C4d as a diagnostic tool in proliferative GN

Proliferative GN is classified as immune complex-mediated or complement-mediated (C3 glomerulopathy). Immune complex-mediatedGNresults fromglomerulardeposition of immune-complexes/Ig andC3; theC3 is derived from activation of the classical and/or lectin pathways of complement. C3 glomerulopathy results fromdeposition ofC3 and other complement fragmentswithminimal or no deposition of immune complexes/ Ig; the C3 is derived from activation of the alternative pathway of complement. C4d is a byproduct of activation of the classic and lectin pathways. Although widely used as a marker for antibody-mediated rejection, the significance ofC4d in C3 glomerulopathy is undetermined.We studied glomerular C4d staining in 18 biopsy specimens of immune-complex GN, 30 biopsy specimens of C3 GN, and 13 biopsy specimens of postinfectious GN. All specimens of immune complex-mediated GN, except two specimens of IgA nephropathy and one specimen of sclerosingmembranoproliferativeGN, showed bright (2-3+)C4d staining. The staining pattern of C4d mirrored the staining patterns of Ig and C3. Conversely, C4d staining was completely negative in 24 (80%) of 30 specimens of C3 glomerulopathy, and only trace/1+ C4d staining was detected in six (20%) specimens. With regard to postinfectious GN, C4d staining was negative in six (46%) of 13 specimens, suggesting an abnormality in the alternative pathway, and it was positive in seven (54%) specimens. To summarize,C4d serves as a positivemarker for immune complex-mediatedGNbut is absent or minimally detected in C3 glomerulopathy.