Kidney stones are common, costly, and painful. We propose to delineate kidney stone (KS) risk factors that may lead to new treatment or prevention strategies (Aim 1), to identify a serious preventable co-morbidity associated with KS (Aim 2), and to provide a new way to assess response to existing therapies (Aim 3). Higher urine calcium is a major risk factor for KS. Existing human studies of calcium-phosphorus regulatory hormones on KS formation are widely cited and substantially impact clinical care and KS research. However, these studies are limited by small size, conflicting results, and/or cross-sectional design.
In Aim 1, we will examine associations between plasma biomarkers of calcium-phosphorus homeostasis and incident KS in prospective nested case-control studies of 2,400 participants using stored blood samples in the Health Professionals Follow-up Study and the Nurses'Health Study (NHS) II. Animal KS models and data from human KS formers suggest a metabolic abnormality shared by bone and kidney that decreases bone mineral density via a combination of increased mobilization of skeletal calcium and increased loss of urine calcium. Higher urine calcium is associated with lower bone mineral density in KS formers. Previous reports, albeit small and unadjusted for dietary intakes, suggest that individuals with KS have higher risk of bone fracture. A link between KS history and hip fracture risk, if established, woul suggest routine screening for low bone mineral density in women with KS, which could prevent many cases of hip fracture.
In Aim 2, we will conduct a prospective cohort study in >75,000 postmenopausal NHS I participants examining associations between KS history and subsequent risk of low to moderate trauma hip fracture. In NHS I and other cohort studies there are no definitive associations between intakes of calcium and bone fracture. However, KS formers have lower dietary calcium and higher urinary calcium than individuals without KS. Thus, in the 5% of women with KS, higher intakes of calcium may mitigate negative calcium balance and reduce subsequent fracture risk. We also will determine whether higher calcium intake is independently associated with decreased risk of low or moderate trauma fracture in women with a history of KS. Because effective treatments for kidney stone recurrence already exist, we also aim to provide a new way of improving adherence to proven prevention strategies.
In Aim 3, we will determine whether spot urine samples scaled to 24-hour urine creatinine can reliably substitute for repeat 24-hour urine quantifications of lithogenic factors i 80 free-living individuals from the Maine Medical Center KS clinic.

Public Health Relevance

The delineation of kidney stone risk factors that may lead to new treatment/prevention strategies and the identification of serious, preventable co-morbidities associated with kidney stones are vital public health issues: kidney stones are common, costly, and painful. In prospective nested case-control studies and cohort studies including more than 75,000 women and men, we will examine associations between calcium-phosphorus regulatory hormones and kidney stone risk and will determine the relations between kidney stone history, calcium intake, and risk of hip fracture. Finally, we aim to provide a new way of improving patient adherence to existing kidney stone prevention strategies by determining whether spot urine samples can reliably substitute for 24-hour urine samples as a means of following urinary response to therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
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Kirkali, Ziya
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Brigham and Women's Hospital
United States
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