Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) Syndrome in the Diabetic, Neuropathic Foot

项目摘要/摘要 糖尿病周围神经病变患者的非创伤性下肢截肢 (DPN)具有破坏性后果，最显著的是3年死亡率高达71%。数据来自我们的 之前的获奖周期支持足部、骨骼和血管通路，最终导致DPN患者的NLEA。 骨骼和血管恶化是无知觉足部NLEA的关键危险因素； 足部畸形、骨折和伤口愈合延迟。然而，目前的骨骼和血管通路 没有解释为什么DPN和终末期慢性肾脏疾病患者的NLEA发生率最高 (CKD)。我们认为CKD-矿物性骨病(CKD-MBD)是足部骨骼和 通往DPN相关NLEA的血管通路。CKD-MBD在髋部和冠状动脉/主动脉血管中被识别为 导致骨-血管矛盾，骨骼体积和强度丧失，血管钙化。 然而，CKD-MBD在DPN相关NLEA中的作用尚不清楚。因此，这份续签申请 将扩展我们的发现并测试CKD-MBD与DPN在 足部骨骼和血管恶化的途径使DPN足部处于NLEA的最高风险。 该应用程序将采用多站点、横截面(n=216)和纵向(n=114)的研究 CKD所有阶段的2型DPN患者：阶段1(无CKD)到5。通过此项目，我们的目标是：1) 量化CKD的严重程度和进展对足骨质、量和血管钙化的影响 (目标1)，2)确定CKD的效果，通过骨量和质量和足部血管介导 钙化，对临床相关的足部结果(目标2)，3)探索CKD的能力，骨质量和 数量和血管钙化变量来预测临床相关的不良足部预后的风险。 来自圣路易斯华盛顿大学、高点大学和华盛顿大学的调查小组 加州旧金山代表了集体和个人临床的独特和强大的结合 在DPN组织恶化、成像和CKD-MBD方面的研究专长。这个项目使用了高度创新的 测量个体足骨数量、质量和踏板血管的前沿技术和加工 CT钙化和足部骨皮质和骨小梁的隐匿性改变 使用高分辨率外周定量的全球骨密度测量中未反映的体系结构 计算机断层扫描(HR-pQCT)。最后，在我们的NLEA风险预测目标中，我们包括CKD-MBD血清 标记物(硬化剂)，这是将CKD-MBD研究从长凳转移到床边的关键一步。了解 通往NLEA的途径将改善对DPN患者的预防性护理和管理，以降低 NLEA，使CKD的预防和治疗不可或缺，确定药物靶点，以及 识别NLEA的危险因素，以便及早干预。

Project Summary/Abstract Non-traumatic lower extremity amputations (NLEA) in people with diabetic peripheral neuropathy (DPN) have devastating consequences, most notable a 3-year mortality rate of up to 71%. Data from our previous award cycle support a foot bone and vascular pathway culminating in NLEA in people with DPN. Bone and vascular deterioration were significantly related to key risk factors for NLEA in the insensate foot; foot deformity, fracture, and delayed wound healing. However, the current bone and vascular pathway does not explain why the highest rate of NLEA occurs in individuals with DPN and end-stage chronic kidney disease (CKD). We believe that CKD-mineral bone disorder (CKD-MBD) is the missing link in the foot bone and vascular pathway to DPN-associated NLEA. CKD-MBD is recognized, in the hip and coronary/aortic vessels, to induce a bone-vascular paradox with loss of skeletal bone volume and strength and vascular calcification. However, the contribution of CKD-MBD to DPN-associated NLEA is unknown. Thus, this renewal application will extend our discoveries and test the central hypothesis that CKD-MBD synergistically combines with DPN in the foot bone and vascular deterioration pathway to place the DPN foot at the highest risk for NLEA. This application will employ a multi-site, cross-sectional (n=216) and longitudinal (n=114), study of people with Type 2 DPN across all stages of CKD: stage 1(No CKD) to 5. Through this project we aim to: 1) quantify the effect of CKD severity and progression on pedal bone quality & quantity and vessel calcification (Aim 1), 2) determine the effect of CKD, mediated through bone quantity and quality and foot vessel calcification, on clinically relevant foot outcomes (Aim 2), 3) explore the ability of CKD, bone quality and quantity, and vascular calcification variables to predict risk for clinically relevant poor foot outcomes. The investigative team from Washington University in St. Louis, High Point University, and University of California San Francisco represents a unique and powerful combination of collective and individual clinical research expertise in DPN tissue deterioration, imaging, and CKD-MBD. This project uses highly innovative cutting-edge technology and processing to measure individual foot bone quantity & quality and pedal vessel calcification with computed tomography and hidden changes in foot bone cortical and trabecular micro- architecture that are not reflected in global measures of BMD using high resolution peripheral quantitative computed tomography (HR-pQCT). Finally, in our NLEA risk prediction aim we include a CKD-MBD serum marker (sclerostin), a critical step in translating CKD-MBD research from bench to bedside. Understanding the pathway to NLEA will improve preventative care and management of people with DPN to reduce the risk of NLEA by making CKD prevention and treatment indispensable, identifying pharmaceutical targets, and identifying risk factors of NLEA, allowing early intervention.