Cellular Bioenergetics as a Predictor of Diabetic Nephropathy
The pathophysiology of diabetes is associated with a spectrum of complications including renal disease that currently affects about 30% of diabetics. Diabetic nephropathy is usually characterized by variable degrees of albuminuria and a progressive deterioration in glomerular filtration rate (GFR). Importantly, diabetic nephropathy is the leading cause of end stage renal disease in the US accounting for about 45% of all cases. At the present time no clinical test is available to predict which patients will progress rapidly. If such a test were available, it would greatly aid in management allowing more effective timing of dialysis and transplant and so improve therapeutic outcome and quality of life. Since diabetes is a systemic disease associated with severe bioenergetic dysfunction in a broad range of tissues, we hypothesized that those patients with severe cellular bioenergetic defects detectable in circulating platelets, lymphocytes and monocytes will progress more rapidly to end stage renal disease. Although the concept that circulating blood cells can serve as a biomarker for the severity of diabetes has been recognized previously it has not been exploited for patient management. A major breakthrough in this area has been the development of novel methods to assess cellular bioenergetics in peripheral blood mononuclear cells and platelets using only 20ml of blood. Importantly, we have shown that mitochondrial function is quite different in different cell types necessitating an independent evaluation of the potential to predict severity of renal disease in diabetic patients. This translational pilot proposal builds on these findings with a collaborative project between clinicians with expertise in the management of diabetic patients with renal disease and basic researchers who are expert in cellular bioenergetics at UAB. In this proposal we will test this concept using an adaptive study design to determine whether the severity of bioenergetic dysfunction is a predictor of the rate of progression of renal disease. The project will serve the diabetic community by introducing a novel biomarker for the progression of diabetic nephropathy and serve as the basis for the possible future development of novel bioenergetic based therapeutics.

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