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

被引：959

作者：

Kashani, Kianoush ^{[1
]}

Al-Khafaji, Ali ^{[2
]}

Ardiles, Thomas ^{[3
]}

Artigas, Antonio ^{[4
]}

Bagshaw, Sean M. ^{[5
]}

Bell, Max ^{[6
]}

Bihorac, Azra ^{[7
]}

Birkhahn, Robert ^{[8
]}

Cely, Cynthia M. ^{[9
]}

Chawla, Lakhmir S. ^{[10
]}

Davison, Danielle L. ^{[10
]}

Feldkamp, Thorsten ^{[11
]}

Forni, Lui G. ^{[12
]}

Gong, Michelle Ng ^{[13
]}

Gunnerson, Kyle J. ^{[14
,15
]}

Haase, Michael ^{[16
]}

Hackett, James ^{[17
]}

Honore, Patrick M. ^{[18
]}

Hoste, Eric A. J. ^{[19
]}

Joannes-Boyau, Olivier ^{[20
]}

Joannidis, Michael ^{[21
]}

Kim, Patrick ^{[22
]}

Koyner, Jay L. ^{[23
]}

Laskowitz, Daniel T. ^{[24
]}

Lissauer, Matthew E. ^{[25
]}

Marx, Gernot ^{[26
]}

McCullough, Peter A. ^{[27
]}

Mullaney, Scott ^{[28
]}

Ostermann, Marlies ^{[29
]}

Rimmele, Thomas ^{[30
]}

Shapiro, Nathan I. ^{[31
]}

Shaw, Andrew D. ^{[32
]}

Shi, Jing ^{[33
]}

Sprague, Amy M. ^{[34
]}

Vincent, Jean-Louis ^{[35
]}

Vinsonneau, Christophe ^{[36
]}

Wagner, Ludwig ^{[37
]}

Walker, Michael G. ^{[33
]}

Wilkerson, R. Gentry ^{[38
]}

Zacharowski, Kai ^{[39
]}

Kellum, John A. ^{[40
]}

机构：

[1] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN 55905 USA

[2] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Pittsburgh, PA 15213 USA

[3] Maricopa Integrated Hlth Syst, Dept Crit Care, Phoenix, AZ 85008 USA

[4] Autonomous Univ Barcelona, CIBER Enfermedades Respiratorias, Sabadell Hosp, Crit Care Ctr, Barcelona 8208, Spain

[5] Univ Alberta, Fac Med & Dent, Div Crit Care Med, Edmonton, AB T6G 2B7, Canada

[6] Karolinska Univ Hosp, Dept Anesthesia & Intens Care Med, SE-17176 Stockholm, Sweden

[7] Univ Florida, Dept Anesthesiol, Gainesville, FL 32611 USA

[8] New York Methodist Hosp, Dept Emergency Med, Brooklyn, NY 11215 USA

[9] Vet Affairs Med Ctr, Bruce W Carter Dept, Miami, FL 33125 USA

[10] George Washington Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, Washington, DC 20037 USA

[11] Univ Duisburg Essen, Univ Hosp Essen, Dept Nephrol, D-45147 Essen, Germany

[12] Western Sussex Hosp Trust, Worthing BN11 2DH, W Sussex, England

[13] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA

[14] Virginia Commonwealth Univ, Med Ctr, Dept Anesthesiol, Richmond, VA 23298 USA

[15] Virginia Commonwealth Univ, Med Ctr, Dept Emergency Med, Richmond, VA 23298 USA

[16] Otto Von Guericke Univ, Dept Nephrol, D-39120 Magdeburg, Germany

[17] Hackett & Associates Inc, San Diego, CA 92127 USA

[18] Vrije Univ Brussel, Univ Ziekenhuis Brussel, ICU Dept, B-1090 Brussels, Belgium

[19] Ghent Univ Hosp, Intens Care Unit, B-9000 Ghent, Belgium

[20] Univ Hosp Bordeaux, Anaesthesiol & Crit Care Dept 2, F-33600 Pessac, France

[21] Med Univ Innsbruck, ICU, Dept Internal Med, A-6020 Innsbruck, Austria

[22] Hosp Univ Penn, Philadelphia, PA 19104 USA

[23] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[24] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[25] Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA

[26] Rhein Westfal TH Aachen, Univ Klinikum, Dept Intens Care, D-52074 Aachen, Germany

[27] Providence Pk Heart Inst, Providence Hosp & Med Ctr, St John Providence Hlth Syst, Dept Med, Novi, MI 48374 USA

[28] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA

[29] Kings Coll London, Guys & St Thomas Hosp, Dept Crit Care, London SE1 7EH, England

[30] Hosp Civils Lyon, Edouard Herriot Hosp, Serv Anesthesie Reanimat, F-69003 Lyon, France

[31] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA

[32] Duke Univ, Med Ctr, Durham Vet Affairs Med Ctr, Dept Anesthesia, Durham, NC 27705 USA

[33] Walker Biosci, Carlsbad, CA 92009 USA

[34] Joseph M Still Res Fdn, Dept Med, Augusta, GA 30909 USA

[35] Erasme Univ Hosp, Dept Intens Care, B-1070 Brussels, Belgium

[36] Hosp Marc Jacquet, Dept Intens Care, F-77011 Melun, France

[37] Med Univ Vienna, Dept Internal Med, A-1090 Vienna, Austria

[38] Tampa Gen Hosp, Dept Emergency Med, Tampa, FL 33606 USA

[39] Univ Hosp Frankfurt, Clin Anesthesiol Intens Care Med & Pain Therapy, D-60590 Frankfurt, Germany

[40] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Pittsburgh, PA 15213 USA

来源：

CRITICAL CARE | 2013年 / 17卷 / 01期

关键词：

CRITICALLY-ILL PATIENTS; ACUTE-RENAL-FAILURE; ANIMAL-MODELS; MORTALITY; LONG; PATHOPHYSIOLOGY; PROGRESSION; SENESCENCE; SEPSIS;

D O I：

10.1186/cc12503

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

引用

页数：12

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