Non-HLA antibodies in kidney transplantation: comprehensive insights and clinical implications

While HLA donor-specific antibodies (DSAs) are the primary mediators of allograft rejection, 20-30% of antibody-mediated rejection (ABMR) episodes occur in their absence. These 'DSA-negative' rejections represent a significant clinical challenge. This review explores the role of non-HLA antibodies (n-HLab) as potential markers of unexplained graft injury. Pathophysiologically, ischemia-reperfusion injury and endothelial stress trigger the release of cryptic autoantigens, transforming the allograft into a source of self-antigens. Key targets include AT1R, ETAR, LG3, vimentin, and MICA. While observational studies show an association between these antibodies and severe vascular rejection, a causal link and the therapeutic impact of their removal remain undefined. Currently, there is no definitive evidence that monitoring or therapeutically targeting n-HLab translates into improved long-term clinical outcomes. Diagnosis is currently limited by a lack of standardized assays and consensus thresholds. Management remains largely empirical. In conclusion, while n-HLab represent a promising area for risk stratification, further research and clinical validation are required before their routine implementation in clinical practice can be recommended.