Faculty Bibliography

BACKGROUND:Transplant waitlist registrants in the United States may be delisted because of receipt of a transplant abroad. Although not universally unethical, "travel for transplantation" poses risks to posttransplant care. To better understand this phenomenon, this study identifies temporal trends, geographic patterns, and demographic factors associated with cross-border transplantation. METHODS:Using Scientific Registry of Transplant Recipients data, we identified 818 US waitlist candidates who were removed because of transplantation abroad between 2010 and 2023. We described recipient characteristics overall, by organ, and by top transplant destinations. We used a Cox regression framework to identify characteristics associated with waitlist removal due to transplantation abroad. RESULTS:Transplants abroad averaged 58.4 per year. Incidence peaked at 80 transplants in 2017, with an upward trend after 2021. Kidney transplants made up 92.1% of cases. The most common destinations were the Philippines (19.8%), India (16.5%), Mexico (9.4%), China (8.4%), and Iran (4.4%). India and Mexico experienced the smallest drop-off during the height of the COVID-19 pandemic 2020-2021. Most recipients were US citizens (65.0%) or residents (23.5%). Female (adjusted hazard ratio [aHR], 0.520.610.71; P < 0.001) and Black candidates (aHR, 0.120.180.26; P < 0.001) were less likely to travel abroad compared with Asian candidates (aHR, 5.927.108.52; P < 0.001). Nonresidents (aHR, 6.708.6911.26; P < 0.001) and, among registrations in 2012 or later, nonresidents who traveled to the United States for transplantation (aHR, 27.2738.9155.50; P < 0.001) had a greater chance of undergoing transplantation abroad. CONCLUSIONS:Understanding patterns of international travel for transplantation is key not only for preventing resource drains from destination countries but also for providing adequate posttransplant care for recipients.

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia. METHODS:This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events. RESULTS:7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%. CONCLUSION/CONCLUSIONS:A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.

Procurement biopsies are routinely obtained in the United States to evaluate kidneys considered for transplantation, but some argue that they may contribute to kidney nonutilization. Historically, biopsy decisions have been left solely to the discretion of organ procurement organizations (OPOs) and transplant centers. In September 2022, an organ procurement and transplantation network (OPTN) policy designating donors meeting specific clinical criteria as "biopsy-required" went into effect. Using OPTN data from 1 year before and after policy implementation, we used causal inference methods to estimate the policy's impacts on biopsy practices and kidney utilization. The overall biopsy rate remained stable at 62%, rising from 90.6% to 95.8% (P < .001) among biopsy-required kidneys while falling from 49.1% to 43.4% (P < .001) among biopsy-optional kidneys. After adjusting for changing donor characteristics, the policy was associated with a 5% decline in the biopsy rate (adjusted risk ratio = 0.95; P = .007). The overall kidney nonuse rate rose from 27.2% to 28.7%. After accounting for changes in donor characteristics, the policy was not associated with elevated nonuse (adjusted risk ratio = 0.96, P = .06). Although most OPOs are now biopsying nearly all required kidneys, practices still vary widely regarding biopsy-optional kidneys. No correlation was found between OPO-level changes in adjusted biopsy and nonuse rates (ρ = 0.05, P = .70). The OPTN policy has partially standardized biopsy practices without harming kidney utilization.

Human leukocyte antigen-level matching in US kidney allocation has been deemphasized due to its role in elevating racial disparities. Molecular matching based on eplets might improve risk stratification compared to antigen matching, but the magnitude of racial disparities in molecular matching is not known. To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high-resolution allele-level human leukocyte antigen genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased-donor pool, we profiled the percentage of well-matched donors available for candidates by ethnicity. The prevalence of well-matched donors with 0-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates and 2-fold less for Latino candidates compared to 0-ABDR antigen mismatches. Compared to 0-DR antigen mismatch, 0-DR eplet mismatch was 1.33-fold more racially disparate for Asian and 1.28-fold more for Latino, with similar disparity for Black candidates, whereas 0-DQ eplet mismatch reduced disparities, showing 1.26-fold less disparity for Black, 1.14-fold less for Latino, but 1.26-fold higher for Asian candidates. The prevalence of well-matched donors for candidates of different ethnicities varied according to which molecules were chosen to define a low-risk match.

