Introduction: It is generally accepted that HLA-DP mismatches (MM) do not impact the survival of first transplants but that they may exert a deleterious effect in retransplants. This study aimed to investigate the impact of HLA-DPB1 allele and molecular MM (mMM) on the occurrence of acute rejection (AR) and low 5-year graft function (5-yGF) in first kidney transplants (KT).

Method: HLA-DPB1 allele and mMM were determined in 130 first KT from deceased donors, performed between 2014 and 2016. The following mMM models were investigated: expression MM, with the high expression G allele in the donor, T cell epitope (TCE) MM, classified as permissive and nonpermissive MM, epitope MM (EMM), considering all six HLA-DPB1 hypervariable regions (EMM-ABCDEF HVR) or only ABEF regions (EMM-ABEF HVR), Eplet MM (EpMM), considering all or only antibody-verified (AbVer) eplets, and solvent accessible amino acid MM (SAMM). EMM, EpletMM and SAMM loads were categorized using thresholds determined by ROC analysis for each outcome. The outcomes were AR and 5-yGF (estimated by CKD-EPI). Logistic and Cox regressions were used to investigate variables associated with 5-yGF and AR, respectively.

Results: 119 (91.5%) KT were performed with one or two HLA-DPB1 allele MM. The overall incidence of AR was 17.7% and the median 5-yGF was 40.3 (27.0 - 51.7) mL/min/1.73m2. No association between HLA-DPB1 allele MM and 5-yGF or rejection was observed. Considering only recipients of standard criteria donor, five logistic models for 5-yGF were built including variables that reached a p-value <0.10 in the univariable analysis (age and donor sex, cause of brain death, ABDR MM and AR) and the mMM (TCE, SAMM, all and AbVer EpMM, EMM-ABCDEF and ABEF HVR). In the model 2, variables associated with 5-yGF≤ 40 were donor age (OR=1.08; CI95%=1.02-1.14; p=0.005) and SAMM≥7 (OR=4.40; CI95%=1.56-12.36, p<0.005), while in the model 4, donor age (OR= 1.09; CI95%=1.03-1.15; p=0.003) and EpMM(AbVer≥2 (OR=3.39; CI95%=1.2-9.45, p=0.02) were associated with low GF. The AUC-ROC for predicting 5-yGF was 0.83 (0.75-0.92) for the model 2, and 0.68 (0.57-0.79) for the model 4. Lastly, for the outcome AR in all recipients, beyond the final donor creatinine, the following mMM models were statistically significant: TCE (HR=3.01; CI95%=1.33-6.84; p=0.008), SAMM≥5 (HR=2.69; CI95%=1.10-6.56; p=0.03), AbVerEpMM ≥3 (HR=3.38; 95%CI=1.32-8.70; p=0.01), and EMM-ABCDEF HVR ≥ 6 (HR=5.08; 95%CI=2.19-11.82; p<0.001).

Conclusion: To the best of our knowledge, this is the first study that shows that some mMM, in contrast to classical allele HLA-DPB1 MM, are associated with acute rejection and long-term graft function in a population of exclusively first kidney transplants.