Complement Terminal Pathway Activation and Intrarenal Immune Response in C3 Glomerulopathy

Key Points We evidenced terminal pathway activation (C5b-9 deposits) in most of the glomeruli on kidney biopsy of C3 glomerulopathy. The amount of C5b-9 deposits correlated with disease prognosis in C3 glomerulopathy. Increased terminal pathway activation was found predominantly in a subgroup exhibiting an immuno-fibroblastic signature. Background C3 glomerulopathy is a rare disease resulting from an overactivation of the complement alternative pathway. Although there is also evidence of terminal pathway activation, its occurrence and consequences on the disease have been poorly studied. Methods We retrospectively studied a cohort of 42 patients diagnosed with C3 glomerulopathy. We performed centralized extensive characterization of histological parameters. Kidney C5b-9 staining was performed as a marker of terminal pathway activation; intrarenal immune response was characterized through transcriptomic analysis. Results Eighty-eight percent of biopsies showed C5b-9 deposits in glomeruli. Biopsies were grouped according to the amount of C5b-9 deposits (no or low n =15/42, 36%; intermediate n =15/42, 36%; and high n =12/42, 28%). Patients with high C5b-9 deposits significantly differed from the two other groups of patients and were characterized by a significant higher histological chronicity score ( P = 0.005) and lower outcome-free survival ( P = 0.001). In multivariable analysis, higher glomerular C5b-9 remained associated with poor kidney prognosis after adjustment. One third of the 847 studied immune genes were upregulated in C3 glomerulopathy biopsies compared with controls. Unsupervised clustering on differentially expressed genes identified a group of kidney biopsies enriched in high glomerular C5b-9 with high immune and fibroblastic signature and showed high chronicity scores on histological examination. Conclusions In a cohort of patients with C3 glomerulopathy, intrarenal terminal pathway activation was associated with specific histological phenotype and disease prognosis.