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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Kianoush Kashani1, Ali Al-Khafaji2, Thomas Ardiles3, Antonio Artigas4, Sean M Bagshaw5, Max Bell6, Azra Bihorac7, Robert Birkhahn8, Cynthia M Cely9, Lakhmir S Chawla10, Danielle L Davison10, Thorsten Feldkamp11, Lui G Forni12, Michelle Ng Gong13, Kyle J Gunnerson14, Michael Haase15, James Hackett16, Patrick M Honore17, Eric AJ Hoste18, Olivier Joannes-Boyau19, Michael Joannidis20, Patrick Kim21, Jay L Koyner22, Daniel T Laskowitz23, Matthew E Lissauer24, Gernot Marx25, Peter A McCullough26, Scott Mullaney27, Marlies Ostermann28, Thomas Rimmelé29, Nathan I Shapiro30, Andrew D Shaw31, Jing Shi32, Amy M Sprague33, Jean-Louis Vincent34, Christophe Vinsonneau35, Ludwig Wagner36, Michael G Walker32, R Gentry Wilkerson37, Kai Zacharowski38 and John A Kellum39*

Author Affiliations

1 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

2 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, USA

3 Department of Critical Care, Maricopa Integrated Health System, 2601 E Roosevelt Street, Phoenix, AZ 85008, USA

4 Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Parc Tauli s/n, Sabadell, Barcelona 8208, Spain

5 Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C. Mackenzie Centre, 8440 112 Street NW, Edmonton, Alberta T6G 2B7, Canada

6 Department of Anesthesia and Intensive Care Medicine, Karolinska University Hospital, Karolinskavagen, Solna, Stockholm SE-171 76, Sweden

7 Department of Anesthesiology, University of Florida, 1660 SW Archer Road, Gainesville, FL 32611, USA

8 Department of Emergency Medicine, New York Methodist Hospital, 506 6th Street, Brooklyn, NY 11215, USA

9 Bruce W. Carter Department of Veterans Affairs Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA

10 Department of Anesthesiology and Critical Care Medicine, George Washington University Medical Center, 900 23rd Street NW, Washington, DC 20037, USA

11 Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, Essen, 45147, Germany

12 Intensive Care Medicine, Western Sussex Hospitals Trust, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK

13 Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA

14 Departments of Anesthesiology and Emergency Medicine, Virginia Commonwealth University Medical Center, 1200 East Broad Street, Richmond, VA 23298, USA

15 Department of Nephrology, Otto-von-Guericke-Universitat Magdeburg, Leipziger Strasse 44, Magdeburg, 39120, Germany

16 Hackett & Associates, Inc., 14419 Rancho Del Prado Trail, San Diego, CA 92127, USA

17 ICU Department, Universitair Ziekenhuis Brussel (UZB), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, Brussels 1090, Belgium

18 Intensive Care Unit, Ghent University Hospital, De Pintelaan 185, Ghent, 9000, Belgium

19 Anaesthesiology and Critical Care Department 2, University Hospital of Bordeaux, 1 Avenue De Magellon, Pessac, 33600, France

20 Department of Internal Medicine, ICU, Medical University Innsbruck, Anichstrasse 35, Innsbruck, A-6020, Austria

21 Traumatology, Surgical Critical Care and Emergency Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

22 Department of Medicine, University of Chicago, 6030 South Ellis Avenue, Chicago, IL 60637, USA

23 Department of Medicine, Duke University Medical Center, 2301 Erwin Road, Durham, NC 27710, USA

24 Department of Surgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA

25 Department of Intensive Care, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, Aachen, 52074, Germany

26 Department of Medicine, St John Providence Health System, Providence Hospitals and Medical Centers, Providence Park Heart Institute, 47601 Grand River Avenue, Novi, MI 48374, USA

27 Department of Medicine, University of California San Diego, 200 West Arbor Drive, San Diego, CA 92103, USA

28 Department of Critical Care, King's College London, Guy's and St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK

29 Service D'Anesthésie Réanimation, Edouard Herriot Hospital, Hospices civils de Lyon, 5 Place d'Arsonval, Lyon, 69003, France

30 Department of Emergency Medicine, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, MA 2215, USA

31 Department of Anesthesia, Duke University Medical Center/Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705, USA

32 Walker Biosciences, 6321 Allston Street, Carlsbad, CA 92009, USA

33 Department of Medicine, Joseph M. Still Research Foundation, 3675 J. Dewey Gray Circle, Augusta, GA 30909, USA

34 Department of Intensive Care, Erasme University Hospital, Route De Lennik 808, Brussels, 1070, Belgium

35 Department of Intensive Care, Hospital Marc Jacquet, 2 Rue Freteau De Peny, Melun, 77011, France

36 Department of Internal Medicine, Medical University of Vienna, Spitalgasse 23, Vienna 1090, Austria

37 Department of Emergency Medicine, Tampa General Hospital, 1 Davis Boulevard, Tampa, FL 33606, USA

38 Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, Germany

39 Department of Critical Care Medicine, University of Pittsburgh, School of Medicine, 3550 Terrace Street, Pittsburgh, PA 15213, USA

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Critical Care 2013, 17:R25  doi:10.1186/cc12503

See related commentary by Ronco et al.,

Published: 6 February 2013



Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.


We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.


Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.


Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.

Trial registration number NCT01209169.