Mechanisms and management of IgA nephropathy progression to end-stage renal disease: From the “four-hit” theory to precision medicine

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BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with ~ 30% of patients progressing to end-stage kidney disease (ESKD) within 20 years of diagnosis, imposing a significant disease burden. OBJECTIVE: To systematically review the progression of IgAN from its pathogenesis to ESKD and explore modern management strategies based on precise risk stratification. MATERIALS AND METHODS: A systematic review of existing literature was conducted to integrate key evidence in the fields of IgAN pathogenesis, risk assessment, and treatment. RESULTS: The progression of IgAN is driven by the "four-hit" theory, with abnormal activation of the complement system being a key amplifier of injury. Persistent proteinuria, hypertension, and tubular atrophy/interstitial fibrosis (T lesion) on renal biopsy are the strongest predictors of disease progression. Modern management emphasizes precise risk stratification integrating clinical and pathological indicators. In terms of treatment, renin-angiotensin system inhibitors (RASi) and SGLT2 inhibitors are the cornerstone of supportive therapy for all patients with proteinuria. For those with rapid progression and remaining at high risk despite optimized supportive treatment, glucocorticoids or novel targeted drugs may be considered as appropriate. CONCLUSION: The management of IgAN has entered the era of precision medicine, with the integration of mechanism research, risk prediction, and diversified treatment strategies being the core for delaying disease progression.

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