Honoring the gift: The transformative potential of transplant-declined human organs.

For decades, transplantation has been a life-saving treatment for those fortunate enough to gain access. Nevertheless, many patients die waiting for an organ and countless more never make it onto the waitlist because of a shortage of donor organs. Concurrently, thousands of donated organs are declined for transplant each year because of concerns about poor outcomes post-transplant. The decline of any donated organ-even if medically justified-is tragic for both the donor family and potential recipients. In this Personal Viewpoint, we discuss the need for a new mindset in how we honor the gift of organ donation. We believe that the use of transplant-declined human organs in translational research has the potential to hasten breakthrough discoveries in a multitude of scientific and medical areas. More importantly, such breakthroughs will allow us to properly value every donated organ. We further discuss the many practical challenges that such research presents and offer some possible solutions based on experiences in our own research laboratories. Finally, we share our perspective on what we believe are the necessary next steps to ensure a future where every donated organ realizes its full potential to impact the lives of current and future patients.

Information design to support growth, quality, and equity of the US transplant system.

The Organ Procurement and Transplantation Network, an arm of the Health Resources and Services Administration, has a contract with the United Network for Organ Sharing since 1986 to provide central oversight of organ donation and transplants in the United States. The United Network for Organ Sharing has recently come under scrutiny, prompting a review by the National Academies of Sciences, Engineering, and Medicine as summarized in its recent report and also by the US Senate Finance Committee. The national news services have opined about organ donation ethics, access to transplantation particularly for medically underserved populations, and management of organ transplantation data. These critiques raise important concerns that deserve our best response as a transplant community. Broadly, we suggest that the data management approach of the Organ Procurement and Transplantation Network be replaced with a patient-centric omnichannel network in which all donor and recipient data exist in a single longitudinal record that can be used by all applications. A more comprehensive and standardized approach to donor data collection would drive quality improvement across organ procurement organizations and help address inequities in transplantation. Finally, a substantial increase in organ donation would be prompted by considering organ donors as a public health resource, meriting transparent publicly available data collection with respect to organ donor referral, screening, and management.

Implicit bias and the gender inequity in liver transplantation.

Women with cirrhosis awaiting liver transplantation are less likely to receive a transplant and more likely to die than men. While differences in body size and estimation of kidney function are well-studied contributors to this gender inequity, what has received relatively little mention as a potential contributing factor is the possibility of implicit bias. Implicit bias is defined as "any unconscious or unacknowledged preference that affects a person's outlook or behavior." The undeniable presence of implicit bias, a factor that is known to negatively influence health outcomes for women, within our health care system means that patients interacting within our transplant system may still experience unequal treatment despite our best efforts to modify the allocation system at the national level. Awareness of this additional source of gender-based disparities is the first step. In this article, we posit that implicit bias in liver transplantation may exacerbate the gender inequity in transplant access and provide examples in the literature to support this assertion. Lastly, we offer strategies that could be applied at the individual or the healthcare delivery system levels to help reduce the influence of implicit bias on the gender inequity in liver transplantation.

Emerging technologies and ethics-exogenic chimeric humanized organs.

Organ transplantation is limited due to the scarcity of donor organs. In order to expand the supply of organs for transplantation, interspecies chimeras have been examined as a potential future source of humanized organs. Recent studies using gene editing technologies in combination with somatic cell nuclear transfer technology and hiPSCs successfully engineered humanized skeletal muscle in the porcine embryo. As these technologies progress, there are ethical issues that warrant consideration and dialogue.

The 21st Century Cures Act and psychosocial electronic documentation in solid organ transplantation: Potential harms and practical strategies.

Recent health system initiatives and government legislation have enhanced electronic health information (EHI) sharing in the healthcare technology environment. These measures are favorably viewed by most patients and clinicians. The 21st Century Cures Act, whose final rules went into effect in the United States in 2021, prohibits information blocking practices except in the case of potential harm. The definition of such harm, particularly regarding psychosocial EHI, is unclear and little guidance has been published. No articles address the matter in solid organ transplantation (SOT) despite the crucial role of psychosocial data in organ allocation. This article describes the implications of patient and family access to psychosocial EHI in SOT, discusses potential mechanisms of harm, and suggests practical communication strategies relevant to clinicians of all disciplines to promote high quality care and favorable interactions with patients and families.

