Association of HLA Mismatches and Histology Suggestive of Antibody-Mediated Injury in Absence of Donor-Specific Anti-HLA Antibodies

Abstract

Background: The histology of antibody-mediated rejection after kidney transplantation is observed frequently in absence of detectable donor-specific anti-HLA antibodies. While there is an active interest in the role of non-HLA antibodies in this phenotype, it remains unknown whether HLA mismatches play an antibody-independent role in this phenotype of microcirculation inflammation.

Methods: To study this, HLAMatchmaker, EMS-3D, HLA-EMMA and PIRCHE-II tools were used to determine the degree of HLA molecular mismatches in 893 kidney transplant recipients with available biopsy follow-up. Multivariable Cox proportional hazards models were applied to quantify the cause-specific hazard ratios of the different types of HLA mismatch scores for developing antibody-mediated rejection or histology of antibody-mediated rejection in the absence of donorspecific anti-HLA antibodies. In all survival analyses, the patients were censored at the time of the last biopsy

Results: In total, 121 (14%) patients developed histology of antibody-mediated rejection in the absence of donor-specific anti-HLA antibodies, of which 44 (36%) patients had concomitant T-cell mediated rejection. In multivariable Cox analysis, all different calculations of the degree of HLA mismatch associated with developing histology of antibody-mediated rejection in absence of donor-specific anti-HLA antibodies. This association was neither dependent on the presence of missing self (potentially related to natural killer cell activation), nor on the formation of de novo HLA antibodies. Also, glomerulitis and complement C4d deposition in peritubular capillaries associated with the degree of HLA mismatch in the absence of anti-HLA antibodies.

Conclusions: The histology of antibody-mediated rejection and its defining lesions are also observed in patients without circulating anti-HLA antibodies and relate to the degree of HLA mismatch.