There is considerable uncertainty regarding the benefit of liver transplantation in adult candidates with low MELD scores. Prior work demonstrated little or no net survival benefit for transplant candidates with low MELD scores (MELD<15) who received deceased donor liver transplant
in the U.S.(5
). This observation resulted in a major change in deceased donor liver allocation policy in the U.S., termed Share15, in a manner that markedly limited the opportunity for receipt of DDLT for adult candidates with low MELD scores. Subsequent analysis employing SRTR data suggested a positive transplant benefit (incorporating pre-transplant and post-transplant mortality risk measures) for transplant candidates at somewhat lower MELD scores(6
). The majority of liver transplant candidates with MELD scores of 12 or greater would benefit by liver transplantation based on that analysis. Timely receipt of DDLT for such liver transplant candidates with MELD scores of 12–15, however, is unlikely in the setting of allocation policies that preferentially offer DDLT to candidates with the highest MELD scores in order to minimize waitlist mortality. For example, in the current analysis, only 42% of candidates with MELD< 15 who did not undergo LDLT received DDLT within 12 months of donor evaluation.
An alternative strategy to achieve timely transplantation for candidates with lower MELD scores is LDLT. The A2ALL consortium enrolled a large cohort of patients with low MELD scores for whom LDLT was an option, and thus analysis of patients enrolled in this study provided an opportunity to ascertain whether LDLT in patients with low MELD offers transplant survival benefit. As detailed above, receipt of LDLT in candidates without HCC whose MELD scores were less than 15 at time of study enrollment was associated with significant survival advantage in comparison to waiting for, or receiving, DDLT. Such benefit could be the result of either diminished waitlist mortality, or improved post-transplant survival. As post-transplant survival was similar in both LDLT and DDLT recipients in the MELD<15 group, the net survival benefit must be attributed largely to reduced waitlist mortality. Although low MELD scores have been associated with relatively low risk of death at 90 days and one year(10
), 10.8% of low MELD patients died on the waitlist at a median of 9.8 months following entry into this cohort. This number approximates the percentage difference in estimated 3-year mortality between the LDLT recipients and non-LDLT recipients (). Avoidance of waitlist deaths as a consequence of timely transplant, as reflected by a median wait for LDLT of 3.0 months after study entry, thus appears to be the major contributor to favorable outcomes in the low MELD group. Additional support for the notion that the primary survival benefit associated with LDLT is avoidance of waitlist mortality is derived from analysis of outcomes in the candidates with HCC with MELD <15. LDLT was not associated with significant survival benefit in this group, for whom waiting time for LDLT (median 1.6 months) was only slightly less than waiting time to DDLT (median 2.2 months).
We considered an alternative explanation for the survival benefit experienced by LDLT recipients in the MELD<15 group and explored the possibility that the quality of the DDLT grafts received by these patients was inferior, and resulted in higher post-transplant mortality following DDLT. Three lines of evidence refute this speculation. First, as mentioned above, post-transplant survival was not different in low MELD patients who received LDLT and those who received DDLT (HR=0.96, p=0.91 for non-HCC recipients). Second, we examined the DRI for the DDLT organs received by the low MELD candidates enrolled in A2ALL, and compared that to the median DRI of high MELD patients receiving DDLT at the participating centers. The median DRI for the DDLT organs received by the MELD<15 candidates without HCC who were enrolled in A2ALL was very similar to the median DRI for DDLT organs transplanted during the post-MELD era into recipients at A2ALL centers with MELD15+ at listing who had not enrolled in A2ALL. Most importantly, recipients of DDLT enrolled in A2ALL did not have higher post-transplant mortality than non-A2ALL-enrolled recipients of DDLT at the same centers.
