Evaluating Glomerular Filtration Rate Slope as a Surrogate End Point for ESKD in Clinical Trials: An Individual Participant Meta-Analysis of Observational Data

Significance Statement Randomized clinical trials of treatments to slow CKD progression often require large sample sizes and long follow-up to understand their effects on clinical events. This is especially true in patients with earlier stages of kidney disease who are unlikely to experience ESKD for many years. Surrogate study end points that occur earlier during disease progression could help. To evaluate whether eGFR decline over time may be a good surrogate end point, the authors did a meta-analysis of 14 cohorts. They found that slower eGFR decline was significantly associated with lower risk of ESKD in all populations, including those with better kidney function. The results suggest that change in the slope of eGFR decline may be a good surrogate end point for ESKD in clinical trials, particularly in longer trials with patients with rapidly progressive disease. Background Decline in eGFR is a biologically plausible surrogate end point for the progression of CKD in clinical trials. However, it must first be tested to ensure strong associations with clinical outcomes in diverse populations, including patients with higher eGFR. Methods To investigate the association between 1-, 2-, and 3-year changes in eGFR (slope) with clinical outcomes over the long term, we conducted a random effects meta-analysis of 3,758,551 participants with baseline eGFR≥60 ml/min per 1.73 m 2 and 122,664 participants with eGFR<60 ml/min per 1.73 m 2 from 14 cohorts followed for an average of 4.2 years. Results Slower eGFR decline by 0.75 ml/min per 1.73 m 2 per year over 2 years was associated with lower risk of ESKD in participants with baseline eGFR≥60 ml/min per 1.73 m 2 (adjusted hazard ratio, 0.70; 95% CI, 0.68 to 0.72) and eGFR<60 ml/min per 1.73 m 2 (0.71; 95% CI, 0.68 to 0.74). The relationship was stronger with 3-year slope. For a rapidly progressing population with predicted 5-year risk of ESKD of 8.3%, an intervention that reduced eGFR decline by 0.75 ml/min per 1.73 m 2 per year over 2 years would reduce the ESKD risk by 1.6%. For a hypothetical low-risk population with a predicted 5-year ESKD risk of 0.58%, the same intervention would reduce the risk by only 0.13%. Conclusions Slower decline in eGFR was associated with lower risk of subsequent ESKD, even in participants with eGFR≥60 ml/min per 1.73 m 2 , but those with the highest risk would be expected to benefit the most.