Correlations in Histology and Complement Biomarkers in C3 Glomerulopathy

Background: C3 Glomerulopathy (C3G) is characterized by complement dysregulation and C3 deposition in glomeruli. We reviewed characteristics of baseline kidney biopsies to determine whether features of activity and/or chronicity correlate with clinical parameters and/or complement biomarkers at presentation. Methods: Data from the University of Iowa’s C3G Natural History Study were used. Criteria for entry included baseline native biopsy diagnosis of C3G and complement biomarkers within 1 year of biopsy. Patients with a history of dialysis, transplant, or anti-complement therapy were excluded. Significance was assessed using Pearson correlation coefficients with two-tailed p values (95% confidence) and one-way ANOVA analysis; p-values <0.05 were considered significant. Results: 57 of 104 subjects (54.8%) presented with an activity score of ≥9; 18 (17.3%) presented with a chronicity score of ≥4 (the a priori determinants of increased risk for progression to renal failure). Higher activity scores were associated with elevated C5Nefs (p = 0.012, R = 0.255) and soluble C5b-9 (p = 0.013, R = 0.259) levels. Higher chronicity scores were associated most strongly with an increase in Ba (p = 8.183e-10, R = 0.677) and a lower GFR (p = 1.665e-9, R = -0.558) and less strongly with increased C3 (p = 0.022, R = 0.265), C5 (p = 0.014, R = 0.331) and Bb (p = 0.037, R = 0.263) levels, and decreased C5Nefs (p = 0.012, R = -0.262 and soluble C5b-9 (p = 0.026, R = -0.232) levels. Conclusion: The association of higher C5Nefs and soluble C5b-9 levels with increased activity scores is consistent with terminal pathway activity being a driver of inflammation, while the association of increased chronicity scores with a lower GFR and higher Ba reflects declining renal function independent of complement activity. While the increase in C3 and C5 and the decrease in soluble C5b-9 levels reflect decreased complement activity, Bb levels suggest some component of continued alternative pathway activity. In aggregate, these data support a role for complement biomarker testing in C3G. Funding: NIDDK Support