Mandating COVID-19 vaccination prior to kidney transplantation in the United States: No solutions, only decisions.

The question of whether transplant clinicians should mandate COVID-19 vaccination as a condition of transplant candidacy is complex. A vaccine mandate may be defensible on the grounds that transplant clinicians are obligated to ensure transplantation is conducted safely, and in a manner that entails the best use of a scarce public good. However, mandate proponents will inexorably predicate their arguments on contingent clinical judgments that meliorate rather than resolve core value disagreements. Vaccine mandates are conceivably defensible on narrow grounds, but may prove to be purchased at the expense of an attenuation of shared decision-making, proffering claims of risk reduction from a vaccine mandate beyond what the current evidence base supports, and unintentionally exacerbating durable inequities in access to transplantation.

Robotic donor hepatectomy: A major breakthrough in living donor liver transplantation.

Living donation in many countries is the main resource of organs. Healthy, volunteering individuals deserve the highest safety standards possible in addition to the least invasive technique to procure the organs. Since the introduction of living donor liver transplantation, many efforts have been made to minimize the surgical trauma inherent to living donor surgery. The journey started with a large Mercedes incision and evolved to reverse L-shaped and small upper midline incisions before the introduction of minimally invasive laparoscopic techniques originated. The technical difficulties of the laparoscopic approach due to suboptimal instrumentation, challenging ergonomics, and the long learning curve limited the application of the fully laparoscopic approach to a few centers. The recent introduction of the robotic platform with its superb optical system and advanced instruments allows for the first time, a genuine emulation of open donor surgery in a closed abdomen, thus allowing all liver donors to benefit from minimally invasive surgery (better cosmesis, less pain and morbidity, and better quality of life) without compromising donor safety. This attribute in combination with the ubiquitous presence of the robot in major transplant centers may well lead to the desired endpoint of this technology, namely, the widespread dissemination of minimally invasive donor surgery.

COVID-19 and transplantation-Data censoring.

During the early wave of the COVID-19 pandemic, the Scientific Registry of Transplant Recipients (SRTR) designated a "black out" period between March 12, 2020, and June 12, 2020, for transplant outcomes reporting. We discuss the implications and potential bias it has introduced as it may selectively favor the outcomes for certain regions and harm other regions due to varied effects of different waves of COVID-19 infections across the United States.

Rethinking incompatibility in kidney transplantation.

Donor/recipient incompatibility in kidney transplantation classically refers to ABO/HLA-incompatibility. Kidney paired donation (KPD) was historically established to circumvent ABO/HLA-incompatibility, with the goal of identifying ABO/HLA-compatible matches. However, there is a broad range of donor factors known to impact recipient outcomes beyond ABO/HLA-incompatibility, such as age and weight, and quantitative tools are now available to empirically compare potential living donors across many of these factors, such as the living donor kidney donor profile index (LKDPI). Moreover, the detrimental impact of mismatch at other HLA antigens (such as DQ) and epitope mismatching on posttransplant outcomes has become increasingly recognized. Thus, it is time for a new paradigm of incompatibility that considers all of these risks factors together in assessing donor/recipient compatibility and the potential utility for KPD. Under this new paradigm of incompatibility, we show how the LKDPI and other tools can be used to identify donor/recipient incompatibilities that could be improved through KPD, even for those with a traditionally "compatible" living donor.

Wanted: An endothelial cell targeting atlas for nanotherapeutic delivery in allograft organs.

Despite the profound shortage of organs available for transplant in the U.S., over 5,000 donated organs were declined for use in 2020. Many of these organs were declined due to donor comorbidities or preservation injuries that predispose grafts to rejection and loss. The risks of these poor outcomes can potentially be reduced by pre-transplant application of normothermic machine perfusion (NMP). To date, the clinical use of NMP has focused on extending preservation and improving organ assessment, but the opportunity for ex situ therapeutic delivery may be the most transformative aspect of this technology. In this Personal Viewpoint, we argue that the endothelial cells (ECs) that line the graft vasculature are an accessible, under-exploited, and attractive target for transplant therapeutics delivered during NMP. We further contend that molecularly targeted nanoparticles (NPs) represent a promising therapeutic vehicle particularly well-suited to NMP. However, to achieve this potential, we need to answer the following three key questions: (1) What EC sub-populations exist within an organ? (2) How can these cells be accessed? (3) And most important, how can preferential retention of NPs by the cells of interest be maximized? Here we argue for creating an EC-targeting atlas as a body of knowledge that answers these questions.

