C4d as a Diagnostic Tool in Proliferative GN

J Am Soc Nephrol. 2015 Nov;26(11):2852-9. doi: 10.1681/ASN.2014040406. Epub 2015 May 19.


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.

Keywords: glomerulonephritis; immunology and pathology; kidney biopsy; membranoproliferative glomerulonephritis (MPGN); renal pathology.

MeSH terms

  • Antigen-Antibody Complex
  • Biopsy
  • Complement C3 / chemistry
  • Complement C4b / chemistry*
  • Glomerulonephritis / blood*
  • Glomerulonephritis / diagnosis
  • Glomerulonephritis, IGA / blood*
  • Glomerulonephritis, IGA / diagnosis
  • Glomerulonephritis, Membranoproliferative / blood*
  • Glomerulonephritis, Membranoproliferative / diagnosis
  • Humans
  • Immunoglobulins / chemistry
  • Kidney / pathology
  • Kidney Glomerulus / immunology*
  • Kidney Glomerulus / pathology
  • Microscopy, Fluorescence
  • Peptide Fragments / chemistry*


  • Antigen-Antibody Complex
  • Complement C3
  • Immunoglobulins
  • Peptide Fragments
  • Complement C4b
  • complement C4d