Living donor liver transplantation: The ethics and the practice
Authors: David C. Cronin, J. Michael Millis
Journal: Hepatology (2007)

Success of solid organ transplantation has been inexorably linked to the use of the living donor. The most obvious justification for the continued use and expansion of the living donor results from the increasing imbalance between the numbers of candidates listed for transplantation and the inadequate supply of deceased donor organs. Since the first successful transplant using a living donor in 1954, more than 88,000 living donors have provided various organs for transplantation in the United States alone (Based on OPTN/SRTR data as of October 28, 2007). In fact, living donors outnumbered deceased donors as a source for organs in 2001 (Based on OPTN/SRTR data as of May 1, 2006). In this issue of HEPATOLOGY, Egawa et al. describe a retrospective summary of the Japanese experience in ABO-incompatible liver transplantation using living donors (ABO-I LDLT).1 Data were collected from 28 institutions using an evolving and heterogeneous treatment strategy for recipients of an ABO-I LDLT. Three-year patient survival among adult recipients of ABO-I LDLT improved from 29% to 61% over the 3 time periods presented. This report presents the transplant community with an example of the complex inter-relationship between ethics, medical care, and research all focused on application of a life-saving procedure using a scarce resource: the living donor. Taking account of and deriving a positive balance between recipient and donor risk/benefit ratio has always been an implicit, although ill-defined, requirement in the use of living donors, a situation that we referred to as double equipoise.2, 3 In the report by Egawa et al., there are many similarities that medically and ethically justified the use of the first living donor in 1954 for kidney transplantation and in 1989 for liver transplantation:4 a nonexistent supply of deceased donor organs; availability of a close family member willing to serve as the donor; a candidate with a potentially fatal disease for which transplantation is life-saving; and the belief that the psychological benefit experienced by the donor would offset the physical harms and mortality risk associated with donation. Unfortunately, it is the dissimilarities from those index cases which are most troubling and may tip the balance against the use of the living donor in ABO-incompatible transplantation: performance of liver transplantation for “nonstandard” indications; an insurmountable immunologic barrier secondary to limited and ineffective pharmacologic therapy; use of the living donor in research investigation without a standardized research protocol or oversight to insure protection of recipients, donors, and surgeons; and limited interpretation and application of the results due to insufficient study design. ABO-I LDLT, ABO-incompatible living donor liver transplantation; ALDLT, Adult living donor liver transplantation; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; UNOS, United Network for Organ Sharing. The Vancouver Forum explicitly recommended that when using a living donor for liver transplantation: (1) a potential recipient should be determined to be a suitable candidate for liver transplantation; (2) living liver donation should only be performed if there is an expectation of an acceptable outcome in the recipient; and (3) candidate selection for living donor liver transplantation be confined to UNOS accepted criteria.5 These recommendations imply that the use of the living donor for liver transplantation should be performed (justified) in situations where the expected outcome (patient-survival and graft-survival) is similar to if not greater than that achieved with deceased donor liver transplantation. However, absent formal regulatory oversight, transplant programs are free to select candidates (both recipients and donors) for living donor liver transplantation. Situations in which the expected recipient-outcome from liver transplantation is sufficiently durable to justify application of adult LDLT (ALDLT) include: situations in which the Model for End-Stage Liver Disease (MELD) does not adequately represent the candidate's potential mortality risk;6, 7 regions within the United States with high variability in allocation for nonrecognized exceptional diagnoses;8 and in countries without deceased donors where availability of the ALDLT can be life-saving and has been associated with acceptable outcomes in selected recipients. Some programs, however, have used the availability of a living donor graft as an opportunity to provide liver transplantation for indications beyond what is traditionally accepted as standard criteria.9-11 Although some success has been demonstrated in ABO-incompatible living donor kidney transplantation,12 failure of such transplants does not usually result in recipient death. Conversely, with the exception of infants, transplantation across ABO-incompatible blood-types has remained a significant limitation in liver transplantation. Consequently, ABO-incompatible liver transplantation into adult recipients has traditionally