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Background: Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population but not individual risk., Methods: We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF = 20.4%) and investigated potential improvements., Results: We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable with that reported by Irish et al. For cohorts excluded by Irish: (a) in pump-perfused kidneys, the IC overestimated DGF risk; (b) in simultaneous pancreas kidney transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF-excluding those with single dialysis in the first 24 h posttransplant-we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC-predicted risk., Conclusions: The IC can be a useful population guide for predicting DGF in the population for which it was intended but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease., Competing Interests: R.B.M. was supported in part by the UAB-UCSD O’Brien Core Center for Acute Kidney Injury Research (NIH P30-DK079337) (5UO1DK115997) and Department of Veterans Affairs (5-IO1-BX003272). The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: African American (AA) recipients of deceased-donor (DD) kidney transplants (KT) have shorter allograft survival than recipients of other ethnic groups. Reasons for this disparity encompass complex interactions between donors and recipients characteristics., Methods: Outcomes from 3872 AA and 19,719 European American (EA) DDs who had one kidney transplanted in an AA recipient and one in an EA recipient were analyzed. Four donor/recipient pair groups (DRP) were studied, AA/AA, AA/EA, EA/AA, and EA/EA. Survival random forests and Cox proportional hazard models were fitted to rank and evaluate modifying effects of DRP on variables associated with allograft survival. These analyses sought to identify factors contributing to the observed disparities in transplant outcomes among AA and EA DDKT recipients., Results: Transplant era, discharge serum creatinine, delayed graft function, and DRP were among the top predictors of allograft survival and mortality among DDKT recipients. Interaction effects between DRP with the kidney donor risk index and transplant era showed significant improvement in allograft survival over time in EA recipients. However, AA recipients appeared to have similar or poorer outcomes for DDKT performed after 2010 versus before 2001; allograft survival hazard ratios (95% CI) were 1.15 (0.74, 1.76) and 1.07 (0.8, 1.45) for AA/AA and EA/AA, compared to 0.62 (0.54, 0.71) and 0.5 (0.41, 0.62) for EA/EA and AA/EA DRP, respectively. Recipient mortality improved over time among all DRP, except unemployed AA/AAs. Relative to DDKT performed pre-2001, employed AA/AAs had HR = 0.37 (0.2, 0.69) versus 0.59 (0.31, 1.11) for unemployed AA/AA after 2010., Conclusion: Relative to DDKT performed before 2001, similar or worse overall DCAS was observed among AA/AAs, while EA/EAs experienced considerable improvement regardless of employment status, KDRI, and EPTS. AA recipients of an AA DDKT, especially if unemployed, had worse allograft survival and mortality and did not appear to benefit from advances in care over the past 20 years., (© 2021. The Author(s).)

