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）是一组心血管危险因素，包括肥胖、胰岛素抵抗、血脂异常和高血压，并以大量炎症为特征。肥胖在met的病理机制中起着特别重要的作用，并将慢性肾脏疾病的风险提高了约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，但其对肾脏的影响的性质和机制尚未阐明。研究肾微血管（MV）的新成像技术，以及模拟人类肾脏生理和病理生理的模型，现在提供了一个独特的机会来评估MetS对肾微血管功能和结构的影响。这一假说的基础是，MetS引发了部分由炎症介导的肾MV重塑，其中单核细胞化学引诱蛋白-1 （MCP-1）起着关键作用。我们假设，由此导致的中压完整性丧失干扰了旨在保护肾脏免受缺血或其他损伤的代偿机制。第二个假设是，成像技术可以解决中压功能和结构，从而证明MetS对肾脏的影响并探索其机制。为了验证这一假设，我们将利用肥胖猪，这是一种独特的大型动物模型，具有自然发生的一系列MetS特征，并结合了强大的体内和体外成像技术。多探测器计算机断层扫描（MDCT）将量化无创肾灌注和功能，并与血氧水平依赖（BOLD）肾氧合和肾小管功能的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。然后使用微型ct原位重建肾MV，并使用新型工具量化其结构和完整性。重要的是，慢性阻断MCP-1将确定炎症和MCP-1作为MetS对肾脏影响的机制的作用。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、炎症和中压重塑损害肾中压功能和完整性，这些在饮食改变后是可逆的；2. 中压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诱导的肾脏微血管改变。面对流行的超重和久坐不动的生活方式，制定适当的策略来早期识别、治疗和预防MetS，对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MetS早期有害影响的机制可以极大地促进我们对MetS进化过程中肾损伤发病机制的理解，这种方式可能适用于人类。事实上，这些研究可能会对设计met患者管理的预防和诊断措施有所启发，并具有实质性的影响。

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.