Glomerular C4d for Diagnosis of Proliferative Glomerulonephritis

Proliferative glomerulonephritis (GN) has recently been classified into immune complex-mediated GN and complement-mediated GN, also known as C3 glomerulopathy. The classification is on the basis of pathophysiology and is guided by immunofluorescence findings. Immune complex-mediated GN is caused by glomerular deposition of immune complexes or Igs as a result of infections, autoimmune diseases, or monoclonal gammopathy, pathologies characterized by activation of the classical pathway (CP) or lectin pathway (LP) of complement.

Sanjeev Sethi, M.D., Ph.D.

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. Mayo Clinic researchers, first author Sanjeev Sethi, M.D., Ph.D., studied glomerular C4d for diagnosis of immune complex-mediated GN. The study was recently published in the Journal of the American Society of Nephrology.

Researchers 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 C4d staining.

C3 and C4d staining in immune complex (IC)-mediated GN. Top panel shows staining for C3, and bottom panel shows staining for C4d.
C3 and C4d staining in immune complex (IC)-mediated GN. Top panel shows staining for C3, and bottom panel shows staining for C4d.


The staining pattern of C4d mirrored the staining patterns of Ig and C3. Conversely, C4d staining was completely negative in 8o percent of specimens of C3 glomerulopathy, and only trace C4d staining was detected in 20 percent specimens.

With regard to postinfectious GN, C4d staining was negative in 46 percent of 13 specimens, suggesting an abnormality in the alternative pathway, and it was positive in 54 percent specimens.

To summarize, C4d serves as a positive marker for immune complex-mediated GN. The C4d stain helps to determine whether the proliferative GN is mediated by the activation of the AP or the activation of the CP/LP. However, C4d is absent or minimally detected in C3 glomerulopathy.

Kelley Luedke

Kelley Luedke

Kelley Luedke is a Marketing Channel Manager at Mayo Clinic Laboratories. She is the principle editor and writer of Insights and leads social media and direct marketing strategy. Kelley has worked at Mayo Clinic since 2013. Outside of work, you can find Kelley running, traveling, playing with her kitty, and exploring new foods.