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An explanation for the unmitigated disparity in patient survival between Black and White liver transplant recipients

To the Editor: Lee et al.1 nicely demonstrate that between 2002– 2018 the adjusted hazard ratio (aHR) of patient death postliver transplant (LT) was significantly higher for Black versus White recipients, with the aHR narrowing toward one during 2002– 2009 but not thereafter (and possibly even trending higher). Unfortunately, the authors were not able to more completely explain why this racial disparity in postLT survival persists; the accompanying editorial2 even asked, “What is missing?” We believe that a competing risks explanation (i.e., changes over time in the causespecific components of allcause mortality)3,4 for the unexplained portion of this unmitigated (and possibly increasing) disparity exists. In an analysis of 877 adults who received a primary, deceased donor LT at our center between 1996 and 2004 and were treated with a tacrolimus plus steroids based immunosuppressive regimen,5 325 patients experienced causespecific graft loss due to infection (N = 82), cardiovascular/ cerebrovascular event (N = 40), vascular thrombosis (N = 36), primary dysfunction (N = 35), HCV recurrence (N = 29), chronic rejection (CHR) (N = 23), etc. The hazard rate of graft failuredueto CHR was much higher among Blacks compared with nonBlacks (HR = 12.9, p < .000001; Figure 1A)5; however, we found no association of recipient race with any of the other causespecific hazards (HR = 0.84, p = .48 when combining graft losses across all other causes; Figure 1B). Although most of the graft lossesdueto primary dysfunction, vascular thrombosis, infection, and cardiovascular/cerebrovascular events occurred during the first year postLT, 91.3% (21/23) of the graft failuresdueto CHR occurred beyond the first year. Specifically, among graft losses occurring during 0– 6, 7– 12, 13– 24, and >24 months postLT, the observed percentages of graft failuresdueto CHR were as follows: 0.0% (0/144), 4.7% (2/43), 8.2% (4/49), and 19.1% (17/89), respectively (CHR was a major cause of graft loss beyond 2 years postLT). Thus, if a larger percentage of patients are now surviving graft failurefree beyond 12– 24 months postLT compared with 1025 years ago, then even if the hazard rates of graft failuredueto CHR for Blacks and Whites (and their HR) have remained unchanged, this larger risk set of patients followed beyond 12– 24 months would generate a larger percentage who experience graft failuredueto CHR, translating into an even larger Black versus White disparity today compared with past years. For instance, Figure 1C shows that in our study,5 there was a nonsignificant poorer graft survival for Blacks (N = 64, 29 graft losses) versus nonBlacks (N = 813, 296 graft losses) (HR = 1.31, p = .17). Using the reported unadjusted HR of 0.98 by Lee et al.1 for the effect of transplant year, and assuming an exponential distribution for the hazard rate of graft loss, our cohort's 5year graft survival would be expected to improve (if moved 16 years forward in time) from 63.8% (observed) to 72.3%. We then performed a simple simulation to achieve this amount of graft survival improvement whereby patients who previously experienced graft loss during the first 6 months posttransplant were randomly selected to instead experience graft survival >6 months (also, causespecific graft loss hazards >6 months remained unchanged, and median timestocausespecific graft loss were assumed for additional patients experiencing causespecific graft loss >6 months). Under this simulation, 108/144 patients who previously experienced graft loss during the first 6mo now had graft survival >6 months (34/108 experienced subsequent graft loss, and 74/108 were assumed to survive graft lossfree through the median, 73.3mo posttransplant). Two additional Black patients and three additional nonBlack patients experienced graft lossdueto CHR, and the difference in graft survival between Blacks and nonBlacks became closer to being statistically significant (HR = 1.43, p = .09; Figure 1C). Under this simulation, the percentage of graft lossesdueto CHR increased from 37.9% (11/29) to 54.2% (13/24) among Blacks and 4.1% (12/296) to 6.6% (15/227) among nonBlacks. In conclusion, improving early postLT survival and the consequential increased influence of late graft lossdueto CHR appears to explain at least part of the unexplained portion of Lee et al.1’s unmitigated racial disparity effect. Determination as to whether other changes in causespecific hazard rates and/or HRs have also occurred that influence racial disparity would first require careful reporting of the underlying cause of graft loss for all patients, as was suggested in Lee et al.1’s Discussion.