Abstract: TH-PO004

Abnormalities of Alternative Pathway of Complement in C3 Glomerulopathy

Session Information

Category: Glomerular

  • 1004 Clinical/Diagnostic Renal Pathology and Lab Medicine

Authors

  • Ravindran, Aishwarya, Mayo Clinic, Rochester, Minnesota, United States
  • Fervenza, Fernando C., Mayo Clinic, Rochester, Minnesota, United States
  • Sethi, Sanjeev, Mayo Clinic, Rochester, Minnesota, United States
Background

C3G, comprising C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), is characterized by glomerular accumulation of complement proteins due to abnormal regulation of the alternative pathway (AP) of complement. Large scale studies describing genetic and acquired abnormalities of AP associated with C3G are lacking. We describe our institutional experience of the abnormalities of AP associated with C3G.

Methods

Of the 114 C3G patients seen at the Mayo Clinic, 76 (66.7%) patients (65 C3GN/11 DDD) were evaluated for abnormalities of the AP of complement during the period 2007-2016.

Results

C3 levels were low in only 44.6% patients, while 11.8% patients also had low C4 levels. Overall, 29 (43.9%) were positive for mutations of complement factors/complement regulating proteins, the most common (15.2%) was a heterozygous mutation in complement factor H (CFH). Other less common heterozygous mutations included mutations in CFI, C3, C5, C8 and C9, and in the CFH-related genes, CFHR2 and CFHR5. Forty-five (97.8%) patients were positive for genetic polymorphisms associated with C3G, the most common being CFH allele variants, which were present in 44 (95.7%) patients; CFH V62 (78.2%) and H402 (73.9%) were the most common. C3 nephritic factor was present in 29 (43.9%) patients; 1 patient also had a positive C5 nephritic factor. Seven (10.9%) patients were positive for other auto-antibodies, 3 (4.7%) to CFH and 4 (6.3%) to CFB. These findings are quite distinct from atypical HUS, where antibodies to CFH are frequently detected. There was no significant difference in prevalence of polymorphisms/mutations or C3 nephritic factors/autoantibodies between C3GN and DDD.

Conclusion

Our studies show that the common drivers for C3G are: 1) C3 nephritic factor, and 2) mutations in complement regulating proteins, in particular CFH. Almost all patients carried allele polymorphisms of complement regulating proteins associated with C3G. Autoantibodies to other complement regulating proteins were less commonly present. Our study provides insight into the genetic and acquired abnormalities associated with C3G underscoring that appropriate treatment should be based on treating the abnormality driving the C3G.