Michael J. Casey

Calcineurin inhibitors in kidney transplantation: friend or foe?

Purpose of reviewThe utilization of calcineurin inhibitors (CNI) in kidney transplantation has dramatically improved short-term outcomes but significant gains in long-term outcomes have proved elusive. Nephrotoxicity is the major problem associated with CNIs and is responsible for the disappointing progress seen in long-term graft survival. In this review, we assess CNI efficacy as well as the latest strategies employed to limit long-term CNI nephrotoxicity. Recent findingsThree CNI sparing strategies – CNI withdrawal, CNI avoidance, and CNI minimization – are evaluated with discussion of key studies such as the Efficacy Limiting Toxicity Elimination-Symphony and Spare-the-Nephron studies. Recent breakthroughs in transplant immunosuppression are discussed such as the BENEFIT and BENEFIT-EXT studies, which have led to the recent US Food and Drug Administratrion approval of belatacept, a novel T-cell costimulation blocker. SummaryFor now, CNIs remain the proven standard of care in modern immunosuppression. However, some novel agents may challenge the role CNIs play in kidney transplantation in the very near future.

Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure.

Background When kidney transplants fail, transplant medications are discontinued to reduce immunosuppression-related risks. However, retransplant candidates are at risk for allosensitization which prolonging immunosuppression may minimize. We hypothesized that for these patients, a prolonged immunosuppression withdrawal after graft failure preserves nonsensitization status (PRA 0%) better than early immunosuppression withdrawal. Methods We retrospectively examined subjects transplanted at a single center between July 1, 1999 and December 1, 2009 with a non–death-related graft loss. Subjects were stratified by timing of immunosuppression withdrawal after graft loss: early (⩽3 months) or prolonged (>3 months). Retransplant candidates were eligible for the main study where the primary outcome was nonsensitization at retransplant evaluation. Non-retransplant candidates were included in the safety analysis only. Results We found 102 subjects with non–death-related graft loss of which 49 were eligible for the main study. Nonsensitization rates at retransplant evaluation were 30% and 66% for the early and prolonged immunosuppression withdrawal groups, respectively (P=0.01). After adjusting for cofactors such as blood transfusion and allograft nephrectomy, prolonged immunosuppression withdrawal remained significantly associated with nonsensitization (adjusted odds ratio=5.78, 95% CI [1.37–24.44]). No adverse safety signals were seen in the prolonged immunosuppression withdrawal group compared to the early immunosuppression withdrawal group. Conclusions These results suggest that prolonged immunosuppression may be a safe strategy to minimize sensitization in retransplant candidates and provide the basis for larger or prospective studies for further verification.

Outcomes and survival analysis of old‐to‐old simultaneous pancreas and kidney transplantation

Outcomes of old‐donor simultaneous pancreas–kidney transplantation (SPKT) have not been thoroughly studied. Scientific Registry of Transplant Recipients data reported for SPKT candidates receiving dialysis wait‐listed between 1993 and 2008 (n = 7937) were analyzed for outcomes among those who remained listed (n = 3301) and of SPKT recipients (n = 4636) using multivariable time‐dependent regression models. Recipients were stratified by donor/recipient age (cutoff 40 years) into: young‐to‐young (n = 2099), young‐to‐old (n = 1873), old‐to‐young (n = 293), and old‐to‐old (n = 371). The overall mortality was 12%, 14%, 20%, and 24%, respectively, for those transplanted, and 50% for those remaining on the waiting list. On multivariable analysis, old‐donor SPKT was associated with significantly higher overall risks of patient death, death‐censored pancreas, and kidney graft failure in both young (73%, 53%, and 63% increased risk, respectively) and old (91%, 124%, and 85% increased risk, respectively) recipients. The adjusted relative mortality risk was similar for recipients of old‐donor SPKT compared with wait‐listed patients including those who subsequently received young‐donor transplants (aHR 0.95; 95% CI 0.78, 1.12) except for candidates in OPOs with waiting times ≥604 days (aHR 0.65, 95% CI 0.45–0.94). Old‐donor SPKT results in significantly worse graft survival and patient mortality without any waiting‐time benefit as compared to young‐donor SPKT, except for candidates with expected long waiting times.

Comparison of Utilization and Clinical Outcomes for Belatacept‐ and Tacrolimus‐ Based Immunosuppression in Renal Transplant Recipients

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1‐year clinical outcomes between belatacept‐ and tacrolimus‐treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1‐year acute rejection, with the highest rates associated with non–lymphocyte‐depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90–3.70, p < 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial–Extended Criteria Donors (BENEFIT‐EXT), 1‐year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m2, respectively; p < 0.001). The incidence of new‐onset diabetes after transplantation was significantly lower with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (1.7%, 2.2%, and 3.8%, respectively; p = 0.01). Despite improved graft function and metabolic complications with belatacept alone, it may be advisable to add short‐term tacrolimus in the first year after transplant and to consider lymphocyte‐depleting induction in patients with high rejection risk, as the risk–benefit ratio allows.

