SUMMARY The prevalence of kidney stone disease has dramatically increased in the United States (US) over the last 4 decades, now afflicting 8.8% of the population. Obesity which now affects over 40% of the US population is a recognized risk factor for the development of kidney stones. Calcium oxalate is the most common stone composition in the obese cohort. Urinary oxalate excretion significantly impacts the development of such stones and we and others have demonstrated that it is higher in obese kidney stone formers. Various factors can influence the amount of oxalate excreted in urine including the amount of oxalate consumed, its bio-availability, amount of dietary calcium, gastrointestinal and renal oxalate handling, and endogenous oxalate synthesis. We have found that obesity appears to increase endogenous oxalate synthesis. Others have reported that it disrupts the intestinal barrier which could result in augmented paracellular gut uptake. Obesity also appears to alter renal proximal tubular function. Thus, any one of these factors alone or in combination with the others could drive increased urinary oxalate excretion. The central hypothesis of this grant is that weight loss can reduce urinary oxalate excretion. While previous dietary approaches for kidney stone prevention have focused on macronutrients and micronutrients, caloric restriction has not been employed. We propose using an established and effective dietary weight reduction program, Optifast VLCD®, in obese, adult calcium oxalate stone formers and have crafted specific aims that focus on whether this will promote a reduction of the contribution of endogenous oxalate synthesis to the urinary oxalate pool, a decrease in gastrointestinal oxalate absorption and gut permeability, and/or alterations in renal oxalate handling. The proposed studies will be conducted in collaboration with experts in stone disease, metabolism, nutrition, endocrinology and weight loss at 2 large state institutions who provide care for this afflicted cohort. If the anticipated results of this feasibility study are achieved, this will serve as a strong platform to undertake a large clinical trial which could eventuate in an attenuation of stone disease as well as improvement or reversal of the many other co-morbidities associated with obesity.