CT imaging for the assessment of kidney injury distal to renal artery stenosis

描述(申请人提供)：代谢综合征(METS)是一组心血管危险因素，包括肥胖、胰岛素抵抗、血脂异常和高血压，其特征是大量炎症。肥胖在蛋氨酸肾病的发病机制中扮演着特别重要的角色，并将患慢性肾脏疾病的风险增加约4倍。甲硫氨酸的早期肾功能障碍可能与其对肾脏微循环的直接影响有关，但甲硫氨酸对肾脏的影响的性质和机制尚未阐明。研究肾微血管(MV)的新的成像技术，以及模拟人类肾脏生理和病理生理学的模型，现在提供了一个独特的机会来评估蛋氨酸对肾微血管功能和结构的影响。支持这一假设的假设是蛋氨酸引起的肾脏MV重构部分是由炎症介导的，其中单核细胞趋化蛋白-1(MCP-1)起着关键作用。我们假设，由此导致的MV完整性的丧失干扰了旨在保护肾脏免受缺血或其他损害的代偿机制。第二个假设是，成像技术可以解析MV的功能和结构，从而能够展示Met的肾脏效应并探索其机制。为了验证这一假设，我们将使用肥胖猪，这是一种独特的大型动物模型，具有自然产生的Met特征星座，以及体内和体外强大的成像技术的组合。多探测器计算机断层扫描(MDCT)将非侵入性地量化肾脏的血流灌注和功能，并与肾脏氧合和肾小管功能的血氧水平依赖(BOLD)MRI研究相关联。肾脏脂肪含量和炎症浸润将使用新的MRI技术进行评估。然后，肾脏MV将使用Micro-CT进行原位重建，并使用新工具量化其结构和完整性。重要的是，慢性阻断MCP-1将确立炎症的作用，并将MCP-1作为蛋氨酸对肾脏影响的潜在机制。三个假说将被三个特定的目的验证：1.Mets通过诱导氧化应激、炎症和MV重塑而损害肾脏MV的功能和完整性，这些在改变饮食后是可逆的；2.MV重塑干扰对缺血损伤(急性或慢性肾动脉阻塞)的适应；3.MCP-1参与Mets诱导的肾脏微血管改变。为早期识别、治疗和预防甲型肝炎制定适当的战略，对于面临超重和久坐不动的生活方式的卫生保健专业人员来说是一个重大挑战。在肾脏微循环水平上阐明甲硫氨酸早期有害作用的机制，可以极大地促进我们对甲硫氨酸进化过程中肾脏损伤机制的理解，从而有可能适用于人类。事实上，这些研究可能会对设计预防和诊断措施来管理甲亢症患者提供启发和实质性的指导。 公共卫生相关性：代谢综合征(METS)与严重的心血管风险和肾脏损伤有关。目前的建议利用了一种独特的动物模型，具有许多类似人类的属性，并采用了模拟临床条件的干预措施，这将有助于向人类进行翻译。将使用尖端的CT和MRI技术在体内测试蛋氨酸损伤肾血管功能和加重缺血的能力，并通过在同一动物组织中进行的体外成像和分子生物学研究来补充，从而使它们之间的相关性和功能意义的定义成为可能。在肾脏微循环水平上阐明Mets早期有害作用的机制可以极大地促进我们对Mets在显性CKD前的演变过程中肾脏损伤的发病机制的理解。CT和MRI的研究和临床应用为以一种可能适用于人类的方式研究这些变化提供了一个独特的机会。因此，这些研究可能有助于设计预防措施(例如，针对危险因素)和诊断措施(例如，成像)，以管理有心血管危险因素和甲硫氨酸转运蛋白的患者，并具有实质性的分支作用。

DESCRIPTION (provided by applicant): The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include obesity, insulin resistance, dyslipidemia, and hypertension, and is characterized by substantial inflammation. Obesity plays a particularly central role in the pathomechanisms of MetS and raises the risk for chronic kidney disease by about 4-fold. Early renal dysfunction in MetS may be linked to direct impact on the renal microcirculation, but the nature and mechanisms of the renal effects of MetS have not been elucidated. Novel imaging techniques for studying renal microvessels (MV), and models that mimic human renal physiology and pathophysiology, now provide a unique opportunity to assess the effects of MetS on renal MV function and structure. The hypothesis underlying this proposal is that MetS elicits renal MV remodeling that is partly mediated by inflammation, and in which monocyte chemoattractant protein-1 (MCP-1) plays a pivotal role. We hypothesize that consequent loss of MV integrity interferes with compensatory mechanisms meant to protect the kidney from ischemic or other insults. The secondary hypothesis is that imaging techniques can resolve MV function and architecture to allow demonstration of the renal effects of MetS and exploration of its mechanisms. To test this hypothesis we will utilize obese swine, a unique large animal model with a naturally occurring constellation of features of the MetS, and a combination of powerful imaging techniques both in vivo and in vitro. Multi- detector computed tomography (MDCT) will quantify non-invasively renal perfusion and function, and correlate with blood oxygen level-dependent (BOLD) MRI studies of renal oxygenation and tubular function. Renal fat content and inflammatory infiltration will be assessed using novel MRI techniques. Renal MV will then be reconstructed in situ using micro-CT, and their architecture and integrity quantified using novel tools. Importantly, chronic blockade of MCP-1 will establish the role of inflammation and MCP-1 as a mechanism underlying the effects of MetS on the kidney. Three hypotheses will be tested by 3 specific aims: 1. MetS impairs renal MV function and integrity by inducing oxidative stress, inflammation, and MV remodeling, which are reversible upon a change of diet; 2. MV remodeling interferes with adaptation to ischemic insult (acute or chronic renal artery obstruction); 3. MCP-1 contributes to MetS-induced renal microvascular alterations. Developing adequate strategies for early identification, treatment, and prevention of MetS, present a major challenge for health care professionals, facing an epidemic of overweight and sedentary lifestyle. Elucidation of the mechanisms involved in early deleterious effects of MetS at the level of the renal microcirculation can greatly advance our understanding of the pathogenesis of kidney injury during the evolution of MetS in a manner potentially applicable to humans. Indeed, these studies may shed light into and have a substantial ramification for designing preventive and diagnostic measures for management of patients with MetS. PUBLIC HEALTH RELEVANCE: The metabolic syndrome (MetS) is associated with substantial cardiovascular risk and kidney injury. The current proposal utilizes a unique animal model possessing many human-like attributes, and interventions mimicking clinical conditions, which would facilitate translation to humans. The capability of MetS to impair renal vascular function and aggravate ischemia during insults will be examined in vivo using cutting edge CT and MRI techniques, and complemented by in vitro imaging and molecular biology studies performed in tissue from the same animals, thereby allowing their correlation and definition of functional significance. Elucidation of the mechanisms involved in early deleterious effects of MetS at the level of the renal microcirculation can greatly advance our understanding of the pathogenesis of renal injury during the evolution of MetS preceding overt CKD. The research and clinical availability of CT and MRI provides a unique opportunity to study these alterations in a manner potentially applicable to humans. These studies may therefore shed light into and have a substantial ramification for designing preventive (e.g. targeting risk factors) and diagnostic (e.g. imaging) measures for management of patients with cardiovascular risk factors and MetS.