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsies is part of the diagnostic criteria for chronic active TCMR (CA TCMR -- i-IFTA ≥ 2, ti ≥ 2, t ≥ 2). We evaluated i-IFTA and CA TCMR in the DeKAF indication biopsy cohorts: prospective (n = 585, mean time to biopsy = 1.7 years); cross-sectional (n = 458, mean time to biopsy = 7.8 years). Grouped by i-IFTA scores, the 3-year postbiopsy DC-GS is similar across cohorts. Although a previous acute rejection episode (AR) was more common in those with i-IFTA on biopsy, the majority of those with i-IFTA had not had previous AR. There was no association between type of previous AR (AMR, TCMR) and presence of i-IFTA. In both cohorts, i-IFTA was associated with markers of both cellular (increased Banff i, t, ti) and humoral (increased g, ptc, C4d, DSA) activity. Biopsies with i-IFTA = 1 and i-IFTA ≥ 2 with concurrent t ≥ 2 and ti ≥ 2 had similar DC-GS. These results suggest that (a) i-IFTA≥1 should be considered a threshold for diagnoses incorporating i-IFTA, ti, and t; (b) given that i-IFTA ≥ 2,t ≥ 2, ti ≥ 2 can occur in the absence of preceding TCMR and that the component histologic scores (i-IFTA,t,ti) each indicate an acute change (albeit i-IFTA on the nonspecific background of IFTA), the diagnostic category "CA TCMR" should be reconsidered., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surveillance biopsies permit early detection of subclinical inflammation before clinical dysfunction, but the impact of detecting early subclinical phenotypes remains unclear., Methods: We conducted a single-center retrospective cohort study of 441 consecutive kidney transplant recipients between 2015 and 2018 with surveillance biopsies at 6 months post-transplant. We tested the hypothesis that early subclinical inflammation (subclinical borderline changes, T cell-mediated rejection, or microvascular injury) is associated with increased incidence of a composite endpoint including acute rejection and allograft failure., Results: Using contemporaneous Banff criteria, we detected subclinical inflammation in 31%, with the majority (75%) having a subclinical borderline phenotype (at least minimal inflammation with mild tubulitis [>i0t1]). Overall, subclinical inflammation was independently associated with the composite endpoint (adjusted hazard ratio, 2.88; 1.11-7.51; P  = 0.03). The subgroup with subclinical borderline inflammation, predominantly those meeting the Banff 2019 i1t1 threshold, was independently associated with 5-fold increased hazard for the composite endpoint ( P  = 0.02). Those with concurrent subclinical inflammation and subclinical chronic allograft injury had worse outcomes. The effect of treating subclinical inflammation was difficult to ascertain in small heterogeneous subgroups., Conclusions: Subclinical acute and chronic inflammation are common at 6 months post-transplant in kidney recipients with stable allograft function. The subclinical borderline phenotype with both tubulitis and interstitial inflammation was independently associated with poor long-term outcomes. Further studies are needed to elucidate the role of surveillance biopsies for management of allograft inflammation in kidney transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: About half of late kidney allograft losses are attributed to death with function (DWF), a poorly characterized outcome. An ongoing question is whether DWF is a consequence of chronic allograft dysfunction. Using the prospective Long-term Deterioration of Kidney Allograft Function study database, we sought to better define the impact, phenotype, and clinical course of DWF in the current era., Methods: Three thousand five hundred eighty-seven kidney recipients with functional grafts at 90 days post-transplant were followed prospectively for a median of 5.2 years., Results: Characteristics at transplantation in those with DWF (N = 350, 9.8%) differed from those who otherwise lost their grafts (death-censored graft failure [DC-GF], N = 295, 8.2%) or maintained function (N = 2942, 82.0%); DWF patients were older, sicker, and had been on dialysis longer, with more preexisting cardiovascular disease, whereas DC-GF patients experienced more early rejection, more acute rejection after 90 days, and a clinically significant decrease in kidney function before graft failure. In contrast, the clinical course after transplantation in DWF patients did not differ before death from those who maintained function throughout., Conclusions: DWF and DC-GF in kidney transplant recipients represent differing clinical phenotypes occurring in distinct patient populations. Reducing the impact of DWF requires better definition of causes and clinical course and then trials of therapies to improve outcomes. Composite endpoints in clinical trials that group DWF and DC-GF together may obscure important clinical findings.

