Kidney Week Educational Symposia-Cytokines and IgA Nephropathy: Pathogenesis and Novel Therapies

Video Transcription

Video Summary

The session reviews how cytokines, especially the TNF-family members APRIL and BAFF, contribute to IgA nephropathy (IgAN) and how these pathways are becoming therapeutic targets.<br /><br />Professor Hitoshi Suzuki summarizes IgAN as a common, often progressive disease driven by extrarenal production of galactose-deficient IgA1 (Gd-IgA1). Gd-IgA1 forms immune complexes with IgG/IgM, deposits in glomeruli, and activates complement. Aberrant IgA1 glycosylation reflects both genetic factors (e.g., C1GALT1-related variation) and environmental/mucosal triggers. Innate immune receptors TLR9 and TLR7, stimulated by microbial nucleic acids, worsen IgAN in mouse models; hydroxychloroquine (TLR7/9 inhibitor) reduced IgA/C3 deposition and proteinuria in mice, with human benefit still uncertain. Suzuki highlights mucosal sites—particularly tonsillar/NALT involvement—showing tonsillar B-cell glycosyltransferase abnormalities and increased APRIL signaling; clinical data suggest tonsillectomy may improve outcomes in Japanese cohorts. He emphasizes that plasma cells (often bone marrow–resident) may be key sources of pathogenic IgA, explaining why rituximab failed.<br /><br />APRIL/BAFF regulate B-cell maturation and plasma-cell survival via receptors (BAFF-R, TACI, BCMA). APRIL is genetically and clinically linked to IgAN severity; anti-APRIL therapy reduced IgA immune complexes and kidney deposits in models, and global trials are ongoing. BAFF-only blockade may be insufficient because pathogenic plasma cells are more APRIL/BCMA dependent.<br /><br />Dr. Heather Reich reviews emerging phase 2–3 trials: APRIL-selective antibodies (e.g., sibeprenlimab, zigakibart) show substantial proteinuria and Gd-IgA1 reductions with encouraging safety so far. Dual BAFF/APRIL “TACI-Fc” agents (e.g., atacicept, telitacicept) also reduce immunoglobulins and proteinuria, but long-term safety, infection risk, and optimal treatment duration remain key questions.

Asset Subtitle

Moderator(s): Ali Gharavi

Presentation(s):

Introduction - Ali Gharavi
Roles of APRIL and BAFF in the Pathogenesis of IgA Nephropathy - Hitoshi Suzuki
Therapies Targeting BAFF and APRIL in IgA Nephropathy - Heather Reich

Support is provided by an educational grant from Otsuka America Pharmaceutical, Inc.

Meta Tag

Date 11/4/2023

Pathway 1 Glomerular Diseases

Session ID 464925

Session Type ES - Educational Symposium

Keywords

IgA nephropathy (IgAN)

galactose-deficient IgA1 (Gd-IgA1)

APRIL (TNFSF13)

BAFF (TNFSF13B)

BAFF-R / TACI / BCMA receptors

immune complex deposition and complement activation

TLR7 and TLR9 signaling

tonsillar mucosal immunity and tonsillectomy

APRIL-targeted therapies (sibeprenlimab, zigakibart)

TACI-Fc dual BAFF/APRIL blockade (atacicept, telitacicept)