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Abstract: TH-PO1052

Implications of the Acute and Chronic GFR Slopes for Time-to-Event End Points in Clinical Trials of CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials


  • Greene, Tom, University of Utah Health, Salt Lake City, Utah, United States
  • Inker, Lesley Ann, Tufts Medical Center, Boston, Massachusetts, United States
  • Heerspink, Hiddo Jan L., Universiteit Groningen Afdeling Gezondheidswetenschappen, Groningen, Groningen, Netherlands

Group or Team Name

  • CKD-EPI(CT).

In a companion abstract, we apply a multivariable model to relate treatment effects on the established clinical endpoint (CE) based primarily on serum creatinine (SCR) doubling to treatment effects on the acute (evaluated prior to 3 months) and chronic (evaluated after 3 months) GFR slopes across 66 randomized treatment comparisons (RTCs). Here, we apply the same model to alternative time-to-event (TTE) endpoints defined by progressively larger GFR declines, including the established CE as a special case.


For each RTC, we used mixed effects models and Cox regression, respectively, to estimate treatment effects on the acute and chronic GFR slopes, and on four TTE endpoints (Table heading, expressed as log hazard ratios). We then used multivariable Bayesian meta-regressions to relate the treatment effects on each TTE endpoint jointly to the treatment effects on the acute and chronic slopes.


Treatment effects on the acute and chronic slopes jointly predicted treatment effects on each TTE endpoint with high accuracy (all trial-level R2s ≥ 0.91). After accounting for the treatment effect on the chronic slope, a 1 ml/min/1.73m2 greater negative acute effect led to a positive shift in the HR (against the treatment) by 15.4%, 11.4%, and 5.7%, respectively, for TTE endpoints based on 30% GFR decline, SCR doubling, and KFRT and GFR ≤ 15 ml/min/1.73m2, showing that the role of the acute slope substantially attenuated for TTE endpoints based on larger GFR decline.


Acute effects have a small but measurable impact on KFRT or GFR decline to less than 15 ml/min/1.73m2 after accounting for the chronic slope. However, relative to their small impact on progression to kidney failure, the role of the acute effect is moderately overstated by the established CE based on SCR doubling, and more severely by TTE endpoints based on 30% or 40% GFR decline.

Meta-Regressions Relating Treatment Effects on Time-to-Event Endpoints to Treatment Effects on the Acute and Chronic Slopes
Variable30% GFR decline, GFR≤15, KFRT40% GFR decline, GFR≤15, KFRTSCR Doubling, GFR≤15, KFRTKFRT, GFR ≤15
Summary MeasureMedian (95% Bayesian CI)Median (95% Bayesian CI)Median (95% Bayesian CI)Median (95% Bayesian CI)
Intercept-0.03 (-0.08, 0.01)-0.04 (-0.09, 0.01)-0.03 (-0.10, 0.03)-0.09 (-0.18, -0.02)
(% change in HR for 1 ml/min per 1.73m2 greater negative acute effect)15.3% (12.9%, 17.9%)13.4% (10.8%, 16.1)11.3% (8.0%, 14.9%)5.6% (1.2%, 10.2%)
% change in HR for 0.75 ml/min per 1.73m2 per year greater treatment effect on chronic slope-19.5% (-23.1%, -15.9%)-22.6% (-26.6%, -18.8)-22.8% (-27.6%,-18.0%)-14.2% (-20.0%, -7.1%)
Trial-level R20.93 (0.84, 0.98)0.94 (0.85, 0.99)0.95 (0.78, 1.00)0.91 (0.49, 0.99)

KFRT: Kidney Failure with Renal Replacement Therapy


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