Outcome of kidney transplants for adults with hemolytic uremic syndrome in the U.S.: a ten-year database analysis.

BACKGROUND There is currently no large study of the U.S. transplant registry comparing the outcome of kidney transplantation for adults with and without hemolytic uremic syndrome (HUS). To date, information on the outcome of transplants for HUS in the U.S. is derived from single or combined-centers studies, but none has been of a nationwide scope. MATERIAL AND METHODS We retrospectively studied a US registry for the outcome of 323 kidney transplants in adults with HUS and of 121,311 transplants in adults with other renal diseases during the period 1999-2009. We analyzed patient, over-all, and death-censored graft survival in the 5 years following transplantation using Kaplan-Meir curves and Cox hazard models. RESULTS In the 5 years following kidney transplantation, patient mortality was not significantly different [Hazard Ratio (HR) 1.27, 95% Confidence Interval (CI) 0.78-2.08], but death-censored graft loss was twice as common (HR 2.05, 95% CI 1.53-2.73) for allograft recipients whose native kidney disease was HUS compared to other transplant recipients. The subgroup (n=40 cases) with post-transplant HUS recurrence had a 5-year graft loss rate 5 times that of the subgroup (n=283 cases) without HUS-recurrence (graft survival 14.7% vs.77.4%, log rank 116.5; p<0.001). CONCLUSIONS In the largest US series to date of kidney transplants for adults with HUS, 5-year patient survival was not different, but graft outcome was inferior in recipients whose native renal disease were HUS compared to recipients with other kidney diseases. Native kidney HUS is associated with a 2-fold increased risk of death-censored graft loss after kidney transplantation.

Effect of different tacrolimus levels on early outcomes after kidney transplantation

BACKGROUND There is a paucity of modern data on the impact of high tacrolimus levels early after kidney transplantation. MATERIAL/METHODS This study analyzed the impact of various trough levels of tacrolimus in the first 2 weeks post-transplant on rates of delayed graft function (DGF), length of stay (LoS), hyperkalemia, hyperglycemia, and biopsy-proven acute rejection (BPAR) rates in the first 3 months post-transplant in a retrospective single-center cohort of patients. Patients were divided into 4 groups based on the average of two highest 12-hour trough tacrolimus levels: <10 ng/mL, 10-12 ng/mL, 12-15 ng/mL, >15 ng/mL. RESULTS The incidence of DGF was noted to be significantly higher in the <10 ng/mL, >15 ng/mL and the 12-15 ng/mL tacrolimus groups as compared to the 10-12 ng/mL group (49%, 25% and 4%, respectively, p≤0.0001). Mean LoS was also noted to be significantly higher in the >15 ng/mL tacrolimus group as compared to the 10-12 ng/mL group (7.4 days and 6.1 days respectively, p=0.0007). There was no difference in the rates of hyperkalemia, hyperglycemia or BPAR. CONCLUSIONS This is a modern confirmation of the association between higher tacrolimus levels early after kidney transplantation and increased rate of DGF and increased LoS.

Racial and Socioeconomic Disparities in the Allocation of Expanded Criteria Donor Kidneys

BACKGROUND AND OBJECTIVES In carefully selected individuals, receiving expanded criteria donor (ECD) kidneys confer a survival advantage over remaining on dialysis. However, wait lists for ECD kidneys often include a significant proportion of young patients, who have no predictable survival benefit from ECD kidneys. This study hypothesized that educational and socioeconomic factors might influence a younger patients decision to accept an ECD kidney. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study was a retrospective analysis of all first single-kidney transplants in the Scientific Registry of Transplant Recipients database from 2000 to 2009 in patients aged 18-40 years and waitlisted <3 years. The primary outcome measured was the odds of receiving an ECD kidney compared with an standard criteria donor kidney in different demographic subgroups. Race, income, and education were analyzed in main-effect and two-way interaction models, corrected for candidate panel reactive antibodies and sex. RESULTS Of 13,615 ECD transplants, 591 kidneys (4.3%) went to recipients aged between 18 and 40 years who were waitlisted <3 years. African Americans (odds ratio, 1.71; 95% confidence interval, 1.26 to 2.33) or those with low education (odds ratio, 2.32; 95% confidence interval, 1.38 to 3.89) were more likely to receive an ECD kidney than Caucasians or those with a college degree, respectively. However, African Americans with higher education levels did not have significantly higher odds of receiving an ECD kidney than Caucasians with a college degree. CONCLUSIONS In patients aged <40 years and waitlisted <3 years, African Americans and those with lower educational status and low income are more likely to receive an ECD kidney than Caucasians or those with higher education. It is important that health care providers and patients understand such disparities to facilitate a more rational use of ECD kidneys.

Association of Baseline Viral Serology and Sirolimus Regimens With Kidney Transplant Outcomes: A 14-Year Registry-Based Cohort Study in the United States.

