*Purpose: Solid organ transplant donor-recipient eplet mismatch has been correlated with subsequent donor specific antibody (DSA) formation, antibody mediated rejection, and overall rejection rates. However, studies have been predominantly in patients on tacrolimus-based immunosuppression regimens. Evidence indicates patients on belatacept have lower rates of DSA formation, suggesting mediation of immunogenicity of human leukocyte antigen (HLA) polymorphisms. Using eplet risk stratification to compare rates of immunologic events between immunosuppression regimens will provide additional insight into the risks and benefits of these medications.

*Methods: Adult kidney transplant recipients at Emory University between 01/2009 and 10/2021 were considered for inclusion. EBV seronegative, and HIV positive patients were excluded. Maintenance immunosuppression consisted of mycophenolate mofetil, prednisone, and either tacrolimus (n=790) or belatacept (n=2,442). Cohorts were propensity-score matched by age, gender, race, and donor type using optimal 1:1 selection. Low/intermediate-resolution HLA typing and patient ethnicity were used as input for 9-locus high resolution HLA imputation. Eplet mismatch was calculated with HLAMatchMaker version 2.0 reference tables applied using hlaR. Risk stratification was determined by single molecule DR/DQ eplet mismatch (Wiebe 2018). Endpoints were DSA formation, acute rejection, and eGFR.

*Results: Belatacept (n=790) and tacrolimus (n=790) cohorts were propensity score matched with standardized difference < 0.1 for all variables. In both groups, mean age was 50 years, 62% of patients were male, and 32% received a kidney from a living donor. Median follow-up was 36 months. Single molecule eplet risk level was associated with DSA formation and acute rejection for both groups. The reduced DSA rate in belatacept patients was most pronounced for the intermediate eplet risk group. Conversely, the increased acute rejection rate in belatacept patients was confined to the high-risk group. Notably, mean eGFR was higher in belatacept patients (low-risk: 53.9, intermediate/high-risk: 52.5 ml/min/1.73m²) than tacrolimus (low-risk: 47.9, intermediate/high-risk:47.3 ml/min/1.73m²) over the first three years post-transplant regardless of eplet risk stratification (p<0.01).

*Conclusions: Single molecule HLA-DR/DQ eplet mismatch from imputed HLA typing successfully stratifies the risk of immunologic events for historical belatacept and tacrolimus patients. Additionally, eplet risk stratification identifies subgroups of patients for whom particular risks and benefits of immunosuppressants are more pronounced. Analysis of eplet mismatch burden may be a useful adjunct in determining the most beneficial immunosuppression agents for individual patients.

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