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. 2025 May 1;20(5):632-641.
doi: 10.2215/CJN.0000000662. Epub 2025 Apr 15.

Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression

Tom Greene  1 , Willem Collier  1   2 , Benjamin Haaland  1   3 , Chong Zhang  1 , Sunil V Badve  4 , Fernando Caravaca-Fontán  5 , Lucia Del Vecchio  6 , Jürgen Floege  7 , Thierry Hannedouche  8 , Enyu Imai  9 , Tazeen H Jafar  10 , Julia B Lewis  11 , Philip K T Li  12 , Francesco Locatelli  13 , Bart D Maes  14 , Brendon L Neuen  4 , Ronald D Perrone  15 , Francesco P Schena  16 , Robert Toto  17 , Christoph Wanner  18 , Mark Woodward  4   19 , Arjan van Zuilen  20 , Hiddo J L Heerspink  21 , Lesley A Inker  15 ; CKD-EPI Clinical Trials Consortium
Collaborators, Affiliations

Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression

Tom Greene et al. Clin J Am Soc Nephrol. .

Abstract

Key Points:

  1. Acute effects impact the clinical endpoint independently of treatment effects on the chronic slope.

  2. Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials.

Background: Slope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs).

Methods: We estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes.

Results: Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%–15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years.

Conclusions: Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

Keywords: GFR; clinical trial.

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C258.

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