BackgroundThe risks for transplant outcomes associated with baseline viral serostatus in kidney transplant recipients (KTR) on sirolimus have not been widely studied. MethodsWe performed a cohort-study of 61 590 adult KTR in 2000 to 2013. We used Cox regression models to determine the adjusted hazard ratio (aHR) of patient death, death-censored graft loss and posttransplant malignancy associated with the baseline serostatus (+ or −: hepatitis B core [HBc], hepatitis C virus [HCV], Epstein-Barr virus [EBV], or cytomegalovirus [CMV]) in KTR on sirolimus (SRL) + mycophenolate (MPA) or SRL + tacrolimus (Tac), relative to the control-regimen: Tac + MPA. ResultsCompared with Tac + MPA, SRL + MPA, and SRL + Tac were associated with higher risks of 5-year mortality (aHR, 1.41; 95% CI, 1.23-1.60 and aHR, 1.59; 95% CI, 1.38-1.83, respectively) and death-censored graft loss (aHR, 1.41; 95% CI, 1.24-1.60 and aHR, 1.38; 95% CI, 1.21-1.57, respectively). In KTR with negative pretransplant EBV, CMV, HBc, or HCV serostatus, SRL + MPA not SRL + Tac was associated with a lower risk of posttransplant malignancy compared with control (aHR, 0.27; 95% CI, 0.10-0.72; aHR, 0.61; 95% CI, 0.43-0.88; aHR, 0.79; 95% CI, 0.64-0.97; and aHR, 0.80; 95% CI, 0.65-0.98, respectively, for SRL + MPA and aHR, 0.98: 95% CI, 0.52-1.80; aHR, 0.69; 95% CI, 0.46-1.06; aHR, 0.83; 95% CI, 0.66-1.06 and aHR, 0.85; 95% CI, 0.67-1.07, respectively, for SRL + Tac). In KTR with positive serostatus to any of the above viruses, SRL + MPA or SRL + Tac was not associated with a different malignancy risk compared with control. ConclusionsCompared with Tac + MPA, SRL regimens were associated with higher risks for patient death and graft loss, although SRL + MPA was associated with a lower risk for posttransplant malignancy in kidney allograft recipients with negative pretransplant HBc, HCV, EBV, or CMV serology.

Rethinking the advantage of zero-HLA mismatches in unrelated living donor kidney transplantation: implications on kidney paired donation

The OPTN/UNOS Kidney Paired Donation (KPD) Pilot Program allocates priority to zero‐HLA mismatches. However, in unrelated living donor kidney transplants (LDKT)—the same donor source in KPD—no study has shown whether zero‐HLA mismatches provide any advantage over >0 HLA mismatches. We hypothesize that zero‐HLA mismatches among unrelated LDKT do not benefit graft survival. This retrospective SRTR database study analyzed LDKT recipients from 1987 to 2012. Among unrelated LDKT, subjects with zero‐HLA mismatches were compared to a 1:1–5 matched (by donor age ±1 year and year of transplantation) control cohort with >0 HLA mismatches. The primary endpoint was death‐censored graft survival. Among 32,654 unrelated LDKT recipients, 83 had zero‐HLA mismatches and were matched to 407 controls with >0 HLA mismatches. Kaplan–Meier analyses for death‐censored graft and patient survival showed no difference between study and control cohorts. In multivariate marginal Cox models, zero‐HLA mismatches saw no benefit with death‐censored graft survival (HR = 1.46, 95% CI 0.78–2.73) or patient survival (HR = 1.43, 95% CI 0.68–3.01). Our data suggest that in unrelated LDKT, zero‐HLA mismatches may not offer any survival advantage. Therefore, particular study of zero‐HLA mismatching is needed to validate its place in the OPTN/UNOS KPD Pilot Program allocation algorithm.

Nebivolol Effects on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

In hypertensive kidney transplant recipients, the effects of nebivolol vs metoprolol on nitric oxide (NO) blood level, estimated glomerular filtration rate (eGFR), and blood pressure (BP) have not been previously reported. In a 12‐month prospective, randomized, open‐label, active‐comparator trial, hypertensive kidney transplant recipients were treated with nebivolol (n=15) or metoprolol (n=15). Twenty‐nine patients (nebivolol [n=14], metoprolol [n=15]) completed the trial. The primary endpoint was change in blood NO level after 12 months of treatment. Secondary endpoints were changes in eGFR, BP, and number of antihypertensive drug classes used. After 12 months of treatment, least squares mean change in plasma NO level in the nebivolol kidney transplant recipient group younger than 50 years was higher by 68.19% (99.17% confidence interval [CI], 13.02–123.36), 69.54% (99.17% CI, 12.71–126.37), and 66.80% (99.17% CI, 12.95–120.64) compared with the metoprolol group younger than 50 years, the metoprolol group 50 years and older, and the nebivolol group 50 years and older, respectively. The baseline to month 12 change in mean arterial BP, eGFR, and number of antihypertensive drug classes used was not significantly different between the treatment groups. In hypertensive kidney transplant recipients, nebivolol use in patients younger than 50 years increased blood NO.