Acute kidney injury in the face of chronic kidney disease is a frequent clinical problem with an increasing incidence, an unacceptably high mortality rate that has not improved in more than 50 years, and no specific treatment. Interest is keen for the pursuit of methods for quantifying structural and functional disruption in progressive chronic disease and acute injury that might improve the sensitivity, specificity, and time in which renal injury is diagnosed, and facilitate risk stratification and/or provide prognostic information including prediction of recovery of renal function. We contend that the combination of adjunctive image-based functional and molecular readouts of regional blood volume, oxygenation, and inflammation could enhance these new urinary biomarkers to fully quantify the renal risk state and evaluate therapy in both chronic and acute diseases. We propose to explore and compare an alternative approach to existing methods with the use of native and molecularly targeted perfluorocarbon nanoparticles (PFC NPs) that could offer numerous advantages for diagnostic imaging and drug delivery to chronic and acute kidney diseases. Our preliminary results showed intrarenal oxygenation could be non-invasively mapped by 19F MRI. Renal ischemia-reperfusion (I/R) injury induced outer medullary vascular non-perfusion was directly detected by regional reduction of 19F signal intensity from circulating PFC NPs. Such regional non-perfusion of renal vasculature was effectively inhibited by PFC NPs facilitated anticoagulation therapy. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation because the targeted PFC NPs contrast platform already is in FDA-approved clinical trials for molecular imaging of angiogenesis with fluorine (19F) MRI/MRS. Furthermore, the dual, simultaneous proton and fluorine imaging methods are fundamentally developed and implemented on a clinical 3T scanner, and ready for adoption by any manufacturer. Accordingly our aims are to:
AIM 1. Validate 19F MRI of PFC NPs is a quantitative measure for mapping intrarenal blood volume, PO2, and inflammation using a mouse model of renal ischemia/reperfusion (I/R) injury AIM 2. Evaluate the effect of PPACK NPs on inhibiting intrarenal nonperfusion using 19F MRI in vivo PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

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Chronic renal disease combined with acute kidney injury is a frequent clinical problem with an increasing incidence, an unacceptably high mortality rate that has not improved in more than 50 years, and no specific treatment. We propose to implement adjunctive noninvasive functional and molecular imaging readouts of intrarenal blood volume, oxygenation, and inflammation and to develop a nanoparticle facilitated anticoagulation therapy that should enhance diagnosis and treatment of chronic and acute kidney diseases. The proposal is highly translational and the methods to be developed have a direct path to clinical testing and implementation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-Q (04))
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Flessner, Michael Francis
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Palekar, Rohun U; Jallouk, Andrew P; Myerson, Jacob W et al. (2016) Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis. Arterioscler Thromb Vasc Biol 36:446-55
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