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.

C3 glomerulopathy — understanding a rare complement-driven renal disease

Abstract

The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy — dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) — have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients — namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.

Key points

  • C3 glomerulopathies are rare diseases that share an underlying mechanism of complement dysregulation in the fluid phase and glomerular microenvironment.

  • Diagnosis relies solely on renal biopsy immunofluorescence findings; light microscopy findings and complement biomarker profiles are heterogeneous.

  • Acquired drivers, in the form of autoantibodies, are the abnormalities most frequently associated with complement dysregulation.

  • Genetic variants in the C3, CFB, CFH, CFI and CFHR1–CFHR5 genes are potentially causal; both rare and common variants can coexist and are associated with susceptibility to disease.

  • Convertase dysregulation is central to the pathogenesis of C3 glomerulopathy.

  • Conditions such as post-infectious glomerulonephritis cannot be differentiated from C3 glomerulopathy by renal biopsy alone, which can confound early diagnosis and treatment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: C3-dominant glomerulonephritis.
Fig. 2: Dysregulation of the complement cascade in C3 glomerulopathy.
Fig. 3: Diagnosis, evaluation and treatment of C3 glomerulopathy.

References

  1. 1.

    Pickering, M. C. et al. C3 glomerulopathy: consensus report. Kidney Int. 84, 1079–1089 (2013).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bomback, A. S. et al. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int. 93, 997–985 (2018).

    Google Scholar 

  4. 4.

    Medjeral-Thomas, N. R. et al. C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin. J. Am. Soc. Nephrol. 9, 46–53 (2014).

    CAS  PubMed  Google Scholar 

  5. 5.

    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  PubMed  Google Scholar 

  6. 6.

    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  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Rabasco, C. et al. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int. 88, 1153–1160 (2015).

    CAS  PubMed  Google Scholar 

  8. 8.

    Iatropoulos, P. et al. Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol. Immunol. 71, 131–142 (2016).

    CAS  PubMed  Google Scholar 

  9. 9.

    Angelo, J. R., Bell, C. S. & Braun, M. C. Allograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis. Am. J. Kidney Dis. 57, 291–299 (2011).

    PubMed  Google Scholar 

  10. 10.

    Zand, L. et al. Clinical findings, pathology, and outcomes of C3GN after kidney transplantation. J. Am. Soc. Nephrol. 25, 1110–1117 (2014).

    CAS  PubMed  Google Scholar 

  11. 11.

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

    PubMed  Google Scholar 

  12. 12.

    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  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Sethi, S. et al. Characterization of C3 in C3 glomerulopathy. Nephrol. Dial. Transplant. 32, 459–465 (2017).

    CAS  PubMed  Google Scholar 

  14. 14.

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

    CAS  PubMed  Google Scholar 

  15. 15.

    Hou, J. et al. Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int. 85, 450–456 (2014).

    CAS  PubMed  Google Scholar 

  16. 16.

    Bouatou, Y. et al. Diagnostic accuracy of immunofluorescence versus immunoperoxidase staining to distinguish immune complex-mediated glomerulonephritis and C3 dominant glomerulopathy. Histopathology 72, 601–608 (2018).

    PubMed  Google Scholar 

  17. 17.

    Sethi, S. et al. Atypical post-infectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int. 83, 293–299 (2013).

    CAS  PubMed  Google Scholar 

  18. 18.

    Khalighi, M. A. et al. Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy. Clin. Kidney J. 9, 397–402 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Sethi, S. et al. A proposal for standardized grading of chronic changes in native kidney biopsy specimens. Kidney Int. 91, 787–789 (2017).

    PubMed  Google Scholar 

  20. 20.

    Ricklin, D., Reis, E. S., Mastellos, D. C., Gros, P. & Lambris, J. D. Complement component C3 — the “Swiss army knife” of innate immunity and host defense. Immunol. Rev. 274, 33–58 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Blatt, A. Z., Pathan, S. & Ferreira, V. P. Properdin: a tightly regulated critical inflammatory modulator. Immunol. Rev. 274, 172–190 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wu, J. et al. Structure of complement fragment C3b–factor H and implications for host protection by complement regulators. Nat. Immunol. 10, 728–733 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Pangburn, M. K., Schreiber, R. D. & Müller-Eberhard, H. J. Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein β1H for cleavage of C3b and C4b in solution. J. Exp. Med. 146, 257–270 (1977).

    CAS  PubMed  Google Scholar 

  24. 24.

    Whaley, K. & Ruddy, S. Modulation of the alternative complement pathways by β1H globulin. J. Exp. Med. 144, 1147 (1976).

