Association of Renal Stress/Damage and Filtration Biomarkers with Subsequent AKI during Hospitalization among Patients Presenting to the Emergency Department

Clin J Am Soc Nephrol. 2016 Jun 6;11(6):938-46. doi: 10.2215/CJN.10551015. Epub 2016 Mar 29.


Background and objectives: Emergency departments (EDs) have a growing role in hospital admissions, but few studies address AKI biomarkers in the ED.

Design, setting, participants, & measurements: Patients admitted to the internal medicine service were enrolled during initial workup in the ED at Robert-Bosch-Hospital, Stuttgart, Germany. Daily serum creatinine (sCr) and urine output (UO) were recorded for AKI classification by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Cystatin C, kidney injury molecule-1, liver-type fatty acid-binding protein, and neutrophil gelatinase-associated lipocalin were measured in blood and urine, and IL-18, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and [TIMP-2]⋅[IGFBP7] were measured in urine collected at enrollment, after 6 hours, and the following morning. Association between these biomarkers and the end point of moderate-severe AKI (KDIGO stage 2-3) occurring within 12 hours of each sample collection was examined using generalized estimating equation logistic regression. Performance for prediction of the AKI end point using two previously validated [TIMP-2]-[IGFBP7] cutoffs was also tested.

Results: Of 400 enrolled patients, 298 had sufficient sCr and UO data for classification by KDIGO AKI criteria: AKI stage 2 developed in 37 patients and AKI stage 3 in nine patients. All urinary biomarkers, sCr, and plasma cystatin C had statistically significant (P<0.05) odds ratios (ORs) for the AKI end point. In a multivariable model of the urine biomarkers and sCr, only [TIMP-2]⋅[IGFBP7] and sCr had statistically significant ORs. Compared with [TIMP-2]⋅[IGFBP7]<0.3 (ng/ml)(2)/1000, values between 0.3 and 2.0 (ng/ml)(2)/1000 indicated 2.5 (95% confidence interval [95% CI], 1.1 to 5.2) times the odds for the AKI end point and values >2.0 (ng/ml)(2)/1000 indicated 11.0 (95% CI, 4.4 to 26.9) times the odds. Addition of [TIMP-2]⋅[IGFBP7] to a clinical model significantly improved area under the receiver-operating characteristic curve from 0.67 (95% CI, 0.61 to 0.78) to 0.77 (95% CI, 0.72 to 0.86) (P<0.001); however, including both markers in the model was not significantly different from including either marker alone.

Conclusions: Urinary [TIMP-2]⋅[IGFBP7] with pre-established cutoffs provides valuable information about risk for imminent AKI in the ED that is complementary to sCr and clinical risk factors.

Keywords: acute kidney injury; biomarkers; emergency departments; emergency service, hospital; humans; insulin like-growth factor binding protein-7; kidney risk factors; tissue inhibitor of metalloproteinase-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / blood*
  • Acute Kidney Injury / diagnosis*
  • Acute Kidney Injury / urine
  • Aged
  • Aged, 80 and over
  • Area Under Curve
  • Biomarkers / blood
  • Creatinine / blood*
  • Cystatin C / blood
  • Cystatin C / urine
  • Emergency Service, Hospital
  • Fatty Acid-Binding Proteins / blood
  • Fatty Acid-Binding Proteins / urine
  • Female
  • Hepatitis A Virus Cellular Receptor 1 / metabolism
  • Hospitalization
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / urine*
  • Interleukin-18 / urine
  • Lipocalin-2 / blood
  • Lipocalin-2 / urine
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • ROC Curve
  • Tissue Inhibitor of Metalloproteinase-2 / urine*
  • Urine


  • Biomarkers
  • Cystatin C
  • Fatty Acid-Binding Proteins
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • Insulin-Like Growth Factor Binding Proteins
  • Interleukin-18
  • LCN2 protein, human
  • Lipocalin-2
  • TIMP2 protein, human
  • insulin-like growth factor binding protein-related protein 1
  • Tissue Inhibitor of Metalloproteinase-2
  • Creatinine