C3 Glomerulopathy

Introduction of C3 Glomerulopathy

C3 glomerulopathy stands for complement 3 glomerulopathy (C3G). Based on histomorphological characteristics, C3G is a subtype of membranoproliferative glomerulonephritis. In C3G patients, a key pathogenetic factor is abnormal control of the complement alternative pathway, leading to uncontrolled complement activation, degradation or deposition, predominantly C3 fragment deposition within the glomerulus and glomerular damage. Uncontrolled C3b amplification can be detected in the circulation and/or along the glomerular basement membrane. Researchers have identified two major forms of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), depending on the presence and distribution pattern of electron-dense deposits within the glomerular filter. Although C3GN and DDD cause similar kidney damages, the features of the latter tend to appear earlier than the former, usually in adolescence.

Symptoms of Hemolytic C3 Glomerulopathy

The major features of C3G include blood in the urine (hematuria), high levels of protein in the urine (proteinuria), reduced glomerular filtration rate (reduced ability of the kidney to filter the blood and make urine), elevated creatinine, fatigue, swelling (edema) in many areas of the body. The morbidity of C3G is very rare, affecting 1 to 2 per million people worldwide and the frequency is equal in men and women.

Fig.1 Kidney biopsy findings of C3 glomerulopathy. (Chauvet, 2017)

Pathophysiology of C3 Glomerulopathy

1. Autoantibodies

C3 nephritic factor (C3NeF) is an autoantibody that can bind to a neoepitope on the C3 convertase of alternative pathway, which is beneficial for the stability of the convertase against complement factor H-mediated decay. Meanwhile, the binding can potentiate C3 cleaving action, resulting in uncontrolled C3 activation and low serum C3 levels, but high levels in glomerulus.

1. Genetic Sequence Variation

C3G is associated with sequence changes in many genes. The patients suffering from DDD are seronegative for C3NeF, because of a homozygous missense mutation in the CFH gene. Moreover, deletion of a CFH codon results in circulating mutant CFH that is defective binding to C3b. In a later DDD pedigree, heterozygous deletion of two codons within the C3 gene was found to produce a hyper functional C3 molecule. The heterozygous mutations in CFH, CFI and MCP genes are associated with C3G.

1. Genetic Structure Variation

The structural changes of CFHR proteins are identified by multiplex-ligation probe amplification (MLPA), which are further associated with the presence of CFH autoantibodies in patients with C3G.

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References
1. Chauvet, Sophie, et al. "Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy–associated C3 glomerulopathy." Blood, The Journal of the American Society of Hematology 129.11 (2017): 1437-1447.

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