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

糖尿病神经性足部的慢性肾病-矿物质骨紊乱 (CKD-MBD) 综合征

• 批准号: 10734640
• 负责人: MARY K HASTINGS
• 金额: $ 73.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734640
• 关键词: Affect; Age; Amputation; Aorta; Award; Blood Vessels; Bone Density; Bone Diseases; Bone remodeling; California; Chronic Kidney Failure; Clinical Research; Coronary; Data; Deformity; Deterioration; Diabetes Mellitus; Diabetic Foot; Disease Progression; Early Intervention; Foot Deformities; Fracture; Glomerular Filtration Rate; Hip region structure; Image; Impaired wound healing; Impairment; Individual; Injury to Kidney; Intervention; Kidney Diseases; Link; Lower Extremity; Measurement; Measures; Mediating; Methods; Minerals; Monitor; Natural regeneration; Neuropathy; Osteocytes; Outcome; Participant; Pathway interactions; Perfusion; Peripheral; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Porosity; Predisposing Factor; Prevention; Preventive care; Radiology Specialty; Renal function; Research; Resolution; Risk; Risk Factors; Risk Reduction; Role; San Francisco; Serum Markers; Severity of illness; Site; Skeletal bone; Smoking; Smooth Muscle; Syndrome; Technology; Testing; Tissues; Translating; Trees; Type 2 diabetic; Ulcer; Universities; Vascular calcification; Washington; Weight; Work; X-Ray Computed Tomography; bench to bedside; bone; bone loss; bone quality; calcification; chronic ulcer; clinical practice; clinical risk; clinically relevant; cortical bone; diabetic; disorder prevention; follow-up; foot; foot bone; high risk; improved; inhibitor; innovation; mortality; repaired; response; risk prediction; sex

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.

项目摘要/摘要 糖尿病周围神经病患者的非创伤下肢截肢（NLEA） （DPN）具有毁灭性后果，最值得注意的是3年死亡率高达71％。来自我们的数据 先前的奖励周期支持DPN患者NLEA的脚骨和血管途径。 骨骼和血管恶化与不敏感的脚内NLEA的关键危险因素显着相关。 脚畸形，骨折和延迟伤口愈合。但是，当前的骨骼和血管途径确实 不能解释为什么DPN和终末期慢性肾脏疾病的个体中最高的NLEA发生率 （CKD）。我们认为CKD时段骨障碍（CKD-MBD）是脚骨和 DPN相关NLEA的血管途径。 CKD-MBD在臀部和冠状动脉/主动脉血管中被确认为 诱导骨骼血管悖论，骨骼骨骼体积和强度和血管钙化的损失。 但是，CKD-MBD对DPN相关的NLEA的贡献尚不清楚。因此，此更新应用 将扩展我们的发现并检验CKD-MBD协同结合DPN的中心假设 脚骨和血管劣化途径将DPN脚的NLEA风险最高。 该应用将采用多站点，横截面（n = 216）和纵向（n = 114），研究 CKD的所有阶段的2型DPN的人：1阶段（无CKD）至5。通过此项目，我们的目标是：1） 量化CKD严重程度和进展对踏板骨质质量和数量和血管钙化的影响 （AIM 1），2）确定CKD的效果，通过骨骼数量和质量和脚部介导 钙化，在临床上相关的脚部结果（AIM 2），3）探索CKD，骨骼质量和 数量和血管钙化变量，以预测临床上相关的脚部不良结局的风险。 来自圣路易斯，高点大学华盛顿大学和大学的调查团队 加利福尼亚旧金山代表了集体和个人临床的独特而有力的组合 DPN组织恶化，成像和CKD-MBD的研究专业知识。该项目使用高度创新的 尖端技术和处理以测量单个脚骨数量和质量和踏板容器 计算机断层扫描和脚骨皮质和小梁微型的隐藏变化的钙化 使用高分辨率外围定量的体系结构未反映在BMD的全球度量中 计算机断层扫描（HR-PQCT）。最后，在我们的NLEA风险预测目的中，我们包括CKD-MBD血清 Marker（Sclerostin），将CKD-MBD研究从长凳转换为床边的关键步骤。了解 通往NLEA的途径将改善DPN患者的预防护理和管理，以降低 NLEA通过使CKD预防和治疗必不可少，确定药物目标，并 确定NLEA的危险因素，允许早期干预。

项目成果

Body mass index and maximum available midfoot motion are associated with midfoot angle at peak heel rise in people with type 2 diabetes mellitus and peripheral neuropathy.

• DOI: 10.1016/j.foot.2022.101912
• 发表时间: 2022-05
• 期刊: Foot (Edinburgh, Scotland)
• 作者: Jeong, Hyo-Jung;Mueller, Michael J;Zellers, Jennifer A;Commean, Paul K;Chen, Ling;Hastings, Mary K
• 通讯作者: Hastings, Mary K

Midfoot and ankle movement coordination during heel rise is disrupted in people with diabetes and peripheral neuropathy.

• DOI: 10.1016/j.clinbiomech.2022.105662
• 发表时间: 2022-06
• 期刊: Clinical biomechanics (Bristol, Avon)

Midfoot and ankle motion during heel rise and gait are related in people with diabetes and peripheral neuropathy.

• DOI: 10.1016/j.gaitpost.2020.11.013
• 发表时间: 2021-03
• 期刊: Gait & posture
• 影响因子: 2.4
• 作者: Jeong HJ;Mueller MJ;Zellers JA;Hastings MK
• 通讯作者: Hastings MK

A limited number of slices yields comparable results to all slices in foot intrinsic muscle deterioration ratio on computed tomography and magnetic resonance imaging.

• DOI: 10.1016/j.jbiomech.2021.110750
• 发表时间: 2021-12-02
• 期刊: JOURNAL OF BIOMECHANICS
• 影响因子: 2.4
• 作者: Zellers, Jennifer A.;Commean, Paul K.;Chen, Ling;Mueller, Michael J.;Hastings, Mary K.
• 通讯作者: Hastings, Mary K.