This is the first study to examine the effects of AA race and AA recipient-donor race mismatch on HCV disease severity and HCV-associated graft losses in transplant recipients. We have shown that AA recipients with HCV disease have a 47% higher rate of bridging fibrosis or cirrhosis as compared to non-AA recipients, and AA recipients with a non-AA donor have a higher risk of advanced fibrosis than those with AA donors. Additionally, AA recipients have significantly higher rates of HCV-associated graft loss and AAs with race-mismatched donors appear to be at greater risk than AAs with race-matched donors.
Our study confirms and extends the findings of a prior OPTN-based study that showed that AA donor-recipient race mismatch (versus match) was associated with reduced graft survival [9
]. However, our study establishes the link between advanced disease and graft loss. Our study differs from the prior study from Pang et al, in that we used a contemporary, MELD-era cohort and we did not restrict the analysis to AA and Caucasian races. However, our sensitivity analysis that compared results of AAs to Caucasians suggests that the AA recipient-donor race mismatch effect on advanced fibrosis and graft failure is not specific to Caucasian donors but is more generalizable to all non-AA donors.
The reason for the increased advanced fibrosis associated with AA recipient-donor race mismatch in HCV infected AAs is unknown. We speculate that it may be related to “protective” genetic factors associated with the donor liver. The importance of donor and recipient IL28B
polymorphisms has been highlighted by recent studies. Recipients with favorable alleles have been shown to have less inflammatory activity on biopsies post-LT [14
] and higher rates of response to antiviral therapy [14
]. Interestingly, IL28 SNPs in both the donor and
recipient were predictive of post-transplant outcomes [15
]. While IL28B polymorphisms are critical in understanding HCV-associated outcomes post-LT, especially response to HCV treatment, they are unlikely to explain the race-match and mismatch effects seen in AAs. Population studies have shown that AAs have a substantially lower frequency of the favorable IL28B alleles compared to Caucasians [18
]. If HCV disease outcomes are influenced by IL28B genotype, one could hypothesize that AAs with AA donors are more likely overall to have unfavorable IL28B genotypes than AA with non-AA donors, and yet this group had the best outcomes. Thus, other recipient and donor genetic factors, including but not limited to Killer cell immunoglobulin-like receptor (KIR) receptors and ligands [19
], and/or viral factors [15
] are likely of importance.
Natural killer (NK) cells and KIRs modulate the immunological response to HCV with KIRs specifically recognizing human leukocyte antigen (HLA) class I antigens present on target cells. The effector function of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant. Previous studies have found that a decrease in the number of HLA-C allele mismatches correlated with a decrease in the number of rejection episodes [20
]. Furthermore, mismatched KIR-HLA-C ligands between donor-recipient pairs favored progression to advanced fibrosis in recurrent HCV disease, but only in the presence of KIR2DL3 [19
]. One could hypothesize that mismatching KIR-HLA-C ligands could underscore the race mismatch effect we have shown. However, further studies examining KIR-HLA-C and race mismatch are needed to further examine this hypothesis.
While evaluation of donor-recipient mismatch in non-AA recipients was not the focus of our study, an apparent protective effect of AA donor (vs non-AA) race on risk of advanced fibrosis was seen non-AA recipients. Differences in donor quality (e.g. donor cause of death, donor age) were explored post-hoc and found to not explain this association (data not shown). Thus, other unmeasured donor, recipient and transplant-related factors are likely at play.
In our study, achievement of a sustained virologic response was protective of HCV-associated graft failure and all-cause graft failure, as has been shown in other studies [22
]. Treatment rates were similar between AAs versus non-AAs but rates of sustained virologic response were higher in non-AAs than AAs [2
]. This differential rate of response to therapy, is partially explained by the IL28B polymorphisms [24
] and interestingly, in liver transplant recipients, the IL28B polymorphisms may be an even stronger predictor of response than in non-transplant recipients [14
], suggesting an interaction between IL28B actions and immunosuppression. Given the recognized importance of treatment responses in achieving long-term graft survival, new treatment options with efficacy in patients groups with unfavorable IL28B genotypes, such as AAs, are essential.
In most epidemiologic studies, the gold standard for race classification has been use of “self-identified” race [25
]. In this study, recipient and donor race data was obtained from the UNOS/OPTN database, which does not require self-designation of race and thus some misclassification bias may exist. However, this limitation is not unique to this study but rather a limitation of all studies of race that utilize UNOS/OPTN data [2
]. Moreover, among members of a self-identified race, genetic heterogeneity is recognized due to variable admixtures with other racial groups. [28
There were some limitations of our study. First, due to its retrospective nature and lack of systematic data collection, some factors of potential importance in disease progression, such as donor steatosis or diabetes, IL-28B polymorphisms in recipient/donor and detailed immunosuppression information, are lacking. Second, given our relatively small sample size, interactions could not be statistically examined. Third, despite inclusion of four large U.S. transplant programs, the total number of AAs in the study, particularly those matched to AA donors, is modest and limits our ability to perform extensive multivariable analysis between matched and mismatched recipient-donor subgroups. However, the proportion of AAs in our cohort is very consistent with the proportion of AAs undergoing LT in the U.S. and thus we believe our results are generalizable. Fourth, there is a possibility of misclassification bias within a race group. Despite these limitations, this is the largest cohort of patients with biopsy data evaluating disease severity post-transplantation and includes detailed information on other cofactors known to influence disease progression such as donor age, acute rejection and receipt of HCV treatment.
In conclusion, this study shows that AAs have higher rates of advanced fibrosis and graft loss associated with HCV than non-AAs, and that AAs with recipient-donor race mismatch represent the highest risk group. The importance of donor selection is highlighted by our results, and use of high quality donors, i.e. younger donors, race matched or those with low donor risk index, may be one strategy to minimize the risk of disease progression, especially among high risk groups such as AAs. We do not advocate for routine matching of recipients and donors based upon race, but it may be a factor to be weighed favorably when assessing a graft, particularly if from an extended criteria donor, for an AA recipient. Our results also argue for closer monitoring of disease progression in AA LT recipients, possibly with more frequent use of liver biopsies, and earlier consideration of antiviral therapy. Clearly, there is also a need for antiviral therapies with improved efficacy in all transplant recipients, but among AA, this is particularly critical given their truncated timeline to the development of recurrent cirrhosis.