipients with pretransplant viruria (P .01). By univariate and multivariate analysis, BKV viruria in recipients pretransplant did not impact post-transplant BKV viremia (P=.97 and .97, respectively) even when stratified by type of organ transplant (kidney P=.6; liver P=.5). The peak serum and urine BKV PCR post-transplant were not significantly different in patients with pretransplant BKV viruria and no one developed BK nephropathy. In conclusion, recipient BKV viruria prior to transplant predicts post-transplant viruria but not viremia or BKV nephropathy.

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

The Synergistic Effect of Class II HLA Epitope-Mismatch and Nonadherence on Acute Rejection and Graft Survival.

Predicting long-term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long-term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA-DR, ≥17 HLA-DQ) or low epitope-mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA-DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA-DQ locus nonadherent recipients with HLA-DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring.

OPTN/SRTR 2013 Annual Data Report: kidney.

A new kidney allocation system, expected to be implemented in late 2014, will characterize donors on a percent scale (0%-100%) using the kidney donor profile index (KDPI). The 20% of deceased donor kidneys with the greatest expected posttransplant longevity will be allocated first to the 20% of candidates with the best expected posttransplant survival; kidneys that are not accepted will then be offered to remaining 80% of candidates. Waiting time will start at the time of maintenance dialysis initiation (even if before listing) or at the time of listing with an estimated glomerular filtration rate of 20 mL/min/1.73 m(2) or less. Under the current system, the number of candidates on the waiting list continues to increase, as each year more candidates are added than are removed. Median waiting times for adults increased from 3 years in 2003 to more than 4.5 years in 2009. Donation rates have not increased. Short-term outcomes continue to improve; death-censored graft survival at 90 days posttransplant was 97% or higher for deceased donor transplants and over 99% for living donor transplants. In 2013, 883 pediatric candidates were added to the waiting list; 65.8% of pediatric candidates on the list in 2013 underwent deceased donor transplant. Five-year graft survival was highest for living donor recipients aged younger than 11 years (89%) and lowest for deceased donor recipients aged 11 to 17 years (68%).

Daily fluid intake and outcomes in kidney recipients: post hoc analysis from the randomized ABCAN trial.

Generous and even excessive fluid intake is routinely recommended to kidney transplant recipients despite minimal evidence to support this practice. We hypothesized that increased fluid intake, ascertained by 24-h urine volume output, may adversely affect graft outcomes as it would impose an extra workload on a limited number of nephrons. Kidney transplant recipients who were randomized to losartan vs. placebo in the Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN) trial (n = 153) underwent baseline, five-yr biopsies, and annual iothalamate glomerular filtration rate assessment. Recipients with higher urine volume at randomization had higher urinary sodium and also higher urinary protein. The proportion using diuretics or CNI based regimens were similar across urinary volume tertiles. The highest urinary volume tertile (>2.56 L/d) did not predict the development of interstitial volume doubling or end-stage renal disease (ESRD) from interstitial fibrosis/tubular atrophy (OR = 3.52, 95% CI 0.4, 31.24, p = 0.26), interstitial volume doubling or all-cause ESRD (OR = 7.04, 95% CI 0.66, 74.87, p = 0.11), and was not associated with the conventional endpoint of doubling serum creatinine, all-cause ESRD, or death (OR = 0.89, 95% CI 0.21, 3.71, p = 0.87). These results suggest that the current practice of liberal fluid intake may not be beneficial in low risk and mostly Caucasian transplant recipients.

OPTN/SRTR 2012 Annual Data Report: kidney.

For most end-stage renal disease patients, successful kidney transplant provides substantially longer survival and better quality of life than dialysis, and preemptive transplant is associated with better outcomes than transplants occurring after dialysis initiation. However, kidney transplant numbers in the us have not changed for a decade. Since 2004, the total number of candidates on the waiting list has increased annually. Median time to transplant for wait-listed adult patients increased from 2.7 years in 1998 to 4.2 years in 2008. The discard rate of deceased donor kidneys has also increased, and the annual number of living donor transplants has decreased. The number of pediatric transplants peaked at 899 in 2005, and has remained steady at approximately 750 over the past 3 years; 40.9% of pediatric candidates undergo transplant within 1 year of wait-listing. Graft survival continues to improve for both adult and pediatric recipients. Kidney transplant is one of the most cost-effective surgical interventions; however, average reimbursement for recipients with primary Medicare coverage from transplant through 1 year posttransplant was comparable to the 1-year cost of care for a dialysis patient. Rates of rehospitalization are high in the first year posttransplant; annual costs after the first year are lower.

A composite risk model for predicting technical failure in pancreas transplantation.

Technical failure (TF) continues to have a significant impact on the success of pancreas transplantation. We assessed risk factors for TF in 1115 pancreas transplants performed at a single center between 1998 and 2011. The overall TF rate was 10.2%. In a multivariable model, donor BMI ≥ 30 (HR 1.87, p = 0.005), donor Cr ≥ 2.5 (HR 3.16, p = 0.007), donor age >50 (HR 1.73, p = 0.082) and preservation time >20 h (HR 2.17, p < 0.001) were associated with TF. Bladder drainage of exocrine secretions was protective (HR 0.54, p = 0.002). We incorporated these factors in a Composite Risk Model. In this model the presence of one risk factor did not significantly increase risk of TF (HR 1.35, p = 0.346). Two risk factors in combination increased risk greater than threefold (HR 3.65, p < 0.001) and three risk factors increased risk greater than sevenfold (HR 7.66, p = <0.001). The analysis also identified many factors that were not predictive of TF, including previous transplants, immunosuppressive agent selection, and almost all recipient demographic parameters. While the model suggests that two or more risk factors predict TF, strategies to reduce preservation time may mitigate some of this risk.

