Non-HLA Antibodies in Kidney Transplantation: Mediators of Allograft Injury or Markers of Dysregulated Humoral Immunity?

Antibody-mediated rejection (AMR) remains a major cause of kidney allograft injury and loss. Although donor-specific antibodies against human leukocyte antigens (HLA-DSAs) are central to humoral alloimmunity, they do not explain all cases of microvascular inflammation or graft dysfunction. This review critically evaluates non-HLA antibodies as potential mediators of allograft injury and markers of dysregulated humoral immunity by integrating functional, experimental, clinicopathological, and clinical evidence. Receptor-targeting antibodies, especially those against the angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), have the strongest evidence for direct pathogenicity. Antibodies against major histocompatibility complex class I-related chain A (MICA) and glutathione S-transferase theta-1 (GSTT1) reflect non-HLA alloimmunity, whereas antibodies targeting perlecan-derived LG3, vimentin, and injury-associated antigens may arise through secondary autoimmunity and mark broader humoral activation. We propose that selected pathogenic non-HLA antibodies participate in a feed-forward cycle of graft injury, antigen exposure, epitope spreading, and humoral amplification, although this model requires longitudinal validation. Crucially, non-HLA antibody positivity alone should neither establish AMR nor guide antibody-specific treatment. Its interpretation should be target-specific and integrated with HLA-DSAs, histopathology, molecular findings, graft function, and evidence of immune activation.