Kidney Week Educational Symposia-Targeting Cytokines in IgA Nephropathy: Understanding and Taking Aim at the "First-Hit"

Video Transcription

Video Summary

This recorded symposium session focuses on IgA nephropathy (IgAN) pathogenesis and emerging therapies targeting the “first hit” in the four-hit hypothesis. The moderator, Dr. Elvenia Negre, highlights sobering registry data (UK RADAR) showing that IgAN often progresses to kidney failure over a lifetime—even in patients with relatively low proteinuria—prompting tighter treatment targets in forthcoming KDIGO guidance: reduce proteinuria to ≤0.5 g/day (ideally 0.3) and slow eGFR decline to <1 mL/min/year. While proteinuria remains the only validated early biomarker, speakers emphasize it reflects downstream injury, motivating therapies that target upstream disease drivers.<br /><br />Prof. Bobby Chacko reviews the immunologic basis of IgAN, emphasizing mucosal immune activation and cytokines BAFF and APRIL, which promote B-cell class switching and plasma cell survival leading to production of galactose-deficient IgA1 (Gd-IgA1). Although serum Gd-IgA1 correlates with risk, it lacks diagnostic specificity. Preclinical and clinical evidence suggests APRIL is particularly linked to progression; APRIL inhibition improves histologic findings in models and appears safe without impairing vaccine responses. The relative importance of BAFF vs APRIL may vary by population, and better biomarkers (potentially biopsy transcriptomics) are needed.<br /><br />Dr. Fernando Fervenza summarizes phase 2 trials of APRIL inhibition (sibeprenlimab) and dual APRIL/BAFF blockade (telitacicept, atacicept), showing substantial reductions in proteinuria, Gd-IgA1, and signals for eGFR preservation with generally benign safety. He stresses IgAN is relapsing/remitting and may require long-term or repeat treatment, and argues hematuria—often neglected—may be a key activity marker that improves with effective immunologic therapy.

Asset Subtitle

Moderator(s): Lavinia Negrea

Presentation(s):

Introduction - Lavinia Negrea
The Pathogenic Role of Cytokines BAFF and APRIL in IgAN - Bobby Chacko
Treatment Strategies Targeting the First Hit in IgAN - Fernando Fervenza

Support is provided by an educational grant from Vera Therapeutics.

Meta Tag

Date 10/26/2024

Pathway 1 Glomerular Diseases

Pathway 2 Pharmacology

Session ID 493727

Session Type ES - Educational Symposium

Keywords

IgA nephropathy

IgAN pathogenesis

four-hit hypothesis

first hit targeting

KDIGO proteinuria target

eGFR decline prevention

mucosal immunity

BAFF

APRIL

galactose-deficient IgA1 (Gd-IgA1)

APRIL inhibition therapies (sibeprenlimab, telitacicept, atacicept)