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J Am Soc Nephrol. 2019 Sep;30(9):1735-1745. doi: 10.1681/ASN.2019010007. Epub 2019 Jul 10.

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.

Author information

1
Division of Nephrology and LInker@tuftsmedicalcenter.org.
2
Departments of Clinical Pharmacy and Pharmacology and.
3
The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts.
4
Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts.
5
Division of Nephrology and.
6
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
7
Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
8
Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
9
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.
10
Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany.
11
Division of Nephrology, RWTH Aachen University, Aachen, Germany.
12
Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong; LInker@tuftsmedicalcenter.org.
13
George Institute for Global Health, University of New South Wales, Sydney, Australia; and.
14
Department of Preventive Medicine, Division of Biostatistics, Northwestern University, Chicago, Illinois.

Abstract

BACKGROUND:

Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits.

METHODS:

To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point.

RESULTS:

Across all studies, the treatment effect on 3-year total GFR slope (median R 2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R 2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability.

CONCLUSIONS:

With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

KEYWORDS:

GFR; chronic kidney disease; end stage kidney disease; meta-analysis; randomized controlled trials

Comment in

PMID:
31292197
PMCID:
PMC6727261
[Available on 2020-09-01]
DOI:
10.1681/ASN.2019010007

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