C3 Glomerulopathy

Clinical characteristics: C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity.

Diagnosis/testing: The definitive diagnosis of C3G requires a renal biopsy with specialized immunofluorescence and electron microscopy studies both for diagnosis and to distinguish between the two major subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE).

Management: Treatment of manifestations: Nonspecific therapies used to treat numerous chronic glomerular diseases, including angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, and lipid-lowering agents (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors). Complement inhibition with a terminal pathway blocker may alter disease course in some individuals. When ESRD develops, treatment options are limited to dialysis or transplantation. C3G recurs in nearly all grafts and is the predominant cause of graft failure in 50%-90% of transplant recipients.

Prevention of primary manifestations: Plasma replacement therapy in individuals with pathogenic variants in CFH may be effective in controlling complement activation and slowing progression of ESRD.

Surveillance: Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum, complete biannual assessment of the complement pathway, periodic eye examinations to evaluate the fundus.

Evaluation of relatives at risk: If the family history is positive for renal disease, evaluation of apparently asymptomatic at-risk relatives can include molecular genetic testing (if the pathogenic variants in the family are known), urinalysis, and comprehensive analysis of the complement system.

Genetic counseling: C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both dominant and recessive inheritance being described.