HLA-DR/DQ Single Molecule Eplet Mismatch And Formation Of De Novo Donor-Specific Anti-HLA Antibodies After Kidney Transplantation In Children
Vaka Sigurjonsdottir1,2,3, Kim Piburn1, Paul Grimm1, Bing M. Zhang4.
1 Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, United States; 2Division of Nephrology, Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, FL, United States; 3Faculty of Medicine, School of Health Sciences, Universiy of Iceland, Reykjavik, Iceland; 4Histocompatibility and Immunogenetics Laboratory, Stanford Blood Center, Stanford University, Palo Alto, CA, United States
Purpose: The advances in HLA typing methods and elucidation of three-dimensional molecular structures of HLA antigens in recent years have allowed analysis of donor/recipient HLA mismatches at the structural level, which may be a more precise and optimal approach to determine HLA compatibility and predict transplant outcomes. Eplet mismatches in HLA, especially HLA-DR/DQ at the single-molecule level, have been identified as a prognostic biomarker for primary alloimmunity. There have been limited studies evaluating this approach and the optimal risk stratification cut-offs in racially diverse pediatric patients receiving kidney transplantation.
Methods: Children who underwent kidney transplantation from 1/1/2010-3/1/2018 at Stanford, with at least 12-month follow-up, were included. High-resolution HLA typing was performed using next generation sequencing. HLA Matchmaker software (HLA DRDQDP Matching version 2.0) was used to count eplet mismatches for donor/recipient pairs. Outcome of interest was time to de novo donor specific antibody (dnDSA) formation. dnDSA were screened at the time of transplant, 1, 2, 3, 6, and 12 months following, at least annually thereafter, and as clinically indicated. ROC analysis at the DR and DQ loci was performed to determine risk categories based on total and single-molecule eplet mismatch thresholds. Survival analysis was performed by the Kaplan-Meier method using the log-rank test for significance.
Results: A total of 233 patients were identified. The median age at transplant was 12.3 years, 46.8% were female, and 76% had a deceased donor transplant. The mean follow-up time was 45 (range, 9–108) months. 40% formed Anti-HLA class II dnDSA. Patients with an eplet mismatch sum of HLA DR > 6 and/or DQ >4 had an increased risk of HLA-DR/DQ dnDSA formation.
Similarly, patients with single-molecule mismatch of HLA-DR≥5 and/or DQ≥4 had an increased risk of HLA-DR/DQ dnDSA formation.
Conclusions: Single-molecule eplet mismatch and total eplet mismatch are associated with an increased risk of dnDSA formation. Assessing a patient’s individual risk based on donor/recipient HLA-DR/DQ eplet mismatches may guide immunosuppression regimen in the post-transplant period and predict adverse outcomes.