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single-nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance-weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (P = 1.6 × 10 -8 -2.2 × 10 -8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; P = 2 × 10 -9 -3.7 × 10 -8 ) and plasmacytoma variant translocation 1 (PVT1) genes (P = 4.0 × 10 -8 -7 × 10 -8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli, and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (P = 2 × 10 -9 -5 × 10 -8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Work relative value unit (wRVU)-based fee schedules are predominantly used by both the Centers for Medicare & Medicaid Services (CMS) and private payers to determine the payments for physicians' clinical productivity. However, under the Affordable Care Act, CMS is transitioning into a value-based payment structure that rewards patient-oriented outcomes and cost savings. Moreover, in the context of solid organ transplantation, physicians and surgeons conduct many activities that are neither billable nor accounted for in the wRVU models. New compensation models for transplant professionals must (1) justify payments for nonbillable work related to transplant activity/procedures; (2) capture the entire academic, clinical, and relationship-building work effort as part of RVU determination; and (3) move toward a value-based compensation scheme that aligns the incentives for physicians, surgeons, transplant center, payers, and patients. In this review, we provide an example of redesigning RVUs to address these challenges in compensating transplant physicians and surgeons. We define a customized RVU (cRVU) for activities that typically do not generate wRVUs and create an outcome value unit (OVU) measure that incorporates outcomes and cost savings into RVUs to include value-based compensation., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To examine the largest single-center experience of simultaneous kidney/pancreas transplantation (SPK) transplantation among African-Americans (AAs)., Background: Current dogma suggests that AAs have worse survival following SPK than white recipients. We hypothesize that this national trend may not be ubiquitous., Methods: From August 30, 1999, through October 1, 2014, 188 SPK transplants were performed at the University of Alabama at Birmingham (UAB) and 5523 were performed at other US centers. Using Kaplan-Meier survival estimates and Cox proportional hazards regression, we examined the influence of recipient ethnicity on survival., Results: AAs comprised 36.2% of the UAB cohort compared with only 19.1% nationally (P < 0.01); yet, overall, 3-year graft survival was statistically higher among UAB than US cohort (kidney: 91.5% vs 87.9%, P = 0.11; pancreas: 87.4% vs 81.3%; P = 0.04, respectively) and persisted on adjusted analyses [kidney adjusted hazard ratio (aHR): 0.58, 95% confidence interval (95% CI) 0.35-0.97, P = 0.04; pancreas aHR: 0.54, 95% CI 0.34-0.85, P = 0.01]. Among the UAB cohort, graft survival did not differ between AA and white recipients; in contrast, the US cohort experienced significantly lower graft survival rates among AA than white recipients (kidney 5 years: 76.5% vs 82.3%, P < 0.01; pancreas 5 years: 72.2% vs 76.3%, P = 0.01; respectively)., Conclusion: Among a single-center cohort of SPK transplants overrepresented by AAs, we demonstrated similar outcomes among AA and white recipients and better outcomes than the US experience. These data suggest that current dogma may be incorrect. Identifying best practices for SPK transplantation is imperative to mitigate racial disparities in outcomes observed at the national level.

