Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:The science and practice of xenotransplantation is advancing more rapidly than the regulatory infrastructure that will be necessary to ensure the promise of alleviating the organ shortage can be safely and equitably met. RECENT FINDINGS/RESULTS:While countries leading the way have developed some regulatory guidance to support first in human "compassionate use" xenotransplant interventions and the first clinical trials, existing legislative, regulatory, and operational frameworks for human allotransplantation have not been explicitly extended to nonhuman animal organs. SUMMARY/CONCLUSIONS:To address safety concerns and other ethics challenges unique to xenotransplantation, existing policies must be amended and new policies must be implemented to protect patients and ensure equitable access to xenotransplantation.

With U.S. Food and Drug Administration (FDA) clearance of clinical trials of kidney xenotransplantation (XTx) in living humans, understanding the recipient experience is critical. Semi-structured interviews with the three living XTx recipients identified core domains of the recipient experience, including quality of life (QoL), fears about XTx, and healthcare team communication and support. Transcribed interviews were analyzed by two qualitative researchers using an inductive thematic approach and were mapped onto the Warwick Patient Experience Model, a validated framework to assess key aspects of patient satisfaction with the healthcare experience. All three recipients (53-year-old female; 66-year-old male; 54-year old male) described a restoration of hope, contrasted with their poor quality of life on dialysis. They emphasized that access to XTx and graft survival requires mutual confidence and commitment between recipients and healthcare teams. XTx recipients use dialysis as a point of reference when describing changes in their post-transplant QoL and seemed well-situated to handle the possibility of graft failure. These insights may aid in the creation of decision aids and educational materials tailored to the specific needs of XTx recipients.

This article aims to review unresolved ethical issues and raise additional questions to be answered regarding the use of intraoperative brain monitoring during thoracoabdominal normothermic regional perfusion (TA-NRP). We discuss the following ethical questions, as well as offer preliminary recommendations to advance the discourse around use of brain monitoring during TA-NRP: (1) Does brain monitoring admit violation of the dead donor rule? (2) Which monitoring techniques should be implemented during TA-NRP? (3) How should we manage positive findings? (4) How should we manage ambiguous findings on brain monitoring? (5) What procedural and institutional barriers remain to utilizing intraoperative brain monitoring for TA-NRP on a wider scale? We argue that preventing inadvertent brain reperfusion is central to ensuring TA-NRP complies with ethical standards, and that blood flow monitoring is the most direct monitor for reperfusion. We assess potential brain monitors during TA-NRP and suggest that transcranial doppler (TCD) with cerebral oximetry may be the closest existing tests to an ideal monitor for this application. We likewise review remaining questions regarding diagnostic uncertainty around these tests and the implications of this uncertainty or positive findings of brain reperfusion on the donor, their families, and public trust. To begin addressing these questions, necessary first steps include standardization of surgical protocols to include venting and consolidating data around TA-NRP.

The demand for transplant organs far exceeds the available supply. In the United States alone, more than 90,000 patients are currently on the kidney transplant waitlist, yet only about one third of them will ever receive a transplant. Xenotransplantation, organ transplants from gene edited pigs, offers a potential solution to this shortage. Successful investigational transplants of pig kidneys into brain-dead recipients and expanded access cases involving living human recipients have resulted in the green-lighting of the first human clinical trials. Using the benchmark of 2-year survival of non-human primates in pre-clinical studies, we developed a tool that can identify individual wait-listed patients predicted to have a shorter life expectancy than with a xenotransplant, utilizing Random Survival Forest, DeepSurv and Cox Proportional-Hazards models. We found that it is hard to identify patients that reach clinical equipoise unless the expected xenograft survival exceeds two years, with the Random Survival Forest model identifying less than 5% of such patients. Few patients would benefit based on survival alone and potential beneficiaries are spread across more than 200 transplant centers. Several incentives could allow more patients to reach equipoise. At the same benchmark of 2-year xenograft survival, keeping patients inactive on the waitlist while they have a functioning xeno-kidney increases the percentage achieving equipoise by up to 1.7% across cohorts. Granting patients with failed xenografts the same priority as prior living donors increases this by up to 17.9%, while assigning them the highest priority raises it by up to 28.5%. We are able, however, to identify phenotypes that have a high mortality and low transplant rates in the current allocation system that could serve as acceptable candidates; while not achieving equipoise, they would enjoy the benefits of being dialysis free.

