Intra-renal Bold MRI: Application to Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病是美国终末期肾病(ESRD)最常见的原因，约占新病例的45%，预计到2010年，每年的成本将达到120亿美元。目前的护理状态只涉及控制高血糖，直到出现微量蛋白尿，这可能在检测到高血糖后5至12年内发生。虽然对糖尿病肾病的病理生理机制的了解还不完全，但在过去的十年左右已经取得了重大的进展，新的概念正在被提出。肾低氧已被广泛认为是缺血性肾病的主要原因，正引起人们对糖尿病越来越多的关注。糖尿病患者发生慢性肾脏缺氧至少有两个主要原因：一个是由于超滤导致氧气消耗增加，以支持增强的钠重吸收；另一个是由于氧化应激，最终导致一氧化氮可获得性减少。为了更好地了解低氧的来源和程度，并开发逆转它的方法，需要一种非侵入性的技术来测量/监测动物模型和人类的肾内氧合。血液氧合水平依赖(BOLD)磁共振技术应用于肾内氧合已被证明是评估肾脏缺氧的灵敏和有效的方法，无论是在大鼠肾脏还是在人类肾脏。目前还没有其他已知的技术可以用于监测人类肾脏的肾脏缺氧。此外，已经证实，结合适当的药物操作，BOLD MRI有助于显示受损的内源性保护机制，如前列腺素和一氧化氮。基于这一背景，这项建议扩展了目前在健康和高血压肾脏中的发现，使用BOLD MRI来评估糖尿病患者的肾内氧合。使用糖尿病大鼠肾脏模型，BOLD MRI和GFR测量将与侵入性微探头和菊粉清除测量进行验证。此外，这项技术还将首次扩展到处于疾病发展不同阶段的人类受试者。还将获得试点数据，以跟踪纵向进展。成功的结果将意味着我们将有一种非侵入性的手段来监测肾脏内的氧合，以跟踪糖尿病肾病疾病进展过程中的纵向变化，并在临床前和临床试验期间获得新的治疗方法。

DESCRIPTION (provided by applicant): Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the U.S., accounting for approximately 45% of new cases with costs projected to reach $12 billion each year by 2010. Current state-of-care only involves control of hyperglycemia until microalbuminuria develops which could take any where between 5 to 12 years after detection of hyperglycemia. While a clear understanding of the pathophysiology of diabetic nephropathy is not yet complete, significant progress has been made over the last decade or so and novel concepts are being put forward. Renal hypoxia which has been accepted widely to play a major role in ischemic nephropathy is attracting increasing interest in diabetes. There are at least two major reasons for development of chronic renal hypoxia in diabetes: one is due to hyperfiltration resulting in increased oxygen consumption to support enhanced sodium reabsorption, and the other due to oxidative stress which ultimately causes reduced nitric oxide availability. In order to better understand the origins and degree of hypoxia and develop methods to reverse it, there is a need for non-invasive technique to measure/monitor intra-renal oxygenation both in animal models and in humans. Blood oxygenation level dependent (BOLD) MRI technique as applied to intra-renal oxygenation has been shown to be sensitive and efficacious in evaluating renal hypoxia both in rat and human kidneys. Currently there is no other known technique that can be used to monitor renal hypoxia in human kidneys. Further, it has been established that in combination with suitable pharmacological maneuver, BOLD MRI facilitates demonstration of compromised endogenous protective mechanisms such as prostglandins and nitric oxide. Based on this background, this proposal extends the present findings in healthy and hypertensive kidneys using BOLD MRI to evaluate intra-renal oxygenation in diabetes. Using a diabetic rat kidney model, BOLD MRI and GFR measurements will be validated against invasive microprobe and inulin clearance measurements. Also for the first time the technique will be extended to human subjects at different stages of disease progression. Pilot data will also be obtained to follow longitudinal progression. Successful outcome will mean that we will have a non-invasive means to monitor intra-renal oxygenation to follow longitudinal changes during disease progression in diabetic nephropathy, and novel treatments during pre-clinical and clinical trials.