The use of procurement biopsies in deceased donor kidney acceptance is controversial. We analyzed Scientific Registry of Transplant Recipients data (n = 59 328 allografts, 2014-2018) to describe biopsy practices across US organ procurement organizations (OPOs) and examine relationships with discards, using hierarchical modeling to account for OPO and donor factors. Median odds ratios (MORs) provide the median of the odds that allografts with identical reported traits would be biopsied or discarded from 2 randomly drawn OPOs. Biopsies were obtained for 52.7% of kidneys. Biopsy use rose in a graded manner with kidney donor profile index (KDPI). Biopsy rates differed significantly among OPOs (22.8% to 77.5%), even after adjustment for KDPI and other donor factors. Discard rates also varied from 6.6% to 32.1% across OPOs. After adjustment for donor factors and OPO, biopsy was associated with more than 3 times the likelihood of discard (adjusted odds ratio [ 95%LCL aOR 95 %UCL ], 3.29 3.51 3.76 ). This association was most pronounced for low-risk (KDPI <20) kidneys (aOR, 5.45 6.47 7.69 ), with minimal impact at KDPI >85 (aOR, 0.88 1.15 1.51 ). Adjusted MORs for kidney discard and biopsy were greatest for low-risk kidneys. Reducing the rate of unnecessary biopsy and improving the accuracy of histologic assessments in higher KDPI organs may help reduce graft discard rates., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In accordance with the National Organ Transplant Act and Department of Health and Human Services' Final Rule, the Scientific Registry of Transplant Recipients (SRTR) publicly releases biannual program-specific reports that include analyses of transplant centers' risk-adjusted waitlist mortality, organ acceptance ratios, transplant rates, and graft and patient survival. Since the inception of these center metrics, 1-year posttransplant graft and patient survival have improved, and center variation has decreased, casting uncertainty on their clinical relevance. The SRTR has recently modified center evaluations by ranking centers into 5 tiers rather than 3 tiers in an attempt to discriminate between programs performing within a tight range, further exacerbating this uncertainty. The American Society of Transplantation/American Society of Transplant Surgeons convened an expert taskforce to examine both the utility and unintended consequences of transplant center metrics. Estimates of center variation in outcomes in adjacent tiers are imprecise and fleeting, but can result in consequential changes in clinician and center behavior. The taskforce has concerns that current metrics, based principally on 1-year graft and patient survival, provide minimal if any benefit in informing patient choice and access to transplantation, with the untoward effect of decreased utilization of organs and restriction of research and innovation., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Renal allotransplantation clearly offers better survival and quality of life for end-stage renal disease (ESRD) patients than chronic dialysis. The median waiting time for a deceased donor kidney in a suitable ESRD patient is 3.9 years. The initial candidates for pig kidney xenotransplantation will be those with ESRD unlikely to receive an allograft within a reasonable period of time. It is thus reasonable to ascertain whether clinical trials of xenotransplantation might likewise offer superior outcomes. Chronic dialysis in patients with ESRD is associated with poor quality of life, significant morbidity, and relatively high mortality, with only 56% surviving 3 years and 42% at 5 years. However, a significant number of these patients, because of comorbidities, frailty, etc, would not be considered for renal allotransplantation and likely not for xenotransplantation. As genetically engineered pig kidneys have satisfactorily supported life in immunosuppressed nonhuman primates for many months or even more than a year, consideration in carefully selected patients could be given to pig kidney xenotransplantation. We suggest that, in order to give a patient the best possible outcome, the pig kidney could be transplanted pre-emptively (before dialysis is initiated). If it fails at any stage, the patient would then begin chronic dialysis and continue to await an allograft. The present (limited) evidence is that failure of a pig graft would not be detrimental to a subsequent allograft., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Living donor kidney transplantation has declined in the United States since 2004, but the relationship between population characteristics and rate of living donation is unknown. The goal of our study was to use data on general population health and socioeconomic status to investigate the association with living donation., Methods: This cross-sectional, ecological study used population health and socioeconomic status data from the CDC Behavioral Risk Factor Surveillance System to investigate the association with living donation. Transplant centers performing 10 or greater kidney transplants reported to the Scientific Registry of Transplant Recipients in 2015 were included. Center rate of living donation was defined as the proportion of all kidney transplants performed at a center that were from living donors., Results: In a linear mixed-effects model, a composite index of health and socioeconomic status factors was negatively associated with living donation, with a rate of living donation that was on average 7.3 percentage points lower among centers in areas with more comorbid disease and poorer socioeconomic status (95% confidence interval, -12.2 to -2.3, P = 0.004). Transplant centers in areas with higher prevalence of minorities had a rate of living donation that was 7.1 percentage points lower than centers with fewer minorities (95% confidence interval, -11.8 to -2.3, P = 0.004)., Conclusions: Center-level variation in living donation was associated with population characteristics and minority prevalence. Further examination of these factors in the context of patient and center-level barriers to living donation is warranted.

