Developing an ethics framework for living donor transplantation.

Both living donor transplantation and human subjects research expose one set of individuals to clinical risks for the clinical benefits of others. In the Belmont Report, the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research (National Commission) articulated three principles to serve as the basis for a research ethics framework: respect for persons, beneficence and justice. In contrast, living donor transplantation lacks a framework. In this manuscript, we adapt the three principles articulated in the Belmont Report to serve as the foundation for an ethics framework for living donor transplantation which we supplement with the principles of vulnerability and responsibility. The National Commission supported additional protections for vulnerable groups of potential research participants. In 2001, Kenneth Kipnis effectively argued that the concept of vulnerable groups failed to explore in what ways particular groups of people were vulnerable, thereby risking unnecessary protections for some and inadequate protections for others. He proposed a taxonomy that explored different types of vulnerabilities that all research participants may experience to provide a more robust framework for human subjects protections, which we adapt to living donors. Robert Goodin claims that health professionals, who stand in special relationship with patients, are responsible for promoting and protecting their well-being. In living donor transplantation, the donor transplant team is responsible for empowering prospective donors to address their vulnerabilities and/or for protecting those who cannot by disqualifying them from donation.

Prisoners as Living Donors: A Vulnerabilities Analysis.

Although national guidelines exist for evaluating the eligibility of potential living donors and for procuring their informed consent, no special protections or considerations exist for potential living donors who are incarcerated. Human research subject protections in the United States are codified in the Federal Regulations, 45 CFR 46, and special protections are given to prisoners. Living donor transplantation has parallels with human subject research in that both activities are performed with the primary goal of benefiting third parties. In this article, we describe what special considerations should be provided to prisoners as potential living donors using a vulnerabilities approach adapted from the human research subject protection literature.

Introducing Genetic Tests With Uncertain Implications in Living Donor Kidney Transplantation: ApoL1 as a Case Study.

Genetic mutations in apolipoprotein L1 (ApoL1) are associated with kidney disease. Apolipoprotein L1 mutations are common in African Americans (∼39% and 12% have 1 and 2 high-risk alleles, respectively). Carrying 2 ApoL1 risk alleles may explain much of the excess rate of kidney failure in African Americans compared to European Americans. Apolipoprotein L1 also has implications for kidney transplantation. Kidney grafts from deceased donors with 2 ApoL1 risk alleles have worse graft survival, but outcomes appear unaffected by recipient ApoL1 status. Unknown is whether donation increases the risk of kidney failure in living donors with 2 ApoL1 risk alleles and whether their donated kidneys have worse graft survival. There are 4 options to consider: (1) remain silent about ApoL1 risk alleles and renal failure and wait for more data; (2) counsel about race, ApoL1, and subsequent renal failure abstractly but remain agnostic about donor testing until more data are available; (3) provide counseling and encourage genotyping of prospective living donors of African ancestry as part of the living donor workup; or (4) mandate testing of all prospective living donors. We support option 3, and recommend, with donor permission, to discuss the results with potential recipients to promote informed decision-making. We also argue for a voluntary donor registry that collects long-term follow-up information. We provide ethical arguments to support these recommendations.

Attitudes of Lay Stakeholders and Transplant Professionals About Disclosure to Living Kidney Donors in Exchanges and Chains.

BACKGROUND: Current policies require very limited informational disclosure between living kidney donors and recipients regardless of the relationship type. No specific policies exist to suggest that exchange/chain donors and their recipients should be treated differently. We surveyed transplant professionals (surgeons and nephrologists) and members of the National Kidney Foundation (NKF) to determine their support for disclosing to donors the health, health behavior, and social information of their exchange/chain donors and exchange/chain recipients. METHODS: Twenty questions regarding disclosing to donors information about both their exchange/chain donors and exchange/chain recipients were included in 2 larger surveys on disclosure about kidney transplantation. Survey A was sent electronically to NKF list-servs, and survey B was sent to transplant professionals both electronically and by postal mail. RESULTS: Survey A yielded 236 valid surveys from NKF donors and recipients (lay stakeholders). Survey B yielded 111 valid surveys from transplant professionals. Both sets of stakeholders support disclosing to donors some health and health behavior information of their exchange/chain donor and exchange/chain recipient, and mostly oppose disclosure of social information. Lay stakeholders favored disclosing significantly more information than transplant professionals. Among lay stakeholders, donor respondents were more supportive than recipient respondents in disclosing to donors health information about the exchange/chain recipient. Among transplant professionals, surgeons were more supportive than nephrologists in disclosing to donors information about the exchange/chain recipient that may impact graft survival. CONCLUSIONS: There is broad stakeholder support for disclosing some health and health behavior information to donors about their exchange/chain donors and recipients.

