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

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 R²=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R² 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.

Graphical abstract

Figure 1.

Treatment effect on total slope at 3 years, chronic slope, and on the clinical end point. Shown are treatment effects on total slope at 3 years (left), on chronic slope (middle), and treatment effects on clinical end point (right). Treatment effects on GFR slope are expressed as mean difference in treatment minus control and are expressed in ml/min per 1.73 m²/yr. The clinical end point is defined as ESKD, GFR<15 ml/min per 1.73 m², or doubling of serum creatinine. Treatment effect on the clinical end point is expressed as HR. The circles represent the estimated treatment effect and the horizontal line its 95% confidence interval. Data for all studies are shown in Supplemental Figure 3, A and D, and Supplemental Figure 4. Alb, albuminuria; CCB, calcium channel blocker; RASB, renin angiotensin system blockers.

Figure 2.

Trial-level analyses for the association between treatment effects on GFR slope and treatment effects on the clinical end point. Left panel: Total slope at 3 years. Right panel: Chronic slope. Shown is the relationship between estimated treatment effects on the clinical end point (ESKD, GFR<15 ml/min per 1.73 m², or doubling of serum creatinine) on the vertical axis and estimated treatment effects on the GFR slope on the horizontal axis. Treatment effects on GFR slope are expressed as mean difference in treatment minus control and are expressed in ml/min per 1.73 m²/yr. The clinical end point is defined as treated kidney failure, doubling of creatinine, or GFR<15 ml/min per 1.73 m². Treatment effect on the clinical end point is expressed as HR. The colors indicate intervention type. Each circle is a separate intervention with the size of the circle proportional to the number of events. The black line is the line of regression through the studies. The blue line is the confidence band. The pink lines are the prediction bands computed from the model. Alb, albuminuria; CCB, calcium channel blocker; RASB, renin angiotensin system blockers.