The efficacy and safety of reduced-dose oral methylprednisolone in high-risk IgA nephropathy

Introduction The Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgA nephropathy at high risk of disease progression compared to supportive care alone but is associated with increased serious adverse events (SAEs) primarily with full-dose therapy. The risk-benefit balance of the reduced-dose methylprednisolone regimen is examined in this pre-specified analysis of the reduced-dose cohort of the TESTING trial. Methods Between 2017-2019, patients with IgA nephropathy, proteinuria ≥1g/day despite 3 months of renin-angiotensin-system blockade and estimated glomerular filtration rate (eGFR) 30-120mL/min/1.73m2 were randomised to reduced-dose methylprednisolone 0.4mg/kg/day or placebo. The primary outcome was a composite of a 40% eGFR decline, kidney failure or death due to kidney disease. Results 241 participants were randomised and followed-up for a median of 2.5 years (mean age 37 years, baseline eGFR 65mL/min/1.73m2, proteinuria 2.48g/day). Methylprednisolone was associated with fewer primary outcome events compared to placebo (7/121 vs 22/120, HR 0.24; 95% CI, 0.10-0.58, P = 0.002), lowered proteinuria and reduced eGFR rate of decline from baseline. The mean difference between methylprednisolone and placebo in proteinuria and eGFR from baseline was -1.15g/day and 7.9mL/min/1.73m2 (P <0.001) at 12 months respectively, but these benefits were lost over time. There were 7 vs 3 SAEs in the methylprednisolone vs placebo group (HR 1.97; 95% CI, 0.49-7.90) including 5 vs 2 infections. Conclusion Reduced-dose methylprednisolone is effective in improving kidney outcomes in high-risk IgA nephropathy, however, is associated with a modestly higher number of SAEs compared to placebo.