Deceased organ donation is the greatest source of transplantable whole organs, but registration rates are a limiting factor because they remain low among certain populations. A stratified, nonprobability survey was used to identify population characteristics associated with nonregistration in the United States (N = 11,083). Latent profile analysis (LPA) was used to identify multivariate patterns of demographic, socioeconomic, and health-related factors associated with registration. LPA yielded three distinct profiles, which all reported similar average percentages of driver's license possession, medical insurance coverage, and income, indicating that profiles were not distinguished by these variables. Meaningful differences across the profiles included access to healthcare services, satisfaction with those services, general health and well-being, and age; those who are both healthy and young (mean age = 25.9 years) reported the lowest percentage of organ donation registration (35.3%). For this group, 71.48% listed either low priority or distrust in the donation process as the top reasons for nonregistration. Importantly, age as a standalone variable was not uniformly associated with donation and was conditionally dependent upon health status; poorer health in young adults was associated with greater registration. These findings reveal previously unidentified opportunities for tailoring donor registration campaigns to populations with a high potential for registration behavior change.

Normothermic regional perfusion during controlled donation after circulatory death has emerged as a means to increase the number and viability of organs available for transplant. Because normothermic regional perfusion uses extracorporeal membrane oxygenation, an intervention used for resuscitation under other circumstances, critics have concluded that organ donation using normothermic regional perfusion violates the dead donor rule. As such, the debate about normothermic regional perfusion has been framed as a binary choice between normothermic regional perfusion and the dead donor rule. In this paper, I argue that we should resist this binary framework and instead judge the permissibility of normothermic regional perfusion based on whether it harms organ donors. The obligations owed to organ donors derive from their moral status and include the obligation to prevent harm to donors, protect futures of value and satisfy donors' critical interests. When performed correctly, normothermic regional perfusion does not violate these moral obligations. Therefore, normothermic regional perfusion does not harm organ donors during controlled donation after circulatory death, making it ethically permissible when performed in accordance with standardised protocols.

Current legislation guiding withdrawal of life-sustaining treatment and organ donation after circulatory death (DCD) leaves regulatory gaps that are not optimal for honoring the wishes of patient-donors. We describe these gaps, their consequences, and the need for revision to prevent harm to all parties.

Religious viewpoints have been shown to influence the ways in which many persons approach medical decision-making and have been noted as a potential barrier to xenotransplantation acceptance. This study sought to explore how attitudes toward xenotransplantation differ among various religious beliefs. A national Likert-scale survey was conducted in 2023 with a representative sample in the United States. Religious belief was self-reported. Regression analysis was used to identify associations with religious belief and hesitations about xenotransplantation. Five thousand and eight individuals across the United States responded to the survey. The two biggest concerns about xenotransplantation across religious groups were the current lack of evidence about success and the risk of xenozoonosis. Although they still expressed concerns about certain issues, Catholic and Muslim respondents were most comfortable with xenotransplantation for all. On average, the risk of xenozoonosis was a concern among 25% across all religious beliefs (p <0.0001). Orthodox Christians expressed the highest rate of negative feelings toward the recent xenotransplantation experiments on brain dead and living individuals. Those who reported no religion were most likely to have negative feelings about killing pigs for human organ transplant (OR 1.26; 95% CI: 1.08-1.46). As xenotransplantation progresses from pre-clinical studies to clinical trials, and potentially to clinical therapy, hesitations among religious groups exist. Specific studies should be designed to investigate how religious viewpoints can affect xenotransplantation acceptance.

PURPOSE OF REVIEW/OBJECTIVE:Donation after circulatory death (DCD) is one of the most promising methods for expanding the organ pool for transplantation. Yet realizing the promise of DCD depends on careful coordination of end of life treatment with organ donation authorization, organ preservation, and recovery. RECENT FINDINGS/RESULTS:As organ procurement organizations (OPO) increase their DCD efforts, challenges regarding timely referral, delays in organ recovery coordination, and the requisite separation of clinical decisions from organ donation decisions are potentially preventing successful organ recovery, and having negative consequences for trust between OPOs, hospital staff, and donor families. SUMMARY/CONCLUSIONS:Recent DCD cases should be scientifically studied to understand the variables that lead to successful versus unsuccessful DCD. These variables need to be understood in order to adjust legal, logistical, and ethical approaches to DCD and thus ensure the expansion of the organ pool while preserving trust in organ transplantation.