Evaluation of Variation in the Performance of GFR Slope as a Surrogate End Point for Kidney Failure in Clinical Trials that Differ by Severity of CKD
Collier W., Inker LA., Haaland B., Appel GB., Badve SV., Caravaca-Fontán F., Chalmers J., Floege J., Goicoechea M., Imai E., Jafar TH., Lewis JB., Li PKT., Locatelli F., Maes BD., Neuen BL., Perrone RD., Remuzzi G., Schena FP., Wanner C., Heerspink HJL., Greene T., Estacio RO., Woodward M., Parving HH., Canetta P., Brenner BM., Barrett B., Neal B., Perkovic V., Mahaffey KW., Johnson D., Jardine M., Fervenza F., von Eynatten M., Verde E., Verdalles U., Arroyo D., Chapman A., Torres V., Yu A., Brosnahan G., Hannedouche T., Chow KM., Szeto CC., Leung CB., Xie D., Hou FF., Dwyer J., Pohl M., Raz I., Hunsicker L., Becker GJ., Katafuchi R., Vanacker A., Malfait T., Maschio G., van den Brand J., Wetzels JFM., Blankestijn P., van Zuilen A., Imai E., Kobayashi F., Makino H., Chan JCN., Passerini P., Del Vecchio L., Locatelli F., 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., Toto RD., de Zeeuw D., de Jong PE., Saddelli M., Zucchelli P.
Background The GFR slope has been evaluated as a surrogate end point for kidney failure in meta-analyses on a broad collection of randomized controlled trials (RCTs) in CKD. These analyses evaluate how accurately a treatment effect on GFR slope predicts a treatment effect on kidney failure. We sought to determine whether severity of CKD in the patient population modifies the performance of GFR slope. Methods We performed Bayesian meta-regression analyses on 66 CKD RCTs to evaluate associations between effects on GFR slope (the chronic slope and the total slope over 3 years, expressed as mean differences in ml/min per 1.73 m2/yr) and those of the clinical end point (doubling of serum creatinine, GFR,15 ml/min per 1.73 m2, or kidney failure, expressed as a log-hazard ratio), where models allow interaction with variables defining disease severity. We evaluated three measures (baseline GFR in 10 ml/min per 1.73 m2, baseline urine albumin-to-creatinine ratio [UACR] per doubling in mg/g, and CKD progression rate defined as the control arm chronic slope, in ml/min per 1.73 m2/yr) and defined strong evidence for modification when 95% posterior credible intervals for interaction terms excluded zero. Results There was no evidence for modification by disease severity when evaluating 3-year total slope (95% credible intervals for the interaction slope: baseline GFR [20.05 to 0.03]; baseline UACR [20.02 to 0.04]; CKD progression rate [20.07 to 0.02]). There was strong evidence for modification in evaluations of chronic slope (95% credible intervals: baseline GFR [0.02 to 0.11]; baseline UACR [20.11 to 20.02]; CKD progression rate [0.01 to 0.15]). Conclusions These analyses indicate consistency of the performance of total slope over 3 years, which provides further evidence for its validity as a surrogate end point in RCTs representing varied CKD populations.