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