Understanding the role of non-HLA antibodies in kidney transplantation: a literature review.

Non-HLA antibodies have emerged as important contributors to antibody-mediated rejection and long-term graft dysfunction in kidney transplantation, including in patients without detectable donor-specific antibodies against human leukocyte antigens (HLA-DSAs). This review summarizes current evidence on major non-HLA antibody targets, including angiotensin II type 1 receptor, endothelin A receptor, perlecan fragment LG3, vimentin, major histocompatibility complex class I chain-related molecule A, collagen, fibronectin, natural antibodies, and glutathione S-transferase theta 1, and highlights their mechanisms of formation, pathogenic roles, and clinical associations. These antibodies can arise through alloimmune or autoimmune processes, often driven by endothelial injury, ischemia-reperfusion injury, and inflammatory signaling, which may expose cryptic antigens and promote loss of self-tolerance. Mechanistically, non-HLA antibodies can mediate graft injury through complement activation, Fc receptor-dependent immune responses, and direct signaling effects on endothelial and vascular cells, leading to inflammation, microvascular injury, and fibrosis. Importantly, they can act synergistically with HLA-DSA, amplifying immune responses, and contributing to worse transplant outcomes. However, findings across studies remain inconsistent due to heterogeneity in detection methods, lack of standardized thresholds for positivity, and variability in patient populations. Additionally, temporal dynamics in antibody development and fluctuations over time suggest that static measurements may not fully capture their clinical relevance. The presence of non-HLA antibodies in healthy populations further complicates interpretation and highlights the need to better define clinically meaningful thresholds. Given the wide diversity in antigen targets, biological functions, and mechanisms of action, a one-size-fits-all approach is insufficient. Instead, individual non-HLA antibodies should be investigated through targeted mechanistic and clinical studies to clarify their specific roles in transplant outcomes. Future research should prioritize large-scale, multicenter prospective studies with standardized methodologies, alongside mechanistic investigations, to improve risk stratification and advance understanding of their impact on long-term kidney transplant success.