Molecular diagnostics in HLA-incompatible kidney transplantation.

Human leukocyte antigen-incompatible (HLA-i) kidney transplantation enables access to transplantation for highly sensitized patients with preformed donor-specific antibodies (DSA) but remains associated with frequent early DSA rebound and alloimmune endothelial injury, resulting in a high incidence of antibody-mediated rejection (AMR) despite current desensitization and induction protocols that include imlifidase. Kidney allograft biopsy remains the diagnostic gold standard for detecting overt and subclinical AMR, yet conventional histology does not always capture early or subclinical antibody-mediated injury, particularly in sensitized recipients. Tissue-based transcriptomics, Molecular Microscope Diagnostic system (MMDx) and Banff Human Organ Transplant gene panel (B-HOT), provide enhanced sensitivity for detecting molecular AMR phenotypes that often precede morphologic changes and may be particularly informative in the early post-transplant period. Plasma donor-derived cell-free DNA (dd-cfDNA) as non-invasive biomarker correlates with molecular rejection activity and may support longitudinal monitoring in sensitized high-risk patients, although interpretation is limited in the immediate post-transplant period. The integration of histology, DSA monitoring, transcriptomics, and emerging biomarkers enables a multimodal approach to AMR phenotyping, which is particularly critical in HLA-i transplantation to detect subclinical injury early, guide timely intervention, and prevent the development of chronic and largely untreatable transplant glomerulopathy.