Clinical Significance of Immune Deposits and Complement System Activation in FSGS: Findings from the CureGN Study.

Abstract

Background: The interplay between complement activation and the immune response in focal segmental glomerulosclerosis (FSGS) warrants further investigation. We investigated the association of glomerular C3 and IgM immunostaining with FSGS disease activity, complement system activation, chronicity on kidney biopsy, initial and follow-up clinical data in the Cure Glomerulopathy Network (CureGN) FSGS cohort.

Methods: Data for FSGS patients with available pathology assessment from the CureGN cohort were reviewed. We tested associations between glomerular immunoglobulins and C3 staining intensity by immunofluorescence with the Columbia classification, the urinary membrane attack complex (sC5b9) level, proteinuria, and time to a composite outcome, defined by end stage kidney disease (ESKD) or a 40% decline in eGFR. Urinary sC5b9 levels, expressed as ratios to creatinine (sC5b9CR) and to protein (C5b9uPR), were also examined.

Results: The study cohort comprised 175 FSGS patients, including 63 (36%) incident subjects enrolled within 6 months of pathology review. Glomerular IgM, C3 and IgG deposits were found in 88 (50%), 48 (27.4%) and 27 (15.4%) patients, respectively. C3 deposition was correlated with global sclerosis (r=0.27, p<0.001), tubular microcystic changes (r=0.19, p<0.01), interstitial fibrosis tubular atrophy (IFTA) (r=0.17, p=0.03), interstitial inflammation (r=0.17, p=0.03), and tip lesion (r=-0.16, p=0.04). In incident patients, C5b9uPR correlated with total segmental sclerosis (r=0.35, p<0.01), IF (r=0.33, p=0.01), IFTA (r=0.35, p<0.01), and interstitial inflammation (r=0.29, p=0.03). Only C5b9uPR [HR=1.64 (95%CI 1.03-2.60, p=0.03)] and age at enrollment [HR=1.01 (95%CI 1.00-1.03, p=0.02)] were significantly associated with the composite outcome in the adjusted Cox survival models.

Conclusions: C5b9uPR is emerging as a significant biomarker for FSGS progression, reflecting the complex interplay between complement activation, inflammation, and kidney injury. The evidence suggests that elevated C5b9uPR levels are associated with poor kidney outcomes and may serve as a valuable tool in the non-invasive assessment of kidney fibrosis and disease progression.