title: Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study.
abstract: OBJECTIVE
  CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.
  
  
  METHODS
  Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, andN-acetyl-β-d-glucosaminidase were measured in urine of a subset of CRIC participants (n=2466). We used Cox proportional hazards regression to examine associations between these biomarkers indexed to urinary creatinine (Cr) and (1) HF, (2) a composite of atherosclerotic CVD events (myocardial infarction, ischemic stroke, or peripheral artery disease), and (3) all-cause death.
  
  
  RESULTS
  At baseline, mean age of study participants was 59.5±10.8 years, 46% were women, and 34% had a self-reported history of any CVD. Median follow-up was 6.5 (interquartile range, 5.6-6.8) years. A total of 333 HF events, 282 atherosclerotic CVD events, and 440 deaths were observed during a median follow-up of 6.5 (interquartile range, 5.6-6.8) years. Those in the highest two quintiles of KIM-1/Cr levels had a higher risk of HF relative to the lowest quintile (quintile 5 versus quintile 1 adjusted hazard ratio [aHR] of 1.73 [95% confidence interval, 1.05 to 2.85]).N-acetyl-β-d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death.
  
  
  CONCLUSIONS
  Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.
authors.affiliation: Division of Nephrology, University of California, San Francisco, San Francisco, California.
authors.forename: Meyeon
authors.initials: M
authors.lastname: Park
authors.affiliation: Division of Nephrology, University of California, San Francisco, San Francisco, California.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Go
authors.affiliation: Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Harold I
authors.initials: HI
authors.lastname: Feldman
authors.affiliation: Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Theodore
authors.initials: T
authors.lastname: Mifflin
authors.affiliation: Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sushrut S
authors.initials: SS
authors.lastname: Waikar
authors.affiliation: Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Sabbisetti
authors.affiliation: Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Kimmel
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: John W
authors.initials: JW
authors.lastname: Kusek
authors.affiliation: Division of Nephrology and Hypertension, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Mahboob
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Division of Nephrology and Hypertension, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Schelling
authors.affiliation: Section of Preventive Medicine and Epidemiology, Boston University, Boston, Massachusetts.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: Division of Nephrology, University of California, San Francisco, San Francisco, California.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine*; D000368:Aged; D015415:Biomarkers / Q000652:urine; D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000401:mortality*; D002423:Cause of Death; D050556:Fatty Acid-Binding Proteins / Q000652:urine*; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000032:analysis*; D006801:Humans; D000071068:Lipocalin-2 / Q000652:urine*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000401:mortality* / Q000652:urine*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D016482:Urinalysis
chemical_list: D015415:Biomarkers; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D000118:Acetylglucosaminidase
keywords: Acetylglucosaminidase; Aged; Atherosclerosis; Biomarkers; FABP1 protein, human; Fatty Acid-Binding Proteins; Female; Follow-Up Studies; Humans; Lipocalin-2; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Renal Insufficiency, Chronic; Self Report; Stroke; cardiovascular disease; chronic kidney disease; creatinine; heart failure; mortality risk; risk factors