Outcomes of patients receiving solid organ transplants in the United States are systematically aggregated into bi-annual Program-Specific Reports (PSRs) detailing risk-adjusted survival by transplant center. Recently, the Scientific Registry of Transplant Recipients (SRTR) issued 5-tier ratings evaluating centers based on risk-adjusted 1-year graft survival. Our primary aim was to examine the reliability of 5-tier ratings over time. Using 10 consecutive PSRs for adult kidney transplant centers from June 2012 to December 2016 (n = 208), we applied 5-tier ratings to center outcomes and evaluated ratings over time. From the baseline period (June 2012), 47% of centers had at least a 1-unit tier change within 6 months, 66% by 1 year, and 94% by 3 years. Similarly, 46% of centers had at least a 2-unit tier change by 3 years. In comparison, 15% of centers had a change in the traditional 3-tier rating at 3 years. The 5-tier ratings at 4 years had minimal association with baseline rating (Kappa 0.07, 95% confidence interval [CI] -0.002 to 0.158). Centers had a median of 3 different 5-tier ratings over the period (q1 = 2, q3 = 4). Findings were consistent for center volume, transplant rate, and baseline 5-tier rating. Cumulatively, results suggest that 5-tier ratings are highly volatile, limiting their utility for informing potential stakeholders, particularly transplant candidates given expected waiting times between wait listing and transplantation., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later-onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long-term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Induction therapy in deceased donor kidney transplantation is costly, with wide discrepancy in utilization and a limited evidence base, particularly regarding cost-effectiveness., Methods: We linked the United States Renal Data System data set to Medicare claims to estimate cumulative costs, graft survival, and incremental cost-effectiveness ratio (ICER - cost per additional year of graft survival) within 3 years of transplantation in 19 450 deceased donor kidney transplantation recipients with Medicare as primary payer from 2000 to 2008. We divided the study cohort into high-risk (age > 60 years, panel-reactive antibody > 20%, African American race, Kidney Donor Profile Index > 50%, cold ischemia time > 24 hours) and low-risk (not having any risk factors, comprising approximately 15% of the cohort). After the elimination of dominated options, we estimated expected ICER among induction categories: no-induction, alemtuzumab, rabbit antithymocyte globulin (r-ATG), and interleukin-2 receptor-antagonist., Results: No-induction was the least effective and most costly option in both risk groups. Depletional antibodies (r-ATG and alemtuzumab) were more cost-effective across all willingness-to-pay thresholds in the low-risk group. For the high-risk group and its subcategories, the ICER was very sensitive to the graft survival; overall both depletional antibodies were more cost-effective, mainly for higher willingness to pay threshold (US $100 000 and US $150 000). Rabbit ATG appears to achieve excellent cost-effectiveness acceptability curves (80% of the recipients) in both risk groups at US $50 000 threshold (except age > 60 years). In addition, only r-ATG was associated with graft survival benefit over no-induction category (hazard ratio, 0.91; 95% confidence interval, 0.84-0.99) in a multivariable Cox regression analysis., Conclusions: Antibody-based induction appears to offer substantial advantages in both cost and outcome compared with no-induction. Overall, depletional induction (preferably r-ATG) appears to offer the greatest benefits.

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Since the 1950s, care for kidney transplant recipients in the United States has evolved around a model in which clinical management, quality metrics, and financial underpinnings are focused around the surgical procedure itself reflecting the concept that perioperative and short-term interventions are primary determinants of success. In the current era, short-term results are indeed excellent, but long-term success remains elusive for many. Emerging data, particularly a newfound understanding of donor-specific antibody and its consequences, now challenge the concept that late graft failure is the consequence of early events. Several major longitudinal studies, including the long-term Deterioration of Kidney Allograft Function (DeKAF) project and Clinical Trials in Organ Transplantation-09 (CTOT-09), highlight the primacy of later events in influencing long-term outcomes after kidney transplantation. Proper long-term care and monitoring of kidney recipients, with timely diagnosis and treatment of identifiable injury, offers the best prospect of improving long-term graft survival., Competing Interests: Potential Conflicts of Interest: None disclosed.

