GFR slope as a surrogate endpoint for CKD progression in clinical trials

Abstract

Purpose of review There is a paucity of therapies for chronic kidney disease (CKD), in part because of the slow nature of the disease which poses challenges in selection of endpoints in randomized controlled trials (RCT). There is increasing evidence for the use of glomerular filtration rate (GFR)-based endpoints either as percentage decline using time-to-event analyses, or as difference in slope between treatment arms. We reviewed the rationale for using surrogate endpoints and optimal methods for their evaluation prior to their use and evidence for GFR-based endpoints and particularly GFR slope as validated surrogate endpoints and considerations for their use in RCTs. Recent findings In an individual patient meta-analysis of 47 studies (60 620 participants), treatment effects on the clinical endpoint were accurately predicted from treatment effects on 3-year total slope [median R 2 = 0.97 (95% Bayesian confidence interval (BCI), 0.78–1.00] and on the chronic slope [R 2 = 0.96 (95% BCI, 0.63–1.00)]. In a simulation study, GFR slope substantially reduced the required sample size and duration of follow-up compared to the clinical endpoint given high baseline GFR and absence of acute treatment effect. In the presence of acute effect, results were more complicated. Summary GFR decline is accepted, and GFR slope is being considered, by regulatory authorities as a validated surrogate endpoint for CKD RCTs.

Potential Role and Limitations of Estimated Glomerular Filtration Rate Slope Assessment in Cardiovascular Trials

“…18 eGFR slope can be used in patients with higher baseline eGFR values and may provide CKD progression insights when few hard kidney events are observed, especially in trials with limited follow-up. 5,19 Assuming a normal kidney function trajectory based on eGFR or measured GFR of 1 mL/min/1.73 m 2 /y, literature categorizes slow kidney function trajectory as less than 3 mL/min/1.73 m 2 /y, fast as 3 to 5 mL/min/1.73 m 2 /y, and very fast as more than 5 mL/min/1.73 m 2 /y. 20 The variations in eGFR observed suggest that CKD progression assessment should not rely on a single measurement.…”

“…Among these, 1099 patients (25.5%) died, and only 38 (0.22%) experienced end-stage kidney disease or kidney death. This highlights the need for alternate markers for assessing the impact of novel therapies on kidney function at an earlier and, from a prevention perspective, more relevant stage of the disease . Herein, we discuss the potential role of eGFR slope in clinical trials, its strengths and limitations, and the implications of adopting it as a viable outcome in cardiovascular outcome trials.…”

“…With adequate sample size, treatment effects in the range of 0.5 to 1.00 mL/min/1.73 m 2 /y had 96% probability of predicting CKD progression, defined as doubling of serum creatinine, eGFR less than 15 mL/min/1.73 m 2 , or ESKD . eGFR slope can be used in patients with higher baseline eGFR values and may provide CKD progression insights when few hard kidney events are observed, especially in trials with limited follow-up . Assuming a normal kidney function trajectory based on eGFR or measured GFR of 1 mL/min/1.73 m 2 /y, literature categorizes slow kidney function trajectory as less than 3 mL/min/1.73 m 2 /y, fast as 3 to 5 mL/min/1.73 m 2 /y, and very fast as more than 5 mL/min/1.73 m 2 /y .…”

“…This highlights the need for alternate markers for assessing the impact of novel therapies on kidney function at an earlier and, from a prevention perspective, more relevant stage of the disease. 5 Herein, we discuss the potential role of eGFR slope in clinical trials, its strengths and limitations, and the implications of adopting it as a viable outcome in cardiovascular outcome trials. IMPORTANCE Cardiovascular trials have traditionally been underpowered to assess advanced chronic kidney disease (CKD) outcomes, and when included as a secondary end point, trials have used progression of CKD as incidence of some variation of a composite of end-stage kidney disease (ESKD) outcomes.…”

“…This can help earlier interventions to curb further deterioration of kidney function in due time, thereby preventing subsequent exacerbation of HF. In addition, the efficacy of novel therapeutic interventions and their effect on modulating kidney function can be examined more quickly by using eGFR slope as an end point 5.…”