Brendon L Neuen1, Hocine Tighiouart2,3, Hiddo J L Heerspink4, Edward F Vonesh5, Juhi Chaudhari6, Shiyuan Miao6, Tak Mao Chan7, Fernando C Fervenza8, Jürgen Floege9, Marian Goicoechea10, William G Herrington11, Enyu Imai12, Tazeen H Jafar13,14, Julia B Lewis15, Philip Kam-Tao Li16, Francesco Locatelli17, Bart D Maes18, Ronald D Perrone6, Manuel Praga19, Annalisa Perna20, Francesco P Schena21, Christoph Wanner22, Jack F M Wetzels23, Mark Woodward1,24, Di Xie25, Tom Greene26, Lesley A Inker27. 1. The George Institute for Global Health, University of New South Wales, Sydney, Australia. 2. Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts. 3. Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts. 4. Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands. 5. Department of Preventive Medicine, Northwestern University, Chicago, Illinois. 6. Division of Nephrology, Tufts Medical Center, Boston, Massachusetts. 7. Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong. 8. Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic Rochester, Minnesota. 9. Division of Nephrology, RWTH Aachen University, Aachen, Germany. 10. Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 11. Medical Research Council Population Health Research Unit at the University of Oxford Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. 12. Nakayamadera Imai Clinic, Takarazuka, Japan. 13. Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore. 14. Duke Global Health Institute, Duke University, Durham, North Carolina. 15. Division of Nephrology, Vanderbilt University, Nashville, Tennessee. 16. Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. 17. Department of Nephrology, Alessandro Manzoni Hospital, ASST Lecco, Italy. 18. Department of Nephrology, AZ Delta, Roeselare, Belgium. 19. Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. 20. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy. 21. Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. 22. Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany. 23. Department of Nephrology, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. 24. The George Institute for Global Health, Imperial College London, United Kingdom. 25. Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. 26. Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah. 27. Division of Nephrology, Tufts Medical Center, Boston, Massachusetts LInker@Tuftsmedicalcenter.org.
Abstract
BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.
BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.
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