Age and equity in liver transplantation: An organ allocation model.

A moral liver allocation policy must be fair. We considered a 2-step, 2-principle allocation system called "age mapping." Its first principle, equal opportunity, ensures that candidates of all ages have an equal chance of getting an organ. Its second principle, prudential lifespan equity, allocates younger donor grafts to younger candidates and older donors to older candidates in order to increase the likelihood that all recipients achieve a "full lifespan." Data from 2476 candidates and 1371 consecutive adult liver transplantations (from 1999 to 2012) were used to determine whether age mapping can reduce the gap in years of life lost (YLL) between younger and older recipients. A parametric Weibull prognostic model was developed to estimate total life expectancy after transplantation using survival of the general population matched by sex and age as a reference. Life expectancy from birth was calculated by adding age at transplant and total life expectancy after transplantation. In multivariate analysis, recipient age, hepatitis C virus status, Model for End-Stage Liver Disease score at transplant of >30, and donor age were significantly related to prognosis after surgery (P < 0.05). The mean (and standard deviation) number of years of life from birth, calculated from the current allocation model, for various age groups were: recipients 18-47 years (n = 340) = 65.2 (3.3); 48-55 years (n = 387) = 72.7 (2.1); 56-61 years (n = 372) = 74.7 (1.7) and for recipients >61 years (n = 272) = 77.4 (1.4). The total number of YLL equaled 523 years. Redistributing liver grafts, using an age mapping algorithm, reduces the lifespan gap between younger and older candidates by 33% (from 12.3% to 8.3%) and achieves a 14% overall reduction of YLL (73 years) compared to baseline liver distribution. In conclusion, deliberately incorporating age into an allocation algorithm promotes fairness and increases efficiency.

Racial disparities in reaching the renal transplant waitlist: is geography as important as race?

BACKGROUND: In the United States, African Americans and whites differ in access to the deceased donor renal transplant waitlist. The extent to which racial disparities in waitlisting differ between United Network for Organ Sharing (UNOS) regions is understudied. METHODS: The US Renal Data System (USRDS) was linked with US census data to examine time from dialysis initiation to waitlisting for whites (n = 188,410) and African Americans (n = 144,335) using Cox proportional hazards across 11 UNOS regions, adjusting for potentially confounding individual, neighborhood, and state characteristics. RESULTS: Likelihood of waitlisting varies significantly by UNOS region, overall and by race. Additionally, African Americans face significantly lower likelihood of waitlisting compared to whites in all but two regions (1 and 6). Overall, 39% of African Americans with ESRD reside in Regions 3 and 4--regions with a large racial disparity and where African Americans comprise a large proportion of the ESRD population. In these regions, the African American-white disparity is an important contributor to their overall regional disparity. CONCLUSIONS: Race remains an important factor in time to transplant waitlist in the United States. Race contributes to overall regional disparities; however, the importance of race varies by UNOS region.

Adding Another Voice to the Living Donor Kidney Transplant Discussions at the CIBA Symposium of 1966.

In March 1966, the CIBA Foundation sponsored an international interdisciplinary conference on transplantation. Attendees included surgeons, physicians from many medical disciplines, legal professionals, a minister, and a science reporter. Although the main topic of discussion was the living donor, none was present. This article gives voice to the living donor through two qualitative interviews with men who donated at different centers in the United States in the early 1960s and subsequently developed end-stage renal disease (ESRD). These narratives contribute to five topics discussed at the CIBA meeting that are still relevant today: (1) pressure to donate; (2) special donor categories; (3) donor health; (4) socioeconomic consequences of donation; and (5) lack of regret.

Decision making in liver transplantation--limited application of the liver donor risk index.

The liver donor risk index (LDRI), originally developed in 2006 by Feng et al. and since modified, is a method of evaluating liver grafts from deceased donors through the determination of the relative risk of graft failure after transplantation. Online and paper surveys about attitudes and practices regarding decision making in liver transplantation and the role of the LDRI were sent to liver transplant physicians. One hundred forty-seven of 401 eligible respondents (37%) returned partial or complete surveys. The majority of the respondents were male (116/134 or 87%) and practiced in academic medical centers (128/138 or 93%). Transplant coordinators initially contacted the candidate with an offer in 81% of the programs. Eighty-eight of 143 respondents (62%) reported that they were very familiar with the LDRI, but the vast majority (114/137 or 83%) rarely or never discussed the concept of the LDRI with their patients. A majority of the respondents (96/132 or 73%) believed that the LDRI does not adequately describe a liver's relative risk of graft failure and that there are factors making the LDRI potentially misleading (122/138 or 88%). Nevertheless, 60 of 130 respondents (46%) believed that the LDRI would increase/improve shared decision making. The LDRI has not been widely adopted because of concerns that (1) it does not accurately reflect posttransplant survival, (2) it excludes relevant donor and recipient factors, and (3) it is too complicated for candidates to grasp. There is a need to improve it or to develop other decision-making tools to help promote shared decision making. There is also great diversity in how liver offers are made to ambulatory candidates and in how transplant programs address a candidate's refusal. Research is needed to determine evidence-based best practice.

