title: Evaluation of urinary tissue inhibitor of metalloproteinase-2 in acute kidney injury: a prospective observational study.
abstract: BACKGROUND
  Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an emerging acute kidney injury (AKI) biomarker. We evaluated the performance of urinary TIMP-2 in an adult mixed ICU by comparison with other biomarkers that reflect several different pathways of AKI.
  
  
  METHODS
  In this study, we prospectively enrolled 98 adult critically ill patients who had been admitted to the adult mixed ICU. Urinary TIMP-2 and N-acetyl-β-D-glucosaminidase (NAG) and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and erythropoietin (EPO) were measured on ICU admission. We evaluated these biomarkers' capability of detecting AKI and its severity as determined by using the Kidney Disease Improving Global Outcomes serum creatinine criteria, as well as its capacity to predict in-hospital mortality. The impact of sepsis, the leading cause of AKI in ICUs, was also evaluated.
  
  
  RESULTS
  We found AKI in 42 patients (42.9%). All biomarkers were significantly higher in AKI than in non-AKI. In total, 27 patients (27.6%) developed severe AKI. Urinary TIMP-2 was able to distinguish severe AKI from non-severe AKI with an area under the receiver operating characteristic curve (AUC-ROC) of 0.80 (95% confidence interval, 0.66 to 0.90). A total of 41 cases (41.8%) were complicated with sepsis. Although plasma NGAL and IL-6 were increased by sepsis, urinary TIMP-2 and NAG were increased not by sepsis, but by the presence of severe AKI. Plasma EPO was increased only by septic AKI. In-hospital mortality was 15.3% in this cohort. Urinary TIMP-2 and NAG, and plasma NGAL, were significantly higher in non-survivors than in survivors, although plasma IL-6 and EPO were not. Among the biomarkers, only urinary TIMP-2 was able to predict in-hospital mortality significantly better than serum creatinine.
  
  
  CONCLUSIONS
  Urinary TIMP-2 can detect severe AKI with performance equivalent to plasma NGAL and urinary NAG, with an AUC-ROC value higher than 0.80. Furthermore, urinary TIMP-2 was associated with mortality. Sepsis appeared to have only a limited impact on urinary TIMP-2, in contrast to plasma NGAL.
authors.affiliation: Department of Nephrology and Endocrinology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. teyamashita-tky@umin.ac.jp.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Emergency and Critical Care Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. kdoi-tky@umin.ac.jp.
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.affiliation: 22nd Century Medical and Research Center, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. yhamasaki-tky@umin.ac.jp.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.affiliation: Department of Emergency and Critical Care Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. matsubarat-ort@h.u-tokyo.ac.jp.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Emergency and Critical Care Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. ishiit-eme@h.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Emergency and Critical Care Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. yahagin-eme@h.u-tokyo.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Department of Nephrology and Endocrinology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. mnangaku-tky@umin.ac.jp.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Department of Nephrology and Endocrinology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. noiri-tky@umin.ac.jp.|Japan Science and Technology Agency/Japan International Cooperation Agency (JST/JICA), Science and Technology Research Partnership for Sustainable Development (SATREPS), 7 Gobancho, Chiyoda-ku, Tokyo, 102-0076, Japan. noiri-tky@umin.ac.jp.
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D058186:Acute Kidney Injury / Q000175:diagnosis / Q000401:mortality* / Q000652:urine*; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D005260:Female; D017052:Hospital Mortality / Q000639:trends*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000652:urine*
chemical_list: D015415:Biomarkers; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2