BOLD MRI: Application to Intra-renal Oxygenation

描述（由申请人提供）：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%。随着诊断成像程序数量的不断增加，由于它是一种医院获得性综合征，预防的必要性是最迫切的。然而，RCN发展背后的机制尚不完全清楚。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类生理学，(2)动物模型中使用的结果测量与临床中使用的结果测量不同，(3)无效的假设等。在过去的二十年里，在了解肾脏内的氧合状态方面取得了重大进展，现在人们很清楚肾脏内的区域在缺氧条件下存活。为了使肾脏在低氧环境中存活，已经进化出强大的控制机制，即使在外部刺激（如造影剂）的威胁下也能维持氧气充足。据信，在“压力”下，肾脏激活这些控制机制的能力受损可能是刺激（如造影剂）导致肾功能衰竭的原因。基于这些假设，新的动物模型被提出并验证。与以前需要手术操作的模型相比，这些模型更简单，更重要的是，它们更好地代表了人类状况的功能方面。此外，监测肾内氧合的技术也在不断改进。血氧水平依赖（BOLD） MRI技术已被证明是敏感和有效的评估肾氧合在大鼠和人的肾脏。此外，对氧合状态的更好理解也为干预提供了新的目标。基于此背景，本研究扩展了我们目前在健康和高血压肾脏的BOLD MRI研究结果，以更好地了解RCN功能模型和RCN易发糖尿病大鼠对比剂给药后的急性血流动力学反应。我们还将获得用于临床的标记物。我们还将测试针对缓解缺氧的新型干预措施的有效性。我们将进一步使用钠磁共振成像来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RCN预防战略的制定产生重大影响。造影剂引起的肾衰竭是一种常见的医院获得性综合征，由于后果可能很严重，包括死亡，因此预防策略受到高度关注。随着诊断程序数量的不断增加，这个问题的相关性和重要性也越来越大。我们提出的研究将允许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.