Employment status at transplant influences ethnic disparities in outcomes after deceased donor kidney transplantation.

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.

i-IFTA and chronic active T cell-mediated rejection: A tale of 2 (DeKAF) cohorts.

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.

Transplant physician and surgeon compensation: A sample framework accounting for nonbillable and value-based work.

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.

Redefining the Influence of Ethnicity on Simultaneous Kidney and Pancreas Transplantation Outcomes: A 15-year Single-center Experience.

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.

Genome-wide association study for time to failure of kidney transplants from African American deceased donors.

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.

Time for reform in transplant program-specific reporting: AST/ASTS transplant metrics taskforce.

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.

Variation in use of procurement biopsies and its implications for discard of deceased donor kidneys recovered for transplantation.

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 aOR95%UCL ], 3.29 3.513.76 ). This association was most pronounced for low-risk (KDPI <20) kidneys (aOR, 5.45 6.477.69 ), with minimal impact at KDPI >85 (aOR, 0.88 1.151.51 ). 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.

Chronic dialysis in patients with end-stage renal disease: Relevance to kidney xenotransplantation.

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.

Expanding clarity or confusion? Volatility of the 5-tier ratings assessing quality of transplant centers in the United States.

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.

Late graft failure after kidney transplantation as the consequence of late versus early events.

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.

IMPROVING LONG-TERM OUTCOMES IN KIDNEY TRANSPLANTATION: TOWARDS A NEW PARADIGM OF POST-TRANSPLANT CARE IN THE UNITED STATES.

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.

Reassessing medical risk in living kidney donors.

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.

Through a glass darkly: seeking clarity in preventing late kidney transplant failure.

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.

Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation.

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.

Medical management of chronic kidney disease in the renal transplant recipient.

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.

Prevention of cardiovascular disease in adult recipients of kidney transplants.

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.

Risk Prediction for Delayed Allograft Function: Analysis of the Deterioration of Kidney Allograft Function (DeKAF) Study Data.

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.

Our evolving understanding of late kidney allograft failure.

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.