Principles for Optimal Drug Selection in IgA Nephropathy-Time for Integrating Pathogenesis and Clinical Markers to Guide Therapy.

IgA nephropathy is a progressive glomerular disease with a variable clinical course and a substantial risk of progression to end-stage kidney failure. While proteinuria has long been the central therapeutic target, insights into disease pathogenesis indicate that haematuria should also guide treatment decisions. Based on the pathophysiology of IgA nephropathy-particularly the deposition of galactose-deficient IgA1 (GdIgA1)-containing immune complexes and subsequent complement activation-haematuria reflects active glomerular capillaritis. In this context, haematuria serves as a dynamic marker of immunologic injury, whereas proteinuria without haematuria may reflect irreversible breakdown of the glomerular filtration barrier. Therefore, the presence or absence of haematuria helps clarify the underlying mechanisms of proteinuria and informs the selection of appropriate therapeutic strategies. This review proposes a practical framework for drug selection tailored to both disease stage and clinical phenotype. In early, inflammation-predominant stages marked by haematuria, therapies targeting B/plasma cell function and GdIgA1 production, or complement activation-such as antibodies against APRIL/BAFF or their receptors, and complement inhibitors-may be most effective. In later stages without haematuria, management should focus on chronic structural damage with agents such as RAS inhibitors, SGLT2 inhibitors, and endothelin receptor antagonists. With multiple novel therapies on the horizon, distinguishing between haematuria-positive and haematuria-negative proteinuria-each reflecting distinct pathogenic processes-provides critical guidance for selecting and positioning soon-to-be-available new drugs. Integrating this clinical-pathological understanding into treatment planning enables more precise, individualised therapy for IgA nephropathy.