Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pathogenesis of the C3 glomerulopathies and reclassification of MPGN

Abstract

Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types—type I, type II, and type III—based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.

Key Points

  • A new classification scheme for MPGN, centred on whether or not immunoglobulin accompanies complement on immunofluorescence, aims to capture the pathogenesis behind the MPGN lesion

  • A C3 glomerulopathy is a proliferative glomerulonephritis, usually (but not exclusively) with a MPGN pattern on light microscopy, with C3 staining alone on immunofluorescence, implicating hyperactivity of the alternative complement pathway

  • Mutations in and/or autoantibodies directed at factors that activate or regulate the C3 convertase of the alternative complement pathway can lead to dysregulation of this pathway and subsequent glomerular injury

  • Atypical hemolytic uremic syndrome is distinct from the C3 glomerulopathies in both the pattern of glomerular injury (a thrombotic microangiopathy) and phase of complement dysregulation (solid versus fluid phase)

  • Targeted and effective treatment of the C3 glomerulopathies will likely require an a priori, individualized understanding of the defect in the alternative complement pathway for each affected individual

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The reclassification of MPGN has led to the emergence of a new spectrum of diseases called C3 glomerulopathies.
Figure 2: Activation of C3 convertase is involved in both complement-mediated and immune-complex-mediated MPGN.

References

  1. 1

    Tarshish, P., Bernstein, J., Tobin, J. N. & Edelmann, C. M. Jr. Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone—a report of the International Study of Kidney Disease in Children. Pediatr. Nephrol. 6, 123–130 (1992).

    CAS  Article  Google Scholar 

  2. 2

    Fakhouri, F., Fremeaux-Bacchi, V., Noel, L. H., Cook, H. T. & Pickering, M. C. C3 glomerulopathy: a new classification. Nat. Rev. Nephrol. 6, 494–499 (2010).

    CAS  Article  Google Scholar 

  3. 3

    Sethi, S., Nester, C. M. & Smith, R. J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion. Kidney Int. 81, 434–441 (2012).

    Article  Google Scholar 

  4. 4

    Levy, M., Gubler, M. C., Sich, M., Beziau, A. & Habib, R. Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (type I MPGN). Clin. Immunol. Immunopathol. 10, 477–492 (1978).

    CAS  Article  Google Scholar 

  5. 5

    Habib, R., Gubler, M. C., Loirat, C., Maiz, H. B. & Levy, M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int. 7, 204–215 (1975).

    CAS  Article  Google Scholar 

  6. 6

    Strife, C. F., McEnery, P. T., McAdams, A. J. & West, C. D. Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin. Nephrol. 7, 65–72 (1977).

    CAS  PubMed  Google Scholar 

  7. 7

    Sethi, S. et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int. 75, 952–960 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Sethi, S. & Fervenza, F. C. Membranoproliferative glomerulonephritis—a new look at an old entity. N. Engl. J. Med. 366, 1119–1131 (2012).

    CAS  Article  Google Scholar 

  9. 9

    Sethi, S. & Fervenza, F. C. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin. Nephrol. 31, 341–348 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Walker, P. D., Ferrario, F., Joh, K. & Bonsib, S. M. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod. Pathol. 20, 605–616 (2007).

    Article  Google Scholar 

  11. 11

    D'Agati, V. D. & Bomback, A. S. C3 glomerulopathy: What's in a name? Kidney Int. 82, 379–381 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Zuber, J. et al. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat. Rev. Nephrol. http://dx.doi.org/10.1038/nrneph.2012.214.

  13. 13

    Roumenina, L. T. et al. Alternative complement pathway assessment in patients with atypical HUS. J. Immunol. Methods 365, 8–26 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Zhang, Y. et al. Causes of alternative pathway dysregulation in dense deposit disease. Clin. J. Am. Soc. Nephrol. 7, 265–274 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Licht, C. & Fremeaux-Bacchi, V. Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis. Thromb. Haemost. 101, 271–278 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Herlitz, L. C. et al. Pathology after eculizumab in dense deposit disease and C3 GN. J. Am. Soc. Nephrol. 23, 1229–1237 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Servais, A. et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J. Med. Genet. 44, 193–199 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Licht, C. et al. Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 70, 42–50 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Habbig, S. et al. C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int. 75, 1230–1234 (2009).

