Kidney Week Educational Symposia-IgA Nephropathy: Proteinuria, Vasoactive Peptides, and the Evolving Treatment Landscape

Video Transcription

Video Summary

The session reviews IgA nephropathy (IgAN) as a common, progressive cause of kidney failure and emphasizes that many patients are diagnosed too late—often already with stage 3 CKD, high creatinine, and heavy proteinuria—when irreversible scarring limits benefit from therapy. Natural history data show progression risk is not zero even with “low-grade” proteinuria, reinforcing the need for earlier detection of hematuria/proteinuria and timely biopsy.<br /><br />Using the four-hit hypothesis (galactose-deficient IgA1, autoantibodies, immune complexes, and glomerular injury), the speakers focus on “hit 4” therapies that act after immune injury begins. Proteinuria reduction is highlighted as a validated surrogate endpoint enabling accelerated FDA approvals and fueling a surge in trials.<br /><br />Basic science content details endothelin-1 (ET-1) biology: ETA signaling promotes vasoconstriction, inflammation, fibrosis, mesangial proliferation, and podocyte injury/EMT, while ETB may be protective and helps clear ET-1. ET-1 and its receptors are upregulated in IgAN and correlate with proteinuria. Angiotensin II and ET-1 appear to form a damaging feedback loop across endothelial cells, mesangial cells, and podocytes; dual blockade (e.g., sparsentan) can reduce mesangial proliferation in models.<br /><br />Clinical updates cover supportive care as foundational (max RAAS blockade, BP control, CKD care), but inadequate alone. Emerging/expanding treatments include SGLT2 inhibitors (DAPA-CKD IgAN subgroup benefit), endothelin pathway drugs (sparsentan accelerated approval; ongoing data; other agents like atrasentan), systemic glucocorticoids (TESTING trial efficacy with toxicity), targeted-release budesonide (NefIgArd: sustained proteinuria reduction; questions about duration and eGFR effects), and future approaches targeting APRIL/BAFF and complement. Discussion notes unmet needs in patient selection/biomarkers and debates proteinuria vs pathology, with some advocating follow-up biopsy.

Asset Subtitle

Moderator(s): Daniel Cattran

Presentation(s):

Introduction - Daniel Cattran
Endothelin-1 Effects on Glomerular Filtration, Kidney Inflammation, and Damage - Colin Reily
Emerging Therapeutic Options in IgA Nephropathy - Pietro Canetta

Support is provided by an educational grant from Travere Therapeutics, Inc.

Meta Tag

Date 11/3/2023

Pathway 1 Glomerular Diseases

Session ID 464917

Session Type ES - Educational Symposium

Keywords

IgA nephropathy (IgAN)

chronic kidney disease progression

proteinuria reduction surrogate endpoint

four-hit hypothesis

galactose-deficient IgA1 (Gd-IgA1)

endothelin-1 (ET-1) pathway

ETA/ETB receptors

RAAS blockade and blood pressure control

sparsentan dual angiotensin II/endothelin receptor antagonist

targeted-release budesonide (NefIgArd trial)