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Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray

Rajit K Basu1, Stephen W Standage1, Natalie Z Cvijanovich2, Geoffrey L Allen3, Neal J Thomas4, Robert J Freishtat5, Nick Anas6, Keith Meyer7, Paul A Checchia8, Richard Lin9, Thomas P Shanley10, Michael T Bigham11, Derek S Wheeler1, Prasad Devarajan1, Stuart L Goldstein1 and Hector R Wong1*

Author Affiliations

1 Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45223, USA

2 Children's Hospital and Research Center Oakland, 747 52nd Street, Oakland, CA 94609, USA

3 Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MI 64108, USA

4 Penn State Children's Hospital, 500 University Drive, Hershey, PA 17033, USA

5 Children's National Medical Center, 111 Michigan Avenue, NW, Washington, District of Columbia 20010, USA

6 Children's Hospital of Orange County, 455 South Main Street, Orange, CA 92868, USA

7 Miami Children's Hospital, 3100 SW 62nd Avenue, Miami, FL 33155, USA

8 Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA

9 The Children's Hospital of Philadelphia, 34th Street and Civic Center, Philadelphia, PA 19104, USA

10 CS Mott Children's Hospital at the University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA

11 Akron Children's Hospital, 1 Perkins Square, Akron, OH 44308, USA

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Critical Care 2011, 15:R273  doi:10.1186/cc10554

Published: 18 November 2011



Septic-shock-associated acute kidney injury (SSAKI) carries high morbidity in the pediatric population. Effective treatment strategies are lacking, in part due to poor detection and prediction. There is a need to identify novel candidate biomarkers of SSAKI. The objective of our study was to determine whether microarray data from children with septic shock could be used to derive a panel of candidate biomarkers for predicting SSAKI.


A retrospective cohort study compared microarray data representing the first 24 hours of admission for 179 children with septic shock with those of 53 age-matched normal controls. SSAKI was defined as a >200% increase of baseline serum creatinine, persistent to 7 days after admission.


Patients with SSAKI (n = 31) and patients without SSAKI (n = 148) were clinically similar, but SSAKI carried a higher mortality (45% vs. 10%). Twenty-one unique gene probes were upregulated in SSAKI patients versus patients without SSAKI. Using leave-one-out cross-validation and class prediction modeling, these probes predicted SSAKI with a sensitivity of 98% (95% confidence interval (CI) = 81 to 100) and a specificity of 80% (95% CI = 72 to 86). Serum protein levels of two specific genes showed high sensitivity for predicting SSAKI: matrix metalloproteinase-8 (89%, 95% CI = 64 to 98) and elastase-2 (83%, 95% CI = 58 to 96). Both biomarkers carried a negative predictive value of 95%. When applied to a validation cohort, although both biomarkers carried low specificity (matrix metalloproteinase-8: 41%, 95% CI = 28 to 50; and elastase-2: 49%, 95% CI = 36 to 62), they carried high sensitivity (100%, 95% CI = 68 to 100 for both).


Gene probes upregulated in critically ill pediatric patients with septic shock may allow for the identification of novel candidate serum biomarkers for SSAKI prediction.