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A Multibiomarker-Based Model for Estimating the Risk of Septic Acute Kidney Injury

Wong, Hector R. MD1,2; Cvijanovich, Natalie Z. MD3; Anas, Nick MD4; Allen, Geoffrey L. MD5; Thomas, Neal J. MD6; Bigham, Michael T. MD7; Weiss, Scott L. MD8; Fitzgerald, Julie MD, PhD8; Checchia, Paul A. MD9; Meyer, Keith MD10; Shanley, Thomas P. MD11; Quasney, Michael MD, PhD11; Hall, Mark MD12; Gedeit, Rainer MD13; Freishtat, Robert J. MD14; Nowak, Jeffrey MD15; Raj, Shekhar S. MD16; Gertz, Shira MD17; Dawson, Emily MD18; Howard, Kelli BSN1; Harmon, Kelli MS1; Lahni, Patrick BS1; Frank, Erin BS1; Hart, Kimberly W. MS19; Lindsell, Christopher J. PhD19

doi: 10.1097/CCM.0000000000001079
Clinical Investigations

Objective: The development of acute kidney injury in patients with sepsis is associated with worse outcomes. Identifying those at risk for septic acute kidney injury could help to inform clinical decision making. We derived and tested a multibiomarker-based model to estimate the risk of septic acute kidney injury in children with septic shock.

Design: Candidate serum protein septic acute kidney injury biomarkers were identified from previous transcriptomic studies. Model derivation involved measuring these biomarkers in serum samples from 241 subjects with septic shock obtained during the first 24 hours of admission and then using a Classification and Regression Tree approach to estimate the probability of septic acute kidney injury 3 days after the onset of septic shock, defined as at least two-fold increase from baseline serum creatinine. The model was then tested in a separate cohort of 200 subjects.

Setting: Multiple PICUs in the United States.

Interventions: None other than standard care.

Measurements and Main Results: The decision tree included a first-level decision node based on day 1 septic acute kidney injury status and five subsequent biomarker-based decision nodes. The area under the curve for the tree was 0.95 (CI95, 0.91–0.99), with a sensitivity of 93% and a specificity of 88%. The tree was superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk. In the test cohort, the tree had an area under the curve of 0.83 (0.72–0.95), with a sensitivity of 85% and a specificity of 77% and was also superior to day 1 septic acute kidney injury status alone for estimating day 3 septic acute kidney injury risk.

Conclusions: We have derived and tested a model to estimate the risk of septic acute kidney injury on day 3 of septic shock using a novel panel of biomarkers. The model had very good performance in a test cohort and has test characteristics supporting clinical utility and further prospective evaluation.

1Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation, Cincinnati, OH.

2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

3Division of Critical Care Medicine, UCSF Benioff Children’s Hospital Oakland, Oakland, CA.

4Division of Critical Care Medicine, Children’s Hospital of Orange County, Orange, CA.

5Division of Critical Care Medicine, Children’s Mercy Hospital, Kansas City, MO.

6Division of Critical Care Medicine, Penn State Hershey Children’s Hospital, Hershey, PA.

7Division of Critical Care Medicine, Akron Children’s Hospital, Akron, OH.

8Division of Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA.

9Division of Critical Care Medicine, Texas Children’s Hospital, Houston, TX.

10Division of Critical Care Medicine, Miami Children’s Hospital, Miami, FL.

11Division of Critical Care Medicine, CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, MI.

12Division of Critical Care Medicine, Nationwide Children’s Hospital, Columbus, OH.

13Division of Critical Care Medicine, Children’s Hospital of Wisconsin, Milwaukee, WI.

14Division of Critical Care Medicine, Children’s National Medical Center, Washington, DC.

15Division of Critical Care Medicine, Children’s Hospital and Clinics of Minnesota, Minneapolis, MN.

16Division of Critical Care Medicine, Riley Hospital for Children, Indianapolis, IN.

17Division of Critical Care Medicine, Hackensack University Medical Center, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ.