    Article  Google Scholar 

  20. 20

    Gale, D. P. et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376, 794–801 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Athanasiou, Y. et al. Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin. J. Am. Soc. Nephrol. 6, 1436–1446 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Martinez-Barricarte, R. et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Invest. 120, 3702–3712 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Ruley, E. J., Forristal, J., Davis, N. C., Andres, C. & West, C. D. Hypocomplementemia of membranoproliferative nephritis. Dependence of the nephritic factor reaction on properdin factor B. J. Clin. Invest. 52, 896–904 (1973).

    CAS  Article  Google Scholar 

  24. 24

    Vallota, E. H. et al. A serum factor in chronic hypocomplementemic hephritis distinct from immunoglobulins and activating the alternate pathway of complement. J. Exp. Med. 139, 1249–1261 (1974).

    CAS  Article  Google Scholar 

  25. 25

    West, C. D. Nephritic factors predispose to chronic glomerulonephritis. Am. J. Kidney Dis. 24, 956–963 (1994).

    CAS  Article  Google Scholar 

  26. 26

    West, C. D., Witte, D. P. & McAdams, A. J. Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2. Am. J. Kidney Dis. 37, 1120–1130 (2001).

    CAS  Article  Google Scholar 

  27. 27

    Gewurz, A. T., Imherr, S. M., Strauss, S., Gewurz, H. & Mold, C. C3 nephritic factor and hypocomplementaemia in a clinically healthy individual. Clin. Exp. Immunol. 54, 253–258 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Fremeaux-Bacchi, V. et al. Hypocomplementaemia of poststreptococcal acute glomerulonephritis is associated with C3 nephritic factor (C3NeF) IgG autoantibody activity. Nephrol. Dial. Transplant. 9, 1747–1750 (1994).

    CAS  PubMed  Google Scholar 

  29. 29

    Sissons, J. G. et al. The complement abnormalities of lipodystrophy. N. Engl. J. Med. 294, 461–465 (1976).

    CAS  Article  Google Scholar 

  30. 30

    Sethi, S. et al. C3 Glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up. Kidney Int. 82, 465–473 (2012).

    CAS  Article  Google Scholar 

  31. 31

    Bomback, A. S. et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7, 748–756 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Sethi, S. et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. Clin. J. Am. Soc. Nephrol. 6, 1009–1017 (2011).

    Article  Google Scholar 

  33. 33

    Pickering, M. & Cook, H. T. Complement and glomerular disease: new insights. Curr. Opin. Nephrol. Hypertens. 20, 271–277 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Chen, Q. et al. Combined C3b and factor B autoantibodies and MPGN type II. N. Engl. J. Med. 365, 2340–2342 (2011).

    CAS  Article  Google Scholar 

  35. 35

    Appel, G. B. et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J. Am. Soc. Nephrol. 16, 1392–1403 (2005).

    Article  Google Scholar 

  36. 36

    Radhakrishnan, S. et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N. Engl. J. Med. 366, 1165–1166 (2012).

    CAS  Article  Google Scholar 

  37. 37

    Smith, R. J. et al. New approaches to the treatment of dense deposit disease. J. Am. Soc. Nephrol. 18, 2447–2456 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454–464 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Skerka, C. et al. Autoimmune forms of thrombotic microangiopathy and membranoproliferative glomerulonephritis: Indications for a disease spectrum and common pathogenic principles. Mol. Immunol. 46, 2801–2807 (2009).

    CAS  Article  Google Scholar 

  40. 40

    Noris, M. & Remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 1676–1687 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Maga, T. K., Nishimura, C. J., Weaver, A. E., Frees, K. L. & Smith, R. J. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum. Mutat. 31, E1445–E1460 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Boyer, O. et al. Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. Am. J. Kidney Dis. 51, 671–677 (2008).

    Article  Google Scholar 

  43. 43

    Lorcy, N., Rioux-Leclercq, N., Lombard, M. L., Le Pogamp, P. & Vigneau, C. Three kidneys, two diseases, one antibody? Nephrol. Dial. Transplant. 26, 3811–3813 (2011).

    Article  Google Scholar 

  44. 44

    Smith, R. J., Harris, C. L. & Pickering, M. C. Dense deposit disease. Mol. Immunol. 48, 1604–1610 (2011).

