The significance of C4d staining with minimal histologic abnormalities

C4d deposition within peritubular capillaries (PTCs) in renal allograft biopsies is a specific marker for interaction of antibody with the graft, and is an extremely useful tool for the diagnosis of antibody-mediated rejection (AMR). Whereas PTC C4d itself is not diagnostic of AMR, it is usually accompanied by histologic features of acute and/or chronic AMR. However, some biopsies, mainly from ABO-incompatible renal allografts, show C4d staining without histologic findings of AMR or cell-mediated rejection. The significance of such C4d staining remains a topic of debate, and this finding may have different implications in ABO-incompatible versus conventional renal allografts.

In biopsies of ABO-incompatible renal allografts (particularly protocol biopsies), C4d deposition in the absence of histologic evidence of rejection is a common finding, is not associated with an increased risk of graft scarring, and may even indicate a decreased risk of scarring, at least in the short term. By contrast, in positive cross-match and conventional renal allografts such C4d deposition is uncommon, and may indicate potentially reversible graft injury. However, a state of C4d staining without associated graft injury may be inducible in positive cross-match grafts by complement inhibition.

C4d staining without associated histologic findings of rejection may represent a marker for stable graft accommodation, at least in ABO-incompatible renal allografts. However, further studies are clearly needed to determine what the long-term implications of such C4d deposition are.