Non-HLA antibodies worsen the histological phenotype and prognosis of antibody mediated rejection in kidney allografts.

Abstract

Antibody-mediated rejection (AMR) remains a leading cause of kidney allograft failure, with both HLA and non-HLA antibodies implicated in its pathogenesis. The contribution of non-HLA antibodies (non-HLA Abs) to microvascular inflammation (MVI) and graft outcome, particularly in cases lacking donor-specific anti-HLA antibodies (HLA-DSAs), remains incompletely understood. We analyzed 571 post-transplant serum samples from 326 patients with histological features of AMR (AMRh) and 164 stable control individuals. Non-HLA Abs were detected using the previously developed Non-HLA Antibody Detection Immunoassay (NHADIA), and associations were examined with histological lesions, AMRh persistence, and graft outcomes. Biopsies were scored according to Banff 2022 criteria, and patients were stratified by HLA-DSA and NHADIA status. External validation was also performed in an independent kidney transplant cohort that included 211 biopsies from 189 patients. NHADIA values were significantly higher in patients with AMRh compared to controls, regardless of HLA-DSA status. NHADIA values correlated with the severity of glomerulitis, peritubular capillaritis and global MVI scores. In patients with AMRh and HLA-DSAs, non-HLA Abs remained independently associated with MVI severity. Follow-up biopsies revealed persistent AMR lesions in patients with both HLA-DSAs and non-HLA Abs. Allograft survival was lowest in double-positive patients, and NHADIA positivity independently and significantly predicted graft loss (hazard ratio2.25, 95% confidence interval 1.03-4.92). Association of non-HLA Abs with Banff lesions severity and death-censored graft survival was replicated in the external validation cohort. Post-transplant detection of non-HLA antibodies identifies a distinct subset of AMR with more severe histology and worse graft prognosis, particularly when coexisting with HLA-DSAs. Integrating non-HLA Ab testing into current diagnostic frameworks may refine AMR classification and improve risk stratification.