As has been true throughout the history of LDLT, the survival benefits observed here for LDLT recipients must be balanced by the risks of morbidity and mortality experienced by LDLT donors. It must also be recognized that the A2ALL study does not reflect the outcomes of a randomized trial of LDLT versus those listed for DDLT at the nine A2ALL transplant centers. Rather, the study reports upon the observational outcomes experienced by transplant candidates for whom consideration of living liver donation was felt to be an appropriate option by the treating transplant team, and was possibly available, based on the presence of a donor presenting for evaluation at the participating transplant center. It could be postulated that the candidates with low MELD scores for whom LDLT was seriously entertained by our transplant centers represent a group of individuals with perceived increased risk of mortality beyond that associated with their MELD score. This possibility was explored by examining the frequency of hepatic encephalopathy, ascites, variceal hemorrhage, previous upper abdominal surgery, spontaneous bacterial peritonitis, hyponatremia (Na < 135 mEq/L), and TIPS in patients enrolled in A2ALL at the nine participating centers, as well as in listed transplant candidates at the nine centers who were not enrolled in the A2ALL study. Somewhat unexpectedly, there was no significant difference in the frequency of these complications in those candidates for whom LDLT was seriously contemplated (i.e., for whom a donor was evaluated at their transplant center) and in those who did not have such a donor. Despite this objective finding, there remains the possibility that experienced transplant teams still may have applied some selection bias in the recommendation of pursuit of LDLT in their centers such that the reported survival benefit may not be universally obtained by all candidates. Given this possibility, one should remain cautious about the generalized pursuit of LDLT in all candidates with low MELD scores presenting to transplant centers. Future analyses of very large cohorts of LDLT recipients may permit the further identification of subsets of candidates who receive maximal benefit from this procedure.
The majority of transplant candidates in the A2ALL retrospective study(1
) underwent both listing and transplant prior to the initiation of the MELD-based liver allocation system. In the current MELD era analysis, candidates who enrolled in A2ALL with MELD15+, who did not have HCC, and who received LDLT, had markedly lower mortality compared to those waiting for, or receiving DDLT (HR 0.42, 95% CI 0.26–0.69; p=0.0006). This survival benefit was similar to that previously reported by our group(1
) and strongly supports the continued application of LDLT in this group of patients with higher MELD scores. As there were only 27 patients enrolled in A2ALL in the post-MELD era with MELD scores at enrollment of greater than 30, and only eight of these patients received LDLT, we were unable to perform an analysis restricted to transplant candidates with very high MELD scores and cannot comment on the presence or absence of possible futility associated with LDLT in these high MELD candidates.
Fifteen percent of the patients in the current analysis carried a diagnosis of HCC. As detailed in , patients who ultimately went on to receive LDLT were more likely to have stage T3 or higher tumors than those who received DDLT, most likely as a consequence of standardized (higher) exception MELD scores for those with stage T2 HCC, which permitted relatively expeditious DDLT. It is of note that despite the relatively large percentage of patients with T3 tumors, fairly quick access to DDLT was noted for the HCC patients with lower laboratory MELD scores, such that wait times for DDLT for these patients was far less than that for non-HCC candidates (7.9 months median wait for DDLT for MELD<15 candidates without HCC who received DDLT versus 2.2 months median wait for MELD<15 candidates with HCC). This wait time for DDLT for low MELD HCC patients was similar to the wait time for LDLT in this group (median 1.6 months). In this setting, the lack of a survival advantage associated with receipt of LDLT for low MELD HCC transplant candidates was not surprising. Transplant candidates with MELD15+ with HCC had significantly lower mortality with LDLT.
In summary, results from the A2ALL study in the MELD liver allocation era continued to demonstrate significant survival advantage associated with receipt of LDLT in comparison to continued waiting for DDLT. This survival benefit exists for patients with low laboratory MELD scores and for patients with MELD scores of 15 and higher. These results justify a continued role for LDLT in the U.S., especially in the context of a severe and ongoing limitation in the supply of deceased donor organs and substantial waitlist mortality. The data presented in this study should serve to guide the discussion that occurs between transplant physicians and transplant candidates regarding the survival benefits associated with receipt of a living donor liver transplant. With the identification and quantification of this survival benefit, transplant candidates and centers may be better prepared to advocate for pursuit of living donor liver transplantation in transplant candidates. Future efforts should focus on delineating those transplant candidates that benefit most from receipt of LDLT, and on identifying those patients for whom DDLT serves as the best avenue to successful transplantation.