BOLD MRI: Application to Intra-renal Oxygenation

描述（由申请人提供）：放射性造影剂肾病（RCN）是医院获得性肾衰竭的第三大常见原因，占发病率的11%。随着影像诊断程序数量的不断增加，并且由于它是一种医院获得性综合征，因此预防的必要性非常迫切。然而，RCN发展背后的机制仍然没有得到充分理解。许多基于动物试验提出的干预措施在人体试验中失败了。这种脱节的可能原因可能是：（1）动物模型不能充分代表人体生理学，（2）动物模型中使用的结局指标与临床中使用的不同，（3）无效假设等。在过去的二十年中，在理解肾脏内的氧合状态方面已经取得了重大进展，并且现在很好地理解，肾脏内的区域在缺氧条件下存活。为了使肾脏在缺氧环境中存活，已经发展出强大的控制机制，即使在外部刺激的威胁下，例如在造影剂给药期间，也能维持氧气充足。据信，在“应激”期间肾脏激活这些控制机制的能力的损害可能是在诸如造影剂的刺激之后发生肾衰竭的原因。基于这些假设，已经提出并验证了新的动物模型。与需要手术操作的先前模型相比，这些模型更简单，更重要的是更好地代表了人体状况的功能方面。此外，可用于监测肾内氧合的技术不断改进。血氧水平依赖（BOLD）MRI技术已被证明是敏感和有效的评价肾氧合在大鼠和人的肾脏。此外，对氧合状态的更好理解也产生了新的干预目标。基于这一背景，这一建议扩展了我们目前的研究结果在健康和高血压肾脏与BOLD MRI更好地了解急性血流动力学反应后，造影剂管理的功能模型的RCN和RCN倾向糖尿病大鼠。我们还将获得临床使用的标记物。我们还将测试针对缓解缺氧的新干预措施的有效性。我们将进一步使用钠MRI监测造影剂后的急性变化，并将其与BOLD MRI测量结果相关联。成功的结果应该对制定RCN的预防战略产生重大影响。放射性造影剂诱发的肾衰竭是一种常见的医院获得性综合征，由于其后果可能很严重，包括死亡，因此非常需要采取预防措施。随着诊断程序数量的不断增加，这一问题的相关性和重要性也越来越大。我们提出的研究将有助于更好地了解这种综合征发展背后的机制，并制定新的预防策略。

DESCRIPTION (provided by applicant): Radiocontrast nephropathy (RCN) is a third common cause of hospital acquired renal failure, accounting for 11% of incidence. With the continuing rise in the number of diagnostic imaging procedures and because it is a hospital acquired syndrome, the need for prevention is most compelling. However, the mechanisms behind the development of RCN remain not fully understood. Many interventions proposed based on animal testing have failed in human trials. The possible reasons for this disconnect may be due to: (1) animal models not adequately representing the human physiology, (2) outcome measures used in animal models differ from those used in the clinic, (3) invalid hypothesis etc.. Over the last two decades significant progress has been made in terms of understanding the oxygenation status within the kidney and it is now well appreciated that regions within the kidney survive under hypoxic conditions. In order for the kidney to survive in the hypoxic milieu, powerful control mechanisms have evolved that maintain oxygen sufficiency even under the threat of external stimuli such as during administration of contrast media. It is believed that compromise in the ability of the kidney to activate these control mechanisms during a "stress" may be the cause for the development of renal failure following stimuli such as contrast media. Based on these hypotheses, novel animal models have been proposed and validated. These are simpler compared to previous models that necessitate surgical manipulations, and more importantly better represent the functional aspect of the human condition. Additionally, the techniques available for monitoring intra-renal oxygenation have continuously improved. Blood oxygenation level dependent (BOLD) MRI technique has been shown to be sensitive and efficacious in evaluating renal oxygenation both in rat and human kidneys. In addition, better understanding of the oxygenation status has given rise to new targets for intervention. Based on this background, this proposal extends our present findings in healthy and hypertensive kidneys with BOLD MRI to better understand the acute hemodynamic responses following contrast administration in functional models of RCN and in RCN prone diabetic rats. We will additionally acquire markers that are used in the clinic. We will also test the efficacy of novel interventions targeted at relieving hypoxia. We will further use sodium MRI to monitor acute changes following contrast media and correlate them with BOLD MRI measurements. Successful outcome should have a significant impact on the development of preventive strategies for RCN. PUBLIC HEALTH RELEVANCE Radiocontrast induced renal failure is a common hospital acquired syndrome and because the consequences could be severe including death, preventive strategies are highly sought after. With the continuous increase in the number diagnostic procedures, the relevance and significance of this problem is growing. Our proposed study will allow for better understanding of the mechanisms behind the development of this syndrome and develop novel preventive strategies.