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.This Review presents our current understanding of C3 glomerulopathy. Smith et al. discuss the histopathological diagnosis and the crucial pathogenic role of complement dysregulation. Genetic and acquired drivers of C3 glomerulopathy, potential biomarkers and available treatments are highlighted.Key pointsC3 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.