Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy

ABSTRACT Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin–angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi‐hit hypothesis—while foundational for targeted therapy development—fails to capture IgAN's recurrent, self‐amplifying nature. We introduce the “spiral hypothesis” as a dynamic model of cyclical immune‐injury cascades, better explaining disease chronicity and necessitating sustained maintenance therapy. Emerging targeted therapies—including B‐cell targeted agents (e.g., APRIL/BAFF inhibitors), complement inhibitors (e.g., iptacopan), and mucosal immunomodulators (e.g., TRF‐budesonide)—enable early intervention addressing both upstream immunological drivers and downstream fibrotic pathways. We critically evaluate treat‐to‐target frameworks, defining remission endpoints (proteinuria <0.3 g/day, hematuria resolution, estimated glomerular filtration rate slope <−1 mL/min/year) and emphasizing biomarker‐guided personalization. The paradigm shift toward proactive management prioritizes individualized therapeutic sequencing of novel agents based on dynamic risk stratification. Future priorities include optimizing protocols for high‐risk phenotypes and refining long‐term safety monitoring to ensure sustainable efficacy.