C4d as a Diagnostic Tool in Proliferative GN

Abstract

Proliferative GN is classified as immune complex-mediated or complement-mediated (C3 glomerulopathy). Immune complex-mediated GN results from glomerular deposition of immune-complexes/Ig and C3; the C3 is derived from activation of the classical and/or lectin pathways of complement. C3 glomerulopathy results from deposition of C3 and other complement fragments with minimal 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 of C4d 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 sclerosing membranoproliferative GN, 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 positive marker for immune complex-mediated GN but is absent or minimally detected in C3 glomerulopathy. On the other hand, complement-mediated GN, also termed C3 glomerulopathy, is caused by glomerular deposition of complement factors resulting from dysregulation of the alternative pathway (AP) of complement. 4-7 C3 glomerulopathy includes C3 GN and dense deposit disease (DDD). 8 Immunofluorescence is the key to the Mayo classification. Immune complex-mediated GN shows Ig on immunofluorescence, often along with C3, the latter because of activation of the CP by the immune complexes or LP by microbial surfaces. On the other hand, there is bright staining for C3, and Igs are typically negative in complement-mediated GN/C3 glomerulopathy. However, a proportion of C3 glomerulopathy biopsies may show small amounts of Igs on immunofluorescence. 9,10 As a result, the definition of C3 glomerulopathy now states that C3 staining should be dominant and at least 2 orders of

Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN

“…29,[55][56][57][58][59][60][61] The recommendations for ancillary studies are strong (A; established as contributory to diagnosis or prognosis), moderate (B; probably contributory to diagnosis or prognosis), possibly contributory to diagnosis or prognosis (C), and insufficient data (U). C4d as a prognostic marker for IgA nephropathy.…”

C4d Staining in the Diagnosis of C3 Glomerulopathy

“…In this issue of JASN, Sethi and colleagues 4 propose that staining for C4d may be useful in distinguishing C3 glomerulopathy from other types of glomerular injury. Most renal pathologists will be familiar with staining for C4d in transplant biopsies.…”

C4d deposits in IgA nephropathy: where does complement activation come from?

“…In transplanted kidneys, C4d is a good marker of antidonor antigen antibodies that reacted with graft endothelium and activated the classical complement pathway. In several glomerular diseases, C4d staining is a useful diagnostic factor because it is a sign of antibody-mediated or immune complexinduced glomerulonephritis [25]. The coincidence of C4d with C1q deposits and immunoglobulins is typical of classical complement pathway activation in lupus nephritis.…”