Corticosteroids, serum proteins, and the next phase of precision medicine in IgA nephropathy

Systemic glucocorticoids remain an important but problematic treatment option in high-risk IgA nephropathy, offering kidney protection at the cost of clinically relevant toxicity. Recent serum proteomic analyses embedded within the randomized TESTING trial provide a new framework for identifying patients most likely to benefit from methylprednisolone. In 241 Chinese participants with IgA nephropathy, longitudinal profiling of 479 serum samples showed that methylprednisolone significantly modulated 302 proteins involved in cytoskeletal regulation, extracellular matrix interactions, immunometabolism, coagulation, protein turnover, and related pathways. Importantly, complement- and endothelial injury-associated pathways were incompletely modified and remained linked to adverse kidney outcomes, suggesting residual disease mechanisms that may require complementary targeted therapies. Among baseline proteins, leptin and C1QTNF5 emerged as practical candidate biomarkers of glucocorticoid responsiveness, improving prediction of treatment efficacy beyond conventional clinical variables. These findings support a shift from purely prognostic risk stratification toward treatment-informed precision medicine in IgA nephropathy. However, the biomarker model requires prospective validation across diverse populations, steroid regimens, and background therapies, and future tools must integrate both predicted kidney benefit and treatment-related harm. If confirmed, serum proteomics could help clinicians move beyond population-average steroid decisions toward biologically guided selection of patients most likely to benefit while avoiding unnecessary toxicity.