Precision medicine approaches to renal osteodystrophy

肾性骨营养不良症的精准医学方法

• 批准号: 10539650
• 负责人: Matthew R Allen
• 金额: $ 58.11万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539650
• 关键词: Affect; Aftercare; Alkaline Phosphatase; Area Under Curve; Biochemical Markers; Biological Markers; Biomechanics; Biopsy; Blood; Blood Circulation; Bone Tissue; Cardiovascular system; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials; Complex; Data; Development; Dialysis patients; Discrimination; Disease; Disease Marker; Event; Failure; Fracture; Future; Goals; Gold; Guidelines; Histology; Hormones; Hyperparathyroidism; Impairment; Incidence; Individual; Investigation; Kidney; Kidney Diseases; Kidney Failure; Label; Measures; Mechanics; MicroRNAs; Minerals; Osteoblasts; Osteoclasts; Outcome; PTH gene; Patients; Performance; Peripheral; Population; Property; Publishing; Race; Raman Spectrum Analysis; Recommendation; Renal Osteodystrophy; Resolution; Risk; Site; Testing; Tetracyclines; Vitamin D; X-Ray Computed Tomography; base; biomarker panel; bone; bone loss; bone quality; bone strength; bone turnover; circulating microRNA; cohort; cortical bone; diagnostic accuracy; improved; long bone; microRNA biomarkers; nanoindentation; non-invasive imaging; noninvasive diagnosis; novel; precision medicine; prospective; sex; tool; treatment response

PROJECT SUMMARY/ABSTRACT Renal osteodystrophy (ROD) is a complex disorder of cortical bone quality and strength. Impaired cortical bone is due to the combined actions of elevated parathyroid hormone (PTH) levels and changes in bone hormones as a result of kidney failure. ROD affects nearly all patients with chronic kidney disease (CKD) and results in cortical bone loss, cortical-type fractures and cardiovascular events. The current goal of ROD treatment, to re- duce high bone turnover due to renal hyperparathyroidism, is contraindicated in the presence of low turnover yet reliable ways to determine low turnover status are lacking. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend that treatment is guided by the biomarkers PTH and bone specific alkaline phosphatase (BSAP) and not to treat when turnover is low. However, despite these recommendations, cortical- type fracture incidence has doubled in dialysis patients over the past 25-years, a failure in fracture reduction due in part to PTH and BSAP being developed to identify turnover in trabecular rather than cortical bone. Further- more, although KDIGO recommends tetracycline-labeled bone biopsy to define turnover and guide treatment, the histomorphometry is also based on analysis of trabecular and not cortical bone, the latter being the primary site of PTH action. Our published preliminary data suggest that trabecular turnover is a poor surrogate for cortical turnover, with only moderate correlations between bone compartments (R2 59%). Thus, there is an unmet need to identify biomarkers with high diagnostic accuracy and clinical utility for the identification of low cortical turnover, used without or without trabecular turnover, to guide treatment decisions and for use in clinical trials. In our published data, we hypothesized that an a priori defined subset of microRNAs (miRNA) that regulate osteoblast (miRNA-30c, 30b, 125b) and osteoclast (miRNA-155) development would be accurate biomarkers of low cortical turnover. In 23 CKD patients with bone biopsies, the areas under the curve for discrimination of low from non- low turnover were 0.866, 0.813, 0.813, and 0.723 for miRNAs-30b, 30c, 125b and 155 respectively, 0.925 for a panel of the 4 four miRNAs combined, while PTH and BSAP, individually and together, did not discriminate in this population. Based on these findings, our central hypothesis is that circulating miRNAs discriminate ROD cortical bone subtype. In a cohort of 90 CKD patients with low, normal, and high turnover (30/group; Aim 1) we will use miRNAseq to identify novel miRNAs that correlate with ROD type and determine if their combination with the preliminary panel enhances discrimination. In 40 ROD patients managed with strategies that change turnover from high to low or low to high (n=20/group; Aim 2), we will determine if changes in histology-based turnover are reflected by changes in the optimized panel and if the circulating miRNA panel mirrors bone-tissue miRNA ex- pression. Then, we will determine if the panel is related to bone quality and strength (Aim 3). Our results will determine if the circulating panel can serve as a biomarker for guiding ROD management. This high impact proposal has the potential to result in a paradigm shift in the non-invasive diagnosis and management of ROD.

项目摘要/摘要 肾骨营养不良（ROD）是一种复杂的皮质骨质量和强度疾病。皮质骨骼受损 是由于甲状旁腺激素（PTH）水平升高的综合作用以及骨骼激素的变化 由于肾衰竭。杆几乎影响所有患有慢性肾脏疾病（CKD）的患者，并导致 皮质骨质流失，皮质型骨折和心血管事件。 Rod治疗的当前目标，重新 由于肾脏甲状旁腺功能亢进而导致的高骨转换率是禁忌的 缺乏确定低离职状态的可靠方法。肾脏疾病改善了全球结果 （KDIGO）指南建议治疗以生物标志物PTH和骨骼特异性碱为指导 磷酸酶（BSAP），在营业额较低时不要治疗。但是，尽管有这些建议，但 在过去的25年中，透析患者的类型断裂发病率增加了一倍，减少骨折的失败 在某种程度上开发了PTH和BSAP，以鉴定小梁而不是皮质骨的周转率。更远- 更多，尽管Kdigo建议将四环素标记的骨活检定义营业额和指导治疗，但 组织形态法也基于小梁和不是皮质骨的分析，后者是主要的 PTH动作的位置。我们已发表的初步数据表明，小梁周转率是皮质的替代差。 营业额，仅在骨室之间具有适度的相关性（R2 59％）。因此，有未满足的需求 确定具有高诊断准确性和临床实用性的生物标志物，以鉴定低皮层营业额， 使用或没有小梁周转，用于指导治疗决策并用于临床试验。在我们的 已发布的数据，我们假设一个先验定义的microRNA（miRNA）调节成骨细胞的子集（miRNA） （miRNA-30c，30b，125b）和破骨细胞（miRNA-155）发育将是低皮质的精确生物标志物 周转。在23例骨骼活检的CKD患者中 MiRNAS-30B，30C，125B和155分别为0.866、0.813、0.813、0.813和0.723，A的0.925为0.925 4个四个miRNA的面板合并，而PTH和BSAP单独和一起，没有区分 这个人口。基于这些发现，我们的中心假设是循环miRNA区分杆 皮质骨亚型。在一组90个CKD患者中，流动率低，正常和高的患者（30/组； AIM 1）我们 将使用mirnaseq识别与杆类型相关的新型miRNA，并确定它们是否与 初步面板增强了歧视。在40名杆患者中，他们采用了改变营业额的策略 从高到低或低到高（n = 20/组； AIM 2），我们将确定基于组织学的周转的变化是否为 通过优化面板的变化反映出，循环miRNA面板是否反映了骨 - 组织mirna ex- 压力。然后，我们将确定面板是否与骨骼质量和强度有关（AIM 3）。我们的结果将会 确定循环面板是否可以用作指导杆管理的生物标志物。这种高影响力 提案有可能导致ROD的非侵入性诊断和管理的范式转移。