    CAS  PubMed  Google Scholar 

  25. 25.

    Medjeral-Thomas, N. & Pickering, M. C. The complement factor H-related proteins. Immunol. Rev. 274, 191–201 (2016).

    CAS  PubMed  Google Scholar 

  26. 26.

    Xiao, X. et al. Familial C3 glomerulonephritis caused by a novel CFHR5–CFHR2 fusion gene. Mol. Immunol. 77, 89–96 (2016).

    CAS  PubMed  Google Scholar 

  27. 27.

    Goicoechea de Jorge, E. et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc. Natl Acad. Sci. USA 110, 4685–4690 (2013).

    CAS  PubMed  Google Scholar 

  28. 28.

    Tortajada, A. et al. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J. Clin. Invest. 123, 2434–2446 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Józsi, M. et al. Factor H-related proteins determine complement-activating surfaces. Trends Immunol. 36, 374–384 (2015).

    PubMed  Google Scholar 

  30. 30.

    Høgåsen, K., Jansen, J. H., Mollnes, T. E., Hovdenes, J. & Harboe, M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency. J. Clin. Invest. 95, 1054–1061 (1995).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Pickering, M. C. et al. Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat. Genet. 31, 424–428 (2002).

    CAS  PubMed  Google Scholar 

  32. 32.

    Ruseva, M. M. et al. Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency. J. Am. Soc. Nephrol. 24, 43–52 (2013).

    CAS  PubMed  Google Scholar 

  33. 33.

    Lesher, A. M. et al. Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis. J. Am. Soc. Nephrol. 24, 53–65 (2013).

    CAS  PubMed  Google Scholar 

  34. 34.

    Pickering, M. C. et al. Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc. Natl Acad. Sci. USA 103, 9649–9654 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Rose, K. L. et al. Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice. J. Clin. Invest. 118, 608–618 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Arkill, K. P. et al. Resolution of the three dimensional structure of components of the glomerular filtration barrier. BMC Nephrol. 15, 24 (2014).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lennon, R. et al. Global analysis reveals the complexity of the human glomerular extracellular matrix. J. Am. Soc. Nephrol. 25, 939–951 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Hegermann, J., Lünsdorf, H., Ochs, M. & Haller, H. Visualization of the glomerular endothelial glycocalyx by electron microscopy using cationic colloidal thorium dioxide. Histochem. Cell Biol. 145, 41–51 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Loeven, M. A. et al. Mutations in complement factor H impair alternative pathway regulation on mouse glomerular endothelial cells in vitro. J. Biol. Chem. 291, 4974–4981 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Persson, B. D. et al. Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens. PLOS Pathog. 6, e1001122 (2010).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Heinen, S. et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114, 2439–2447 (2009).

    CAS  PubMed  Google Scholar 

  42. 42.

    Eberhardt, H. U. et al. Human factor H-related protein 2 (CFHR2) regulates complement activation. PLOS ONE 18, e78617 (2013).

    Google Scholar 

  43. 43.

    Chen, Q. et al. Complement factor H-related 5-hybrid proteins anchor properdin and activate complement at self-surfaces. J. Am. Soc. Nephrol. 27, 1413–1425 (2016).

    CAS  PubMed  Google Scholar 

  44. 44.

    Chen, Q. et al. Complement factor H-related hybrid protein deregulates complement in dense deposit disease. J. Clin. Invest. 124, 145–155 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    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  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Malik, T. H. et al. A hybrid CFHR3–1 gene causes familial C3 glomerulopathy. J. Am. Soc. Nephrol. 23, 1155–1160 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Togarsimalemath, S. K. et al. A novel CFHR1–CFHR5 hybrid leads to a familial dominant C3 glomerulopathy. Kidney Int. 92, 876–887 (2017).

    CAS  PubMed  Google Scholar 

  48. 48.

    Csincsi, Á. I. et al. Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation. J. Immunol. 194, 4963–4973 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Larsen, S. Glomerular immune deposits in kidneys from patients with no clinical or light microscopic evidence of glomerulonephritis. Assessment of the influence of autolysis on identification of immunoglobulins and complement. Acta Pathol. Microbiol. Scand. A 87A, 313–319 (1979).

    CAS  PubMed  Google Scholar 

  50. 50.

    Velosa, J., Miller, K. & Michael, A. F. Immunopathology of the end-stage kidney. Immunoglobulin and complement component deposition in nonimmune disease. Am. J. Pathol. 84, 149–162 (1976).

    CAS  PubMed  Google Scholar 

  51. 51.

    Leivo, I. & Engvall, E. C3d fragment of complement interacts with laminin and binds to basement membranes of glomerulus and trophoblast. J. Cell. Biol. 103, 1091–1100 (1986).

