GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials
Authors: Inker Lesley A. , Heerspink Hiddo J. L. , Tighiouart Hocine , Levey Andrew S. , Coresh Josef , Gansevoort Ron T. , Simon Andrew L. , Ying Jian , Beck Gerald J. , Wanner Christoph , Floege Jürgen , Li Philip Kam-Tao , Perkovic Vlado , Vonesh Edward F. , Greene Tom 
Published: July 2019

Significance Statement
Surrogate end points are needed to assess whether treatments are effective in the earlier stages of CKD. Measuring the effects of treatments on GFR decline, which leads to kidney failure, might be one way to identify early benefits of CKD treatments. So far regulators have not approved the use of GFR slope, the difference in the change in GFR between treatment groups over time, as an end point in CKD randomized, controlled trials because they are concerned that small treatment effects on GFR may not translate into meaningful clinical benefits. Using a Bayesian individual patient meta-analysis of 47 studies including 60,620 participants, the authors found, that for sufficiently large studies, treatment effects on GFR slope from baseline and from 3-month follow-up of 0.5–1.0 ml/min per 1.73 m2/yr strongly predict benefits on clinical end points such as doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD. GFR slope can play a useful role as a surrogate end point for CKD progression in clinical trials.

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.