C4d and C3d Staining in Biopsies of ABO- and HLA-Incompatible Renal Allografts: Correlation with Histologic Findings

Abstract

In ABO-incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA-incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0-4+ scale), diffuse PTC C4d had ≥1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d-negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO-incompatible, but not HLA-incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABOincompatible grafts.

Antibody-Mediated Renal Allograft Rejection

“…Antibodies to donor HLA class I or II antigens are present in 88 to 95% of the patients who have C4d deposition and acute graft dysfunction versus less than 10% in C4d-negative acute rejection (2,7,8). Antibodies to donor ABO antigens show a similar association.…”

“…C3d (or C3c) was found in PTC in 39 to 60% of biopsies from HLA-mismatched grafts with diffuse PTC C4d (8,(27)(28)(29). In general C3d and C4d were correlated.…”

“…This finding may be related to C3 activation via the alternative pathway, independent of C4. In the most comprehensive study, C3d was found only in conjunction with C4d in sensitized patients (8). Neutrophils in PTC or features of thrombotic microangiopathy correlated with C3d deposition in one study (8) but not in two others (8,29 prognosis than C4d alone (30).…”

“…Autoantibodies to the angiotensin II type 1 receptor have also been associated with graft loss and fibrinoid necrosis that resembles alloantibody-mediated rejection except for the common absence of PTC C4d (22). Lack of C4d deposition in protocol biopsies in the presence of circulating donorreactive antibody has been observed using flow cytometric assays and donor cells (7,8), perhaps in part because of antibodies of too low avidity or inability to fix complement. Fc receptors on NK cells (FcRIIA) may also play a role in acute rejection, and it is possible that some examples of AHR in biopsies that lack C4d are due to this mechanism.…”

“…No functional role of C4d per se has been reported. C4d deposition is strongly associated with circulating antibody to donor HLA class I or class II antigens (2,7,8) and is currently the best single marker of complement-fixing circulating antibodies to the endothelium.…”