Background: Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors., Methods: The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed., Results: Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant., Conclusions: Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Purpose of Review: An updated overview of the state-of-the-art approaches to the care of chronic kidney disease-related issues in renal transplant recipients., Recent Findings: These include the impact of immunosuppression therapy on kidney function, the management of cardiovascular risk, metabolic bone disease, and hematologic complications, with a focus on the care of the patient with a failing allograft., Summary: A kidney transplant improves patient morbidity and mortality, but almost all transplant patients continue to have morbidity related to chronic kidney disease. It is increasingly clear that the provision of adequate immunosuppression is important to preserve allograft function. Recent studies have lent support to current guidelines for the management of cardiovascular risk factors in transplant patients. New data regarding the management of metabolic bone disease are sparse. Erythropoietin replacement may improve outcomes in transplant recipients, but the optimal target hemoglobin level is not known. Cessation of immunosuppression in the failed allograft carries the risk of rejection and allosensitization. New evidence suggests that nephrectomy may reduce mortality in patients with a failed allograft, but likely enhances sensitization in the patient awaiting retransplantation.

Variants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors.

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The short- and long-term effects of unilateral nephrectomy on living donors have been important considerations for 60 years. Short-term risk is well established (0.03% mortality and <1% risk of major morbidity), but characterization of long-term risk is evolving. Relative to the general population, risk of mortality, ESRD, hypertension, proteinuria, and cardiovascular disease is comparable or lower. However, new studies comparing previous donors with equally healthy controls indicate increased risk of metabolic derangements (particularly involving calcium homeostasis), renal failure, and possibly, mortality. We discuss how these results should be interpreted and their influence on the practice of living donor kidney transplantation., (Copyright © 2015 by the American Society of Nephrology.)

A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made-in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in long-term studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival., (Copyright © 2015 by the American Society of Nephrology.)

Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI)>85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80-90% and >90%). Kidneys with KDPI>90% were associated with increased odds of discard (OR=1.99, 95% CI 1.74-2.29) compared to ones with KDPI<80%. DKTs of KDPI>90% were associated with lower overall allograft failure (HR=0.74, 95% CI 0.62-0.89) and better patient survival (HR=0.79, 95% CI 0.64-0.98) compared to single ECD kidneys with KDPI>90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Kidney transplantation is the preferred treatment for patients with ESRD. It improves the quality of life in recipients, increases patient survival, and is also substantially less costly than maintenance dialysis. Long-term transplant success requires immunosuppressant drug therapy for the life of the allograft. Under current law, Medicare coverage for most recipients (except for those recipients over 65 years of age or with nonkidney-related disabilities) lasts only 3 years, leaving many recipients unable to afford these medications. Lack of drug therapy often leads to allograft rejection, resulting in premature graft failure, return to dialysis, or death. This article reviews the current policy for Medicare immunosuppressive drug coverage and analyzes the potential impact of pending legislative proposals H.R. 2969 and S. 1454 and the Patient Protection and Affordable Care Act.

Public reports of organ transplant program outcomes by the US Scientific Registry of Transplant Recipients have been both groundbreaking and controversial. The reports are used by regulatory agencies, private insurance providers, transplant centers and patients. Failure to adequately adjust outcomes for risk may cause programs to avoid performing transplants involving suitable but high-risk candidates and donors. At a consensus conference of stakeholders held February 13-15, 2012, the participants recommended that program-specific reports be better designed to address the needs of all users. Additional comorbidity variables should be collected, but innovation should also be protected by excluding patients who are in approved protocols from statistical models that identify underperforming centers. The potential benefits of hierarchical and mixed-effects statistical methods should be studied. Transplant centers should be provided with tools to facilitate quality assessment and performance improvement. Additional statistical methods to assess outcomes at small-volume transplant programs should be developed. More data on waiting list risk and outcomes should be provided. Monitoring and reporting of short-term living donor outcomes should be enhanced. Overall, there was broad consensus that substantial improvement in reporting outcomes of transplant programs in the United States could and should be made in a cost-effective manner., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: Dramatic improvement in short-term results after kidney transplantation has fostered a change in focus for clinical research: further improvement in patient outcomes requires better understanding of late allograft failure., Recent Findings: As recently as a decade ago, with clinicians and investigators besot by the mistaken assumption that 'rejection' was under control, most late allograft failure was attributed to calcineurin inhibitor nephrotoxicity. Application of newer laboratory-based techniques (C4d staining, solid-phase antibody assays, and molecular profiling) has resulted in a major shift in understanding late graft failure. New data from both clinic and laboratory indicate immunologic injury, perhaps potentiated by drug minimization, as the predominant cause of late allograft failure., Summary: This review traces our evolving understanding of the problem and what looks to be a paradigm change that offers new promise of effective intervention to improve long-term outcomes.