    CAS  PubMed  Google Scholar 

  52. 52.

    Bu, F. et al. High-throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies. J. Am. Soc. Nephrol. 27, 1245–1253 (2016).

    CAS  PubMed  Google Scholar 

  53. 53.

    Osborne, A. J. et al. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J. Immunol. 200, 2464–2478 (2018).

    CAS  PubMed  Google Scholar 

  54. 54.

    Noris, M. & Remuzzi, G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015. Am. J. Kidney Dis. 66, 359–375 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Barbour, T. D. et al. Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy. Kidney Int. 89, 823–832 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Marinozzi, M. C. et al. C5 nephritic factors drive the biological phenotype of C3 glomerulopathies. Kidney Int. 92, 1232–1241 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

    Blanc, C. et al. Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases. J. Immunol. 194, 5129–5138 (2015).

    CAS  PubMed  Google Scholar 

  59. 59.

    Marinozzi, M. C. et al. Anti-factor B and anti-C3b autoantibodies in C3 glomerulopathy and Ig-associated membranoproliferative GN. J. Am. Soc. Nephrol. 28, 1603–1613 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zhang, Y. et al. C4 nephritic factors in C3 glomerulopathy: a case series. Am. J. Kidney Dis. 70, 834–843 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Strobel, S., Zimmering, M., Papp, K., Prechl, J. & Józsi, M. Anti-factor B autoantibody in dense deposit disease. Mol. Immunol. 47, 1476–1483 (2010).

    CAS  PubMed  Google Scholar 

  62. 62.

    Blom, A. M. et al. Testing the activity of complement convertases in serum/plasma for diagnosis of C4Nef-mediated C3 glomerulonephritis. J. Clin. Immunol. 36, 517–527 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Meri, S., Koistinen, V., Miettinen, A., Törnroth, T. & Seppälä, I. J. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J. Exp. Med. 175, 939–950 (1992).

    CAS  PubMed  Google Scholar 

  64. 64.

    Hauer, J. J. et al. Complement biomarkers as predictors of disease outcome in C3 glomerulopathy. Mol. Immunol. 102, 160 (2018).

    Google Scholar 

  65. 65.

    Ravindran, A., Fervenza, F. C., Smith, R. J. H. & Sethi, S. C3 glomerulopathy associated with monoclonal Ig is a distinct subtype. Kidney Int. 94, 178–186 (2018).

    CAS  PubMed  Google Scholar 

  66. 66.

    Ravindran, A., Fervenza, F. C., Smith, R. J. H., De Vriese, A. S. & Sethi, S. C3 glomerulopathy: ten years’ experience at Mayo Clinic. Mayo Clin. Proc. 93, 991–1008 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    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).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Servais, A., Noël, L. H., Frémeaux-Bacchi, V. & Lesavre, P. C3 glomerulopathy. Contrib. Nephrol. 181, 185–193 (2013).

    PubMed  Google Scholar 

  69. 69.

    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  PubMed  Google Scholar 

  70. 70.

    Chauvet, S. et al. Treatment of B cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood 129, 1437–1447 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    Lloyd, I. E. et al. C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome. Clin. Kidney J. 9, 794–799 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Goodship, T. H. et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference. Kidney Int. 91, 539–551 (2017).

    CAS  PubMed  Google Scholar 

  73. 73.

    Maisch, N. M. & Pezzillo, K. K. HMG-CoA reductase inhibitors for the prevention of nephropathy. Ann. Pharmacother. 38, 342–345 (2004).

    CAS  PubMed  Google Scholar 

  74. 74.

    Nickolas, T. L., Radhakrishnan, J. & Appel, G. B. Hyperlipidemia and thrombotic complications in patients with membranous nephropathy. Semin. Nephrol. 23, 406–411 (2003).

    PubMed  Google Scholar 

  75. 75.

    Licht, C. et al. Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am. J. Kidney Dis. 45, 415–421 (2005).

    CAS  PubMed  Google Scholar 

  76. 76.

    Kurtz, K. A. & Schlueter, A. J. Management of membranoproliferative glomerulonephritis type II with plasmapheresis. J. Clin. Apher. 17, 135–137 (2002).

    PubMed  Google Scholar 

  77. 77.

    Avasare, R. S. et al. Mycophenolate mofetil in combination with steroids for treatment of C3 glomerulopathy: a case series. Clin. J. Am. Soc. Nephrol. 13, 406–413 (2018).

    CAS  PubMed  Google Scholar 

  78. 78.

