C4d-negative antibody-mediated rejection in renal allografts: evidence for its existence and effect on graft survival

The use of C4d staining as a tissue marker for humoral immunity has served an important role in allowing pathologists to more accurately diagnose acute antibody-mediated rejection (AMR) in renal and other allograft biopsies, and also to recognize the contribution of humoral immunity to lesions of chronic renal allograft rejection, including transplant glomerulopathy. However, while C4d remains a specific marker of a humoral response, recent evidence indicates that a considerable fraction of renal allograft biopsies showing antibody-mediated injury are C4d-negative, even by immunofluorescence. This review summarizes the current evidence supporting the existence of C4d-negative AMR, as well as evidence that this entity may, if untreated, lead to the development of scarring within the graft, transplant glomerulopathy and even graft loss.