*Purpose: Recent studies have investigated epitope matching in order to determine its predictive power in determining renal transplant outcomes, both in terms of de novo donor specific antibody (DSA) development, and graft rejection. However, these studies lack donor and recipient HLA diversity, focusing mainly on populations with Caucasian majorities. Our study aims to broaden epitope matching to determine if de novo DSA development and graft rejection are related to epitope mismatch levels in an HLA diverse patient population.

*Methods: We sampled a cohort of Houston patients with kidney transplants from 2016 to 2019 with full (ABCDRDQDP) HLA testing, including both deceased donor and living donor transplants (n=63, 44.4% Hispanic ,30.2% African American, 4.8% Asian, 17.5% Caucasian, 3.2% Unknown). We first performed epitope matching for each HLA loci between our transplant patients and their donors using HLA Matchmaker and recorded the number of epitope mismatches. We then compared the number of epitope mismatches in various loci to clinical parameters by gathering anti-HLA Ab MFI data on historic, current, and de novo DSAs as well as biopsy data including presence of T cell and Antibody mediated rejection, C4d result, and Banff grade.

*Results: We observed renal transplant patients with de novo DSA had a significantly higher amount of epitope mismatches greater than 20 in DR and DQ (p=0.001). This was not found analyzing HLA class I epitope mismatches. Furthermore, the presence of current or historical anti-HLA antibody was not correlative with the number of epitope mismatches. Patients with biopsy proven rejection had significantly higher epitope mismatch values for DR and DQ compared to patients without rejection (p=0.045). This was specific to class II as this was not observed with class I epitope matching levels. C4d staining was not correlative with the number of epitope mismatches. Our HLA diverse population of donors and recipients had an overall average of 38 Class I epitope mismatches at the HLA-A,B and C loci and 31 Class I epitope mismatches at HLA-DR and DQ. Between our various ethnic cohorts we did not observe a significant bias in the number of epitope mismatches.

*Conclusions: The number of HLA DR and DQ epitope mismatches remained predictive of both de novo DSA production and biopsy proven rejection. We found our HLA DR-DQ mismatch epitope sum threshold of 20 to be greater than previously published epitope mismatch thresholds. Overall HLA diversity in our population lead to an increase in the observed average number of epitope mismatches. This increase was not attributed to any specific ethnic group and is more likely due to heterogeneity within HLA. These data suggest, HLA diversity needs to be accounted for when establishing epitope mismatch thresholds used to modify patient’s immunosuppression or predict clinical outcomes.

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