Complement Activation Products in Kidneys of Patients with Primary Focal Segmental Glomerulosclerosis

Background: Plasma and urinary complement profile of patients with primary focal segmental glomerulosclerosis (FSGS) have provided compelling evidence indicating the participation of complement system in FSGS pathogenesis. However, the profile of complement activation in glomeruli of primary FSGS requires clarification. Methods: Fifty-four patients with primary FSGS were enrolled. Kidney deposition of complement C1q, MBL, C4d, Bb, C3d and C5b-9 was detected by immunohistochemistry. The correlations between clinical features and glomerular complement deposits were analyzed. Results: The percentages of glomeruli with positive staining of C1q, C4d, Bb, C3d and C5b-9, and the IOD of MBL were significantly higher in patients with primary FSGS than those in healthy controls (all P<0.001). Among FSGS patients in comparison with tip variant, the percentages of C4d positive glomeruli were significantly higher in NOS variant (P=0.03), cellular variant (P=0.003), and perilihar variant (P=0.007); the percentage of Bb positive glomeruli was significantly higher in cellular variant (P=0.02); the percentages of C5b-9 positive glomeruli were significantly higher in NOS variant (P=0.001) and cellular variant (P=0.001). The percentage of C4d positive glomeruli exhibited positive correlation with the percentage of segmental glomerulosclerosis (r=0.33, P=0.02). The percentage of C5b-9 positive glomeruli exhibited negative correlation with eGFR (r=-0.29, P=0.04) and positive correlation with the percentage of segmental glomerulosclerosis (r=0.37, P=0.008). The percentage of C3d positive glomeruli was significantly higher in the relapse cases than the non-relapse ones (P=0.02). The patients with a higher percentage of C5b-9 positive glomeruli had worse kidney prognosis during follow-up (Log-rank, P=0.02). Conclusion: The complement system is activated in primary FSGS, via the classical pathway and alternative pathway. The complement activation was closely related to the pathogenesis of NOS and cellular variant, and correlated with the severity of nephrotic syndrome and kidney outcome. These findings indicate that complement system may actively participate in the mechanism of FSGS. Funding: Government Support – Non-U.S.