Identifying Risk Factors and Improving Risk Assessment for Nephrolithiasis

描述（由申请人提供）：肾结石是常见的，昂贵的，痛苦的。我们建议描述可能导致新的治疗或预防策略的肾结石（KS）危险因素（目标1），以确定与KS相关的严重可预防的合并症（目标2），并提供一种新的方法来评估对现有治疗的反应（目标3）。较高的尿钙是KS的主要危险因素。现有的钙磷调节激素对KS形成的人类研究被广泛引用，并对临床护理和KS研究产生了重大影响。然而，这些研究受到规模小、结果矛盾和/或横断面设计的限制。在Aim 1中，我们将在2400名参与者的前瞻性巢式病例对照研究中研究钙磷稳态血浆生物标志物与KS事件之间的关系，这些参与者使用了卫生专业人员随访研究和护士健康研究（NHS） II中的储存血液样本。动物KS模型和来自人类KS患者的数据表明，骨骼和肾脏的代谢异常通过增加骨骼钙的动员和增加尿钙的损失来降低骨矿物质密度。较高的尿钙与较低的骨密度有关。先前的报告，尽管数量少且未调整饮食摄入量，但表明患有KS的人骨折的风险更高。如果确定KS病史与髋部骨折风险之间的联系，则建议对患有KS的女性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Aim 2中，我们将对bbbb75000名绝经后的NHS I参与者进行一项前瞻性队列研究，研究KS病史与随后的中低创伤性髋部骨折风险之间的关系。在NHS I和其他队列研究中，钙摄入量和骨折之间没有明确的联系。然而，与没有KS的个体相比，KS患者的饮食钙含量较低，尿钙含量较高。因此，在5%的KS女性中，较高的钙摄入量可以缓解负钙平衡，降低随后的骨折风险。我们还将确定高钙摄入量是否与有KS病史的女性低或中度创伤性骨折风险降低独立相关。由于肾结石复发的有效治疗方法已经存在，我们也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Aim 3中，我们将确定在缅因州医学中心KS诊所的80名自由生活个体中，按24小时尿肌酐比例测量的尿样是否可以可靠地替代重复的24小时尿定量产石因子。

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.