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

描述（由申请人提供）：血管疾病对发病率和死亡率的影响在西方世界呈上升趋势。动脉粥样硬化性肾动脉狭窄（ARAS）是慢性肾脏疾病的常见病因，它会加剧肾功能的恶化，并减弱其在干预后的恢复。然而，导致这些严重后果的机制尚未确定，部分原因是缺乏能够研究ARAS远端肾脏的技术，以及合适的ARAS实验模型。这一提议的假设是动脉粥样硬化通过损害肾功能和加剧氧化应激、炎症和纤维化来减弱干预后狭窄ARAS肾的恢复，并且高分辨率计算机断层扫描（CT）技术将有助于探索和表征肾损伤和对血运重建的反应。这一假设将在我们开发和表征的单侧ARAS的新型猪模型中进行测试，使用我们已经改进的独特成像方法来研究单肾功能和结构。电子束CT（EBCT）将在接受经皮腔内肾血管成形术的猪的狭窄肾脏中，在体内定量肾区域体积、灌注、GFR、节段性肾小管功能和对激发的反应的改变的可逆性。Micro-CT随后将用于评估原位肾微血管重塑，这是动脉粥样硬化的标志。成像研究将与肾脏氧化还原状态、炎症和纤维化的体外研究相关。此外，通过将ARAS叠加在肾小管间质损伤或肾小球硬化上，将探索预先存在的肾损伤对血运重建反应的影响。将使用他汀类药物的长期补充来研究肾损伤衰减的效果，这种药物可以减少氧化应激、炎症和纤维化，并且可能改善干预前后的肾脏结局。此外，肾脏改变将与肾脏恢复相关，并将确定介入成功的潜在预测因素。这些研究可能会大大提高我们对ARAS肾损伤发病机制的认识，并有助于发展成像策略，以检测损伤标志物和确定肾活力的预测因子。因此，这些研究可能有助于肾血管疾病患者的管理。

DESCRIPTION (provided by applicant): The impact of vascular disease on morbidity and mortality is on the rise in the Western world. Atherosclerotic renal artery stenosis (ARAS), a common etiology of chronic kidney disease, amplifies deterioration of renal function and attenuates its recovery following intervention. However, the mechanisms leading to these grave outcomes are yet to be identified, partly due to the lack of techniques capable of studying the kidney distal to ARAS, and of suitable experimental models of ARAS. The hypothesis underlying this proposal is that atherosclerosis blunts the recovery of the stenotic ARAS kidney following intervention by impairing renal function and exacerbating oxidative stress, inflammation, and fibrosis, and that high-resolution computed tomography (CT) techniques would be useful to explore and characterize renal injury and response to revascularization. This hypothesis will be tested in a novel pig model of unilateral ARAS that we have developed and characterized, using unique imaging approaches that we have refined to study single-kidney function and structure. Electron beam CT (EBCT) will quantify in vivo, in the stenotic kidney of pigs undergoing percutaneous transluminal renal angioplasty, the reversibility of alterations in renal regional volume, perfusion, GFR, segmental tubular function, and response to challenge. Micro-CT will be subsequently used to assess in situ renal microvascular remodeling, a hallmark of atherosclerosis. The imaging studies will be correlated with in vitro studies of renal redox status, inflammation, and fibrosis. Furthermore, the impact of preexisting renal injury on the response to revascularization will be explored by superimposing ARAS on tubulointerstitial injury or glomerulosclerosis. The effect of attenuation of renal injury will be studied using chronic supplementation of statins, drugs that decrease oxidative stress, inflammation, and fibrosis, and might improve renal outcomes before as well as after intervention. Moreover, renal alterations will be correlated with renal recovery, and potential predictors of interventional success will be determined. The proposed studies may greatly advance our understanding of the pathogenesis of renal injury in ARAS, and assist in development of imaging strategies to detect injury markers and identify predictors of renal viability. Thus, these studies may contribute towards management of patients with renovascular disease.