Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study

Clin J Am Soc Nephrol. 2017 May 8;12(5):761-771. doi: 10.2215/CJN.08560816. Epub 2017 Mar 2.


Background and objectives: 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.

Design, setting, participants, & measurements: Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, and N-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.

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.

Publication types

  • Multicenter Study

MeSH terms

  • Acetylglucosaminidase / urine*
  • Aged
  • Biomarkers / urine
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / mortality*
  • Cause of Death
  • Fatty Acid-Binding Proteins / urine*
  • Female
  • Hepatitis A Virus Cellular Receptor 1 / analysis*
  • Humans
  • Lipocalin-2 / urine*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Prospective Studies
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / mortality*
  • Renal Insufficiency, Chronic / urine*
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • United States / epidemiology
  • Urinalysis


  • Biomarkers
  • FABP1 protein, human
  • Fatty Acid-Binding Proteins
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • LCN2 protein, human
  • Lipocalin-2
  • Acetylglucosaminidase