title: GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.
abstract: BACKGROUND
  There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials.
  
  
  METHODS
  Diagnostic test study.
  
  
  METHODS
  9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types.
  
  
  METHODS
  Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit.
  
  
  METHODS
  The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration.
  
  
  RESULTS
  Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects.
  
  
  CONCLUSIONS
  Limited variety of interventions tested and low statistical power for many CKD clinical trials.
  
  
  CONCLUSIONS
  These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline.
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address: linker@tuftsmedicalcenter.org.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Inker
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.affiliation: The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center and Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA.
authors.forename: Hasi
authors.initials: H
authors.lastname: Mondal
authors.affiliation: Department of Biostatistics, Brown University School of Public Health, Providence, RI.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Schmid
authors.affiliation: The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center and Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA.
authors.forename: Hocine
authors.initials: H
authors.lastname: Tighiouart
authors.affiliation: The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center and Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA.
authors.forename: Farzad
authors.initials: F
authors.lastname: Noubary
authors.affiliation: Department of Epidemiology, Johns Hopkins, Baltimore, MD.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
mesh_terms: D023381:Endpoint Determination / Q000379:methods* / Q000592:standards; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis* / Q000503:physiopathology / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards; D016896:Treatment Outcome
keywords: Kidney end point; chronic kidney disease (CKD); eGFR trajectory; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR) decline; kidney disease outcome; kidney disease progression; renal end point; renal function; surrogate end point; treatment effect