Faculty Bibliography

BACKGROUND:Organ transplantation from donors with HIV to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV+ donors is critical for safety. METHODS:We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) testing within the HOPE in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262; NCT03500315; NCT03734393). We compared clinical characteristics in HIV+ versus FP donors. We measured CD4+ T cells, HIV viral load (VL), drug resistance mutations (DRMs), co-receptor tropism, and serum antiretroviral therapy (ART) detection using mass spectrometry in HIV+ donors. RESULTS:Between 03/2016-03/2020, 92 donors (58 HIV+, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidney, 46 liver). Each year the number of donors increased. Prevalence of hepatitis B (16% vs. 0%), syphilis (16% vs. 0%), and cytomegalovirus (91% vs. 58%) was higher in HIV+ versus FP donors; hepatitis C viremia was similar (2% vs. 6%). Most HIV+ donors (71%) had known HIV diagnosis, of whom 90% were prescribed ART and 68% had VL<400 copies/mL. Median CD4 count was 194 cells/uL (IQR=77-331); median CD4% was 27.0 (IQR=16.8-36.1). Major HIV DRMs were detected in 42%, including non-nucleoside reverse transcriptase inhibitors (33%), integrase strand transfer inhibitor (INSTI, 4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION/CONCLUSIONS:Utilization of HIV+ donor organs is increasing. HIV DRMs are common, yet resistance that would compromise INSTI-based regimens is rare, which is reassuring regarding safety.

Background/UNASSIGNED:The development of cytomegalovirus (CMV) infection after kidney transplant remains a significant cause of posttransplant morbidity, graft loss, and mortality. Despite appropriate antiviral therapy, recipients without previous CMV exposure can currently be allocated a kidney from a donor with previous CMV infection (D+R-) which carries the greatest risk of posttransplant CMV infection and associated complications. Preferential placement of CMV D- organs in negative recipients (R-) has been shown to reduce the risk of viral infection and associated complications. Methods/UNASSIGNED:To assess the long-term survival and economic benefits of allocation policy reforms, a decision analytic model was constructed to compare receipt of CMV D- with CMV D+ organ in CMV R- recipients using data from transplant registry, Medicare claims, and pharmaceutical costs. Results/UNASSIGNED:For CMV R- patients, receipt of a CMV D- organ was associated with greater average survival (14.3 vs 12.6 years), superior quality-adjusted life years (12.6 vs 9.8), and lower costs ($529 512 vs $542 963). One-way sensitivity analysis demonstrated a survival advantage for patients waiting as long as 30 months for a CMV D- kidney. Conclusions/UNASSIGNED:Altering national allocation policy to preferentially offer CMV D- organs to CMV R- recipients could improve survival and lower costs after transplant if appropriately implemented.

Introduction/UNASSIGNED:Depressive symptoms, even without a clinical diagnosis of depression, are common in kidney failure patients and may be a barrier to completing the complex process of kidney transplant (KT) evaluation. We assessed depressive symptom burden and association between depressive symptoms and access to KT waitlist by age. Methods/UNASSIGNED:In a prospective cohort of 3728 KT patients (aged 18-88 years), the Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms at evaluation. Depressive symptom severity was defined as follows: none: 0; minimal: 1 to 15; mild: 16 to 20; moderate: 21 to 25; severe: 26 to 60. Hazard ratios (HRs) of active listing within 1 year after evaluation were estimated using Cox proportional hazards models, adjusted for clinical and social factors. Results/UNASSIGNED: < 0.001). After adjustment, every 5-point higher CES-D score (more depressive symptoms) was associated with a 13% lower chance of listing (HR = 0.87, 95% CI: 0.85-0.90); the strongest association was found among patients aged ≥70 years (adjusted HR [aHR] = 0.73, 95% CI: 0.62-0.86). Furthermore, minimal (HR = 0.69, 95% CI: 0.60-0.79), mild (HR = 0.57, 95% CI: 0.44-0.72), moderate (HR = 0.53, 95% CI: 0.39-0.71), and severe (HR = 0.44, 95% CI: 0.34-0.57) depressive symptoms were all associated with a lower chance of listing. Conclusion/UNASSIGNED:Older candidates were less likely to report depressive symptoms at KT evaluation. Regardless of age, candidates who did report depressive symptoms, and even minimal symptoms, had a lower chance of listing. Transplant centers should routinely screen patients for depressive symptoms and refer the affected patients to mental health services to improve access to KT.

