title: Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis.
abstract: BACKGROUND
  The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated.
  
  
  METHODS
  Individual patient-level meta-analysis.
  
  
  METHODS
  Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system [RAS] blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels.
  
  
  METHODS
  Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome.
  
  
  METHODS
  9-month change in proteinuria.
  
  
  RESULTS
  Doubling of serum creatinine level, end-stage renal disease, or death.
  
  
  RESULTS
  Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, -19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32).
  
  
  CONCLUSIONS
  Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events.
  
  
  CONCLUSIONS
  Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.
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: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Hasi
authors.initials: H
authors.lastname: Mondal
authors.affiliation: Division of Epidemiology, 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: Taylor
authors.initials: T
authors.lastname: Masaschi
authors.affiliation: Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Renal, Dialysis & Transplant Unit, University of Bari, Bari, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Schena
authors.affiliation: National Fukuoka Higashi Medical Center, Koga City, Fukuoka, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Katafuchi
authors.affiliation: The Glomerular Kidney Disease Center, Columbia University College of Physicians and Surgeons, New York, NY.
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Appel
authors.affiliation: Department of Nephrology, AZ Delta, Roeselare, Belgium.
authors.forename: Bart D
authors.initials: BD
authors.lastname: Maes
authors.affiliation: Department of Medicine, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Li
authors.affiliation: Nephrology, Department of Medicine, Hospital Universitario 12 de Octubre, Complutense University, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Praga
authors.affiliation: Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Del Vecchio
authors.affiliation: Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy.
authors.forename: Simeone
authors.initials: S
authors.lastname: Andrulli
authors.affiliation: Renal, Dialysis & Transplant Unit, University of Bari, Bari, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Manno
authors.affiliation: Nephrology, Department of Medicine, Hospital Universitario 12 de Octubre, Complutense University, Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gutierrez
authors.affiliation: Pharmalink AB, Stockholm, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Mercer
authors.affiliation: KJC Statistics Ltd and University of Sheffield, Sheffield, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Carroll
authors.affiliation: Department of Biostatistics and Center for Evidence Based Medicine, Brown University School of Public Health, Providence, RI.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Schmid
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
mesh_terms: D015415:Biomarkers / Q000652:urine; D018450:Disease Progression; D005922:Glomerulonephritis, IGA / Q000652:urine*; D006801:Humans; D011507:Proteinuria / Q000652:urine*; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors
chemical_list: D015415:Biomarkers
keywords: IgA nephropathy (IgAN); Proteinuria; clinical end point; disease progression; end-stage renal disease (ESRD); glomerulonephritis; kidney disease; meta-analysis; prognostic marker; surrogate endpoint; urine protein