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

      1 , 2 , 3 , 4 , 5 , 6 ,   7 , 8 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 32 , 37 , 38 , , 39

      Critical Care

      BioMed Central

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          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 G 1 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.

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          Most cited references 13

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          Pathophysiology of ischemic acute kidney injury.

          Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.
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            Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells.

            Cell cycle progression is regulated by a wide variety of external factors, amongst them are growth factors and extracellular matrix factors. During the last decades evidence has been obtained that reactive oxygen species (ROS) may also play an important role in cell cycle progression. ROS may be generated by external and internal factors. In this overview we describe briefly the generation of ROS and their effects on processes that have been demonstrated to play an essential role in cell cycle progression, including such systems as signal transduction cascades, protein ubiquitination and degradation, and the cytoskeleton. These different effects of ROS influence cell cycle progression dependent upon the amount and duration of ROS exposure. Activation of growth factor stimulated signaling cascades by low levels of ROS result in increased cell cycle progression, or, in case of prolonged exposure, to a differentiation like growth arrest. From many studies it seems clear that the cyclin kinase inhibitor protein p21 plays a prominent role, leading to cell cycle arrest at higher but not directly lethal levels of ROS. Dependent upon the nature of p21 induction, the cell cycle arrest may be transient, coupled to repair processes, or permanent. At high concentrations of ROS all of the above processes are activated, in combination with enhanced damage to the building blocks of the cell, leading to apoptosis or even necrosis.
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              Long-term risk of mortality and acute kidney injury during hospitalization after major surgery.

              To determine the relationship between long-term mortality and acute kidney injury (AKI) during hospitalization after major surgery. AKI is associated with a risk of short-term mortality that is proportional to its severity; however the long-term survival of patients with AKI is poorly studied. This is a retrospective cohort study of 10,518 patients with no history of chronic kidney disease who were discharged after a major surgery between 1992 and 2002. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires at least a 50% increase in serum creatinine (sCr) and stratifies patients into 3 severity stages: risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed using a risk-adjusted Cox proportional hazards regression model. In the risk-adjusted model, survival was worse among patients with AKI and was proportional to its severity with an adjusted hazard ratio of 1.18 (95% confidence interval [CI], 1.08-1.29) for the RIFLE-Risk class and 1.57 (95% CI, 1.40-1.75) for the RIFLE-Failure class, compared with patients without AKI (P < 0.001). Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.20 (95% CI, 1.10-1.31) compared with patients without AKI (P < 0.001). In a large single-center cohort of patients discharged after major surgery, AKI with even small changes in sCr level during hospitalization was associated with an independent long-term risk of death.

                Author and article information

                Crit Care
                Crit Care
                Critical Care
                BioMed Central
                6 February 2013
                : 17
                : 1
                : R25
                [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
                Copyright © 2013 Kashani et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


                Emergency medicine & Trauma


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