RATIONALE & OBJECTIVE/UNASSIGNED:Disorders of bone and mineral metabolism frequently develop with advanced kidney disease, may be exacerbated by immunosuppression after kidney transplantation, and increase the risk of fractures. STUDY DESIGN/UNASSIGNED:Retrospective database study. SETTING & PARTICIPANTS/UNASSIGNED:Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States captured in US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. EXPOSURES/UNASSIGNED:Various immunosuppression regimens in the first 3 months after kidney transplantation. OUTCOMES/UNASSIGNED:The development of fractures, as ascertained using diagnostic codes on Medicare billing claims. ANALYTICAL APPROACH/UNASSIGNED:We used multivariable Cox regression with inverse propensity weighting to compare the incidence of fractures >3 months-to-3 years after kidney transplantation associated with various immunosuppression regimens compared to a reference regimen of antithymocyte globulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse probability treatment weighting. RESULTS/UNASSIGNED: < 0.001]). Induction with TMG or ALEM and the avoidance or early withdrawal of steroids significantly reduced the risk of fractures in younger (aHR, 0.63; 95% CI, 0.54-0.73) and older (aHR, 0.83; 95% CI, 0.74-0.94) patients. The avoidance or early withdrawal of steroids with any induction was associated with a reduced risk of fractures in women. LIMITATIONS/UNASSIGNED:This was a retrospective study which lacked data on immunosuppression levels. CONCLUSIONS/UNASSIGNED:Fractures after kidney transplantation are associated with significantly increased mortality risk and costs. The early avoidance or early withdrawal of steroids after induction with TMG or ALEM reduces the risk of fractures after kidney transplantation and should be considered for patients at high-risk of this complication, including older adults and women.

Patient and graft survival are similar following whole versus split liver transplants (SLT) among pediatric and adult recipients, yet SLTs are rarely used. We sought to determine the survival benefit associated with accepting a splittable offer for SLT versus declining and waiting for a subsequent offer using 2010-2018 SRTR data on 928 pediatric and 1814 adult LT candidates who were ever offered a splittable graft. We compared eventual mortality, regardless of subsequent transplants, between those who accepted versus declined a splittable liver offer with adjustment for PELD/MELD, diagnosis, and weight among pediatric candidates, and matching for MELD, height, and offer among adult candidates. Among pediatric candidates ≤7kg, splittable offer acceptance versus decline was associated with a 63% reduction in mortality (aHR _0.17 0.37_0.80 , p=0.01; 93.1% versus 84.0% one-year survival post-decision). Within one year of decline for those ≤7kg, 6.4% died and 31.1% received a whole liver transplant. Among pediatric candidates >7kg, there was no significant difference associated with acceptance of a splittable offer (aHR _0.63 1.07_1.82 , p=0.81; 91.7% vs 94.4% one-year survival post-decision). Within one year of decline for those >7kg, 1.8% died and 45.8% received a whole liver. Among adult candidates, splittable offer acceptance was associated with a 43% reduction in mortality (aHR _0.39 0.57_0.83, p=0.005; 92.2% vs 84.4% one-year survival post-decision). Within one year of decline for adult candidates, 7.9% died and 39.3% received a whole liver. Conclusion: Accepting splittable offers for SLT could significantly improve survival for small children and adults on the waitlist.

BACKGROUND AND AIMS/OBJECTIVE:Frailty is a well-established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. APPROACH AND RESULTS/UNASSIGNED:Adult LT recipients from 8 US centers (2012-2019) were included. Pre-LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). "Frail" was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define "prolonged" post-LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post-LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre-LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log-rank p = 0.02). Pre-LT frailty was associated with an unadjusted 62% increased risk of post-LT mortality (95% CI, 1.08-2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39-3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47-2.73), ICU stay (OR, 1.56; 95% CI, 1.12-2.14), inpatient days within 90 post-LT days (OR, 1.72; 95% CI, 1.25-2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58-3.97). CONCLUSIONS:Compared with nonfrail patients, frail LT recipients had a higher risk of post-LT death and greater post-LT health care utilization, although overall post-LT survival was acceptable. These data lay the foundation to investigate whether targeting pre-LT frailty will improve post-LT outcomes and reduce resource utilization.