Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression,Journal of the American Society of Nephrology

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Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression
Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2022-02-01 , DOI: 10.1681/asn.2021070948
Brendon L Neuen ₁ , Hocine Tighiouart _{2,

3} , Hiddo J L Heerspink ₄ , Edward F Vonesh ₅ , Juhi Chaudhari ₆ , Shiyuan Miao ₆ , Tak Mao Chan ₇ , Fernando C Fervenza ₈ , Jürgen Floege ₉ , Marian Goicoechea ₁₀ , William G Herrington ₁₁ , Enyu Imai ₁₂ , Tazeen H Jafar _{13,

14} , Julia B Lewis ₁₅ , Philip Kam-Tao Li ₁₆ , Francesco Locatelli ₁₇ , Bart D Maes ₁₈ , Ronald D Perrone ₆ , Manuel Praga ₁₉ , Annalisa Perna ₂₀ , Francesco P Schena ₂₁ , Christoph Wanner ₂₂ , Jack F M Wetzels ₂₃ , Mark Woodward _{1,

24} , Di Xie ₂₅ , Tom Greene ₂₆ , Lesley A Inker ₆ ,

Affiliation

The George Institute for Global Health, University of New South Wales, Sydney, Australia.
Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts.
Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, Netherlands.
Department of Preventive Medicine, Northwestern University, Chicago, Illinois.
Division of Nephrology, Tufts Medical Center, Boston, Massachusetts.
Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong.
Division of Nephrology and Hypertension and Department of Medicine, Mayo Clinic Rochester, Minnesota.
Division of Nephrology, RWTH Aachen University, Aachen, Germany.
Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Medical Research Council Population Health Research Unit at the University of Oxford Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
Nakayamadera Imai Clinic, Takarazuka, Japan.
Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore, Singapore.
Duke Global Health Institute, Duke University, Durham, North Carolina.
Division of Nephrology, Vanderbilt University, Nashville, Tennessee.
Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong.
Department of Nephrology, Alessandro Manzoni Hospital, ASST Lecco, Italy.
Department of Nephrology, AZ Delta, Roeselare, Belgium.
Nephrology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany.
Department of Nephrology, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
The George Institute for Global Health, Imperial College London, United Kingdom.
Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.

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.

中文翻译：

肾脏疾病进展的随机临床试验中对 GFR 的急性治疗效果

背景

在针对 CKD 进展的干预措施启动后，GFR 可能会发生急性变化。这些急性变化使长期治疗效果的解释变得复杂。

方法

为了评估随机临床试验中急性效应的程度和一致性，并探索可能影响这些效应的因素，我们对 53 项 CKD 进展随机临床试验进行了荟萃分析，招募了 56,413 名受试者，在试验后 6 个月时至少进行了一项估计的 GFR 测量。随机化。我们将急性治疗效果定义为随机组之间从基线到 3 个月的 GFR 斜率的平均差异。我们进行了单变量和多变量元回归，以评估干预类型、疾病状态、基线 GFR 和蛋白尿对急性影响程度的影响。

结果

所有研究的平均急性效应在 3 个月内为每 1.73 m ² –0.21 ml/min（95% 置信区间，–0.63 至 0.22），干预措施之间存在显着异质性（跨研究的 95% 覆盖区间，–2.50 至 +2.08）毫升/分钟每 1.73 m ² )。我们在肾素血管紧张素系统阻断、降血压和钠-葡萄糖协同转运蛋白 2 抑制剂试验中观察到负面的平均急性效应，而在免疫抑制剂的试验中观察到正面的急性效应。在平均基线 GFR 较高的试验中观察到较大的负面急性影响。

结论

不同干预措施对急性 GFR 影响的程度和一致性各不相同，并且基线 GFR 较高时影响更大。了解急性效应的性质和程度有助于评估 CKD 疾病进展的随机临床试验的最佳设计。

更新日期：2022-02-01

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