Eplet mismatch imputation studies should include immunologic risk assessment

Abstract

To the Editor: HLA eplet mismatch analysis represents the evolution from antigen-level match assessments and cell-based donor-specific antibody (DSA) identification to an integrated approach combining sophisticated molecular histocompatibility genotyping with solid phase antibody detection techniques. Analyzing eplet mismatches between donor–recipient pairs at each HLA locus and using eplet motifs in the interpretation of posttransplant antibody reactivity has garnered increasing attention in recent years. Seminal studies to date reveal a direct correlation between posttransplant outcomes and the degree of HLA-DR and/or HLA-DQ eplet mismatches, particularly when grouped into high or low eplet mismatch ranges.1Wiebe C Nickerson PW. Human leukocyte antigen molecular mismatch to risk stratify kidney transplant recipients.Current Opinion Organ Transplant. 2020; 25: 8-14Crossref PubMed Scopus (18) Google Scholar While this area of solid organ transplantation continues to develop, there is an anticipation that eplet mismatch analysis will eventually play a role in organ allocation. Two recent studies in AJT by Senev et al2Senev A Emonds MP Van Sandt V et al.Clinical importance of extended second field high-resolution HLA genotyping for kidney transplantation.Am J Transplant. 2020; 20: 3367-3378Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar and Engen et al3Engen RM Jedraszko AM Conciatori MA Tambur AR. Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation.Am J Transplant. 2021; 21 (https://doi.org/10.1111/ajt.16070): 344-352Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar performed stringent analyses of the accuracy of imputing high-resolution typing based on the low-resolution HLA genotyping to identify eplet mismatches in donor–recipient pairs. Using slightly different methods, these groups found that imputation did not agree with high-resolution HLA genotyping in 8.7–18.8% of pairs for HLA-ABC eplets and 37–46.1% of pairs for HLA-DR and DQB1 eplets. The authors concluded that the overall imprecision of imputation was a major limitation to eplet mismatch analysis. However, we believe that the utility and potential application of imputation for determining HLA eplet mismatch burden was not fully addressed in the two studies. While we agree that imputation is not a perfect tool to define high-resolution HLA typing results, we maintain that imputation can nonetheless be a useful approach when high-resolution typing is unavailable. Multiple retrospective studies have correlated clinical outcomes, such as DSA formation and graft rejection, with numerical ranges of eplet mismatches that stratify donor–recipient pairs into high or low immunologic risk groups. As such, risk stratification does not necessarily depend on the correct identification of each individual eplet. For example, if imputation versus high-resolution genotyping increased the mismatch burden by four HLA-DR eplets, but did not change the immunologic risk stratification because the number of eplet mismatches remains below the low-risk cutoff of 10,4Wiebe C Kosmoliaptsis V Pochinco D et al.HLA-DR/DQ molecular mismatch: a prognostic biomarker for primary alloimmunity.Am J Transplant. 2019; 19: 1708-1719Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar then imputation would be useful. Supporting this presumption, Senev et al show in Figure 6 that in 88% of cases the imputed HLA-DR and -DQ eplet mismatch burden is within two eplets of agreement with high-resolution genotyping (Figure 6). Similarly, Engen et al report in Table 8 that in 85.4% of cases, the imputed total Class-I and Class-II eplet mismatch burden is within two eplets of high-resolution genotyping. While a direct analysis was not performed, those data strongly suggest that imputation would result in the correct eplet-based immunologic risk stratification in nearly all cases. In the future, as total eplet mismatch burden is superseded by analysis of the mismatch of specific immunogenic eplets, the need for high-resolution genotyping will grow.5McCaughan JA Battle RK Singh SKS et al.Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation.Am J Transplant. 2018; 18: 2924-2933Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar However, in the current era of eplet mismatch analysis, we believe that imputation is a reasonable approach for retrospective studies when high-resolution genotyping is not available. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.