[1697] C3 Glomerulonephritis: Clinicopathologic Findings, Complement Abnormalities, Glomerular Proteomic Profile, Treatment and Follow-Up

Sanjeev Sethi, Fernando C Fervenza, Julie A Vrana, Samih H Nasr, Yuzhou Zhang, Richard JH Smith. Mayo Clinic, Rochester, MN; Carver College of Medicine, Iowa City, IA

Background: C3 Glomerulonephritis (C3GN) is a recently described glomerulonephritis that results from dysregulation of the alternative pathway of complement (AP). In this study, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, treatment and follow-up in 14 cases of C3GN, two of which were recurrent in allografts following transplantation.
Design: The diagnostic criteria for C3GN were: Proliferative glomerulonephritis on light microscopy, bright C3 staining and the absence of Ig on immunofluorescence microscopy, and mesangial and subendothelial electron dense deposits and occasionally intramembranous and subepithelial deposits on electron microscopy (EM). Dense deposit disease was excuded based on EM.
Results: We found that C3GN affected all ages with equal sex predilection and typically presented with hematuria and proteinuria. In the majority of patients with native kidney disease, renal function remained stable, both in the short and long term. However, in the two patients with recurrent C3GN, recurrence occurred within one year of transplantation and resulted in decline in allograft function. Kidney biopsy showed a predominantly membranoproliferative GN, although both mesangial proliferative and diffuse proliferative GN were noted. The AP abnormalities were heterogeneous and were both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of the Factor H H402 and V62 alleles. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI and the CFHR genes. We also detected 3 novel CFH mutations that were not previously desccribed. Laser dissection and mass spectrometry of glomeruli from 8 C3GN patients and 1 DDD patient showed a similar proteomic profile with accumulation of proteins of the AP and terminal complement complex (TCC).


Conclusions: This study shows that C3GN is a disease associated with genetic and acquired abnormalities of the AP that lead to glomerular accumulation of AP and TCC proteins resulting in a complement-mediated proliferative GN.
Category: Kidney (does not include tumors)

Tuesday, March 20, 2012 8:15 AM

Platform Session: Section H, Tuesday Morning

 

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