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

描述（由申请人提供）：代谢综合征（MetS）是一组心血管风险因素，包括肥胖、胰岛素抵抗、血脂异常和高血压，其特征在于大量炎症。肥胖在代谢综合征的病理机制中起着特别重要的作用，并使慢性肾脏疾病的风险增加约4倍。MetS的早期肾功能障碍可能与对肾脏微循环的直接影响有关，但MetS对肾脏影响的性质和机制尚未阐明。用于研究肾微血管（MV）的新型成像技术以及模拟人类肾脏生理学和病理生理学的模型，现在为评估MetS对肾MV功能和结构的影响提供了独特的机会。这一假设的基础是MetS eliminate肾MV重塑，这是部分由炎症介导的，其中单核细胞趋化蛋白-1（MCP-1）发挥了关键作用。我们假设，随后的MV完整性的损失干扰代偿机制，旨在保护肾脏缺血或其他侮辱。次要假设是成像技术可以解析MV功能和结构，以证明MetS的肾脏效应并探索其机制。为了验证这一假设，我们将利用肥胖猪，一个独特的大型动物模型与自然发生的星座的MetS的功能，并结合强大的成像技术在体内和体外。多探测器计算机断层扫描（MDCT）将非侵入性地量化肾灌注和功能，并与肾氧合和肾小管功能的血氧水平依赖性（BOLD）MRI研究相关。将使用新型MRI技术评估肾脏脂肪含量和炎症浸润。然后使用微型CT原位重建肾MV，并使用新工具量化其结构和完整性。重要的是，MCP-1的慢性阻断将确立炎症和MCP-1作为MetS对肾脏作用的潜在机制的作用。三个假设将通过三个具体目标进行测试：1。MetS通过诱导氧化应激、炎症和MV重塑损害肾MV功能和完整性，这在饮食改变时是可逆的; 2. MV重塑干扰对缺血性损伤（急性或慢性肾动脉阻塞）的适应; 3. MCP-1参与MetS诱导的肾微血管改变。制定适当的策略，早期识别，治疗和预防代谢综合征，提出了一个重大的挑战，卫生保健专业人员，面临着流行的超重和久坐不动的生活方式。阐明代谢综合征在肾脏微循环水平的早期有害作用的机制，可以大大提高我们的理解代谢综合征的演变过程中的肾损伤的发病机制，在一种可能适用于人类。事实上，这些研究可能会揭示和设计预防和诊断措施与代谢综合征患者的管理有很大的分歧。 公共卫生相关性：代谢综合征（MetS）与大量心血管风险和肾损伤相关。目前的提案利用了一种独特的动物模型，具有许多类似人类的属性，以及模拟临床条件的干预措施，这将有助于转化为人类。将使用尖端CT和MRI技术在体内检查MetS损害肾血管功能和加重缺血的能力，并通过在相同动物的组织中进行的体外成像和分子生物学研究进行补充，从而允许它们的相关性和功能意义的定义。阐明代谢综合征在肾脏微循环水平的早期有害作用的机制，可以大大提高我们对代谢综合征在明显的CKD之前的演变过程中肾损伤的发病机制的理解。CT和MRI的研究和临床可用性为以可能适用于人类的方式研究这些改变提供了独特的机会。因此，这些研究可能会揭示并有实质性的分歧，设计预防性（如针对风险因素）和诊断性（如成像）措施，用于管理患者的心血管风险因素和代谢综合征。

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.