Kidney Week Educational Symposia-Regulating the Regulator: Exploring the Therapeutic Landscape for Complement-Mediated Kidney Diseases

Video Transcription

Video Summary

This symposium reviewed how the complement system—three activation pathways (classical, lectin, alternative) converging on C3 and then C5/MAC—drives injury in multiple glomerular diseases and how pathway “fingerprints” on kidney biopsy can guide precision therapy.<br /><br />Dr. Andy Bomback framed complement-targeted drugs as a shift away from broad immunosuppression toward mechanism-based treatment. He emphasized using immunofluorescence patterns to infer pathway involvement: “full house” staining (Ig + C1q + C3) in lupus nephritis implies immune-complex–driven classical pathway activation, with different anatomic sites of activation helping explain proliferative vs membranous phenotypes. Primary membranous nephropathy typically shows IgG (often IgG4) and C3 without C1q; C4d positivity and mannose-binding lectin support lectin pathway activation. C3 glomerulopathy features dominant C3 without immunoglobulins, reflecting antibody-independent alternative pathway dysregulation (genetic variants, autoantibodies, or monoclonal proteins), and highlights disease heterogeneity based on where and how strongly control is lost. IgA nephropathy was presented as an “overlap” disease involving lectin and alternative pathways.<br /><br />Dr. Chi-Kei Cheng summarized IgA nephropathy’s multi-hit pathogenesis (galactose-deficient IgA1, anti-glycan antibodies, immune complexes) and extensive evidence for complement activation (C3, properdin, MAC; C4d without C1q in ~40%). He reviewed emerging therapies across the cascade: C5/C5aR blockers (including positive proteinuria signals), C3 inhibition, lectin-pathway MASP-2 inhibition (a phase 3 trial stopped for lack of benefit), and alternative-pathway factor B/D inhibitors (notably factor B agents with encouraging phase 2/3 signals).<br /><br />Panel Q&A addressed possible complement roles in atypical FSGS subsets, the need for better biomarkers and patient enrichment (e.g., C4d) in trials, whether kidney-level complement suppression is adequately measured (repeat biopsies), and infection risks (vaccination requirements; safety monitoring).

Asset Subtitle

Moderator(s): Duvuru Geetha

Presentation(s):

Introduction - Duvuru Geetha
Complement-Mediated Kidney Diseases: Novel Insights and New Possibilities - Andrew Bomback
New Horizons: Considering the Evolving Therapeutic Landscape for IgA Nephropathy - Chee Kay Cheung

Support is provided by an educational grant from Novartis Pharmaceuticals Corporation.

Meta Tag

Date 11/3/2023

Pathway 1 Glomerular Diseases

Session ID 464918

Session Type ES - Educational Symposium

Keywords

complement system

classical lectin alternative pathways

C3 and C5 MAC

glomerular diseases

kidney biopsy immunofluorescence fingerprints

lupus nephritis full house staining

primary membranous nephropathy IgG4 C4d

C3 glomerulopathy alternative pathway dysregulation

IgA nephropathy complement activation

complement-targeted therapy C5 C3 MASP-2 factor B/D inhibitors