Noninvasive Nephritis Imaging

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Project Summary/Abstract. Inflammation plays a key pathogenic role in numerous kidney disease states. Accordingly, procedures to diagnose, map, and longitudinally monitor kidney inflammation can greatly enhance our ability to identify and treat patients suffering from kidney injury related to drug toxicity, ischemia, infection, autoimmune diseases, and allograft dysfunction. Unfortunately, definitive diagnosis of kidney inflammation requires biopsy, which is invasive, costly, poses substantial bleeding risk, and samples only a small segment of the kidney. Repeat biopsy is impractical for longitudinal patient monitoring. Furthermore, many patients requiring biopsy have contraindications including obesity, anticoagulation, severe hypertension, or single kidney. There is an urgent unmet need to noninvasively detect, map, quantify, and monitor inflammation in numerous kidney disease states. Currently available imaging technologies which could potentially identify kidney inflammation, such as [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) have important limitations, lacking sufficient spatial resolution for disease mapping, exposing patients to ionizing radiation, and the fact that FDG is both renally excreted and partially reabsorbed in proximal tubules blunts visualization of parenchymal inflammatory infiltrates. Experimental ultrasmall paramagnetic iron-oxide nanoparticles (USPIONs) targeted to phagocytic cells have been used to image kidney inflammation in clinical trials, but this approach is limited by slow USPION pharmacokinetics, requiring several days between injection and imaging readout. An ideal technology for molecular imaging of kidney inflammation should generate no background signal in the kidney, generate positive signal enhancement in the presence of inflammation, and yield an inflammation- specific imaging readout within minutes of injection. We posit that we can satisfy these technologic criteria using new class of reactive oxygen species (ROS) responsive MR imaging probe recently invented by our lab. Elevated extracellular ROS concentrations are a hallmark feature of inflamed tissue, as granulocytic cells of the innate immune system undergo respiratory burst resulting in an aberrant oxidizing tissue microenvironment. Our ROS-specific contrast agent, Fe-PyC3A, is a low molecular weight iron complex that instantaneously switches between an MR silent and MR visible states in the presence ROS. The goals of this R21 are to advance Fe-PyC3A as tool for imaging kidney inflammation by demonstrating proof of concept in murine models of ischemia- and immune-related kidney diseases, optimizing the dose for kidney MR imaging, and demonstrating safety for kidney imaging applications. This proposal is written in response to PAR-20-140 “Catalytic Tool and Technology Development in Kidney, Urologic, and Hemotologic Diseases,” and specifically addresses calls for “innovative new radiologic methods and novel imaging probes.” kidney compartments in the rejection model.