been limited to performance under extreme situations with inferior results.13 The report by Egawa and colleagues spans 15 years of LDLT and represents surgical research rather than application of an innovative procedure designed to benefit an individual patient.1 As a research initiative, it requires the current standards, practices, and protections required for human research investigation. In research involving living donors, our interest should not be confined only to the recipient participants, but extend to include the living donors. Local oversight by an investigational review board or Research Ethics Review Board should be required for the conduct of surgical research, to provide participant (donor and recipient) protection, to ensure adequate resource allocation (minimum patient survival and graft survival), to provide ethics education to those involved in the project, and to foster transparency of the research protocol within the community, as well as among the researchers and participants. Although this level of oversight is often resisted in surgical research,14 its requirement and inclusion might have allowed for greater applicability of the research presented. Without additional data, it appears that across all 3 eras described, the recipient mortality risk associated with ABO-I LDLT may have been greater than the mortality risk from end-stage liver disease.15 A significant number of recipients were underwent transplantation from home and/or with MELD scores as low as 6. Despite the improved patient survival demonstrated in the most recent era, it remains lower than that obtained in ABO-compatible liver transplants. Lower patient survival and graft survival among ABO-I LDLT recipients is at least contributed to by the inability to predictably suppress and control the B cell–mediated immune response. Despite significant immunosuppressive and surgical interventions, many patients succumb to the consequences of excess immunosuppression (infection), or inadequate immunosuppression (hepatic necrosis and intrahepatic biliary complications). Optimal treatment of the adult recipient of an ABO-I LDLT is difficult to determine due to the wide variability in treatment protocols among many institutions over the 15-year time period. In this situation, it is difficult to derive a positive balance from the recipient and donor risk/benefit ratio. A potential solution to the current dilemma of a severely limited source of organs for transplantation, suboptimal patient survival and graft survival, and an inadequate understanding of and treatment for antibody-mediated rejection would be the application of a paired-liver-exchange program similar to that proposed by Ross et al. for ABO-I kidney pairs.16 Under a research protocol, one ABO-incompatible donor-recipient pair would be matched with another ABO-incompatible donor-recipient pair with both pairs sharing compatibility across the pair. Under such an arrangement, donor and recipient surgical risks of the transplant procedure would remain unchanged. Recipients would benefit from avoidance of intensive surgical and immunosuppressive therapies needed to offset life-threatening hepatic necrosis and antibody-mediated rejection resulting in improved patient and graft survival. Donor benefit would be enriched by realizing that the paired-donation facilitated the opportunity to provide a transplant to 2 recipients with improved survival as compared to an ABO-I LDLT. Unlike the paired-exchange programs in kidney transplantation, liver transplantation is associated with a greater and more variable surgical risk for both the donor and recipient. Therefore, candidates and donors would require prospective selection and matching for similar degrees of surgical intervention and expected outcomes. Consequently, the balance of the donor and recipient risk/benefit may shift in favor of procedure. Under this proposal, informed consent of both donor and recipient would be required for participation in the protocol. Both parties would be given the opportunity for withdrawal and both surgical procedures would need to be conducted simultaneously. Under this protocol, the traditional direct first-degree relationship between donor and recipient pair would be preserved and expanded by enabling a LDLT across pairs. For more than a decade, ALDLT has been practiced worldwide and, in some countries, represents the only option to perform life-saving liver transplantation. Consequently, the different social, cultural, economic, religious, and political preferences heighten the complexity of the practice. Despite these differences, fundamental principles exist that provide a uniform basis for ethical care: informed consent, transparency, protection of research subjects, and in the case of living donors, provision of donor safety. Despite the thousands of donors used and surveys and reports of donor deaths17 and complications,18 professional groups have only recently begun to explicitly address the balance between donor and recipient risk/benefit.2, 19 The Kyoto group should be commended for their expert surgical skill and persistent investigation and effort in this difficult biologic system.