American Journal of Kidney Diseases

C4 Glomerulopathy: A Disease Entity Associated With C4d Deposition

Published:February 17, 2016DOI:
      Complement-mediated glomerulonephritis, which includes C3 glomerulopathy, is characterized by dominant staining of C3 with minimal or no immunoglobulin deposits on immunofluorescence studies. We describe a new entity of complement-mediated glomerulonephritis that is characterized by bright C4d staining but with no or minimal C3 or immunoglobulin deposits on immunofluorescence studies. We label this entity as C4 glomerulopathy. C4 glomerulopathy includes C4 dense deposit disease and C4 glomerulonephritis. C4 dense deposit disease is characterized by bright C4d staining and dense deposits along glomerular basement membranes. C4 glomerulonephritis is characterized by bright C4d staining and many mesangial electron-dense deposits, with or without rare intramembranous electron-dense deposits. We describe clinical features and kidney biopsy results in a short series of 3 patients to highlight these findings. All 3 patients presented with proteinuria, and 2 patients also had hematuria. Kidney function was preserved in 2 patients, whereas 1 patient presented with declining kidney function. Evaluation for autoimmune disease, infection, and paraprotein yielded negative results in all patients. Complement levels were normal, although 1 patient had borderline low C4 levels. Kidney biopsy showed mesangial proliferative or membranoproliferative glomerulonephritis with bright C4d staining and absent or minimal C1q, C3, and immunoglobulin. Laser microdissection and mass spectrometry of glomeruli in all 3 patients showed large to moderate numbers of spectra matching C4. Furthermore, analysis of amino acid sequences showed that they were localized to the C4d portion of C4, consistent with immunofluorescence findings. Further studies are required to determine the underlying cause. In summary, we describe a novel complement-mediated glomerulonephritis that is characterized by bright glomerular C4d staining with minimal or absent staining for C1q, C3, and immunoglobulin.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Sethi S.
        • Fervenza F.C.
        Membranoproliferative glomerulonephritis: a new look at an old entity.
        N Engl J Med. 2012; 366: 1119-1131
        • Sethi S.
        • Fervenza F.C.
        Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.
        Semin Nephrol. 2011; 31: 341-348
        • Pickering M.C.
        • D'Agati V.D.
        • Nester C.M.
        • et al.
        C3 glomerulopathy: consensus report.
        Kidney Int. 2013; 84: 1079-1089
        • Servais A.
        • Fremeaux-Bacchi V.
        • Lequintrec M.
        • et al.
        Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.
        J Med Genet. 2007; 44: 193-199
        • Appel G.B.
        • Cook H.T.
        • Hageman G.
        • et al.
        Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.
        J Am Soc Nephrol. 2005; 16: 1392-1403
        • Smith R.J.H.
        • Alexander J.
        • Barlow P.N.
        • et al.
        New approaches to the treatment of dense deposit disease.
        J Am Soc Nephrol. 2007; 18: 2447-2456
        • Sethi S.
        • Fervenza F.C.
        • Zhang Y.
        • et al.
        C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
        Kidney Int. 2012; 82: 465-473
        • Sethi S.
        • Nasr S.H.
        • De Vriese A.S.
        • et al.
        C4d as a diagnostic tool in proliferative GN.
        J Am Soc Nephrol. 2015; 26: 2852-2859
        • Sethi S.
        • Sullivan A.
        • Smith R.J.H.
        C4 dense-deposit disease.
        N Engl J Med. 2014; 370: 784-786
        • Dasari S.
        • Chambers M.C.
        • Slebos R.J.
        • et al.
        TagRecon: high-throughput mutation identification through sequence tagging.
        J Proteome Res. 2010; 9: 1716-1726
        • Larsen C.P.
        • Messias N.C.
        • Walker P.D.
        • et al.
        Membranoproliferative glomerulonephritis with masked monotypic immunoglobulin deposits.
        Kidney Int. 2015; 88: 867-873
        • Weening J.J.
        • D’Agati V.D.
        • Schwartz M.M.
        • et al.
        The classification of glomerulonephritis in systemic lupus erythematosus revisited.
        J Am Soc Nephrol. 2004; 15: 241-250
        • Batal I.
        • Liang K.
        • Bastacky S.
        • et al.
        Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study.
        Lupus. 2012; 21: 13-26
        • Ohsawa I.
        • Ohi H.
        • Endo M.
        • et al.
        Evidence of lectin complement pathway activation in poststreptococcal glomerulonephritis.
        Kidney Int. 1999; 56: 1158-1159
        • Espinosa M.
        • Ortega R.
        • Sánchez M.
        • et al.
        Association of C4d deposition with clinical outcomes in IgA nephropathy.
        Clin J Am Soc Nephrol. 2014; 9: 897-904
      1. Ali A, Schlanger L, Nasr SH, et al. Proliferative C4 dense deposit disease, acute thrombotic microangiopathy, a monoclonal gammopathy, and acute kidney failure [published online ahead of print December 15, 2015]. Am J Kidney Dis.