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.
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