Intra-renal Bold MRI: Application to Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病是美国终末期肾病（ESRD）的最常见原因，约占新病例的45%，预计到2010年，每年的费用将达到120亿美元。目前的护理状态仅涉及控制高血糖症，直到出现微量白蛋白尿，这可能需要检测到高血糖症后5至12年的任何时间。虽然对糖尿病肾病的病理生理学还没有完全清楚的了解，但在过去十年左右已经取得了重大进展，并提出了新的概念。肾组织缺氧是糖尿病肾病的重要发病机制，近年来引起了人们越来越多的关注。糖尿病患者慢性肾缺氧的发生至少有两个主要原因：一个是由于超滤导致氧消耗增加以支持钠重吸收增强，另一个是由于氧化应激最终导致一氧化氮可用性降低。为了更好地了解缺氧的起源和程度并开发逆转缺氧的方法，需要非侵入性技术来测量/监测动物模型和人体中的肾内氧合。血氧水平依赖（BOLD）MRI技术应用于肾内氧合已被证明是敏感和有效的评价肾缺氧在大鼠和人的肾脏。目前还没有其他已知的技术可以用于监测人肾脏中的肾缺氧。此外，已经确定，结合适当的药理学操作，BOLD MRI有助于证明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，该建议扩展了目前在健康和高血压肾脏中使用BOLD MRI评估糖尿病肾内氧合的研究结果。使用糖尿病大鼠肾脏模型，将针对侵入性微探针和菊粉清除测量来验证BOLD MRI和GFR测量。该技术还将首次扩展到处于疾病进展不同阶段的人类受试者。还将获得初步数据，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方法来监测肾内氧合，以跟踪糖尿病肾病疾病进展期间的纵向变化，以及临床前和临床试验期间的新治疗方法。

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.