Faculty Bibliography

A more granular donor kidney grading scale, the kidney donor profile index (KDPI), has recently emerged in contradistinction to the standard criteria donor/expanded criteria donor framework. In this paper, we built a Markov decision process model to evaluate the survival, quality-adjusted life years (QALY), and cost advantages of using high-KDPI kidneys based on multiple KDPI strata over a 60-month time horizon as opposed to remaining on the waiting list waiting for a lower-KDPI kidney. Data for the model were gathered from the Scientific Registry of Transplant Recipients and the United States Renal Data System Medicare parts A, B, and D databases. Of the 129,024 phenotypes delineated in this model, 65% of them would experience a survival benefit, 81% would experience an increase in QALYs, 87% would see cost-savings, and 76% would experience cost-savings per QALY from accepting a high-KDPI kidney rather than remaining on the waiting list waiting for a kidney of lower-KDPI. Classification and regression tree analysis (CART) revealed the main drivers of increased survival in accepting high-KDPI kidneys were wait time ≥30 months, panel reactive antibody (PRA) <90, age ≥45 to 65, diagnosis leading to renal failure, and prior transplantation. The CART analysis showed the main drivers of increased QALYs in accepting high-kidneys were wait time ≥30 months, PRA <90, and age ≥55 to 65.

BACKGROUND/UNASSIGNED:Advancements in medical technology, healthcare delivery, and organ allocation resulted in improved patient/graft survival for older (age ≥65) kidney transplant (KT) recipients. However, the recent trends in these post-KT outcomes are uncertain in light of the mounting burden of cardiovascular disease, changing kidney allocation policies, heterogeneity in candidates' risk profile, and the coronavirus disease 2019 pandemic. Thus, we examined secular trends in post-KT outcomes among older and younger KT recipients over the last 3 decades. METHODS/UNASSIGNED:We identified 73 078 older and 378 800 younger adult (aged 18-64) recipients using Scientific Registry of Transplant Recipients (1990-2022). KTs were grouped into 6 prepandemic eras and 1 postpandemic-onset era. Kaplan-Meier and Cox proportional hazards models were used to examine temporal trends in post-KT mortality and death-censored graft failure. RESULTS/UNASSIGNED:From 1990 to 2022, a 19-fold increase in the proportion of older KT recipients was observed compared to a 2-fold increase in younger adults despite a slight decline in the absolute number of older recipients in 2020. The mortality risk for older recipients between 2015 and March 14, 2020, was 39% (adjusted hazard ratio [aHR] = 0.61, 95% confidence interval [CI], 0.50-0.75) lower compared to 1990-1994, whereas that for younger adults was 47% lower (aHR = 0.53, 95% CI, 0.48-0.59). However, mortality risk during the pandemic was 25% lower (aHR = 0.75, 95% CI, 0.61-0.93) in older adults and 37% lower in younger adults (aHR = 0.63, 95% CI, 0.56-0.70) relative to 1990-1994. For both populations, the risk of graft failure declined over time and was unaffected during the pandemic relative to the preceding period. CONCLUSIONS/UNASSIGNED:The steady improvements in 5-y mortality and graft survival were disrupted during the pandemic, particularly among older adults. Specifically, mortality among older adults reflected rates seen 20 y prior.

Purpose of Review: This review presents an overview of the clinical syndrome of frailty and its association with kidney transplantation outcomes, recent developments in refining frailty assessment, and considerations for its implementation into kidney transplant evaluation. Recent Findings: Recent studies show that frailty is associated with adverse clinical outcomes before and after kidney transplantation, including decreased likelihood of listing and increased risks of mortality. However, frailty assessment has yet to be fully adopted by transplant centers; a study found that 40.9% of centers reported never assessing frailty at evaluation of kidney transplant candidates. Geriatric transplant experts and kidney transplant candidates agree that frailty is a valid consideration for evaluating candidacy. Summary: While frailty is an important consideration for treatment of patients with end-stage renal disease, its use in kidney transplant evaluation remains under-utilized. Future research is necessary to refine the frailty phenotype for effective integration into a kidney transplant context.

Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.

BACKGROUND/UNASSIGNED:Living kidney donation is possible for people living with HIV (PLWH) in the United States within research studies under the HIV Organ Policy Equity (HOPE) Act. There are concerns that donor nephrectomy may have an increased risk of end-stage renal disease (ESRD) in PLWH due to HIV-associated kidney disease and antiretroviral therapy (ART) nephrotoxicity. Here we report the first 3 cases of living kidney donors with HIV under the HOPE Act in the United States. METHODS/UNASSIGNED:Within the HOPE in Action Multicenter Consortium, we conducted a prospective study of living kidney donors with HIV. Pre-donation, we estimated the 9-year cumulative incidence of ESRD, performed genetic testing of apolipoprotein L1 (APOL1), excluding individuals with high-risk variants, and performed pre-donation kidney biopsies (HOPE Act requirement). The primary endpoint was ≥grade 3 nephrectomy-related adverse events (AEs) in year one. Post-donation, we monitored glomerular filtration rate (measured by iohexol/Tc-99m DTPA [mGFR] or estimated with serum creatinine [eGFR]), HIV RNA, CD4 count, and ART. FINDINGS/UNASSIGNED: at two years (eGFR) in donor 3. HIV RNA remained <20 copies/mL and CD4 count remained stable in all donors. INTERPRETATION/UNASSIGNED:The first three living kidney donors with HIV under the HOPE Act in the United States have had promising outcomes at two-four years, providing proof-of-concept to support living donation from PLWH to recipients with HIV. FUNDING/UNASSIGNED:National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Anti-spike binding antibody (Ab) levels are used by some providers to inform COVID-19 risk assessment for solid organ transplant recipients (SOTRs). As has been observed with other Ab assays, in the setting of high binding Ab, quantitative results may demonstrate artifactually low values (i.e., “hook” or prozone effect). Within two studies of SARS-CoV-2 vaccination of SOTRs (an observational cohort and a single-center trial), Ab levels were assessed using the semiquantitative Roche Elecsys anti-SARS-CoV-2 S assay. In the observational cohort, we flagged 9 samples with either a paradoxical decrease or weak (<10x) rise after Tixagevimab/Cilgavimab (T/C) administration. This prompted retesting with up-front 1:50 dilution, with serial dilution performed until returning two results within expected assay variation. Subsequently, all post-vaccination clinical trial samples were retested. Hook effect was suspected if retest level was both ≥15% and ≥200U/mL higher than original level. From the observational cohort, all 9 flagged samples demonstrated a hook effect. Of 377 clinical trial samples (all rerun), 34/377 (9%) demonstrated a hook effect. Among the hook effect samples (n=43), the original median (IQR) titer was 1950 (650 – 4390) U/mL, and upon retesting this increased to 5685 (2981 – 9853) U/mL representing a 1.6 (1.3–6.0)-fold increase (p=0.03). Marked hook effect (>700x increase) was observed in two participants with recent vaccination plus breakthrough infection. Hook effect was observed in SOTRs tested using a SARS-CoV-2 clinical Ab assay in the setting of high analyte. Laboratories and clinicians should be aware of this artifact and consider serial dilution to confirm accurate quantitative results.