Anti-PAR2 autoantibodies are associated with chronic histological injury in kidney transplant recipients.

INTRODUCTION: Non-HLA autoantibodies directed against G protein-coupled receptors (GPCRs) have emerged as potential contributors to endothelial activation, vascular injury, rejection, and chronic allograft dysfunction after kidney transplantation. Protease-activated receptors 1 and 2 (PAR1 and PAR2) are GPCRs located at the interface of coagulation, inflammation, endothelial signaling, and tissue remodeling. However, the clinical relevance of circulating anti-PAR1 and anti-PAR2 autoantibodies in kidney transplant recipients remains undetermined. METHODS: We performed a retrospective observational study including 123 kidney transplant recipients who underwent clinically indicated allograft biopsy between 2018 and 2025. The primary objective was to evaluate associations between serum anti-PAR1 and anti-PAR2 autoantibody concentrations and the severity of Banff histopathological lesions. Associations with rejection phenotypes, selected clinical variables, and graft outcomes were also evaluated. Antibody concentrations were measured by ELISA. Correlation analyses, non-parametric group comparisons, logistic regression models, and exploratory landmark analyses of death-censored graft survival from serum sampling were performed. Correction for multiple testing was applied using the Benjamini-Hochberg false discovery rate procedure. RESULTS: Anti-PAR2 concentrations showed weak but statistically significant associations with interstitial fibrosis (Kendall τ = 0.221, pFDR = 0.005), tubular atrophy (Kendall τ = 0.216, pFDR = 0.005), arteriolar hyalinosis (Kendall τ = 0.193, pFDR = 0.018), and total inflammation (Kendall τ = 0.226, pFDR = 0.005). Borderline associations were observed for peritubular capillaritis, transplant glomerulopathy, and inflammation in areas of interstitial fibrosis and tubular atrophy (all pFDR = 0.052). No histopathological associations remained significant for anti-PAR1. Both anti-PAR1 and anti-PAR2 concentrations varied with time from transplantation to biopsy, while anti-PAR2 was additionally associated with recipient age at transplantation. Neither antibody was significantly associated with rejection phenotypes. In the exploratory landmark analysis, anti-PAR2 concentrations above the cohort median were associated with a higher hazard of death-censored graft loss (HR = 2.136, 95% CI 1.202-3.795; p = 0.010). DISCUSSION: Higher anti-PAR2 autoantibody concentrations were weakly associated with several chronic histological lesion scores in kidney allograft biopsies. An exploratory landmark analysis showed poorer death-censored graft survival among recipients with anti-PAR2 concentrations above the cohort median, although this association was not significant when anti-PAR2 was analyzed continuously. These findings require prospective validation.