Although advances in immunosuppression, tissue typing, surgery, and medical management have made transplantation a routine and preferred treatment for patients with irreversible renal failure, successful transplant recipients have a greatly increased risk of premature mortality because of cardiovascular disease and malignancy compared with the general population. Conventional cardiovascular risk factors such as hyperlipidaemia, hypertension, and diabetes are common in transplant recipients, partly because of the effects of immunosuppressive drugs, and are associated with adverse outcomes. However, the natural history of cardiovascular disease in such recipients differs from that in the general population, and only statin therapy has been studied in a large-scale interventional trial. Thus, the management of this disease and the balance between management of conventional risk factors and modification of immunosuppression is complex., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation ('iatr') and tubulitis ('tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10-4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16-5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure., (© 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF., Methods: One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations., Results: Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF., Conclusions: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Nonadherence of transplant recipients to prescribed medical regimens has been identified as a major cause of allograft failure. Although recent studies offer new insight into the clinical phenotypes of nonadherence, advances in defining risk factors and appropriate interventions have been limited because of variable definitions, inadequate clinical metrics, and the challenges associated with healthcare delivery. Significant nonadherence is estimated to occur in 22% of renal allograft recipients and may be a component of allograft loss in approximately 36% of patients. It is associated with increased incidence of rejection (acute and chronic) and, consequently, shortened renal allograft survival, requiring reinstitution of costly chronic renal replacement therapy with an incumbent effect on morbidity and mortality. The economic effect of nonadherence approaches similar magnitude. Identification of risk factors, coupled with measures that effectively address them, can have a positive effect at many levels--medically, socially, and economically. Further advances are likely to be dependent on improving interactions between patients and caregivers, broadening immunosuppressant availability, and newer therapeutics that move toward simpler regimens.

The Opticept trial was an open-label, randomized, multicenter trial involving 720 kidney recipients. Three immunosuppressant dosing regimens were evaluated, including both fixed and concentration-controlled dosing of mycophenolate mofetil in combination with standard and reduced calcineurin inhibitor levels. Mycophenolic acid (MPA) levels were measured, yielding one of the largest databases to assess the impact of variables on MPA exposure. The present subset analysis evaluated the effect of baseline body weight in three noncontiguous weight categories on MPA exposure at steady state (Day 90) in patients receiving tacrolimus. Multivariate linear regression models assessed the relationship between area under the concentration-time curve (AUC) and several variables. In all, 219 patients had baseline weights in the three categories and an MPA AUC at Day 90: 50 kg or less (n = 12, all female); 60 to 80 kg (n = 136); or 100 kg or greater (n = 71). In overall comparisons by weight class, clearance increased with increased weight, resulting in an inverse relationship between dose-corrected MPA AUCs and weight at Day 90 (P < 0.0001). In patients of extreme weight, wide disparities of MPA exposure were measured despite the mean mycophenolate mofetil dose, notably in those 50 kg or less who had comparatively high dose-corrected MPA AUCs. Patients at the extremes of weight might be at risk of over- or underimmunosuppression unless doses are adjusted.

