Urine Markers of Kidney Tubule Cell Injury and Kidney Function Decline in SPRINT Trial Participants with CKD

Clin J Am Soc Nephrol. 2020 Mar 6;15(3):349-358. doi: 10.2215/CJN.02780319. Epub 2020 Feb 28.


Background and objectives: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT).

Design, setting, participants, & measurements: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR.

Results: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT.

Conclusions: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

Keywords: acute kidney injury; albuminuria; blood pressure; chemokine CCL2; chitinase-3-like protein 1; chronic kidney disease; chronic renal insufficiency; confidence intervals; follow-up studies; glomerular filtration rate; hepatitis A virus cellular receptor 1; human CCL2 protein; human CHI3L1 protein; human HAVCR1 protein; human LCN2 protein; humans; inflammation; interleukin-18; kidney function decline; kidney transplantation; kidney tubules; lipocalin-2; male; proportional hazards models; tubule injury biomarkers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Albuminuria / diagnosis
  • Albuminuria / etiology
  • Albuminuria / physiopathology
  • Albuminuria / urine*
  • Biomarkers / urine
  • Chemokine CCL2 / urine*
  • Chitinase-3-Like Protein 1 / urine*
  • Disease Progression
  • Female
  • Glomerular Filtration Rate*
  • Hepatitis A Virus Cellular Receptor 1 / metabolism*
  • Humans
  • Hypertension / complications
  • Interleukin-18 / urine*
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Kidney Tubules / physiopathology
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Randomized Controlled Trials as Topic
  • Renal Insufficiency, Chronic / diagnosis
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / physiopathology
  • Renal Insufficiency, Chronic / urine*
  • Risk Assessment
  • Risk Factors
  • Urinalysis


  • Biomarkers
  • CCL2 protein, human
  • CHI3L1 protein, human
  • Chemokine CCL2
  • Chitinase-3-Like Protein 1
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • IL18 protein, human
  • Interleukin-18