Non-human leukocyte antigen antibodies in kidney transplantation: pathogenic mechanisms, detection methods, and clinical implications

The importance of non-human leukocyte antigen (HLA) antibodies in transplant immunology has become increasingly evident, as their pathogenic role in kidney allograft injury is being clarified beyond the well-established effects of donor-specific anti-HLA antibodies. This review summarizes current evidence regarding antigenic targets, pathogenic mechanisms, detection platforms, and clinical implications of non-HLA antibodies in kidney transplantation. Major antigenic targets include angiotensin II type 1 receptor (AT1R), endothelin A receptor (ETAR), major histocompatibility complex class I-related chain A (MICA), vimentin, perlecan fragment LG3 (LG3), collagen, and fibronectin. These contribute to graft injury through both complement-dependent mechanisms (e.g., LG3, MICA) and complement-independent pathways, such as G protein-coupled receptor agonism by AT1R/ETAR and natural killer cell-mediated antibody-dependent cellular cytotoxicity, frequently acting together with HLA antibodies to exacerbate microvascular inflammation. Detection methods range from traditional cell-based assays to high-throughput multiplex bead arrays. However, lack of assay standardization and variability in interpretation remain major barriers to clinical implementation. Approaches such as assessing antibody burden and profiling antibody signatures using multiplex platforms show promise for enhancing immunological risk stratification, although further research and multicenter validation are required. Integrating non-HLA with HLA antibody evaluation, supported by standardized protocols and incorporation of multiomics data, may improve prognostication, guide personalized immunosuppressive strategies, and ultimately enhance kidney transplant outcomes.