Repeated HLA-DRB1 and HLA-DQB1 Mismatches Without Preformed DSA Affect Graft Survival, Rejection and DSA Development: A Multicenter Analysis

Abstract

Repeat transplantations represent up to 20% of all kidney transplants. Whereas repeat transplantations in the presence of circulating donor-specific HLA-antibodies are generally avoided, the risk of repeated HLA-mismatches (RMM) without detectable antibodies remains debated. This multicenter study evaluated the hazard of RMM, stratified by HLA-class, on transplant outcomes in the absence of preformed donor-specific antibodies. We included repeat kidney transplant recipients from January 2009 onward with available HLA typing for HLA-A, -B, -C, -DRB1, -DRB3/4/5 and -DQB1 from current and previous donors. RMM were defined at the split serological antigen level, excluding patients with only HLA-DP or HLA-DRB3/4/5 RMM. Patients were included if: (a) preformed donor-specific HLA-antibodies (DSA) had never been detected and (b) this was confirmed by Luminex assays within 6 months pre-transplantation. A competing risk model, adjusting for demographic factors and total HLA-mismatch load while accounting for death as a competing risk, showed that HLA-DRB1 and/or HLA-DQB1 RMM significantly increased the risk of graft loss within 1 year post-transplant (HR 3.75 [95% CI 1.51–9.34], p = 0.004). Cox proportional hazard models further linked these HLA-class II RMM to higher risks of biopsy-proven rejection (HR 1.98 [95% CI 1.04–3.76], p = 0.037) and DSA development (HR 9.89 [95% CI 1.92–50.99], p = 0.006), while no significant risks were observed for HLA-class I RMM. Sensitivity analyses in patients screened for pretransplant DSA via single antigen bead assays, those with similar immunosuppression, and those with allelic RMM further confirmed these findings. These results suggest that avoiding HLA-DRB1 and HLA-DQB1 RMM, when feasible, may improve transplant outcomes.