Complement activation in acute humoral renal allograft rejection: Diagnostic significance of C4d deposits in peritubular capillaries

The distinction between acute humoral rejection (AHR) and acute cellular re jection (ACR) in renal allografts is therapeutically important, but patholo gically difficult. Since AHR is probably mediated by antibodies to the dono r endothelium that activate the classical complement pathway, it was hypoth esized that peritubular capillary C4d deposition might distinguish this gro up. Renal biopsies (n = 16) from 10 patients with AHR who had acute graft d ysfunction, neutrophils in peritubular capillaries, and a concurrent positi ve crossmatch were stained for C4d by immunofluorescence. Control biopsies for comparison showed ACR (n = 14), cyclosporin A toxicity (n = 6), or no a bnormality (n = 4). Peribiopsy sera were tested for anti-donor HLA antibody . C4d deposited prominently and diffusely in the peritubular capillaries in all AHR biopsies (16 of 16). IgM and/or C3 were also present in 19 and 44% respectively. With two-color immunofluorescence, C4d was localized in base ment membranes (type IV colagen(+)) and in the endothelium (Ulex europaeus agglutinin-I+). In ACR, no more than trace C4d was found in peritubular cap illaries (P < 0.0001 verses AHR), and no patient had anti-donor HLA antibod ies (0 of 8); 27% had neutrophils in peritubular capillaries. One of six bi opsies with cyclosporin A toxicity had similar C4d deposits, and circulatin g anti-donor class I antibody was detected. Grafts with AHR were lost (40%) more often than those with ACR (0%; P < 0.02). C4d in peritubular capillar y wails distinguishes AHR from ACR, is more specific and sensitive than tra ditional criteria, and is a potentially valuable adjunct in the diagnosis o f graft dysfunction.