Kidney Week Educational Symposia-Complement in IgA Nephropathy and Lupus Nephritis: Role in Pathogenesis and Implications for Treatment

Video Transcription

Video Summary

The transcript reviews how the complement system—over 30 plasma and membrane proteins—links innate and adaptive immunity through three activation pathways: classical (triggered by IgG/IgM immune complexes), lectin (recognition of microbial carbohydrates), and alternative (constitutive low-level “tick-over” via C3 hydrolysis). All pathways generate C3 convertase (cleaving C3 to C3a/C3b) and then C5 convertase (C5a/C5b), culminating in terminal pathway activation (MAC/C5b-9). Complement-driven kidney diseases are grouped into: (1) primary complement disorders (e.g., C3 glomerulopathy), (2) immune-complex/autoantibody diseases where complement amplifies injury (IgA nephropathy, membranous nephropathy, lupus nephritis), (3) inflammatory GN/vasculitis (e.g., ANCA-associated), and (4) complement-mediated thrombotic microangiopathy (TMA). Diagnostic/monitoring tools include C3/C4 and activation products, functional hemolytic assays, complement gene testing, and tissue staining (C3, C4, C1q). Approved anti-complement drugs include eculizumab/ravulizumab (aHUS) and avacopan (C5aR; ANCA vasculitis), with multiple modalities (mAbs, peptides, aptamers, regulator-derived conjugates).<br /><br />In IgA nephropathy, Dr. Medjeral-Thomas argues complement helps explain disease heterogeneity beyond the “four-hit” model. Genetic associations (notably factor H–related proteins), biopsy staining (C3, lectin/terminal markers), and circulating markers correlate with severity and progression. A surge of clinical trials targets different complement nodes (MASP-2/lectin, factor B/alternative, C5/terminal), showing promising proteinuria reductions and the potential for biomarker-guided patient selection.<br /><br />In lupus nephritis, Dr. Rovin emphasizes pathway specificity: early classical components may be protective (deficiencies predispose to lupus), while alternative and terminal pathway activity worsens disease in models. Human kidney transcriptomics show complement upregulation, and urine biomarkers (Ba, C5a, soluble C5b-9) appear to reflect intrarenal activation; urine C5b-9 correlates with histologic activity and falls in responders, suggesting a tool for monitoring and trial enrichment.

Asset Subtitle

Moderators: Duvuru Geetha

Introduction - Duvuru Geetha
Complement in IgA Nephropathy: Pathogenic Role and Potential Therapeutic Target - Nicholas Medjeral-Thomas
Glomerulonephritis and Thrombotic Microangiopathy in Lupus Nephritis: Role of Complement in Pathogenesis and Therapeutic Implications - Brad Rovin

Support is provided by an educational grant from Alexion Pharmaceuticals, Inc.

Meta Tag

Date 11/4/2022

Pathway 1 Glomerular Diseases

Pathway 2 Kidney Biology and Physiology

Session ID 440375

Session Type ES - Educational Symposium

Keywords

complement system

classical lectin alternative pathways

C3 convertase C5 convertase

membrane attack complex C5b-9

complement-mediated kidney disease

C3 glomerulopathy

IgA nephropathy complement biomarkers

lupus nephritis urine C5b-9

anti-complement therapy eculizumab ravulizumab avacopan

complement gene testing and tissue staining