Clinical and Ethical Framework for Liver Retransplantation Using Living Donor Grafts: A Western Perspective

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE 887 Patients undergoing liver retransplantation are faced with a double‐edged sword: less competitive Model for End‐Stage Liver Disease (MELD) score and the need for a good‐quality organ while facing poor survival on the waiting list. This dilemma is also shared by the transplant physician, which gains intensity when considering living donor liver grafts for retransplantation attributed to (1) technical complexity, (2) historical poor outcomes, and (3) the ethical challenge to uphold high utility while considering donor safety. The questions thus arises, whether these 3 considerations are interrelated and whether they can be adequately balanced. Technical complexity is largely the result of the adhesions and inadequacy of vasculature. Poor outcomes are largely attributed to infection and disease severity,(1,2) hence the low‐utility/high‐futility ethical conundrum with living donor liver transplantation (LDLT) for retransplantation. To draw the ethical boundaries of utility, one must consider the survival benefit with retransplantation, which is wholly dependent on the waitlist mortality rate without a retransplant. Hence a plausible argument can be made to ethically consider LDLT for retransplant as long as the survival outcomes are significantly greater than the waitlist mortality rate. The question then arises, how much greater should the survival benefit with retransplant be in comparison to their waitlist mortality to sufficiently define clinical and ethical acceptability. To this effect, we discuss some clinical and ethical constructs to aid in the difficult discussions and decisions when considering LDLT for retransplantation. Clinical Outcomes Center Experience In the United States, 95% of liver transplantations are from deceased donors, whereas in the East 95% are LDLTs. Thus, it is obvious that the Eastern world has a very concentrated and focused skill set and infrastructure that caters primarily to LDLT. Despite the disparity in focus, the national data of survival outcomes comparing West and East (United States, Japan) for LDLT is the same: 79% versus 81% 3‐year patient survival.(3,4) A deep dive into the outcomes at busy living donor liver transplant centers across both regions (West and East) of the world reaffirms the notion set by the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study that higher volume centers performing LDLT tend to have better graft and patient survival rates.(3) For example, the 3‐year patient survival rate is as high as 86% for a center in Pennsylvania, United States, and 90% for a similarly busy transplant center in Seoul, South Korea, which has performed more than 5000 LDLTs to date. Now, considering center experience for LDLT in retransplants, in a national survey of all centers in Japan with 194 LDLT retransplants, patient survival was found to be 59% and 56% for 3 years and 5 years, respectively,(2) which is the largest reported national experience to date. Looking further and individually at large LDLT centers in the East, it is obvious that they too have been cautious with only a handful of retransplants, for example, the University of Hong Kong performed 11 retransplants in 16 years and Asan Medical Center 16 retransplants in 21 years(5,6) with varying results (53%‐90%, 5‐year survival). Just as the Eastern centers are carefully selecting the recipients for retransplantation with LDLT, the Western centers are under the scrutiny of their transplant outcomes as reported by the Scientific Registry of Transplant Recipients for both living and deceased donation. As retransplantation in general shows lower long‐term survival, this is likely weighed by some Western centers in their decision making. Thus, as center experience is essential in the safe practice of LDLT for primary transplants, it is even more true for retransplants, which explains its cautious practice even in busy LDLT centers. Patient Selection Multivariate analysis has shown that MELD/Pediatric End‐Stage Liver Disease scores >25 and adult age at retransplantation are independent risk factors for patient survival. Furthermore, recurrence of disease and chronic rejection has superior outcomes compared with vascular or biliary complications when considering pediatric retransplant, whereas recurrence of disease has the best, and chronic rejection the worst, outcomes for adult recipients.(2) In addition, the timing of retransplant for both adult and pediatric patients within 1 year is considered a strong predictor of poor patient survival.(2,6) Therefore, careful patient selection is the key to promising results with LDLT for retransplants. Survival Advantage LDLT in United States confers a 5‐year survival advantage to patients on the waiting list, ranging from 76% to 95% (first‐time liver transplantation) when compared with no transplant (hazard ratio, 0.38‐0.44),(7) which underscores the need and utility of LDLT. When the 5‐year survival percentage with LDLT for retransplantation drops to 50% to 60%,(2,6) the utility of retransplant is seriously questioned. However, this almost seems hypocritical, especially when LDLT is accepted by many for hepatocellular carcinoma beyond the Milan criteria or University of California, San Francisco criteria, with 5‐year survival rates as low as 44.5% and 36.4%, respectively.(8) It therefore makes sense to be very careful in balancing the ethics of LDLT practice for retransplants and not completely shut the door on its practice. Ethical Viewpoint Donor Autonomy Among the 4 pillars (autonomy, beneficence, nonmaleficence, justice) of the “principlism” theory for the practice of clinical ethics, autonomy tends to serve as the anchor. The autonomous decision of a living liver donor to donate often has an emotional impetus and occasionally collides with the imposition of the living donor team to not allow the donation if there is an imbalance to the donor risk/recipient benefit.(9) In doing so, although beneficence and nonmaleficence is upheld (justice does not apply in LDLT), autonomy of the donor is severely compromised. We do not suggest that “nonmaleficence” be sacrificed by taking an untoward donor risk, just not be overly expressed, at the expense of “autonomy.” Thus, although the survival benefit to the recipient with an LDLT in retransplantation may not be as good as the primary transplant in anyone else, a comparison of survival benefit needs to be made with the same patient in mind in the absence of a retransplant. This framework will help untangle the ethical unacceptability when balancing donor risk/recipient benefit. Shared Decision Making The double benefit of LDLT—psychological benefit to the donor and clinical benefit to the recipient—is obvious; however, the resulting effect of LDLT for other waiting patients, that is, reduced competing share of the intended LDLT recipient on other deceased donor organs, is of extreme importance. Thus, it is obvious that LDLT directly impacts 3 lives and indirectly several others dependent on the former 3! Hence, so long as LDLT meets the double equipoise upholding donor safety and recipient outcomes, it mostly completes the ethical requirement and also that of the 2005 Vancouver forum for the practice of LDLT.(10) With this in mind, if a living donor who is counseled appropriately of the potential poor recipient outcomes with retransplant,(11) as long as donor safety is not compromised (nonmaleficence for the donor), the donor autonomy (including beneficence for the donor) should drive the procedure and not be chained within the bounds of physician paternalism. Hence, it appears that doing so (LDLT for retransplant) is ethically superior, and as long as it is technically feasible, it is better for patient (donor) experience as it upholds “shared‐decision‐making;” and lastly, also serves as an important step towards preserving high utility expectation from the most competitively shared deceased donor organ when considering the not‐so‐good outcomes from a retransplant. Summary In summary, we consider LDLT for retransplant a viable clinical option, as long as there is balance to the double equipoise of donor safety and recipient outcome; and ethical acceptability so long as the triad of beneficence, nonmaleficence, and donor autonomy are equally weighted. LDLT for retransplant yields survival benefit to carefully selected patients (pediatric more than adults) as long as the timing of the surgery, center experience, technical feasibility, and etiology of primary graft failure is considered. Lastly, the living donor teams in order to uphold the informed consent of living donation, should critically discuss transplant outcomes including the morbidity and mortality data, but should also not ignore the emotional, social, and psychological connections between the donor/recipient, which frequently serve as the impetus for living donation. This shared‐decision‐making will hopefully fan the flames of living liver donation in the West and help to bridge the gap between the need for liver transplant and available organs.

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