Challenges encountered in conducting donor-based research: Lessons learned from the Donor Heart Study.

Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

Response to American College of Physician's statement on the ethics of transplant after normothermic regional perfusion.

This paper responds to the position statement released by the American College of Physicians (ACP) entitled "Ethics, Determination of Death, and Organ Transplantation in Normothermic Regional Perfusion (NRP) with Controlled Donation after Circulatory Determination of Death (cDCD): American College of Physicians Statement of Concern." The ACP's statement engages with critical ethical issues surrounding cDCD NRP, but several of their conclusions are flawed. Contrary to the statement, the practice respects the dead donor rule and the legal definition of death while honoring the wishes of the deceased and their loved ones to help save the lives of those in need of organ transplants. cDCD NRP is well established in many countries, it can enhance trust in medical practice and organ donation, and will increase the availability of optimal organs for life-saving transplants.

A regulated system of incentives for living kidney donation: Clearing the way for an informed assessment.

The kidney shortage continues to be a crisis for our patients. Despite numerous attempts to increase living and deceased donation, annually in the United States, thousands of candidates are removed from the kidney transplant waiting list because of either death or becoming too sick to transplant. To increase living donation, trials of a regulated system of incentives for living donation have been proposed. Such trials may show: (1) a significant increase in donation, and (2) that informed, incentivized donors, making an autonomous decision to donate, have the same medical and psychosocial outcomes as our conventional donors. Given the stakes, the proposal warrants careful consideration. However, to date, much discussion of the proposal has been unproductive. Objections commonly leveled against it: fail to engage with it; conflate it with underground, unregulated markets; speculate without evidence; and reason fallaciously, favoring rhetorical impact over logic. The present paper is a corrective. It identifies these common errors so they are not repeated, thus allowing space for an assessment of the proposal on its merits.

Inflammation in the early phase after kidney transplantation is associated with increased long-term all-cause mortality.

In the general population, low-grade inflammation has been established as a risk factor for all-cause mortality. We hypothesized that an inflammatory milieu beyond the time of recovery from the surgical trauma could be associated with increased long-term mortality in kidney transplant recipients (KTRs). This cohort study included 1044 KTRs. Median follow-up time post-engraftment was 10.3 years. Inflammation was assessed 10 weeks after transplantation by different composite inflammation scores based on 21 biomarkers. We constructed an overall inflammation score and five pathway-specific inflammation scores (fibrogenesis, vascular inflammation, metabolic inflammation, growth/angiogenesis, leukocyte activation). Mortality was assessed with Cox regression models adjusted for traditional risk factors. A total of 312 (29.9%) patients died during the follow-up period. The hazard ratio (HR) for death was 4.71 (95% CI: 2.85-7.81, p < .001) for patients in the highest quartile of the overall inflammation score and HRs 2.35-2.54 (95% CI: 1.40-3.96, 1.52-4.22, p = .001) for patients in the intermediate groups. The results were persistent when the score was analyzed as a continuous variable (HR 1.046, 95% CI: 1.033-1.056, p < .001). All pathway-specific analyses showed the same pattern with HRs ranging from 1.19 to 2.70. In conclusion, we found a strong and consistent association between low-grade systemic inflammation 10 weeks after kidney transplantation and long-term mortality.

Ethical review of COVID-19 vaccination requirements for transplant center staff and patients.

Transplant centers seeking to increase coronavirus disease 2019 (COVID-19) vaccine coverage may consider requiring vaccination for healthcare workers or for candidates. The authors summarize current data to inform an ethical analysis of the harms, benefits, and individual and societal impact of mandatory vaccination, concluding that vaccine requirements for healthcare workers and transplant candidates are ethically justified by beneficence, net utility, and fiduciary duty to patients and public health. Implementation strategies should mitigate concerns about respect for autonomy and transparency for both groups. We clarify how the same arguments might be applied to related questions of caregiver vaccination, allocation of other healthcare resources, and mandates for non-COVID-19 vaccines. Finally, we call for effort to achieve global equity in vaccination as soon as possible.

