The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy

Dana Kim; Jicheng Lv; Michelle Hladunewich; Vivekanand Jha; Lai Seong Hooi; Helen Monaghan; Sana Shan; Heather N Reich; Sean Barbour; Laurent Billot; Hong Zhang; Vlado Perkovic; Muh Geot Wong; TESTING trial steering committee

doi:10.1016/j.ekir.2024.03.032

The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy

Kidney Int Rep. 2024 Apr 3;9(7):2168-2179. doi: 10.1016/j.ekir.2024.03.032. eCollection 2024 Jul.

Authors

Dana Kim^{1

2}, Jicheng Lv³, Michelle Hladunewich⁴, Vivekanand Jha^{5

6

7}, Lai Seong Hooi⁸, Helen Monaghan¹, Sana Shan¹, Heather N Reich⁹, Sean Barbour¹⁰, Laurent Billot¹, Hong Zhang³, Vlado Perkovic¹, Muh Geot Wong^{1

2

11}; TESTING trial steering committee

Collaborators

TESTING trial steering committee:
Adeera Levin, Daniel Cattran, David W Johnson, David Wheeler, Jürgen Flöge, Mark Woodward, Meg Jardine, Ming-Hui Zhao, Rajiv Agarwal, Richard Glassock, Tak Mao Chan, Yangfeng Wu, Zhihong Liu

Affiliations

¹ The George Institute for Global Health, University of New South Wales, Sydney, Australia.
² Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
³ Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
⁴ Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada.
⁵ The George Institute for Global Health India, UNSW, New Delhi, India.
⁶ Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, India.
⁷ The George Institute for Global Health, School of Public Health, Imperial College London, UK.
⁸ Sultanah Aminah Hospital, Johor Bahru, Malaysia.
⁹ Division of Nephrology, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
¹¹ Department of Renal Medicine, Concord Repatriation General Hospital, Australia.

Abstract

Introduction: The therapeutic effects of steroids in immunoglobulin A nephropathy (IgAN) global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgAN 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 prespecified analysis of the reduced-dose cohort of the TESTING trial.

Methods: Between 2017 and 2019, patients with IgAN, proteinuria ≥1 g/d despite 3 months of renin-angiotensin-system blockade and estimated glomerular filtration rate (eGFR) 30 to 120 ml/min per 1.73 m² were randomized to reduced-dose methylprednisolone 0.4 mg/kg/d or placebo. The primary outcome was a composite of a 40% eGFR decline, kidney failure, or death due to kidney disease.

Results: A total of 241 participants were randomized and followed-up with for a median of 2.5 years (mean age: 37 years; baseline eGFR: 65 ml/min per 1.73 m²; proteinuria: 2.48 g/d). Methylprednisolone was associated with fewer primary outcome events compared to placebo (7/121 vs. 22/120; hazard ratio [HR]: 0.24; 95% confidence interval [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 -1.15 g/d and 7.9 ml/min per 1.73 m² (P < 0.001) at 12 months, respectively; however, these benefits were lost over time. There were 7 versus 3 SAEs in the methylprednisolone versus placebo group (HR: 1.97; 95% CI: 0.49-7.90), including 5 versus 2 infections.

Conclusion: Reduced-dose methylprednisolone is effective in improving kidney outcomes in high risk IgAN; however, it is associated with a modestly higher number of SAEs compared to placebo.

Keywords: IgA nephropathy; corticosteroids; glomerulonephritis.