C3 glomerulopathy.

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• C3 glomerulopathy is a classification of rare glomerulonephritis, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
• Histological hallmarks include glomerular deposition of C3, primarily in the mesangium and along the glomerular basement membrane (GBM).
• The complement alternative pathway (AP) plays a crucial role, with identified acquired or genetic abnormalities.

Purpose of the Study:

• To review the classification, pathogenesis, clinical presentation, and therapeutic perspectives of C3 glomerulopathies.
• To highlight the role of complement alternative pathway dysregulation and genetic factors.
• To discuss the current understanding and future directions in managing these rare kidney diseases.

Main Methods:

• Review of existing literature on C3 glomerulopathy, focusing on pathogenesis, genetics, clinical features, and treatment.
• Analysis of histological findings, complement pathway abnormalities, and genetic associations.
• Synthesis of information regarding clinical presentation, disease progression, and therapeutic strategies.

Main Results:

• Low serum C3 with normal C4 is a common laboratory finding.
• C3 nephritic factor (C3NeF) is implicated in acquired AP dysregulation, found in 80% of DDD and 45% of C3GN patients.
• Mutations in complement regulatory proteins (CFH, CFI, C3) and genetic variants (SNPs in CFH, C3, CFHR5) are associated with disease development.

Conclusions:

• C3 glomerulopathies are characterized by complement alternative pathway dysregulation, with varying genetic and acquired causes.
• These diseases present with diverse renal manifestations and have a high risk of progression to end-stage renal disease (ESRD) and graft failure post-transplant.
• Therapeutic strategies are evolving, with a focus on inhibiting complement components C3 and C5, and potential benefits from recombinant factor H or plasma exchange in specific deficiencies.