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Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury *

Liu, Kathleen D. MD, PhD, MCR; Glidden, David V. PhD; Eisner, Mark D. MD, MPH; Parsons, Polly E. MD; Ware, Lorraine B. MD; Wheeler, Arthur MD; Korpak, Anna BA; Thompson, Taylor B MD; Chertow, Glenn M. MD, MPH; Matthay, Michael A. MD the National Heart, Lung, and Blood Institute ARDS Network Clinical Trials Group

Clinical Investigations
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Objective: To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury.

Design: Secondary data analysis from a multicenter, randomized clinical trial.

Setting: Intensive care units in ten university medical centers.

Patients: A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial.

Interventions: Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design.

Measurements and Main Results: We tested the association of baseline levels of interleukin-6, interleukin-8, interleukin-10, von Willebrand factor, tumor necrosis factor-[alpha], type I and II soluble tumor necrosis factor receptors (sTNFR-I and -II), protein C, plasminogen activator inhibitor-1 (PAI-1), surfactant protein-A, surfactant protein-D, and intracellular adhesion molecule-1 with subsequent acute kidney injury. Of 876 study participants who did not have end-stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180-day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p< .001). Interleukin-6, sTNFR-I, sTNFR-II, and PAI-1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR-I and PAI-1 to this model was highly significant (p= .0003).

Conclusions: Elevations in PAI-1, interleukin-6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil–endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury.

From the Divisions of Nephrology (KDL, GMC) and Occupational Medicine (MDE), Department of Medicine (MAM), and the Departments of Epidemiology and Biostatistics (DVG, GMC) and Anesthesia (MAM), University of California, San Francisco, CA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Vermont, Burlington, VT (PEP); Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN (LBW, AW); and Department of Biostatistics (AK) and Pulmonary and Critical Care Unit, Department of Medicine (BTT), Massachusetts General Hospital, Boston, MA.

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Dr. Chertow is a scientific advisor to RenaMed Biologic, Westborough, MA. The remaining authors have not disclosed any potential conflicts of interest.

Supported, in part, by contracts N01-HR46054–46064 from the National Heart, Lung, and Blood Institute, National Institutes of Health (awarded to the ARDS Network), and 8 K12 RR023262 from the National Institutes of Health Roadmap for Medical Research (awarded to the University of California, San Francisco).

For information regarding this article, E-mail: Kathleen.liu@ucsf.edu

*See also p. 000.

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