Use of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus has revolutionized solid organ transplantation. For more than 30 yr, the transplant community has dealt with nephrotoxicity attributed to these agents. Acute renal vasoconstriction (as described by many investigators, including John Curtis and colleagues) is the unequivocal consequence of their use; chronic CNI nephropathy, although indistinct in terms of histology and pathophysiology, has become accepted as a major cause of late kidney allograft failure. This article examines clinical, laboratory, and histologic findings that evolved into a paradigm that was never fully consistent with observed outcomes and new evidence that may offer an alternative interpretation for adverse events that are attributed to CNI nephrotoxicity in kidney transplant recipients.

Background: Patients who receive kidney transplants before beginning dialysis (known as preemptive transplantation) have lower rates of morbidity and mortality and a longer work life than do those who receive them after beginning dialysis. But in the United States fewer than 2.5% of patients with end-stage kidney disease undergo transplantation as their initial therapy., Objective: To understand barriers to early transplantation, the National Kidney Foundation (NKF) surveyed patients randomly selected from its database., Methods: A 28-question survey on socioeconomic factors; perceptions, fears, and concerns about living-donor transplantation; and education regarding transplantation as a treatment option was distributed to a total of 3,586 people randomly chosen from the NKF's database. The database is not limited to kidney patients, and 19.3% of the responses were disqualified because the respondents didn't have chronic kidney disease (CKD) or hadn't undergone kidney transplantation. The 417 responses acceptable for analysis represented at least 12% of qualified survey recipients. Of these, 316 (76%) were kidney transplant recipients from either living or deceased donors and 101 (24%) were patients with CKD who had never undergone transplantation. The surveys sent to the latter group contained slight modifications from those sent to the transplant recipients. We compared responses from people who had undergone kidney transplantation with responses from those who hadn't undergone the procedure., Results: Renal transplant recipients had higher incomes and more education, were more often white, and were more likely to have learned about treatment options from a physician than were those who hadn't undergone transplantation. Half of the respondents who hadn't undergone the procedure believed that dialysis must precede transplantation, and 60% viewed transplantation as a last resort. Out-of-pocket expenses were greater for transplant recipients, even though worries about future medical costs were common in both groups. Most respondents were willing to accept a kidney from a living donor, although they were uncomfortable with asking someone to donate., Conclusions: Substantial barriers to preemptive kidney transplantation remain for patients with CKD; a lack of financial resources and educational deficits were the most common barriers found in the survey.

Death with function causes half of late kidney transplant failures, and cardiovascular disease (CVD) is the most common cause of death in these patients. We examined the use of potentially cardioprotective medications in a prospective observational study at seven transplant centers in the United States and Canada. Among 935 patients, 87% received antihypertensive medications at both 1 and 6 months after transplantation. Similar antihypertensive regimens were used for patients with and without diabetes and CVD, but with wide variability among centers. In contrast, while 44% of patients were on angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) at the time of transplantation, the proportion taking these agents dropped to 12% at month 1, then increased to 24% at 6 months. Fewer than 30% with CVD or diabetes received ACEI/ARB therapy 6 months posttransplant. Aspirin use was uncommon (<40% of patients). Even among those with diabetes and/or CVD, fewer than 60% received aspirin and only half received a statin at 1 and 6 months. This study demonstrates marked variability in the use of cardioprotective medications in kidney transplant recipients, a finding that may reflect, among several possible explanations, clinical uncertainty due the lack of randomized trials for these medications in this population.

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMF(CC)) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF(CC) and reduced-level calcineurin inhibitor (MMF(CC)/CNI(RL)); (B) MMF(CC) and standard-level CNI (MMF(CC)/CNI(SL)); or (C) fixed-dose MMF and CNI(SL) (MMF(FD)/CNI(SL)). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (alpha= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p < or = 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMF(CC) with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF(FD), indicating potential utility of MMF(CC) in CNI-sparing regimens.