Sex-based differences in antibody-mediated rejection among highly sensitized kidney transplant recipients

Abstract Background Antibody-mediated rejection (AMR) remains a major determinant of graft failure in kidney transplantation, particularly among highly sensitized recipients. Whether biological sex independently influences the incidence and determinants of AMR in this high-risk population remains uncertain. We hypothesized that recipient sex may be associated with early AMR risk beyond conventional immunologic risk factors. We therefore evaluated the association between sex and early AMR, explored sex-specific immunologic determinants, and assessed the impact of AMR on long-term graft survival. Methods We performed a multicenter retrospective cohort study of 438 highly sensitized deceased-donor kidney transplant recipients with cPRA ≥ 90% transplanted in Catalonia, Spain, between 2015 and 2021. The primary outcome was AMR within the first post-transplant year. Secondary outcomes included five-year death-censored graft survival and sex-specific associations with AMR. Median follow-up was 42.5 months. Results Within the first year, 51 recipients (11.6%) developed AMR. Men exhibited a higher incidence of AMR compared with women (16.2% vs. 8.5%; P = 0.01). In sex-stratified analyses, antibody strength was the dominant determinant in men, whereas DQB1 eplet mismatch was more strongly associated with AMR in women, although formal interaction testing was not statistically significant. AMR occurring within the first year was the strongest predictor of five-year graft failure (HR 8.3; P < 0.001), while recipient sex was not independently associated with graft loss. Conclusions In highly sensitized recipients, male sex was modestly associated with early rejection. AMR emerged as the main driver of long-term graft loss. The impact of epitope-level HLA mismatch on AMR risk may differ between sexes, particularly at the HLA-DQB1 locus, and warrants further investigation.