Hyperpolarized 13C Metabolic MRI for Noninvasive Monitoring of Kidney Injury

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The overarching goal of this project is to develop a kidney metabolic imaging tool based on hyperpolarized (HP) 13C pyruvate MRI to investigate kidney energy metabolism for noninvasive monitoring of human kidney injury. This is in response to PAR-20-140: Catalytic Tool and Technology Development in Kidney, Urologic, and Hematologic Diseases encouraging “innovative radiological or intravital imaging methods, or novel imaging probes for study of the kidney”. The kidney is a highly energy-dependent organ requiring mitochondrial oxidative metabolism for key renal functions. Increasing evidence indicates that a shift from pyruvate mitochondrial oxidative phosphorylation to glycolysis and lactate production plays a central role in many etiologies of kidney injury leading to chronic kidney disease, which represents a major public health problem in the United States. Notably, currently available clinical tests such as serum creatine are known to be insensitive for monitoring kidney injury, and better noninvasive tools are needed. HP 13C MRI is an innovative technology platform that provides unprecedented gains in sensitivity (>10,000-fold signal increase) for imaging 13C-labeled bio-molecules, thereby permitting rapid and noninvasive investigation of dynamic metabolic processes. We have shown in a murine model of kidney ischemia-reperfusion injury that HP 13C pyruvate MRI can monitor the impaired mitochondrial pyruvate dehydrogenase (PDH) activity and the shift from oxidative metabolism to glycolysis in injured kidneys. Importantly, HP 13C pyruvate as a contrast agent has already been shown to be safe in initial cancer patient studies. However, human kidney studies with this approach require kidney-specific technology development. We propose to develop imaging tools to enable increased sensitivity to multiple metabolic pathways including PDH-mediated conversion to bicarbonate that is limited in signal with current methods, to ensure reproducibility, and to address issues of high perfusion unique to the kidneys for metabolism quantification. For an initial demonstration study, we propose to image patients with kidney allograft in order to correlate HP 13C pyruvate MRI with histopathology from biopsies; this will enable understanding of the molecular underpinning of the imaging findings that will be important for developing future studies in various kidney diseases. This enabling technology has an outstanding potential to advance our understanding of energy metabolism in kidney disease, to improve its timely diagnosis and therapy monitoring for both clinical research and clinical care. The tools from this technology development project can be readily disseminated to other sites, allowing broader adoption of the technology for studying kidney disease.