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

doi:10.1681/ASN.2021070948

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Visual Abstract

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.

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