18Division of Critical Care Medicine, The University of Chicago Comer Children’s Hospital, Chicago, IL.

19Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Dr. Wong conceived and developed the study, obtained funding for the study, conducted the analysis, and edited the article. Dr. Cvijanovich, Dr. Anas, Dr. Allen, Dr. Thomas, Dr. Bigham, Dr. Weiss, Ms. Fitzgerald, Dr. Checchia, Dr. Meyer, Dr. Shanley, Dr. Quasney, Dr. Hall, Dr. Gedeit, Dr. Freishtat, Dr. Nowak, Dr. Shekhar, Dr. Gertz, and Dr. Dawson enrolled subjects at the participating institutions, provided clinical data and biological samples, and edited the article. Ms. Howard and Ms. Frank maintained the clinical database and coordinated all interinstitutional research activity. Ms. Harmon maintained the biological repository and processed all biological samples. Mr. Lahni conducted all biomarker assays. Ms. Hart assisted with statistical analysis. Dr. Lindsell developed the study, assisted with analysis, and edited the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by an Institutional Clinical and Translational Science Award, National Institutes of Health (NIH) and National Center for Research Resources (8UL1 TR000077).

Dr. Wong received support for article research from the NIH. His institution received grant support from the NIH and has biomarker patents (not related to the current work). Dr. Cvijanovich is employed by the Children’s Critical Care Medical Group; lectured for the American Society for Parenteral and Enteral Research (speaker at annual conference 2014); and received support for article research from the NIH. Her institution received grant support from the Cincinnati Children’s Hospital Medical Center (per patient fee via subcontract) and the U.S. Army Medical Research and Material Command (award no. W81XWH-BAA-11-1). Dr. Anas served as a board member for Children's Hospital of Orange County (CHOC) Health Alliance, consulted for CHOC Children’s, is employed by CHOC Children’s, and has retirement stock. Dr. Allen received support for article research from the NIH. His institution received grant support (subcontract for NIH grant). Dr. Thomas served as an Advisory Board Member for and Ikaria and received support for article research from the NIH. His institution received grant support from the Children’s Hospital of Cincinnati (subcontract grant). Dr. Weiss is employed by The Children’s Hospital of Philadelphia and received royalties from Up-To-Date. He and his institution received grant support from the NICHD (K12HD047349). Ms. Fitzgerald C/F and her institution received grant support from the NIH (grant nos. RO1GM064619, RO1GM099773, and R01GM108025). Dr. Meyer received support for article research from the NIH. His institution received grant support from the NIH. Dr. Shanley served as a board member for the International Pediatric Research Foundation (Trustee of Executive Committee), consulted for External Advisory Boards (U-Cinn, U-Minn, Case West), and received support for article research from the NIH. His institution received grant support from the NIH (Clinical and Translational Science Award principal investigator). Dr. Hall lectured for the Society of Critical Care Medicine and received support for article research from the NIH. His institution received grant support from the NIH. Dr. Freishtat received support for article research from the NIH. Dr. Gertz is employed by and received support for travel from the Hackensack University Medical Center. She received support for article research from the NIH. Her institution received grant support from the Hackensack University Medical Center. Dr. Dawson received support for article research from the NIH. Ms. Howard received support for article research from the NIH. Her institution received grant support from the NIH. Mr. Lahni received support for article research from the NIH. Ms. Frank received support for article research from the NIH. Her institution received grant support from the NIH, and she has disclosed employment, has a patent, and received support for travel. Dr. Lindsell received support for article research from the NIH. His institution received grant support from the NIH (He is a coinvestigator on NIH-funded grants supporting the work developing biomarkers and risk models in sepsis and coinvestigator on grants submitted to NIH exploring biomarkers and risk stratification in sepsis. The grants are not directly related to acute kidney injury.) and has patents with the U.S. Patent Office (Dr. Lindsell is a coinventor on patents for Pediatric Sepsis Biomarker Risk Model, the mortality risk model in pediatric sepsis, and its temporal version). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: hector.wong@cchmc.org

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