BACKGROUND:Given the cardiovascular, renal, and survival benefits of GLP-1 receptor agonists for diabetes, these agents could be effective among kidney transplant recipients. However, kidney transplant recipients are distinct from GLP-1 receptor agonist trial participants, with longer diabetes duration and severity, greater end-organ damage, increased cardiovascular risk, and multimorbidity. We examined GLP-1 receptor agonist real-world effectiveness and safety in kidney transplant recipients with diabetes. METHODS:This USA-based retrospective cohort study included kidney transplant recipients with type 2 diabetes at transplantation and Medicare as their primary insurance from a national registry linked with Medicare claims. Post-transplantation GLP-1 receptor agonist use was identified through Medicare claims. Death-censored graft loss was estimated using the Fine-Gray sub-distribution hazard model and extended Cox models were used for mortality and safety endpoints. Models incorporated inverse probability of treatment weights. To further test whether bias could affect the main results, a cohort was created in which each GLP-1 receptor agonist user was matched with a kidney transplant recipient who had not started a GLP-1 receptor agonist, was alive with a functioning graft, and had accrued the same amount of post-transplant survival time. FINDINGS/RESULTS:Between Jan 1, 2013 and Dec 31, 2020, we identified 44 536 first time kidney transplant recipients with Medicare as primary payer in the 6 months before and at transplantation. 24 192 patients were excluded as they did not have type 2 diabetes. 2328 patients were ineligible (1916 had missing values and 412 used GLP-1 receptor agonists before transplantation). The primary cohort thus consisted of 18 016 kidney transplant recipients with diabetes. Of these patients, 1969 (10·9%) had at least one GLP-1 receptor agonist prescription filled post-transplant. Compared with patients who had not received a GLP-1 receptor agonist, GLP-1 receptor agonist users were younger (median age at transplant 57 years [IQR 49-64] vs 60 years [51-66], p<0·0001) and more likely to be female (786 [39·9%] vs 5645 [35·2%], p<0·0001). Among GLP-1 receptor agonist users, 552 [28·0%] were non-Hispanic White, 703 [35·7%] were non-Hispanic Black, and 568 [28·8%] were Hispanic. The 5-year unadjusted cumulative incidence of death-censored graft loss from a cohort matched on survival time before GLP-1 receptor agonist initiation was 6·0% for GLP-1 receptor agonist users and 10·7% for non-users (Gray's test p=0·004). The 5-year unadjusted cumulative incidence for mortality from a cohort matched on survival time before GLP-1 receptor agonist initiation was 17·0% for GLP-1 receptor agonist users and 25·8% for non-users (log-rank p=0·0006). The 5-year unadjusted cumulative incidence for mortality was 13·5% for GLP-1 receptor agonist users and 19·9% for non-users (log-rank p<0·0001). GLP-1 receptor agonist use was associated with a 49% lower incidence of death-censored graft loss (adjusted subhazard ratio [aSHR] 0·51, 95% CI 0·36-0·71; p=0·0001) and 31% lower mortality (adjusted hazard ratio [aHR] 0·69, 95% CI 0·55-0·86; p=0·001). Inferences were robust when matched on survival time (death-censored graft loss aSHR 0·53, 95% CI 0·37-0·75; p=0·0005; mortality aHR 0·70, 95% CI 0·55-0·88; p=0·003). Safety endpoints were rare and not associated with GLP-1 receptor agonists, with the exception of diabetic retinopathy (aHR 1·49, 1·11-2·00; p=0·008). INTERPRETATION/CONCLUSIONS:GLP-1 receptor agonists were associated with better graft and patient survival. Clinical trials are needed to confirm these findings. FUNDING/BACKGROUND:National Institutes of Health.

Developing real-world evidence from electronic health records (EHR) is vital to advance kidney transplantation (KT). We assessed the feasibility of studying KT using the Epic Cosmos aggregated EHR dataset, which includes 274 million unique individuals cared for in 238 U.S. health systems, by comparing it with the Scientific Registry of Transplant Recipients (SRTR). We identified 69,418 KT recipients transplanted between January 2014 and December 2022 in Cosmos (39.4% of all US KT transplants during this period). Demographics and clinical characteristics of recipients captured in Cosmos were consistent with the overall SRTR cohort. Survival estimates were generally comparable, although there were some differences in long-term survival. At 7 years post-transplant, patient survival was 80.4% in Cosmos and 77.8% in SRTR. Multivariable Cox regression showed consistent associations between clinical factors and mortality in both cohorts, with minor discrepancies in the associations between death and both age and race. In summary, Cosmos provides a reliable platform for KT research, allowing EHR-level clinical granularity not available with either the transplant registry or healthcare claims. Consequently, Cosmos will enable novel analyses to improve our understanding of KT management on a national scale.

BACKGROUND/UNASSIGNED:Imlifidase is an IgG-cleaving endopeptidase conditionally approved in Europe for desensitization of highly sensitized patients before kidney transplantation. We present 5-y outcomes and donor-specific antibody (DSA) levels for clinical trial participants from a single site who received imlifidase for desensitization before incompatible transplantation (NCT02790437). METHODS/UNASSIGNED:Imlifidase was administered up to 24 h before living or deceased donor kidney transplantation. DSAs were monitored before transplantation, at days 7 and 28, and at 5 y posttransplant. RESULTS/UNASSIGNED:At 5 y, 7 of 8 participants were alive. One of these 7 had suboptimal graft function secondary to donor-derived disease but remained dialysis independent. Three participants had antibody-mediated rejection (AMR), which occurred in the first 30 d in all cases and was successfully treated. No new episodes of suspected or biopsy-proven AMR occurred after 30 d posttransplant. Seven participants had DSA rebound. DSAs commonly persisted 5 y posttransplant, although they were generally lower strength compared with pre-imlifidase. Dilution studies of sensitized serum enabled the identification of lower AMR risk phenotypes for persisting DSAs. Severe and/or opportunistic infections were not observed at greater than expected frequency. CONCLUSIONS/UNASSIGNED:Five-year outcomes of imlifidase-enabled incompatible transplants are overall favorable. DSA rebound is common, but antibody strength lessens in the long term, and longitudinally persisting DSAs did not lead to premature graft failure.