Jicheng Lv1,2, Muh Geot Wong2,3, Michelle A Hladunewich4, Vivekanand Jha5,6,7, Lai Seong Hooi8, Helen Monaghan2, Minghui Zhao1, Sean Barbour9, Meg J Jardine10, Heather N Reich11, Daniel Cattran11, Richard Glassock12, Adeera Levin9, David C Wheeler13, Mark Woodward7, Laurent Billot2, Sandrine Stepien2, Kris Rogers2, Tak Mao Chan14, Zhi-Hong Liu15, David W Johnson16, Alan Cass2,17, John Feehally18, Jürgen Floege19, Giuseppe Remuzzi20, Yangfeng Wu21, Rajiv Agarwal22, Hong Zhang1, Vlado Perkovic2. 1. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China. 2. The George Institute for Global Health, University of New South Wales, Sydney, Australia. 3. Department of Renal Medicine, Royal North Shore Hospital, Australia. 4. Sunnybrook Health Sciences Centre, 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, United Kingdom. 8. Sultanah Aminah Hospital, Johor Bahru, Malaysia. 9. The University of British Columbia, Vancouver, British Columbia, Canada. 10. NHMRC Clinical Trials Centre, University of Sydney, Australia. 11. University Health Network, Toronto, Ontario, Canada. 12. David Geffen School of Medicine, University of California, Los Angeles. 13. Department of Renal Medicine, University College London, United Kingdom. 14. Department of Medicine, The University of Hong Kong, Hong Kong, SAR of China. 15. Research Institute of Nephrology, Jinling Hospital, Nanjing, China. 16. Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia. 17. Menzies School of Health Research, Charles Darwin University, Darwin, Australia. 18. University of Leicester, Leicester, United Kingdom. 19. Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. 20. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. 21. Peking University Clinical Research Institute, Beijing, China. 22. Indiana University School of Medicine, Indianapolis.
Abstract
Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. Design, Setting, and Participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021. Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group). Main Outcomes And Measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure. Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]). Conclusions and Relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01560052.
Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain. Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline. Design, Setting, and Participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021. Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group). Main Outcomes And Measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure. Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]). Conclusions and Relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01560052.
Authors: Hernán Trimarchi; Jonathan Barratt; Daniel C Cattran; H Terence Cook; Rosanna Coppo; Mark Haas; Zhi-Hong Liu; Ian S D Roberts; Yukio Yuzawa; Hong Zhang; John Feehally Journal: Kidney Int Date: 2017-03-22 Impact factor: 10.612
Authors: Thomas Rauen; Stephanie Wied; Christina Fitzner; Frank Eitner; Claudia Sommerer; Martin Zeier; Britta Otte; Ulf Panzer; Klemens Budde; Urs Benck; Peter R Mertens; Uwe Kuhlmann; Oliver Witzke; Oliver Gross; Volker Vielhauer; Johannes F E Mann; Ralf-Dieter Hilgers; Jürgen Floege Journal: Kidney Int Date: 2020-05-22 Impact factor: 10.612
Authors: Sean J Barbour; Daniel C Cattran; S Joseph Kim; Adeera Levin; Ron Wald; Michelle A Hladunewich; Heather N Reich Journal: Kidney Int Date: 2013-06-05 Impact factor: 10.612
Authors: Thomas Rauen; Frank Eitner; Christina Fitzner; Claudia Sommerer; Martin Zeier; Britta Otte; Ulf Panzer; Harm Peters; Urs Benck; Peter R Mertens; Uwe Kuhlmann; Oliver Witzke; Oliver Gross; Volker Vielhauer; Johannes F E Mann; Ralf-Dieter Hilgers; Jürgen Floege Journal: N Engl J Med Date: 2015-12-03 Impact factor: 91.245
Authors: Jicheng Lv; Hong Zhang; Muh Geot Wong; Meg J Jardine; Michelle Hladunewich; Vivek Jha; Helen Monaghan; Minghui Zhao; Sean Barbour; Heather Reich; Daniel Cattran; Richard Glassock; Adeera Levin; David Wheeler; Mark Woodward; Laurent Billot; Tak Mao Chan; Zhi-Hong Liu; David W Johnson; Alan Cass; John Feehally; Jürgen Floege; Giuseppe Remuzzi; Yangfeng Wu; Rajiv Agarwal; Hai-Yan Wang; Vlado Perkovic Journal: JAMA Date: 2017-08-01 Impact factor: 56.272
Authors: Patrizia Natale; Suetonia C Palmer; Marinella Ruospo; Valeria M Saglimbene; Jonathan C Craig; Mariacristina Vecchio; Joshua A Samuels; Donald A Molony; Francesco Paolo Schena; Giovanni Fm Strippoli Journal: Cochrane Database Syst Rev Date: 2020-03-12