Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Aug;21(4):541-551.
doi: 10.1007/s10157-016-1358-5. Epub 2016 Nov 23.

C3 glomerulopathy and current dilemmas

Naoko Ito  1 , Ryuji Ohashi  2 , Michio Nagata  3
Affiliations
Review

C3 glomerulopathy and current dilemmas

Naoko Ito et al. Clin Exp Nephrol. 2017 Aug.

Erratum in

Abstract

C3 glomerulopathy (C3G) is a recently identified disease entity caused by dysregulation of the alternative complement pathway, and dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are its components. Because laboratory detection of complement dysregulation is still uncommon in practice, "dominant C3 deposition by two orders greater than that of immunoglobulins in the glomeruli by immunofluorescence", as stated in the consensus report, defines C3G. However, this morphological definition possibly includes the cases with glomerular diseases of different mechanisms such as post-infectious glomerulonephritis. In addition, the differential diagnosis between DDD and C3GN is often difficult because the distinction between these two diseases is based solely on electron microscopic features. Recent molecular and genetic advances provide information to characterize C3G. Some C3G cases are found with genetic abnormalities in complement regulatory factors, but majority of cases seem to be associated with acquired factors that dysregulate the alternative complement pathway. Because clinical courses and prognoses among glomerular diseases with dominant C3 deposition differ, further understanding the background mechanism, particularly complement dysregulation in C3G, is needed. This may resolve current dilemmas in practice and shed light on novel targeted therapies to remedy the dysregulated alternative complement pathway in C3G.

Keywords: Alternative complement pathway; C3 glomerulonephritis; C3 glomerulopathy; Dense deposit disease; Dominant C3 deposition; Membranoproliferative glomerulonephritis.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no conflicts of interest exist.

Figures

Fig. 1
Fig. 1
Schema illustrates the complement cascade and CRFs of the alternative pathway in C3G. The key events in C3G in this cascade include abnormal amplification of C3b production by activation of C3 to C3b through the following pathways. (1) Accelerated forming C3bBb by CFB through gain of function. Activation of C3b convertase by (2) dysfunction of CFH which degrades C3bBb, (3) enhancing CFH deregulation by dysfunction of CFHR, or (4) production of C3NeF which inhibits the degradation of C3bBb. (5) Suppression of C3b inactivation by CFH/CFI/MCP/CFHR also amplifies C3b activation. This dysregulation of CRFs may be caused not only by inherited mutations in the genes responsible for these factors but also in acquired factors such as auto-antibodies for CRFs and C3NeF. CFH complement factor H, CFI complement factor I, CFHR complement factor H-related proteins, MCP membrane cofactor protein, CFB complement factor B, C3NeF complement component 3 nephritic factor
Fig. 2
Fig. 2
Representative glomerular features of DDD and C3GN by light microscopy (LM) and electron microscopy (EM). DDD by LM (a) shows thickened glomerular basement membrane (GBM) stained negatively with methenamine silver, giving pink color with hematoxylin. In C3GN, LM (b) reveals irregular GBM with double contours stained on the background of mesangial proliferation. By EM, a highly electron-dense deposition replaces the lamina densa of GBM (c) in DDD, whereas C3GN shows thickened GBM with mottled and less osmiophilic deposits versus those of DDD (d)
Fig. 3
Fig. 3
Pediatric case with low serum C3 levels over five years showing the MPGN pattern by light microscopy (a Periodic acid-Schiff stain and b Periodic acid-methenamine silver stain) with isolated granular C3 deposition by immunofluorescence (middle panels). Electron microscopy shows mesangial and intramembranous deposits that are not very dense (c), as usually seen in DDD (Fig. 1). In a portion, intramembranous continuous deposition with moderate density was seen (d). This case was presented at international conferences, and there were inconsistent diagnoses among renal pathologists. Abnormalities of complement factors are under investigation
Fig. 4
Fig. 4
Current status of C3G. Glomerular deposition of predominant C3 suggests the possibility of C3G, which needs to be discriminated from immune complex-mediated GN. By LM, C3G shows various glomerular patterns. DDD and C3GN are discriminated by EM features, but a clear distinction to differentiate these two diseases is often difficult. Alternative complement dysregulation is an ultimate definition of C3G, and several factors may amplify alternative complement activation such as CRF gene mutations causing loss or gain of function, and auto-antibodies such as C3NeF stabilizing C3 convertase. In most cases, however, the cause remains unknown. Monoclonal immunoglobulin occasionally functions as an auto-antibody. IF immunofluorescence, LM light microscopy, EM electron microscopy, C3G C3 glomerulopathy, PIGN post-infectious glomerulonephritis, GN glomerulonephritis, DDD dense deposit disease, C3GN C3 glomerulonephritis, CRFs complement regulatory factors, C3NeF complement component 3 nephritic factor
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Fakhouri F, Fremeaux-Bacchi V, Noel LH, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol. 2010;6:494–499. doi: 10.1038/nrneph.2010.85. - DOI - PubMed
    1. Barbour TD, Ruseva MM, Pickering MC. Update on C3 glomerulopathy. Nephrol Dial Transplant. 2016;31:717–725. doi: 10.1093/ndt/gfu317. - DOI - PMC - PubMed
    1. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin J Am Soc Nephrol. 2011;6:1009–1017. doi: 10.2215/CJN.07110810. - DOI - PMC - PubMed
    1. Barbour TD, Pickering MC, Terence Cook H. Dense deposit disease and C3 glomerulopathy. Semin Nephrol. 2013;33:493–507. doi: 10.1016/j.semnephrol.2013.08.002. - DOI - PMC - PubMed
    1. Thomas S, Ranganathan D, Francis L, Madhan K, John GT. Current concepts in C3 glomerulopathy. Indian J Nephrol. 2014;24:339–348. doi: 10.4103/0971-4065.134089. - DOI - PMC - PubMed

MeSH terms