Age should not be considered in the allocation of deceased donor kidneys.

In this manuscript, we examine what role age can morally play in the allocation of deceased donor kidneys for transplantation into adult candidates. Our focus is on the equity concerns raised by recent proposals that give younger adults in end-stage renal disease priority to more and better deceased donor kidneys. We begin with a description of four models: the current allocation method ("baseline proposal"), the two models offered by the Kidney Transplant Committee in February 2011: a pure ±15 years age-matching model and a 20/80 proposal (http://optn.transplant.hrsa.gov/SharedContentDocuments/KidneyConceptDocument.PDF), and a new model entitled Equal Opportunity supplemented by Fair Innings (EOFI) described by Ross et al. earlier this year. We then consider the requirement of the National Organ Transplantation Act (NOTA) of 1984 that allocation policies balance efficiency and equity. The models all define efficiency as promoting graft and patient survival but use various conceptions of equity. We discuss the various conceptions of equity employed in the various models. We show that only the new proposal, EOFI, can meet the NOTA requirements using a multiprincipled equity approach to kidney allocation.

Different standards are not double standards: all elective surgical patients are not alike.

Testa and colleagues argue that evaluation for suitability for living donor surgery is rooted in paternalism in contrast with the evaluation for most operative interventions, which is rooted in the autonomy of patients. We examine two key ethical concepts that Testa and colleagues use: paternalism and autonomy, and two related ethical concepts: moral agency and shared decision making. We show that by moving the conversation from paternalism, negative autonomy, and informed consent to moral agency, relational autonomy, and shared decision making, one better understands why the arguments given by Testa and colleagues fail. We argue (1) why the hurdles that one must overcome to become a living donor are appropriate; and (2) that the similarities between living donor transplant surgery and cosmetic plastic surgery that the authors describe are inaccurate. Finally, we consider the recommendation to treat plastic surgery patients and living donors more similarly. We argue that any change should not be in the direction of becoming less protective of living donors, but more protective of cosmetic plastic surgery candidates.

Gender and race/ethnicity differences in living kidney donor demographics: Preference or disparity?

In the United States, women are over-represented and Blacks are under-represented as living kidney donors. A traditional bioethics approach would state that as long as living donors believe that the benefits of participation outweigh the risks and harms (beneficence) and they give a voluntary and informed consent, then the demographics reflect a mere difference in preferences. Such an analysis, however, ignores the social, economic and cultural determinants as well as various forms of structural discrimination (e.g., racism, sexism) that may imply that the distribution is less voluntary than may appear initially. The distribution also raises justice concerns regarding the fair recruitment and selection of living donors. We examine the differences in living kidney donor demographics using a vulnerabilities analysis and argue that these gender and racial differences may not reflect mere preferences, but rather, serious justice concerns that need to be addressed at both the individual and systems level.

Living Donation by Individuals with Life-Limiting Conditions.

The traditional living donor was very healthy. However, as the supply-demand gap continues to expand, transplant programs have become more accepting of less healthy donors. This paper focuses on the other extreme, asking whether and when individuals who have life-limiting conditions (LLC) should be considered for living organ donation. We discuss ethical issues raised by 1) donation by individuals with progressive severe debilitating disease for whom there is no ameliorative therapy; and 2) donation by individuals who are imminently dying or would die by the donation process itself.

An empirical investigation of physicians' attitudes toward intrasibling kidney donation by minor twins.

