Introduction: HLA class II eplet mismatch (epMM) and predicted indirectly recognizable HLA epitopes (PIRCHE-II) algorithms represent promising tools for immune risk assessment post-transplant. Yet, only few studies have explored the value of a combined (i.e. epMM and PIRCHE-II) molecular mismatch score for post-transplant immune risk stratification.
Methods: We included 545 patients who received kidney transplantation between 2011 and 2016 in three centers in Paris. High resolution HLA typing was performed via NGS sequencing to determine HLAMatchmaker epMM and PIRCHE-II scores for DR, DQ and DR+DQ loci. Risk cut-offs for post-transplant DSA were determined based on the epMM and PIRCHE-II scores that corresponded to 95% or greater sensitivity and maximized specificity. Combined (epMM and PIRCHE-II) scores were calculated and assigned to three risk categories (low, intermediate and high) for DR, DQ and DR+DQ loci and Kaplan Meir analyses for DSA and antibody-mediated rejection (ABMR) were performed.
Results: EpMM risk cut-offs predicted the risk of post-transplant DSA and ABMR. When used in combination with PIRCHE-II risk cut-offs, patients could be further stratified into low-, intermediate-, and high-risk categories. Combined scores for DR were significantly associated with risk of developing DR-DSA, patients at low risk exhibited a higher rate of freedom from DR-DSA compared to patients at high risk (P<0.0001). Patients with low combined scores for DQ had a low risk of developing DQ-DSA compared to patients at intermediate and high risk (P=0.0059). Combined low scores for both DR+DQ loci were also significantly associated with freedom from DR and DQ DSA (P=0.02). Finally, combined scores for DR+DQ could stratify patients at low risk of developing ABMR from patients at intermediate and high risk (P=0.027).
Conclusion: Integration of both HLA class II epMM and PIRCHE-II algorithms into a combined molecular mismatch score enables more granular immune risk stratification for post-transplant DSA and ABMR. This risk evaluation strategy may enable individualized immune monitoring and thus personalized immunosuppression in kidney transplantation.