Urinary Biomarkers of Tubular Damage Are Associated with Mortality but Not Cardiovascular Risk among Systolic Blood Pressure Intervention Trial Participants with Chronic Kidney Disease

Am J Nephrol. 2019;49(5):346-355. doi: 10.1159/000499531. Epub 2019 Apr 2.


Background: Kidney tubulointerstitial fibrosis on biopsy is a strong predictor of chronic kidney disease (CKD) progression, and CKD is associated with elevated risk of cardiovascular disease (CVD). Tubular health is poorly quantified by traditional kidney function measures, including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of tubular injury, inflammation, and repair would be associated with higher risk of CVD and mortality in persons with CKD.

Methods: We measured urinary concentrations of interleukin-18 (IL-18), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and chitinase-3-like protein-1 (YKL-40) at baseline among 2,377 participants of the Systolic Blood Pressure Intervention Trial who had an eGFR < 60 mL/min/1.73 m2. We used Cox proportional hazards models to evaluate biomarker associations with CVD events and all-cause mortality.

Results: At baseline, the mean age of participants was 72 ± 9 years, and eGFR was 48 ± 11 mL/min/1.73 m2. Over a median follow-up of 3.8 years, 305 CVD events (3.6% per year) and 233 all-cause deaths (2.6% per year) occurred. After multivariable adjustment including eGFR, albuminuria, and urinary creatinine, none of the biomarkers showed statistically significant associations with CVD risk. Urinary IL-18 (hazard ratio [HR] per 2-fold higher value, 1.14; 95% CI 1.01-1.29) and YKL-40 (HR per 2-fold higher value, 1.08; 95% CI 1.02-1.14) concentrations were each incrementally associated with higher mortality risk. Associations were similar when stratified by randomized blood pressure arm.

Conclusions: Among hypertensive trial participants with CKD, higher urinary IL-18 and YKL-40 were associated with higher risk of mortality, but not CVD.

Keywords: Chitinase-3-like protein-1; Interleukin-18; Kidney injury; Urinary biomarkers.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Albuminuria / diagnosis*
  • Albuminuria / immunology
  • Albuminuria / pathology
  • Albuminuria / urine
  • Antihypertensive Agents / administration & dosage
  • Biomarkers / urine
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Blood Pressure Determination / standards
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / etiology
  • Disease Progression
  • Female
  • Fibrosis
  • Glomerular Filtration Rate / physiology
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / physiopathology
  • Hypertension / urine
  • Kidney Tubules / immunology
  • Kidney Tubules / pathology*
  • Male
  • Prognosis
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / immunology
  • Renal Insufficiency, Chronic / mortality*
  • Renal Insufficiency, Chronic / urine


  • Antihypertensive Agents
  • Biomarkers