Abstract
KEY POINTS: Existing and novel therapies reduce proteinuria and slow eGFR rate of decline in IgA nephropathy, with some heterogeneity across drug classes. Benefits and limitations of each drug class must be considered, and longer-term Phase 3 data on several therapies are awaited. Emerging data support the potential of novel therapies to improve kidney outcomes in IgA nephropathy in the near future. BACKGROUND: Substantial advances have been made in therapeutics for IgA nephropathy. We conducted a systematic review and meta-analysis to evaluate the comparative efficacy and safety of existing and novel IgA nephropathy therapies. METHODS: We searched MEDLINE and Embase databases from inception to May 21, 2025, for Phase 2b and 3 multicenter, randomized, placebo-controlled trials enrolling patients with IgA nephropathy that reported treatment effects on proteinuria and/or eGFR slope. Trials were categorized into four drug classes: Nonimmunologic therapies, corticosteroids, B-cell modulating agents, and complement inhibitors. Treatment effects on proteinuria and eGFR slope were pooled overall and by drug class using random-effects meta-analysis. RESULTS: Fourteen trials were identified of which proteinuria and eGFR outcomes were available in 13 trials (93%) and seven trials (50%), respectively. Pooled data demonstrated all therapies reduced proteinuria, although the magnitude of effect varied across classes: −34% with nonimmunologic therapies, −51% with corticosteroids, −45% with B-cell modulating agents, and −35% with complement inhibitors (P heterogeneity <0.001). Data from trials reporting eGFR slope over a minimum of 12 months indicated benefits for all drug classes, but again with some evidence that effects varied by class. The absolute and relative effect on eGFR slope was 1.1 ml/min per 1.73 m(2) per year and −28% with nonimmunologic therapies, 2.3 ml/min per 1.73 m(2) per year and −52% with corticosteroids, and 4.3 ml/min per 1.73 m(2) per year and −73% with B-cell modulating agents (P heterogeneity = 0.03). Corticosteroids, particularly at higher doses, increased the risk of serious adverse events, but other drug classes were generally well tolerated. Longer-term data on clinical kidney outcomes and safety are awaited. CONCLUSIONS: All four drug classes improve kidney outcomes in IgA nephropathy, with some evidence of differential effects on proteinuria and eGFR slope. The varying mechanisms and effects of different therapies suggest a potential for combination therapy, although selection of the optimal combination of therapies for individuals remain to be determined.