Targeted-release Budesonide (Nefecon) versus systemic glucocorticoids for IgA nephropathy: a placebo-anchored indirect treatment comparison of randomized controlled trials

IgA nephropathy (IgAN) is a leading cause of end-stage renal disease, particularly in East Asia. Although systemic glucocorticoids are commonly used to delay progression, they are associated with significant adverse effects. Targeted-release budesonide (Nefecon) offers localized immunosuppression, targeting the gut-associated lymphoid tissue (Peyer’s patches), with the aim of reducing systemic exposure. This study evaluates the efficacy and safety of Nefecon compared to systemic glucocorticoids through a placebo-anchored indirect treatment comparison. PubMed, Embase, and the Cochrane Library were systematically searched for randomized controlled trials evaluating Nefecon (16 mg/day), systemic glucocorticoids, or placebo in adults with IgAN. The primary efficacy outcome was annualized preservation of estimated glomerular filtration rate (eGFR), and secondary outcomes included annualized proteinuria reduction and serious infections. Placebo-anchored indirect treatment comparisons were performed using the Bucher difference-of-estimates method. This study was registered in PROSPERO (CRD420261357809). Three independent randomized controlled trials were included. Nefecon improved the annualized eGFR trajectory by 2.95 mL/min/1.73 m 2 per year compared with placebo (95% CI, 1.68–4.58), whereas systemic methylprednisolone produced an improvement of 2.46 mL/min/1.73 m 2 per year (95% CI, 0.94–3.99). The placebo-anchored indirect comparison showed no statistically significant difference in eGFR preservation between the two treatments (MD, 0.49 mL/min/1.73 m 2 per year; 95% CI, −1.62 to 2.59; P indirect = 0.651). For annualized absolute proteinuria reduction, the pooled estimate for Nefecon versus placebo was −0.26 g/g per year (95% CI, −0.34 to −0.18), compared with −0.69 g/g per year (95% CI, −0.97 to −0.41) for systemic methylprednisolone. The indirect comparison favored systemic methylprednisolone (MD, 0.43 g/g per year; 95% CI, 0.13–0.73; P indirect = 0.004), although this analysis was exploratory because proteinuria measures and follow-up durations required harmonization. The indirect comparison of serious infections was not statistically significant (RR, 0.55; 95% CI, 0.04–7.16; P indirect = 0.650). In this indirect comparison, both Nefecon and systemic glucocorticoids were associated with improved kidney outcomes versus placebo in IgAN. No statistically significant indirect difference was observed for eGFR preservation, while proteinuria and safety findings require cautious interpretation. Head-to-head trials are needed to further define their relative efficacy and safety.