Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression
Greene T., Collier W., Haaland B., Zhang C., Badve SV., Caravaca-Fontán F., Del Vecchio L., Floege J., Hannedouche T., Imai E., Jafar TH., Lewis JB., Li PKT., Locatelli F., Maes BD., Neuen BL., Perrone RD., Schena FP., Toto R., Wanner C., Woodward M., Van Zuilen A., Heerspink HJL., Inker LA., Estacio RO., Hanratty R., Chalmers J., Parving HH., Appel GB., Canetta P., Brenner BM., Barrett B., Neal B., Mahafey KW., Neuen B., Johnson D., Perkovic V., Mahaffey KW., Jardine M., Fervenza F., Von Eynatten M., Goicoechea M., Verde E., Verdalles U., Arroyo D., Chapman A., Torres V., Yu A., Brosnahan G., Kam-Tao Li P., Chow KM., Szeto CC., Leung CB., Xie D., Hou FF., Dwyer J., Pohl M., Raz I., Hunsicker L., Becker GJ., Ihle BU., Kincaid-Smith PS., Kamper A., Katafuchi R., Vanacker A., Malfait T., Maschio G., Van Kruijsdijk R., Vernooij RWM., Kobayashi F., Makino H., Chan JCN., Passerini P., Andrulli S., Pozzi C., Casartelli D., Praga M., Trujillo H., Cavero T., Sevillano A., Ruggenenti P., Perna A., Carrara F., Gherardi G., Keane WF., Manno C., Haynes R., Herrington WG., Baigent C., Landray M., Rauen T., Seikrit C., Wied S., De Zeeuw D., De Jong PE., Saddelli M., Zucchelli P.
BackgroundSlope 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).MethodsWe 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.ResultsTreatment 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.ConclusionsTreatment 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.