Kidney Week Educational Symposia-Accepting the Complement: Understanding the Role of Complement and Its Targeted Therapies in IgA Nephropathy

Accepting the Complement: Understanding the Role of Complement and Its Targeted Therapies in IgA Nephropathy

Video Transcription

Video Summary

The session focused on how complement contributes to IgA nephropathy (IgAN) and how complement-targeted drugs are emerging treatments. Dr. Lars Popper reviewed evidence that complement activation in IgAN is heterogeneous across patients. GWAS studies repeatedly identify a protective deletion of factor H–related proteins (FHR1/FHR3), which increases factor H activity and reduces C3 activation and kidney C3 deposition. Biopsy findings show C3 intensity and C5b-9 correlate with worse histology and progression. Although classical pathway activity is usually absent (no C1q), a subgroup shows lectin pathway activation; glomerular C4D (a surrogate for lectin activity) is an independent prognostic marker. FHR5 deposition and circulating FHR markers may also predict progression, but need further validation.<br /><br />Dr. Rizk reviewed complement inhibitor trials. Iptacopan (oral factor B inhibitor) showed ~44% proteinuria reduction at 9 months in the APPLAUSE phase 3 interim analysis and received accelerated FDA approval for high-risk IgAN. Other approaches include MASP2 inhibition (failed phase 3), factor B antisense (phase 3 ongoing), C5 inhibition (ravulizumab phase 3), C5aR blockade (limited early data), and C5 siRNA (promising phase 2). Discussion emphasized the current lack of biomarkers to personalize therapy, uncertainty about treatment duration/withdrawal, and the need for better risk stratification beyond proteinuria and eGFR.

Asset Subtitle

Moderator(s): Sayna Norouzi

Presentation(s):

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

Meta Tag

Date 10/24/2024

Pathway 1 Glomerular Diseases

Session ID 495534

Session Type ES - Educational Symposium

Keywords

IgA nephropathy (IgAN)

complement activation heterogeneity

factor H–related proteins FHR1/FHR3 deletion

factor H regulation and C3 deposition

lectin pathway and glomerular C4D

C5b-9 (membrane attack complex)

FHR5 deposition biomarkers

iptacopan (factor B inhibitor) APPLAUSE trial

complement inhibitor clinical trials (MASP2, C5, C5aR, siRNA)