Jicheng Lv1, Hong Zhang2, Muh Geot Wong3, Meg J Jardine3, Michelle Hladunewich4, Vivek Jha5, Helen Monaghan3, Minghui Zhao2, Sean Barbour6, Heather Reich7, Daniel Cattran7, Richard Glassock8, Adeera Levin6, David Wheeler9, Mark Woodward10, Laurent Billot3, Tak Mao Chan11, Zhi-Hong Liu12, David W Johnson13, Alan Cass14, John Feehally15, Jürgen Floege16, Giuseppe Remuzzi17, Yangfeng Wu18, Rajiv Agarwal19, Hai-Yan Wang2, Vlado Perkovic3. 1. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China2The George Institute for Global Health, University of New South Wales, Sydney, Australia. 2. Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China. 3. The George Institute for Global Health, University of New South Wales, Sydney, Australia. 4. Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 5. The George Institute for Global Health, New Delhi, India5University of Oxford, Oxford, United Kingdom. 6. The University of British Columbia, Vancouver, British Columbia, Canada. 7. University Health Network, Toronto, Ontario, Canada. 8. David Geffen School of Medicine, University of California-Los Angeles. 9. Royal Free and University College Medical School, London, United Kingdom. 10. The George Institute for Global Health, University of New South Wales, Sydney, Australia10The George Institute for Global Health, University of Oxford, Oxford, United Kingdom11Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland. 11. University of Hong Kong, Hong Kong, China. 12. Research Institute of Nephrology, Jinling Hospital, Nanjing, China. 13. Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia. 14. The George Institute for Global Health, University of New South Wales, Sydney, Australia15Menzies School of Health Research, Charles Darwin University, Darwin, Australia. 15. University of Leicester, Leicester, United Kingdom. 16. Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany. 17. Mario Negri Institute for Pharmacological Research and Clinical Research Centre for Rare Diseases, Bergamo, Italy. 18. Peking University Clinical Research Institute, Beijing, China. 19. Indiana University School of Medicine, Indianapolis.
Abstract
Importance: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). Conclusions and Relevance: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oralmethylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration: clinicaltrials.gov Identifier: NCT01560052.
RCT Entities:
Importance: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02). Conclusions and Relevance: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial. Trial Registration: clinicaltrials.gov Identifier: NCT01560052.
Authors: Jicheng Lv; Damin Xu; Vlado Perkovic; Xinxin Ma; David W Johnson; Mark Woodward; Adeera Levin; Hong Zhang; Haiyan Wang Journal: J Am Soc Nephrol Date: 2012-04-26 Impact factor: 10.121
Authors: Daniel C Cattran; Rosanna Coppo; H Terence Cook; John Feehally; Ian S D Roberts; Stéphan Troyanov; Charles E Alpers; Alessandro Amore; Jonathan Barratt; Francois Berthoux; Stephen Bonsib; Jan A Bruijn; Vivette D'Agati; Giuseppe D'Amico; Steven Emancipator; Francesco Emma; Franco Ferrario; Fernando C Fervenza; Sandrine Florquin; Agnes Fogo; Colin C Geddes; Hermann-Josef Groene; Mark Haas; Andrew M Herzenberg; Prue A Hill; Ronald J Hogg; Stephen I Hsu; J Charles Jennette; Kensuke Joh; Bruce A Julian; Tetsuya Kawamura; Fernand M Lai; Chi Bon Leung; Lei-Shi Li; Philip K T Li; Zhi-Hong Liu; Bruce Mackinnon; Sergio Mezzano; F Paolo Schena; Yasuhiko Tomino; Patrick D Walker; Haiyan Wang; Jan J Weening; Nori Yoshikawa; Hong Zhang Journal: Kidney Int Date: 2009-07-01 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: Andrew S Levey; Lesley A Stevens; Christopher H Schmid; Yaping Lucy Zhang; Alejandro F Castro; Harold I Feldman; John W Kusek; Paul Eggers; Frederick Van Lente; Tom Greene; Josef Coresh Journal: Ann Intern Med Date: 2009-05-05 Impact factor: 25.391