    CAS  Article  Google Scholar 

  45. 45

    Schifferli, J. A., Ng, Y. C. & Peters, D. K. The role of complement and its receptor in the elimination of immune complexes. N. Engl. J. Med. 315, 488–495 (1986).

    CAS  Article  Google Scholar 

  46. 46

    Bao, L., Haas, M. & Quigg, R. J. Complement factor H deficiency accelerates development of lupus nephritis. J. Am. Soc. Nephrol. 22, 285–295 (2011).

    Article  Google Scholar 

  47. 47

    Alexander, J. J. et al. Mouse podocyte complement factor H: the functional analog to human complement receptor 1. J. Am. Soc. Nephrol. 18, 1157–1166 (2007).

    CAS  Article  Google Scholar 

  48. 48

    Bridoux, F. et al. Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association? Clin. J. Am. Soc. Nephrol. 6, 2165–2174 (2011).

    CAS  Article  Google Scholar 

  49. 49

    Sethi, S. et al. Dense deposit disease associated with monoclonal gammopathy of undetermined significance. Am. J. Kidney Dis. 56, 977–982 (2010).

    Article  Google Scholar 

  50. 50

    Sandhu, G. et al. C3 Glomerulopathy masquerading as acute postinfectious glomerulonephritis. Am. J. Kidney Dis. http://dx.doi.org/10.1053/j.ajkd.2012.04.032.

  51. 51

    Halbwachs, L., Leveille, M., Lesavre, P., Wattel, S. & Leibowitch, J. Nephritic factor of the classical pathway of complement: immunoglobulin G autoantibody directed against the classical pathway C3 convertase enzyme. J. Clin. Invest. 65, 1249–1256 (1980).

    CAS  Article  Google Scholar 

  52. 52

    Nasr, S. H. et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin. J. Am. Soc. Nephrol. 4, 22–32 (2009).

    Article  Google Scholar 

  53. 53

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int. Suppl. 2, 139–274 (2012).

  54. 54

    Fakhouri, F. et al. Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice. Kidney Int. 78, 279–286 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006).

    CAS  Article  Google Scholar 

  56. 56

    Kose, O., Zimmerhackl, L. B., Jungraithmayr, T., Mache, C. & Nurnberger, J. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin. Thromb. Hemost. 36, 669–672 (2010).

    Article  Google Scholar 

  57. 57

    Vivarelli, M., Pasini, A. & Emma, F. Eculizumab for the treatment of dense-deposit disease. N. Engl. J. Med. 366, 1163–1165 (2012).

    CAS  Article  Google Scholar 

  58. 58

    Daina, E., Noris, M. & Remuzzi, G. Eculizumab in a patient with dense-deposit disease. N. Engl. J. Med. 366, 1161–1163 (2012).

    CAS  Article  Google Scholar 

  59. 59

    McCaughan, J. A., O'Rourke, D. M. & Courtney, A. E. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am. J. Transplant. 12, 1046–1051 (2012).

    CAS  Article  Google Scholar 

  60. 60

    Lorenz, E. C. et al. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int. 77, 721–728 (2010).

    Article  Google Scholar 

  61. 61

    Karakayali, F. Y. et al. Recurrent glomerular diseases after renal transplantation. Transplant. Proc. 38, 470–472 (2006).

    CAS  Article  Google Scholar 

  62. 62

    Saxena, R., Frankel, W. L., Sedmak, D. D., Falkenhain, M. E. & Cosio, F. G. Recurrent type I membranoproliferative glomerulonephritis in a renal allograft: successful treatment with plasmapheresis. Am. J. Kidney Dis. 35, 749–752 (2000).

    CAS  Article  Google Scholar 

  63. 63

    Mache, C. J. et al. Complement inhibitor eculizumab in atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1312–1316 (2009).

    CAS  Article  Google Scholar 

  64. 64

    Nester, C. et al. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 6, 1488–1494 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors of this manuscript are supported by the Center for Glomerular Diseases at Columbia University, New York, USA.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Gerald B. Appel.

Ethics declarations

Competing interests

A. S. Bomback declares an association with the following company: Alexion Pharmaceuticals (grant/research support).

G. B. Appel declares an association with the following company: Alexion Pharmaceuticals (consultant; grant/research support).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bomback, A., Appel, G. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol 8, 634–642 (2012). https://doi.org/10.1038/nrneph.2012.213

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing