Faculty Bibliography

PURPOSE/OBJECTIVE:In October 2018, the OPTN changed adult heart transplant (HT) allocation policy, increasing the number of adult candidates that had higher priority than pediatric candidates, potentially disadvantaging pediatric waitlist registrants. METHODS:To understand the impact of this policy change, we used SRTR data to identify 1469 pre-policy (7/2016-9/2018) and 2901 (10/2018-12/2022) post-policy pediatric (< 18 years) HT registrants. We quantified mortality and transplant risks using weighted cause-specific hazard models, and then using weighted competing risks regression. We further stratified these analyses by age to understand risks for those in direct competition with adults for organs (≥ 12 years). RESULTS:, p = 0.02). Post policy, 1-year transplant rate did not change in those < 12years (68.2%-71.0%, p = 0.77), but in those ≥ 12years, transplant rate increased (77.3%-81.0%, p = 0.003). CONCLUSIONS:Mortality on the waitlist decreased and access to HT for pediatric registrants did not decline following the 2018 policy change. The decreased mortality rate may reflect changes in patient casemix and/or improved patient care. Continued surveillance is important in ensuring equity in pediatric, and adult, HT.

BACKGROUND/UNASSIGNED:For patients with alpha-1 antitrypsin (AAT) deficiency, AAT augmentation therapy can be an important part of care. However, for those who require a lung transplant (LT), there is currently only limited information to guide the use of AAT augmentation therapy post-LT. METHODS/UNASSIGNED:We identified all LT recipients from 2011-2021 in the Scientific Registry of Transplant Recipients with an AAT deficiency diagnosis. We categorized recipients by use of AAT augmentation therapy post-LT and compared their baseline characteristics using Fisher's exact test and Wilcoxon rank-sum tests. We used Kaplan-Meier analyses and estimated the average treatment effect (ATE) of post-LT AAT augmentation therapy on mortality and all-cause graft failure (ACGF). The ATE measures the observed effect we would see if everyone in the population received the intervention as opposed to just a subset. RESULTS/UNASSIGNED: = 0.02, log-rank test). CONCLUSIONS/UNASSIGNED:In our study, the use of augmentation therapy post-LT was associated with improved survival. Confirmatory prospective studies should be considered to inform post-LT AAT therapy guidelines.

The adoption of large language models (LLMs) in healthcare demands a careful analysis of their potential to spread false medical knowledge. Because LLMs ingest massive volumes of data from the open Internet during training, they are potentially exposed to unverified medical knowledge that may include deliberately planted misinformation. Here, we perform a threat assessment that simulates a data-poisoning attack against The Pile, a popular dataset used for LLM development. We find that replacement of just 0.001% of training tokens with medical misinformation results in harmful models more likely to propagate medical errors. Furthermore, we discover that corrupted models match the performance of their corruption-free counterparts on open-source benchmarks routinely used to evaluate medical LLMs. Using biomedical knowledge graphs to screen medical LLM outputs, we propose a harm mitigation strategy that captures 91.9% of harmful content (F1 = 85.7%). Our algorithm provides a unique method to validate stochastically generated LLM outputs against hard-coded relationships in knowledge graphs. In view of current calls for improved data provenance and transparent LLM development, we hope to raise awareness of emergent risks from LLMs trained indiscriminately on web-scraped data, particularly in healthcare where misinformation can potentially compromise patient safety.

Since 2021, the Organ Procurement and Transplantation Network has reported a nearly 10-fold rise in out-of-sequence (OOS) kidney allocation, generating concern and halting development of continuous distribution policies. We report contemporary (2022-2023) practice patterns in OOS allocation using Organ Procurement and Transplantation Network data. We examined in sequence vs OOS donors with multivariable logistic regression and skipped vs OOS-accepting recipients with conditional logistic regression. Nearly 20% of kidney placements were OOS, varying from 0% to 43% acsoss organ procurement organizations; the 5 highest OOS-organ procurement organizations accounted for 29% of all OOS. Of OOS kidneys, 33% were declined ≥100 times in the standard allocation sequence and 51% were declined by ≥10 centers before OOS allocation began; 4.5% were made without any in-sequence declines. Nearly, all OOS offers were open offers. OOS kidneys were more likely to be from female, Black, older, donation after cardiac death, hypertensive, diabetic, and elevated creatinine donors. Candidates receiving OOS kidneys were more likely female, Asian, and older than skipped candidates. Higher-volume centers and centers with more White, fewer Hispanic, and more educated waiting list patients underwent transplantation disproportionately with more OOS kidneys. These findings suggest that the current, highly variable, discretionary use of OOS might exacerbate disparities, yet the impact of OOS on organ utilization cannot be determined with data now collected.

Graft failure and recipient death with functioning graft are important competing outcomes after kidney transplantation. Risk prediction models typically censor for the competing outcome thereby overestimating the cumulative incidence. The magnitude of this overestimation is not well described in real-world transplant data. This retrospective cohort study analyzed data from the European Collaborative Transplant Study (n = 125 250) and from the American Scientific Registry of Transplant Recipients (n = 190 258). Separate cause-specific hazard models using donor and recipient age as continuous predictors were developed for graft failure and recipient death. The hazard of graft failure increased quadratically with increasing donor age and decreased decaying with increasing recipient age. The hazard of recipient death increased linearly with increasing donor and recipient age. The cumulative incidence overestimation due to competing risk-censoring was largest in high-risk populations for both outcomes (old donors/recipients), sometimes amounting to 8.4 and 18.8 percentage points for graft failure and recipient death, respectively. In our illustrative model for posttransplant risk prediction, the absolute risk of graft failure and death is overestimated when censoring for the competing event, mainly in older donors and recipients. Prediction models for absolute risks should treat graft failure and death as competing events.

Solid organ transplant recipients (SOTRs) suffer more frequent and more severe infections due to their compromised immune responses resulting from immunosuppressive treatments designed to prevent organ rejection. Pharmacological immunosuppression can adversely affect immune responses to vaccination. A cohort of kidney transplant recipients (KTRs) received their third dose of ancestral, monovalent COVID-19 vaccine in the context of a clinical trial and antibody responses to the vaccine strain, as well as two Omicron variants BA.1 and BA.5 were investigated and compared with healthy controls who also received a third dose of mRNA vaccine (HCs). Total IgG and live virus neutralizing antibody titers were reduced in KTRs compared with controls for all variants. KTRs displayed altered IgG subclass switching, with significantly lower IgG3 antibodies. Responses in KTRs were also very heterogeneous, with some individuals showing strong responses but a significant number showing no Omicron-specific neutralizing antibodies. Taken together, immune responses after COVID-19 vaccination in KTRs were not only lower than HCs but highly variable, indicating that simply increasing the number of vaccine doses alone may not be sufficient to provide greater protection in this population. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations, such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies.IMPORTANCEThis study addresses the challenges faced by kidney transplant recipients (KTRs) in mounting effective immune responses against COVID-19. By evaluating the antibody responses to a third dose of monovalent mRNA COVID-19 vaccine and its effectiveness against Omicron subvariants (BA.1 and BA.5), this study reveals significant reductions in both binding and neutralizing antibodies in KTRs compared with healthy controls. The research highlights altered IgG subclass switching and heterogeneous responses within the KTR population. Reduced recognition of variants, coupled with differences in IgG subclasses, decreases both the quality and quantity of protective antibodies after vaccination in KTRs. These findings underscore the need for tailored vaccination strategies for immunosuppressed populations, such as KTRs. Alternative formulations and doses of COVID-19 vaccines should be considered for people with severely compromised immune systems, as more frequent vaccinations may not significantly improve the response, especially regarding neutralizing antibodies.