BACKGROUND: A United States consensus group on the live donor concluded that minors (<18 years) can ethically serve as live solid organ donors in exceptional circumstances. More recent international guidelines reject this position. Recent United Network of Organ Sharing data show that minors serve as living donors, albeit infrequently. We examined the attitudes of US physicians toward minors as living donors. METHODS: Four hundred members of the American Society of Transplantation and 160 physicians from the American Academy of Pediatrics Section of Nephrology or Bioethics were surveyed. The physicians were asked whether minors should be permitted to serve as living donors and how their opinion would change depending on the twins' zygosity, age, and increased waitlist time. RESULTS: One hundred seventy of 436 eligible participants (39%) returned surveys. Thirty-two and 39% of respondents would permit a kidney donation between 15-year-old fraternal and identical twins, respectively (P=NS). If the wait time increased from 1 to 6 years, willingness increased to 39% and 45%, respectively (P=NS). Pediatric bioethicists were the most reluctant to prohibit minors as living donors. CONCLUSION: Approximately one-third of US physicians would permit children to serve as donors. Lengthening the wait time is associated with a trend toward greater willingness to permit minor donations. Current policies that give preferential status for a deceased donor organ to minors may help minimize donations by their minor siblings. Nontransplant physicians need education about donor risks to ensure that donations are in the best interest of pediatric donors and recipients.

Ethical Analysis and Policy Recommendations Regarding Domino Liver Transplantation.

Due to the widening gap between supply and demand, patients who need a liver transplant due to metabolic disease may be asked to serve as domino liver donors-to have their native liver transplanted into another candidate. We here analyze the ethical problems surrounding informed consent for the implant and explant procedures in transplant candidates who will serve as domino donors, using the case of a child with maple syrup urine disease. We discuss the need for 2 distinct consent processes separated in time to ensure that potential domino donors (or their surrogates) give a truly voluntary consent. We propose a Domino Donor Advocate-based on the concept of the independent living donor advocate to help the patient and/or his or her surrogates consider the risks, benefits and alternatives. Finally, we evaluate the Organ Procurement and Transplantation Network policy regarding "therapeutic organ donation" and propose several modifications to ensure that the decision by the potential domino donor (and/or his or her surrogate) is voluntary and informed.

The 1966 Ciba Symposium on Transplantation Ethics: 50 Years Later.

In March 1966, the Ciba Foundation sponsored the first international, interdisciplinary symposium focused on ethical and legal issues in transplantation. The attendees included not only physicians and surgeons but also judges and legal scholars, a minister, and a science journalist. In this article, we will consider some of the topics in organ transplantation that were discussed by the attendees, what we have learned in the intervening half century, and the relevance of their discussions today. Specifically, we examine the definition of death and its implications for organ procurement, whether it is ethical and legal to "maim" a living individual for the benefit of another, how to ensure that the consent of the living donor is voluntary and informed, the case of identical twins, the question of whether ethically minors can serve as living donors, the health risks of living donation, the ethics and legality of an organ market, and the economic barriers to living donation. We show that many of the concerns discussed at the Ciba symposium remain highly relevant, and their discussions have helped to shape the ethical boundaries of organ transplantation today.

Kidney Donor Profile Index Does Not Accurately Predict the Graft Survival of Pediatric Deceased Donor Kidneys.

BACKGROUND: The new deceased donor kidney allocation algorithm uses a Kidney Donor Profile Index (KDPI) based on donor characteristics to predict graft survival and divides kidneys into 4 quality groups (ie, KDPI-A, -B, -C, and -D). Pediatric kidneys constitute 10% to 12% of deceased donor kidneys. We hypothesized that KDPI would not accurately predict pediatric donor graft survival and superior predictive models could be created. METHODS: Scientific Registry of Transplant Recipients data for years 2000 to 2010 for transplants from child (<10 years) and adolescent (10-17 years inclusive) donors into first-time adult recipients were analyzed with graft failure as the principle outcome. Two novel indices, Child Donor Index (CDI) and Adolescent Donor Index (ADI), were developed using stepwise variable deletion to identify significant model covariates in a Cox Regression. Pediatric donor kidneys were then classified into the 4 quality groups based on both KDPI and CDI/ADI scores. The performance of the KDPI, CDI, and ADI models were compared with respect to the 4 quality groups defined by the new allocation system. RESULTS: The KDPI did not effectively discriminate between quality groups (P > 0.05 for all but 1 comparison) in Kaplan-Meier survival analyses. The CDI and ADI included novel variables (eg, body mass index percentiles) and successfully discriminated between quality groups (P < 0.05 by log rank test). The Net Reclassification Index showed improvement when switching from KDPI to CDI and ADI, with values of 0.09 (P < 0.001) and 0.073 (P < 0.001), respectively. CONCLUSIONS: The KDPI does not accurately predict pediatric kidney graft survival. Alternative indices can improve allocation efficiency.

Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago.

OBJECTIVE: The aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago. MATERIALS AND METHODS: Nine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus. RESULTS: Nine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function. CONCLUSIONS: Pancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success.