IgA nephropathy: evolving pathogenic concepts and emerging targeted therapies

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Up to 40% of patients progress to end-stage kidney disease (ESKD) within 20-30 years of diagnosis. The "Four-hit" pathogenesis model has provided a foundational framework for understanding disease initiation and progression, yet recent mechanistic discoveries have substantially refined this paradigm.

This review was conducted by searching relevant literature from databases including PubMed and Web of Science, with a focus on recent advances in IgAN pathogenesis and therapeutic development. A narrative review approach was adopted, incorporating a broad range of experimental and clinical studies, without following the formal systematic review paradigm.

Emerging evidence identifies the Krüppel-like factor 4 (KLF4)/interleukin-6 (IL-6) axis and mucosa-bone marrow homing as key drivers of galactose-deficient IgA1 (Gd-IgA1) production; complement activation mediates downstream renal injury. Foundation therapy includes renin-angiotensin system (RAS) blockers and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Approved targeted agents include budesonide enteric capsules, iptacopan, and endothelin receptor antagonists. Late-stage inhibitors targeting B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) substantially reduce Gd-IgA1 and proteinuria. However, validated predictive biomarkers remain lacking, and high-quality data for combination therapy are still absent.

IgAN therapy is shifting from supportive care to mechanism-based targeted therapy. Validated biomarkers for selecting pathway-specific therapy remain limited, and biomarker-guided precision medicine has not yet been realized; cross-trial comparisons should be interpreted within each trial's endpoint and follow-up context.