Original Article

Ann Lab Med 2022; 42(2): 178-187

Published online March 1, 2022

Copyright © Korean Society for Laboratory Medicine.

Biomarker Rule-in or Rule-out in Patients With Acute Diseases for Validation of Acute Kidney Injury in the Emergency Department (BRAVA): A Multicenter Study Evaluating Urinary TIMP-2/IGFBP7

Hyun Suk Yang, M.D., Ph.D.1 , Mina Hur, M.D., Ph.D.2 , Kyeong Ryong Lee, M.D., Ph.D.3 , Hanah Kim, M.D., Ph.D.2 , Hahn Young Kim, M.D., Ph.D.4 , Jong Won Kim, M.D., Ph.D.3 , Mui Teng Chua, M.D.5 , Win Sen Kuan, M.D.5 , Horng Ruey Chua, M.D.6 , Chagriya Kitiyakara, M.D.7 , Phatthranit Phattharapornjaroen, M.D.8 , Anchalee Chittamma, Ph.D.9 , Thiyapha Werayachankul, M.Sc.10,11 , Urmila Anandh, M.D.12 , Sanjeeva Herath, M.B., Ch.B.13 , Zoltan Endre, M.D., Ph.D.13 , Andrea Rita Horvath, M.D., Ph.D.14 , Paola Antonini, M.D.15 , and Salvatore Di Somma, M.D., Ph.D.15,16 on behalf of the GREAT Network

1Departments of Cardiovascular Medicine, 2Laboratory Medicine, 3Emergency Medicine, and 4Neurology, Konkuk University School of Medicine, Seoul, Korea; 5Department of Emergency Medicine, Division of Nephrology, 6Department of Medicine, National University Hospital, National University Health System, Singapore; 7Departments of Medicine, 8Emergency Medicine, 9Pathology, and 10Section of Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 11Section of Pharmaceutical Care, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand; 12Department of Nephrology, Yashoda Hospital, Secunderabad, India; 13Department of Nephrology, 14New South Wales Health Pathology, Department of Chemical Pathology, Prince of Wales Hospital, Sydney, Australia; 15GREAT Network Italy, 16Department of Medical-Surgery Sciences and Translational Medicine, University of Rome La Sapienza, Rome, Italy

Correspondence to: Mina Hur, M.D., Ph.D.
Department of Laboratory Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea
Tel: +82-2-2030-5581

Salvatore Di Somma, M.D., Ph.D.
Department of Medical-Surgery Sciences and Translational Medicine, University La Sapienza Rome, Sant’Andrea Hospital, Via di Grottarossa 1035/1039, 00189 Rome, Italy
Tel: +39-0633775581
Fax: +39-0633775890

Received: May 16, 2021; Revised: August 7, 2021; Accepted: September 13, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background: Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED.
Methods: This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses.
Results: Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P<0.05). The T0 NephroCheck value predicted 30-day mortality (AUC, 0.68; P<0.001).
Conclusions: NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Keywords: Acute kidney injury, Mortality, Emergency department, TIMP-2/IGFBP7, NephroCheck