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Meta-Analysis
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Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression

Brendon L. Neuen, Hocine Tighiouart, Hiddo J.L. Heerspink, Edward F. Vonesh, Juhi Chaudhari, Shiyuan Miao, Tak Mao Chan, Fernando C. Fervenza, Jürgen Floege, Marian Goicoechea, William G. Herrington, Enyu Imai, Tazeen H. Jafar, Julia B. Lewis, Philip Kam-Tao Li, Francesco Locatelli, Bart D. Maes, Ronald D. Perrone, Manuel Praga, Annalisa Perna, Francesco P. Schena, Christoph Wanner, Jack F.M. Wetzels, Mark Woodward, Di Xie, Tom Greene, Lesley A. Inker and on behalf of CKD-EPI Clinical Trials
JASN February 2022, 33 (2) 291-303; DOI: https://doi.org/10.1681/ASN.2021070948
Brendon L. Neuen
1The George Institute for Global Health, University of New South Wales, Sydney, Australia
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Hocine Tighiouart
2Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts
3Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts
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Hiddo J.L. Heerspink
4Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands
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Edward F. Vonesh
5Department of Preventive Medicine, Northwestern University, Chicago, Illinois
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Juhi Chaudhari
6Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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Shiyuan Miao
6Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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Tak Mao Chan
7Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong
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Fernando C. Fervenza
8Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic Rochester, Minnesota
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Jürgen Floege
9Division of Nephrology, RWTH Aachen University, Aachen, Germany
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Marian Goicoechea
10Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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William G. Herrington
11Medical Research Council Population Health Research Unit at the University of Oxford Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
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Enyu Imai
12Nakayamadera Imai Clinic, Takarazuka, Japan
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Tazeen H. Jafar
13Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore
14Duke Global Health Institute, Duke University, Durham, North Carolina
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Julia B. Lewis
15Division of Nephrology, Vanderbilt University, Nashville, Tennessee
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Philip Kam-Tao Li
16Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong
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Francesco Locatelli
17Department of Nephrology, Alessandro Manzoni Hospital, ASST Lecco, Italy
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Bart D. Maes
18Department of Nephrology, AZ Delta, Roeselare, Belgium
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Ronald D. Perrone
6Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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Manuel Praga
19Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
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Annalisa Perna
20Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Francesco P. Schena
21Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
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Christoph Wanner
22Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany
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Jack F.M. Wetzels
23Department of Nephrology, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
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Mark Woodward
1The George Institute for Global Health, University of New South Wales, Sydney, Australia
24The George Institute for Global Health, Imperial College London, United Kingdom
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Di Xie
25Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Tom Greene
26Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah
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Lesley A. Inker
6Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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Significance Statement

GFR slope has been proposed as a surrogate endpoint for progression to kidney failure in clinical trials studying patients with CKD. Acute or immediate effects on GFR after treatment initiation may complicate the interpretation of long-term treatment effects. In this large meta-analysis of 53 randomized clinical studies of CKD progression, the authors found the magnitude and nature of acute effects are variable across different interventions and may be larger at a higher baseline GFR. Negative acute effects (such as an acute reduction in GFR) were observed in trials of renin-angiotensin system blockade and BP lowering, whereas positive acute effects were more common in trials of immunosuppressive therapies. Such information can inform the optimal design and analysis plan for randomized clinical trials in CKD.

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.

  • chronic kidney disease
  • glomerular filtration rate
  • acute decline in GFR
  • randomized controlled trials
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (2)
Journal of the American Society of Nephrology
Vol. 33, Issue 2
February 2022
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Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression
Brendon L. Neuen, Hocine Tighiouart, Hiddo J.L. Heerspink, Edward F. Vonesh, Juhi Chaudhari, Shiyuan Miao, Tak Mao Chan, Fernando C. Fervenza, Jürgen Floege, Marian Goicoechea, William G. Herrington, Enyu Imai, Tazeen H. Jafar, Julia B. Lewis, Philip Kam-Tao Li, Francesco Locatelli, Bart D. Maes, Ronald D. Perrone, Manuel Praga, Annalisa Perna, Francesco P. Schena, Christoph Wanner, Jack F.M. Wetzels, Mark Woodward, Di Xie, Tom Greene, Lesley A. Inker, on behalf of CKD-EPI Clinical Trials
JASN Feb 2022, 33 (2) 291-303; DOI: 10.1681/ASN.2021070948

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Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression
Brendon L. Neuen, Hocine Tighiouart, Hiddo J.L. Heerspink, Edward F. Vonesh, Juhi Chaudhari, Shiyuan Miao, Tak Mao Chan, Fernando C. Fervenza, Jürgen Floege, Marian Goicoechea, William G. Herrington, Enyu Imai, Tazeen H. Jafar, Julia B. Lewis, Philip Kam-Tao Li, Francesco Locatelli, Bart D. Maes, Ronald D. Perrone, Manuel Praga, Annalisa Perna, Francesco P. Schena, Christoph Wanner, Jack F.M. Wetzels, Mark Woodward, Di Xie, Tom Greene, Lesley A. Inker, on behalf of CKD-EPI Clinical Trials
JASN Feb 2022, 33 (2) 291-303; DOI: 10.1681/ASN.2021070948
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  • Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin
  • Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD
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