Acute renal failure (ARF) is an increasingly common complication in hospitalized patients and is associated with extremely high mortality rates. The classical method of assessing renal function by measurement of serum creatinine is insensitive, especially in the setting of acute kidney injury (AKI) or ARF. The overall goal of these studies is to develop and validate urinary and serum biomarkers of AKI that will identify the onset and severity of kidney injury at an earlier stage than is currently possible. The availability of such biomarkers will improve the care of patients with and at risk for AKI as well as aid the development of novel therapeutic and prevention strategies. During the R21 phase, we will establish the optimal methods of collecting and processing urine and develop the analytical capability to quantitatively analyze urine for the following potential biomarkers of AKI: kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9), glutathione-S-transferases (alpha and pi-GST), actin, interleukin-18 (IL-18), cysteine rich protein 61 (Cyr-61), and cystatin C. We will test the ability of these biomarkers to identify AKI in a cross-sectional study involving 200 patients with and without AKI. We will use statistical techniques such as multivariate receiver operating characteristic curve analysis to identify a panel of biomarkers that is sensitive and specific for the diagnosis of AKI, with an area under the receiver operating characteristics curve of at least 0.85. We will also measure urinary biomarkers from samples sent to us from six collaborating centers involved in prospective studies of AKI. On the basis of successful achievement of our aims in the R21 phase, we propose in the R33 phase a prospective study involving 400 patients undergoing coronary artery bypass graft surgery and 350 patients admitted to the medical intensive care unit. In these patients, we will test a panel of biomarkers identified during the R21 phase for their ability to identify prospectively AKI 24 hours before serum creatinine. The identification of early biomarkers of AKI will be a major step forward in the clinical care of patients at risk for AKI and will tremendously aid research on novel strategies for its prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33DK074099-04
Application #
7485815
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O3))
Program Officer
Kimmel, Paul
Project Start
2005-09-30
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$594,095
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Waikar, Sushrut S; Betensky, Rebecca A; Emerson, Sarah C et al. (2012) Imperfect gold standards for kidney injury biomarker evaluation. J Am Soc Nephrol 23:13-21
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Hoffmann, Dana; Adler, Melanie; Vaidya, Vishal S et al. (2010) Performance of novel kidney biomarkers in preclinical toxicity studies. Toxicol Sci 116:8-22
Damman, Kevin; Van Veldhuisen, Dirk J; Navis, Gerjan et al. (2010) Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart 96:1297-302
Koyner, Jay L; Vaidya, Vishal S; Bennett, Michael R et al. (2010) Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 5:2154-65

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