    Nester, C. M. & Smith, R. J. Complement inhibition in C3 glomerulopathy. Semin. Immunol. 28, 241–249 (2016).

    CAS  PubMed  Google Scholar 

  79. 79.

    Bomback, A. S. et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7, 748–7560 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Le Quintrec, M. et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am. J. Kidney Dis. 72, 84–92 (2018).

    PubMed  Google Scholar 

  81. 81.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03301467 (2018).

  82. 82.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03369236 (2018).

  83. 83.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03459443 (2018).

  84. 84.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02682407 (2018).

  85. 85.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03453619 (2018).

  86. 86.

    Lu, D. F., Moon, M., Lanning, L. D., McCarthy, A. M. & Smith, R. J. H. Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr. Nephrol. 27, 773–781 (2012).

    PubMed  Google Scholar 

  87. 87.

    Burdett, L. et al. DRB-DQB1 diversity in the analysis of 4727 donors typed by SBT. Hum. Immunol. 64 (Suppl.), S6 (2003).

    Google Scholar 

  88. 88.

    De Vriese, A. S. et al. Kidney disease caused by dysregulation of the complement alternative pathway: an etiologic approach. J. Am. Soc. Nephrol. 26, 2917–2929 (2015).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors’ research is supported in part by the US National Institutes of Health grant R01 DK110023 to R.J.H.S. and C.M.N.; by the Kidneeds Foundation, the National Research, Development and Innovation Fund of Hungary (grants K 109055 and K 125219) and the Institutional Excellence Program of the Ministry of Human Capacities of Hungary, all to M.J.; by the National Institute for Health Research Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London to M.C.P., who is a Wellcome Trust Senior Fellow in Clinical Science (WT082291MA); by the Spanish Ministerio de Economía y Competitividad/FEDER (grant SAF2015-66287-R), the Autonomous Region of Madrid (grant S2017/BMD-3673) and the Fundación Inocente Inocente to S.R.d.C.; and by the Deutsche Forschungsgemeinschaft (grant DFG CRC 1192) to P.F.Z.

Reviewer information

Nature Reviews Nephrology thanks C. Licht, F. Fervenza and the other anonymous reviewer(s) for their contributions to the peer review of this manuscript.

Author information

Affiliations

Authors

Contributions

R.J.H.S. researched data for the article, made substantial contributions to discussions of the article content, wrote the initial draft of the manuscript and participated in review or editing of the manuscript before submission. G.B.A., C.M.N., D.K., F.F. and G.R. had primary responsibility for the section on treatment; A.M.B., M.J. and J.V.d.V. had primary responsibility for the section on the glomerular microenvironment; J.D.L., V.F.-B., M.N., S.R.d.C., M.C.P. and P.F.Z. had primary responsibility for the sections on complement, genetics and autoantibodies; S.S., H.T.C. and V.D.D. had primary responsibility for the section on pathology. All authors reviewed, edited and approved all drafts of this paper.

Corresponding author

Correspondence to Richard J. H. Smith.

Ethics declarations

Competing interests

R.J.H.S. declares that he is Director of the Molecular Otolaryngology and Renal Research Laboratories (which provides genetic and functional testing for complement-mediated renal diseases). G.A. declares that he acts as a consultant for Achillion, Alexion, Chemocentryx and Omeros and has received research grants from Achillion and Chemocentryx. H.T.C. declares that he acts as a consultant for Alexion and Achillion. J.L. declares that he is the founder of Amyndas Pharmaceuticals, is named as an inventor on patents or patent applications describing the therapeutic use of complement inhibitors (some of which are being developed by Amyndas Pharmaceuticals) and is the inventor of the compstatin analogue licensed to Apellis Pharmaceuticals termed 4(1MeW)7 W (also known as POT4 and APL1) and pegylated derivatives such as APL2. M.N. declares that he has received honoraria for lecturing and participation in advisory boards from Alexion Pharmaceuticals and has received research grants from Chemocentryx and Omeros. M.C.P. declares that he has received research grants from Achillion, Alexion and Ra Pharma and has acted as a consultant for Achillion, Alexion, Chemocentryx and Ra Pharma. G.R. declares that he acts as a consultant for Alnylam, Boehringer Ingelheim, Handok, Hoffmann–La Roche and Janssen Research and Development (he has not accepted any personal remuneration from Alnylam or Hoffmann–La Roche; this compensation is used to support his research and educational activities). C.M.N. declares that he is Associate Director of the Molecular Otolaryngology and Renal Research Laboratories. All other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Smith, R.J.H., Appel, G.B., Blom, A.M. et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nat Rev Nephrol 15, 129–143 (2019). https://doi.org/10.1038/s41581-018-0107-2

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