TY - JOUR
T1 - Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression
AU - CKD-EPI Clinical Trials Consortium
AU - Greene, Tom
AU - Collier, Willem
AU - Haaland, Benjamin
AU - Zhang, Chong
AU - Badve, Sunil V.
AU - Caravaca-Fontán, Fernando
AU - Del Vecchio, Lucia
AU - Floege, Jürgen
AU - Hannedouche, Thierry
AU - Imai, Enyu
AU - Jafar, Tazeen H.
AU - Lewis, Julia B.
AU - Li, Philip K.T.
AU - Locatelli, Francesco
AU - Maes, Bart D.
AU - Neuen, Brendon
AU - Perrone, Ronald D.
AU - Schena, Francesco P.
AU - Toto, Robert
AU - Wanner, Christoph
AU - Woodward, Mark
AU - Van Zuilen, Arjan
AU - Heerspink, Hiddo J.L.
AU - Inker, Lesley A.
AU - Estacio, Raymond O.
AU - Hanratty, Rebecca
AU - Chalmers, John
AU - Parving, Hans Henry
AU - Appel, Gerald B.
AU - Canetta, Pietro
AU - Brenner, Barry M.
AU - Barrett, Brendan
AU - Neal, Bruce
AU - Mahafey, Kenneth W.
AU - Neuen, Brendon
AU - Johnson, David
AU - Perkovic, Vlado
AU - Mahaffey, Kenneth W.
AU - Jardine, Meg
AU - Fervenza, Fernando
AU - Von Eynatten, Maximilian
AU - Goicoechea, Marian
AU - Verde, Eduardo
AU - Verdalles, Ursula
AU - Arroyo, David
AU - Chapman, Arlene
AU - Torres, Vicente
AU - Xie, Di
AU - De Zeeuw, Dick
AU - De Jong, Paul E.
N1 - Publisher Copyright:
Copyright © 2025 by the American Society of Nephrology.
PY - 2025/5
Y1 - 2025/5
N2 - 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.
AB - 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.
KW - clinical trial
KW - GFR
UR - https://www.scopus.com/pages/publications/105004308638
U2 - 10.2215/CJN.0000000662
DO - 10.2215/CJN.0000000662
M3 - Article
C2 - 40237639
AN - SCOPUS:105004308638
SN - 1555-9041
VL - 20
SP - 632
EP - 641
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 5
ER -