Identifying Risk Factors and Improving Risk Assessment for Nephrolithiasis

描述（由申请人提供）：肾结石是常见的，昂贵，痛苦。我们建议描述可能导致新的治疗或预防策略的肾结石（KS）风险因素（目的1），以确定与KS相关的严重可预防的合并症（目的2），并提供一种新的方法来评估对现有疗法的反应（目的3）。高尿钙是KS的主要危险因素。钙磷调节激素对KS形成的现有人类研究被广泛引用，并对临床护理和KS研究产生重大影响。然而，这些研究受到样本量小、相互矛盾的结果和/或横断面设计的限制。在目标1中，我们将在2,400名参与者的前瞻性巢式病例对照研究中，使用卫生专业人员随访研究和护士健康研究（NHS）II中储存的血液样本，检查钙磷稳态的血浆生物标志物与KS事件之间的关联。动物KS模型和来自人类KS形成者的数据表明，骨骼和肾脏共有代谢异常，通过骨骼钙动员增加和尿钙丢失增加的组合降低骨矿物质密度。高尿钙与KS形成者的低骨密度相关。以前的报告，虽然小，未经调整的饮食摄入量，表明与KS的个人有较高的骨折风险。KS病史和髋部骨折风险之间的联系，如果建立，将建议KS妇女进行低骨密度的常规筛查，这可以预防许多髋部骨折病例。在目标2中，我们将在> 75，000名绝经后NHS I参与者中进行前瞻性队列研究，检查KS病史与随后的低至中度创伤性髋部骨折风险之间的相关性。在NHS I和其他队列研究中，钙摄入量与骨折之间没有明确的相关性。然而，KS形成者比没有KS的个体具有较低的膳食钙和较高的尿钙。因此，在5%的KS女性中，较高的钙摄入量可能会减轻负钙平衡并降低随后的骨折风险。我们还将确定是否较高的钙摄入量是独立相关的低或中度创伤骨折的风险降低，在妇女与KS的历史。由于肾结石复发的有效治疗方法已经存在，我们还旨在提供一种新的方法来提高对已证实的预防策略的依从性。在目标3中，我们将确定是否现场尿液样本缩放到24小时尿肌酐可以可靠地替代重复24小时尿液定量的致石因子在80个自由生活的个体从缅因州医疗中心KS诊所。

DESCRIPTION (provided by applicant): 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.