C4d at Crossroads Between Post-Infectious Glomerulonephritis and C3 Glomerulopathy

Abstract

Background Post-infectious glomerulonephritis (PIGN) (immune complex-mediated glomerulonephritis) and C3 glomerulopathy are sub-types of glomerulonephritis (GN) with hypercellularity. Both have overlapping clinical and morphologic features on a kidney biopsy, however, the treatment and prognosis of these diseases are quite different making their distinction of utmost importance. Immune complex-mediated glomerulonephritis arises from glomerular deposition of immune-complexes (Igs) and C3 as a result of activation of classical (CP) and lectin pathways (LP). C4d is produced as a result of activation of the CP/LP. On the other hand, C3 glomerulopathy results from activation of alternative pathway of complement. Aim To distinguish between PIGN and C3 glomerulopathy with the help of C4d IHC stain. Materials and Methods We studied 28 biopsies reported as GN with hypercellularity from January 2015 to January 2020. Clinical information, histological features and immunofluorescence patterns were analyzed. C4d IHC was performed on all the biopsies. Six known cases of immune complex-mediated GN were selected to act as a positive control for C4d staining. Results Amongst 28 cases originally reported as GN with hypercellularity, 18 were labeled as post-infectious GN and 10 as C3 glomerulopathy based on clinical information and serological findings. 13 of 18 (72.2%) cases of PIGN had mild to moderate (1–2+) C4d staining, 2 (11.1%) had strong (3+) staining and 3 (16.7%) cases were negative for C4d staining. In the 10 biopsies of C3 glomerulopathy, mild (1+) C4d staining was noted only in 3 (30%) biopsies. C4d had moderate to strong (2–3+) staining in the control group. Conclusion C4d IHC stain can be helpful in distinguishing PIGN from C3 glomerulopathy.

Utility of C4d Immunohistochemistry as an Adjunct Stain in Diagnostic Renal Pathology of Glomerular Diseases

“…All our biopsies of immune complex-mediated MPGN showed a continuous granular pattern of c4d deposits along GBM in subendothelial and subepithelial locations while C3G showed variable C4d deposits. C3G studies by Sethi et al and Bashir et al 10 showed a majority of them being C4d negative, and C4d reactivity in our C3G biopsies is in concordance with the possibility of precipitation of alternate pathway abnormalities by infections and lectin pathway activation. Thus, C4d deposition in MPGN does not exclude the possibility of C3G.…”

The C3 conundrum

“…C4d is positive in the majority of PIGN cases and is typically negative in C3G. 16 In our patient's case, C4d staining was performed; however, it was only weakly positive, so it could not be used for differentiation.…”

“…C4d is a marker of classical pathway activation through immune‐complex formation, which is commonly used after kidney transplant to detect antibody‐mediated rejection. C4d is positive in the majority of PIGN cases and is typically negative in C3G 16 . In our patient's case, C4d staining was performed; however, it was only weakly positive, so it could not be used for differentiation.…”

The diagnostic significance of C4d deposits, as an immunohistochemical proof of complement activation, in kidney glomerular pathologies and kidney transplantation

“…C4d immunohistochemistry/immunofluorescence may be a valuable biomarker associated with other kidney diseases histopathologic diagnostic and/or progression, as the thrombotic microangiopathy (27,28), human anti-glomerular basement membrane disease (29) or post-infectious glomerulonephritis (30).…”