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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
4R01DK094910-04
Application #
9084542
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Kirkali, Ziya
Project Start
2013-07-22
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Ferraro, Pietro Manuel; Taylor, Eric N; Gambaro, Giovanni et al. (2018) Vitamin B6 intake and the risk of incident kidney stones. Urolithiasis 46:265-270
Ferraro, Pietro Manuel; Taylor, Eric N; Gambaro, Giovanni et al. (2017) Dietary and Lifestyle Risk Factors Associated with Incident Kidney Stones in Men and Women. J Urol 198:858-863
Ferraro, Pietro Manuel; Taylor, Eric N; Gambaro, Giovanni et al. (2017) Vitamin D Intake and the Risk of Incident Kidney Stones. J Urol 197:405-410
Prochaska, Megan; Taylor, Eric; Vaidya, Anand et al. (2017) Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones. Clin J Am Soc Nephrol 12:1284-1290
Taylor, Eric N; Feskanich, Diane; Paik, Julie M et al. (2016) Nephrolithiasis and Risk of Incident Bone Fracture. J Urol 195:1482-1486
Ferraro, Pietro Manuel; Mandel, Ernest I; Curhan, Gary C et al. (2016) Dietary Protein and Potassium, Diet-Dependent Net Acid Load, and Risk of Incident Kidney Stones. Clin J Am Soc Nephrol 11:1834-1844
Ferraro, Pietro Manuel; Curhan, Gary C; Gambaro, Giovanni et al. (2016) Total, Dietary, and Supplemental Vitamin C Intake and Risk of Incident Kidney Stones. Am J Kidney Dis 67:400-7
Prochaska, Megan L; Taylor, Eric N; Curhan, Gary C (2016) Insights Into Nephrolithiasis From the Nurses' Health Studies. Am J Public Health 106:1638-43
Taylor, Eric N (2015) Stones, bones, and cardiovascular groans. Clin J Am Soc Nephrol 10:174-6
Ferraro, Pietro Manuel; Curhan, Gary C; Sorensen, Mathew D et al. (2015) Physical activity, energy intake and the risk of incident kidney stones. J Urol 193:864-8

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