Kidney Week 2025 Annual Meeting-Breaking Barriers: Advances in Understanding and Treating Complement-Mediated Kidney Diseases

Video Transcription

Video Summary

The session “Breaking Barriers: Advances in Understanding and Treating Complement‑Mediated Kidney Diseases” reviewed how complement drives kidney injury and how emerging targeted therapies are changing care, especially for IgA nephropathy (IgAN) and C3 glomerulopathy (C3G).<br /><br />An overview explained that the classical, lectin, and alternative pathways converge on C3 convertase, leading to downstream C5 activation and terminal pathway inflammation. Clinically, complement evaluation includes serum levels/activation fragments, CH50/AH50, autoantibodies (e.g., nephritic factors), genetics, and kidney biopsy staining patterns.<br /><br />For IgAN, Nicolas Maillard emphasized that galactose‑deficient IgA1 forms immune complexes that deposit in glomeruli and activate complement mainly via the alternative pathway (C3 deposition common), with lectin pathway activation in ~30% (C4d/MBL/MASP). Genetic signals implicate CFH/CFHR variants, and biomarkers like factor B breakdown products may correlate with vascular injury and progression. Trials of complement blockade showed promising proteinuria reductions with C5 inhibition (ravulizumab; small‑interfering RNA approaches) and factor B inhibition (iptacopan), with phase 3 results awaited/ongoing.<br /><br />Carla Nester reviewed C3G as largely alternative‑pathway dysregulation driven by nephritic factors and/or variants in C3, factor B, factor H/I, and CFHR rearrangements. Early terminal blockade often underperformed, but newer agents have advanced: factor B inhibition (iptacopan) and C3 inhibition (pegcetacoplan) showed substantial proteinuria reductions, improved eGFR trends, and decreased C3 deposition on biopsy, leading to FDA approvals in 2025. She highlighted ongoing efforts to use biomarker panels to predict transplant recurrence and drug responsiveness, and urged early biopsy/treatment given rapid progression in some patients.

Asset Subtitle

Moderator(s): Duvuru Geetha

Presentation(s):

Introduction - Duvuru Geetha
Complementing Progress: IgAN Insights and Therapies - Nicolas Maillard
Complementing Progress: C3 Glomerulopathy Insights and Therapies - Carla Nester

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

Meta Tag

Date 11/6/2025

Pathway 1 Glomerular Diseases

Session ID 520002

Keywords

complement-mediated kidney diseases

IgA nephropathy (IgAN)

C3 glomerulopathy (C3G)

alternative complement pathway dysregulation

C3 convertase and C5 terminal pathway

complement biomarkers (CH50/AH50, activation fragments)

nephritic factors and CFH/CFHR genetic variants

factor B inhibition (iptacopan)

C3/C5 targeted therapies (pegcetacoplan, ravulizumab)