KEY POINTS:In frail kidney transplant (KT) candidates with obesity, unintentional weight loss preceding KT evaluation is associated with lower chance of listing. In frail candidates with obesity, both unintentional and intentional weight loss is associated with higher waitlist mortality. Results suggest that in frail candidates with obesity, careful supervision of weight loss prior to KT should be considered, emphasizing strategies to preserve muscle mass and function. BACKGROUND:Unintentional weight loss, a hallmark of frailty, predicts worse post–kidney transplantation (KT) outcomes. However, weight loss in candidates with obesity is often recommended to enhance transplant eligibility. We tested whether pre-evaluation weight change is associated with listing/waitlist mortality, considering intentionality and frailty. METHODS:) enrolled in a prospective multicenter cohort study. We estimated the association between pre-evaluation weight change (stable, gain, unintentional/intentional loss) with chance of listing/waitlist mortality using Cox proportional hazards/competing-risks models. RESULTS:Among candidates with obesity, 48% had stable weight, 17% had weight gain, 16% had unintentional weight loss, and 20% had intentional weight loss over the year before evaluation. Among frail candidates with obesity, stable weight was associated with a 27% lower chance of listing (adjusted hazard ratio [aHR], 0.73; 95% confidence intervals [CI], 0.55 to 0.96), weight gain with a 47% lower chance of listing (aHR, 0.53; 95% CI, 0.34 to 0.80), and unintentional weight loss with a 48% lower chance of listing (aHR, 0.52; 95% CI, 0.32 to 0.84) compared with nonfrail candidates with stable weight. However, in frail candidates with obesity, intentional weight loss was not associated with a significantly lower chance of listing compared with nonfrail candidates with stable weight. In addition, among frail candidates with obesity, stable weight (adjusted subhazard ratio [aSHR], 1.72; 95% CI, 1.01 to 2.90), unintentional weight loss (aSHR, 2.78; 95% CI, 1.23 to 6.27), and intentional weight loss (aSHR, 2.26; 95% CI, 1.05 to 4.85) were associated with higher waitlist mortality compared with nonfrail candidates with stable weight. Among nonfrail candidates, no associations were observed for weight change and frailty status with either chance of listing or waitlist mortality. CONCLUSIONS:Among frail candidates with obesity, unintentional pre-KT weight loss is associated with a lower chance of listing; however, any weight loss is associated with higher waitlist mortality. Our findings suggest that frail candidates with obesity may benefit from clinician supervision of pre-KT weight loss.

BACKGROUND:In recent years, changes to US organ allocation have aimed to improve equity and accessibility across regions. The Organ Procurement and Transplantation Network plans to adopt continuous liver distribution, prioritizing candidates based on a weighted composite allocation score (CAS) incorporating proximity, ABO types, medical urgency, and pediatric priority. The Liver Committee has requested research on CAS variations that account for geographical heterogenicity. METHODS:We describe a method for designing a geographically heterogeneous CAS with targeted broader sharing (CAS-TBS) to balance the highly variable geographic distributions of liver transplant listings and liver donations. CAS-TBS assigns each donor hospital to either broader sharing or nearby sharing, adjusting donor-candidate distance allocation points accordingly. RESULTS:We found that to reduce geographic disparity in the median Model for End-stage Liver Disease at transplant (MMaT), >75% of livers recovered in regions 2 and 10 should be distributed with broader sharing, whereas 95% of livers recovered in regions 5 and 1 should be distributed with nearby sharing. In a 3-y simulation of liver allocation, CAS-TBS decreased MMaT by 2.1 points in high-MMaT areas such as region 5 while increasing MMaT only by 0.65 points in low-MMaT areas such as region 3. CAS-TBS significantly decreased median transport distance from 202 to 167 nautical miles under acuity circles and decreased waitlist deaths. CONCLUSIONS:Our CAS-TBS design methodology could be applied to design geographically heterogeneous allocation scores that reflect transplant community values and priorities within the continuous distribution project of the Organ Procurement and Transplantation Network. In our simulations, the incremental benefit of CAS-TBS over CAS was modest.

The rise in the mean age of the global population has led to an increase in older kidney transplant (KT) patients. This demographic shift, coupled with the ongoing organ shortage, requires a nuanced understanding of which older adults are most suitable for KT. Recognizing the increased heterogeneity among older adults and the limitations of solely relying on chronological age, there is a need to explore alternative aging metrics beyond chronological age. In this review, we discuss the impact of older age on access to KT and postoperative outcomes. Emphasizing the need for a comprehensive evaluation that extends beyond chronological age, we explore alternative aging metrics such as frailty, sarcopenia, and cognitive function, underscoring their potential role in enhancing the KT evaluation process. Most importantly, we aim to contribute to the ongoing discourse, fostering an optimized approach to KT for the rapidly growing population of older adults.