Prospective randomized trial of maintenance immunosuppression with rapid discontinuation of prednisone in adult kidney transplantation.

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 µg/L) and low-level sirolimus (SIR, 3-7 µg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 µg/L) and high-level SIR (8-12 µg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

OPTN/SRTR 2011 Annual Data Report: kidney.

A shortage of kidneys for transplant remains a major problem for patients with end-stage renal disease. The number of candidates on the waiting list continues to increase each year, while organ donation numbers remain flat. Thus, transplant rates for adult wait-listed candidates continue to decrease. However, pretransplant mortality rates also show a decreasing trend. Many kidneys recovered for transplant are discarded, and discard rates are increasing. Living donation rates have been essentially unchanged for the past decade, despite introduction of desensitization, non-directed donations, and kidney paired donation programs. For both living and deceased donor recipients, early posttransplant results have shown ongoing improvement, driven by decreases in rates of graft failure and return to dialysis. Immunosuppressive drug use has changed little, except for the Food and Drug Administration approval of belatacept in 2011, the first approval of a maintenance immunosuppressive drug in more than a decade. Pediatric kidney transplant candidates receive priority under the Share 35 policy. The number of pediatric transplants peaked in 2005, and decreased to a low of 760 in 2011. Graft survival and short-term renal function continue to improve for pediatric recipients. Postransplant lymphoproliferative disorder is an important concern, occurring in about one-third of pediatric recipients.

Demographic, metabolic, and blood pressure characteristics of living kidney donors spanning five decades.

While cautious criteria for selection of living kidney donors are credited for favorable outcomes, recent practice changes may include acceptance of less than ideal donors. To characterize trends in donor acceptance, the Renal and Lung Living Donors Evaluation (RELIVE) Study evaluated 8,951 kidney donors who donated between 1963 and 2007 at three major U.S. transplant centers. Over the study interval, there was an increase in the percentage of donors >40 years old from 38% to 51%; donors >60 years varied between 1% and 4%. The proportion of donors with obesity increased from 8% to 26% and with glucose intolerance from 9% to 25%. The percentage of hypertensive donors was consistent (5-8%). Accepted donors ≥60 years old were more likely to have obesity, glucose intolerance, and/or hypertension compared to younger donors (p<0.0001). Our results demonstrate important trends in acceptance of older and more obese donors. The fraction of older donors accepted with glucose intolerance or hypertension remains small and for the majority includes mild elevations in glucose or blood pressure that were previously classified as within normal limits.

Health-related quality of life in kidney donors from the last five decades: results from the RELIVE study.

Live donation benefits recipients, but the long-term consequences for donors remain uncertain. Renal and Lung Living Donors Evaluation Study surveyed kidney donors (N = 2455; 61% women; mean age 58, aged 24-94; mean time from donation 17 years, range 5-48 years) using the Short Form-36 Health Survey (SF-36). The 95% confidence intervals for White and African-American donors included or exceeded SF-36 norms. Over 80% of donors reported average or above average health for their age and sex (p < 0.0001). Donors' age-sex adjusted physical component summary (PCS) scores declined by half a point each decade after donation (p = 0.0027); there was no decline in mental component summary (MCS) scores. White donors' PCS scores were three points higher (p = 0.0004) than non-Whites'; this difference remained constant over time. Nine percent of donors had impaired health (PCS or MCS score >1 SD below norm). Obesity, history of psychiatric difficulties and non-White race were risk factors for impaired physical health; history of psychiatric difficulties was a risk factor for impaired mental health. Education, older donation age and a first-degree relation to the recipient were protective factors. One percent reported that donation affected their health very negatively. Enhanced predonation evaluation and counseling may be warranted, along with ongoing monitoring for overweight donors.

Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs.

The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to determine if there were age-related differences in metabolism and dose requirements. We studied 348 young (18-34 years), 1831 middle (35-64 years) and 374 older (65-84 years) adult kidney transplant recipients enrolled in a seven-center prospective study. Troughs were obtained from each patient 2×/week in weeks 1-8 and 2×/month in months 3-6. A multivariable linear-mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1-2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age-related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly.

Kidney, pancreas and liver allocation and distribution in the United States.

Kidney transplant and liver transplant are the treatments of choice for patients with end-stage renal disease and end-stage liver disease, respectively. Pancreas transplant is most commonly performed along with kidney transplant in diabetic end-stage renal disease patients. Despite a steady increase in the numbers of kidney and liver transplants performed each year in the United States, a significant shortage of kidneys and livers available for transplant remains. Organ allocation is the process the Organ Procurement and Transplantation Network (OPTN) uses to determine which candidates are offered which deceased donor organs. OPTN is charged with ensuring the effectiveness, efficiency and equity of organ sharing in the national system of organ allocation. The policy has changed incrementally over time in efforts to optimize allocation to meet these often competing goals. This review describes the history, current status and future direction of policies regarding the allocation of abdominal organs for transplant, namely the kidney, liver and pancreas, in the United States.