CFH – Dense Deposit Disease

Complement factor H (CFH) is a key regulator of the alternative complement pathway; pathogenic CFH variants have been implicated in dense deposit disease (DDD). DDD is defined by electron-dense intramembranous deposits within the glomerular basement membrane and presents with hematuria, proteinuria, nephrotic syndrome, hypertension, and acute kidney injury. Four unrelated DDD patients with rare CFH variants have been reported: a homozygous p.Pro139Ser due to paternal isodisomy (PMID:21270828), a homozygous CFH deficiency (PMID:28509298), a heterozygous nonsense change c.694C>T (p.Arg232Ter) (PMID:24672732), and an adolescent carrying the H402 risk allele (PMID:21269585). These variants segregate recessively, with uniparental isodisomy documented in one family, but broader familial segregation remains limited.

Functional studies confirm that CFH mutations impair alternative pathway control, leading to uncontrolled C3 convertase activity consistent with DDD pathology. In a cohort of 32 biopsy‐proven DDD patients, CFH variants were detected in 2 of 7 C3 nephritic factor–negative individuals; complement assays demonstrated persistent C3 activation (PMID:22223606). Biochemical and cell‐based assays of CFH truncating and missense variants show reduced binding to C3b, heparin, and endothelial surfaces, driving complement overactivation. Eculizumab normalized terminal complement levels but failed to improve renal outcomes in one case, highlighting the need for early genetic diagnosis. Together, genetic and experimental data support a Limited clinical validity for CFH in DDD; CFH genetic testing can inform mechanism-directed management.

References

• Clinical nephrology • 2011 • Acute renal failure in dense deposit disease: complete recovery after combination therapy with immunosuppressant and plasma exchange. PMID:21269585
• Genes and immunity • 2011 • Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation. PMID:21270828
• Clinical journal of the American Society of Nephrology • 2012 • Causes of alternative pathway dysregulation in dense deposit disease. PMID:22223606
• Case reports in nephrology • 2014 • Blockade of alternative complement pathway in dense deposit disease. PMID:24672732

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