Bone Quality and Mechanical Competence In Chronic Kidney Disease

描述(由申请人提供)： 慢性肾脏病(CKD)的患病率正在迅速增加，CKD患者的骨折发生率比普通人群高得多。不幸的是，用双能X线骨密度仪(DXA)预测CKD患者的骨折风险比普通人群差，需要改进的成像方法来评估他们的骨折易感性。超高分辨率外周定量计算机断层扫描(HRpQCT；分辨率80-100um)是一种同时表征皮质和小梁微结构的新技术。有限元分析(FEA)是骨强度的一种测量方法，可以应用于HRpQCT数据集。这项应用的假设是，CKD分期3到5与小梁和皮质微结构进行性改变有关，这些改变降低了强度并增加了骨折易感性，HRpQCT和有限元分析在CKD患者中提供了比DXA更大的骨折鉴别能力。我们将在一项横断面研究中验证这一假设，研究对象为150名CKD分期为3到5的受试者(75名为骨折患者)。在一个子集中，我们将验证HRpQCT测量、已建立的和新的骨转换标志物与移行骨活检的组织形态计量学的对比。在CKD分期4的受试者(n=50)中，我们将纵向评估骨微结构与肾功能变化的关系。这项研究与公众健康高度相关，因为CKD患者的骨折风险及其相关的发病率和死亡率非常高，而且CKD和骨质疏松症高度常见。这个项目也构成了我五年职业发展计划的培训平台，其目标是让我成为CKD-矿物质和骨病(MBD)领域的独立临床研究员。该计划包括放射成像、高级生物统计学和流行病学方法方面的授课培训，HRpQCT、有限元分析和过渡骨活检的定量组织形态计量学方面的具体动手培训，与骨生物力学和骨细胞生物学领域的领先专家一起进行，并经常与我的导师和共同导师、代谢性骨疾病和CKD-MBD领域的领导者会面。在获奖期间，我将发展使用这些工具评估CKD患者骨强度的专业知识。在第四年，我将开始计划RO1提交。我在这个奖项中获得的技能和知识将使我发展成为一名富有成效的独立研究员，拥有在肾脏病和内分泌学领域不同寻常的技能。 公共卫生相关性：这项研究与公共健康高度相关，因为CKD患者的骨折风险及其相关的发病率和死亡率非常高，而且CKD和骨质疏松症高度常见。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) prevalence is increasing rapidly and fracture incidence is much higher in patients with CKD than in the general population. Unfortunately, fracture risk prediction by dual energy X-ray absorptiometry (DXA) is poorer among CKD patients than in the general population and improved imaging methods are necessary to evaluate their fracture susceptibility. Ultra high resolution peripheral quantitative computed tomography (HRpQCT; resolution 80-100 um) is a novel technology that characterizes both cortical and trabecular microarchitecture. Finite element analysis (FEA), a measure of bone strength, can be applied to HRpQCT data sets. The hypotheses of this application are that CKD stages 3 to 5 are associated with progressive alterations in trabecular and cortical microarchitecture that reduce strength and increase fracture susceptibility, and HRpQCT with FEA, will provide greater fracture discrimination than DXA in patients with CKD. We will test this hypothesis in a cross-sectional study of 150 subjects with CKD stages 3 to 5 (75 with fracture). In a subset, we will validate HRpQCT measurements, established and novel markers of bone turnover against histomorphometry of transiliac bone biopsies. In CKD stage 4 subjects (n=50) we will longitudinally evaluate bone microarchitecure in relation to changes in kidney function. This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent. This project also forms the training platform of my 5-year career development plan, the goal of which is to allow me to become an independent clinical investigator in the field of CKD-mineral and bone disorders (MBD). The plan includes didactic training in radiographic imaging, advanced biostatistics and epidemiological methods, specific hands-on training in HRpQCT, FEA and quantitative histomorphometry of transiliac bone biopsies with leading experts in the fields of bone biomechanics and bone cell biology, and frequent meetings with my mentor and co-mentor, leaders in the field of metabolic bone disease and CKD-MBD. During the award, I will develop expertise in using these tools to assess bone strength in CKD patients. In the fourth year, I will begin planning an RO1 submission. The skills and knowledge I acquire during this award will allow me to develop into a productive, independent investigator with a skill set that is unusual in the fields of nephrology and endocrinology. PUBLIC HEALTH RELEVANCE: This study is highly relevant to public health, as fracture risk and its associated morbidity and mortality are exceedingly high in CKD patients and CKD and osteoporosis are highly coprevalent.