Obesity and chronic kidney disease are two major growing public health threats. Existent experimental animal and observational human data suggest a link between obesity and two distinct and reversible alterations in kidney function, glomerular hyperfiltration and albuminuria, that may promote and exacerbate kidney disease. However, these studies have not clearly distinguished between the effects and interactions of obesity and dietary protein intake in the pathogenesis of these changes. Therefore, we propose to test the hypothesis that obesity leads to reversible increases in the glomerular filtration rate and urinary albumin excretion that are independent of, and enhanced by, high dietary protein intake. Confirming this hypothesis will be a critical step towards understanding the impact of the obesity pandemic on chronic kidney disease. To test this hypothesis, an interventional dietary study will be conducted in morbidly obese humans to accomplish the following specific aims: (1) To determine whether increased dietary protein intake raises the glomerular filtration rate and level of urinary albumin excretion in morbidly obese humans. This will be achieved by measuring glomerular filtration and renal plasma flow measurements and albuminuria in morbidly obese subjects on high and low protein diets in a crossover trial; (2) To determine whether weight loss in morbidly obese humans lowers the glomerular filtration rate and level of urinary albumin excretion independent of dietary protein intake. This will be achieved by measuring glomerular filtration and renal plasma flow measurements and albuminuria in morbidly obese subjects on a fixed-protein diet before and after surgical weight loss; (3) To determine whether insulin and insulin resistance alter renal hemodynamics in morbidly obese humans. This will be accomplished by performing an insulin clamp study followed by glomerular filtration and renal plasma flow measurements before and after weight loss in morbidly obese subjects in a fixed diet. The principal investigator has formal fellowship training in nephrology and nutrition, and has organized a distinguished team of leading investigators in the areas of nutrition, renal hemodynamic measurements, obesity, adipocyte biology and insulin resistance to advise and mentor him. The proposed practical research experience gained from this project, together with the formal classroom training in a Masters of Science in Clinical Research (K-30) program, will prepare the principal investigator for a successful clinical research career in the overlapping fields of nutrition and nephrology.
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