Hyperpolarized 13C Metabolic MRI for Noninvasive Monitoring of Kidney Injury

该项目的总体目标是开发一种基于 超极化（HP）13 C丙酮酸盐MRI用于研究肾脏能量代谢， 监测人体肾损伤。这是对PAR-20-140：催化工具和技术的回应 肾脏、泌尿系统和血液系统疾病的发展鼓励“创新放射学” 或活体成像方法，或用于肾脏研究的新型成像探针”。肾脏是一个高度 能量依赖性器官，需要线粒体氧化代谢以实现关键肾功能。增加 有证据表明，从丙酮酸线粒体氧化磷酸化到糖酵解的转变， 乳酸盐的产生在导致慢性肾损伤的许多病因中起着中心作用 疾病，这是美国的一个主要公共卫生问题。值得注意的是，目前 已知诸如血清肌酸的临床测试对于监测肾损伤不敏感，并且更好地监测肾损伤。 需要非侵入性工具。HP 13 C MRI是一种创新的技术平台， - 对于成像13 C标记的生物分子，灵敏度的空前提高（> 10，000倍的信号增加）， 从而允许对动态代谢过程进行快速和非侵入性的研究。我们已经表明 在肾缺血-再灌注损伤小鼠模型中，HP 13 C丙酮酸MRI可以监测 线粒体丙酮酸脱氢酶（PDH）活性受损， 到受损肾脏的糖酵解重要的是，HP 13 C丙酮酸盐作为造影剂已经被证明 在最初的癌症患者研究中是安全的。然而，使用这种方法进行的人类肾脏研究需要 肾脏专用技术开发。我们建议开发成像工具， 对多种代谢途径的敏感性，包括PDH介导的碳酸氢盐转化， 目前的方法信号有限，以确保再现性，并解决高灌注问题 肾脏特有的代谢定量。作为初步示范研究，我们建议 对肾移植患者进行成像，以便将HP 13 C丙酮酸MRI与 活检;这将使人们能够理解成像结果的分子基础， 这对发展未来各种肾脏疾病的研究很重要。这项技术具有 这是一个巨大的潜力，可以促进我们对肾脏疾病能量代谢的理解， 为临床研究和临床护理提供及时的诊断和治疗监测。这些工具 技术开发项目可以很容易地传播到其他地点， 研究肾脏疾病的技术。

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.