Mechanisms of disordered citrate and oxalate excretion in nephrolithiasis

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Project Abstract Kidney stones are a major cause of morbidity and account for $11 billion in health care spending in the U.S. Low urine citrate and high urine oxalate both increase risk of stone formation. Mechanisms that regulate renal citrate and oxalate excretion affect kidney stone risk. Physicians use knowledge of mechanisms for stone prevention (e.g. potassium citrate to raise urine citrate, low oxalate diet to lower urine oxalate). The overall objective of this proposal is to expand our knowledge of mechanisms contributing to low urine citrate and high urine oxalate. This will advance scientific knowledge and improve kidney stone prevention strategies. The proposal will include study of mechanisms in two patient groups that are at high risk for kidney stones: obesity and Roux-en-Y gastric bypass (RYGB). Studying risk in these patient groups is important as obesity and bariatric surgery rates are on the rise in the U.S. This study will test the effect of diet on the association between higher urine oxalate and higher urine citrate in non-kidney stone patients that is disrupted in kidney stone patients. This will lead to future studies including testing the oxalate and citrate association under conditions of alkalosis. This may change clinical practice with new strategies such as providing alkali simultaneously with dietary oxalate to improve oxalate-citrate balance. It will also test the contribution of diet and paracellular gastrointestinal oxalate absorption to high urine oxalate in obese and RYGB kidney stone patients. This will lead to improved clinical care by focusing providers on higher yield strategies. Future studies will test these strategies. Furthermore, this study and support from the K23, will be vital to my career development. I will learn how to apply epidemiologic data to clinical research center (CRC) based human studies to investigate mechanisms responsible for the epidemiologic findings. I will learn how to design, implement, and conduct such studies, how to recruit and retain patients, and how to analyze repeated measures data. I will learn about management of kidney stone patients and high risk obese and bariatric surgery patients from a patient-centered perspective. I am in a rich research environment at the University of Chicago. I have developed a strong mentorship team with world experts in human based studies of kidney stone physiology and CRC study design and implementation. My advisory team includes world leaders in basic science, translational, and human studies related to citrate and oxalate and an expert in bariatric surgery. This team will support my scientific and professional development. At the end of the K23 award, I will be prepared to use the data collected to apply for an R01 in a follow up intervention study that I will lead as an independent investigator. My future studies will build on the data and skills I learned from this study. Therefore, through the research experience, training, and mentorship from this award, I will become a leader in kidney stones research and clinical management, including obese and bariatric surgery patients, with the ultimate goal to improve patient care.