Human leukocyte antigen antibody sensitization, lung transplantation, and health equity.

Women with advanced lung disease, particularly Black and Hispanic women, are more likely than other patients to have anti-human leukocyte (HLA) antibodies against potential donors. Sensitized patients, especially those who are highly sensitized, are less likely to be listed for lung transplant or to be considered candidates for mechanical circulatory support. They are also at higher risk for waitlist death. Institutional variability in approach to HLA antibody screening and pre-transplant management creates barriers to transplant that disproportionately impact Black and Hispanic women. At the same time, our understanding of the clinical significance of pre-transplant antibodies lags behind the sophistication of our screening assays. The lack of national data on pre- and post-transplant HLA antibody characteristics hinders research into strategies to mitigate concerns about these antibodies and to improve access to lung transplant among sensitized patients. Ongoing work should be done to identify clinically higher risk antibodies, to develop better strategies for safely crossing antibodies at the time of transplant, and to model changes in lung allocation to give priority to sensitized patients for a HLA antibody-antigen compatible donors. These priorities mandate a commitment to collaborative, multicenter research and to real time translation of results to clinical practice and allocation policy.

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.

Findings and recommendations from the organ transplant caregiver initiative: Moving clinical care and research forward.

Lay-caregivers are essential to the continuum of care in adult organ transplantation. However, we have a limited understanding of the experiences, exigencies, and outcomes associated with lay-caregiving for organ transplant patients. While much discussion and debate has focused on caregiver requirements in relation to transplant candidate selection, little focus has been given to understanding the needs of caregivers themselves. In response to this, the Organ Transplant Caregiver Initiative was created, and a meeting was held during October 6-7, 2019. Transplant healthcare professionals, researchers, and lay-caregivers discussed the experiences, educational needs, existing research, and research recommendations to improve the experience of lay-caregivers for adult organ transplant patients. In this report, we summarize the Organ Transplant Caregiver Initiative and meeting findings, providing a preliminary action plan to improve education, research, and advocacy for organ transplant caregivers.

An opt-out model for kidney transplant referral: The time has come.

Disparities that affect equity in access to kidney transplantation for patients with kidney failure have been well described. Many robust clinical trials have tested the effectiveness of interventions to reduce disparities and equilibrate access to kidney transplantation. Moreover, policy changes have been enacted to achieve the same aims. Despite these efforts, rates of kidney transplant waitlisting within the first year of end-stage kidney disease have remained unchanged over the past 2 decades, while incident rates of end-stage kidney disease have climbed. Because prior interventions have not durably increased transplant access, disruptive change is clearly needed. The Advancing American Kidney Health Executive Order sets bold goals to transform kidney care for patients and caregivers. In this spirit, we discuss an Opt-Out for Transplant Referral Model as a compelling solution to improve equity in access to kidney transplantation.

Examining the critical role of advanced practice providers on a multidisciplinary transplant team.

It is well documented that Physician Assistants (PAs) and Nurse Practitioners (NPs), collectively known as Advanced Practice Providers (APPs), have a beneficial role beyond the field of primary care. APPs broad spectrum of knowledge make them particularly well suited for specializing in complex fields such as transplant. Variations in practice across transplant centers lead to questions regarding optimal use of APPs. Using job descriptions from transplant centers currently employing APPs, we sought to examine the critical role of transplant APPs beyond clinical care alone. In this review, we explore not only the general training of APPs and current utilization of APPs in transplant, but also safety, cost effectiveness, and comparison of APPs to other transplant providers. We aimed to highlight the importance of recruitment and retention of transplant specific trained APPs to provide continuity in transplant programs. Additionally, APPs expansion into transplant research, quality improvement, leadership, and management must be considered. We challenge transplant centers utilizing APPs to consider these important aspects when seeking ways to expand and optimize the critical role APPs provide on the transplant team.