Precision medicine approaches to renal osteodystrophy

肾性骨营养不良症的精准医学方法

• 批准号: 10685341
• 负责人: Matthew R Allen
• 金额: $ 55万
• 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/10685341
• 关键词: Affect; Aftercare; Alkaline Phosphatase; Area Under Curve; Biochemical Markers; Biological Markers; Biomechanics; Biopsy; Blood; Bone Tissue; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Circulation; Clinic; Clinical; Clinical Trials; Complex; Data; Development; Dialysis patients; Discrimination; Disease; Disease Marker; Event; Failure; Fracture; Future; Goals; 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; Publications; Publishing; Race; Raman Spectrum Analysis; Recommendation; Renal Osteodystrophy; Resolution; Risk; Site; Testing; Tetracyclines; Vitamin D; X-Ray Computed Tomography; biomarker identification; biomarker panel; bone; bone loss; bone quality; bone strength; bone turnover; circulating microRNA; cohort; cortical bone; diagnostic accuracy; improved; long bone; microRNA biomarkers; nanoindentation; nanomechanics; 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.

项目概要/摘要 肾性骨营养不良 (ROD) 是一种复杂的皮质骨质量和强度疾病。皮质骨受损 是由于甲状旁腺激素 (PTH) 水平升高和骨激素变化共同作用所致 由于肾衰竭。 ROD 影响几乎所有慢性肾病 (CKD) 患者，并导致 皮质骨丢失、皮质型骨折和心血管事件。目前ROD治疗的目标是重新 因肾性甲状旁腺功能亢进引起骨转换率高，但在骨转换率低的情况下是禁忌的 缺乏确定低流动率状态的可靠方法。肾脏疾病改善全球成果 (KDIGO) 指南建议以生物标志物 PTH 和骨特异性碱性物质为指导进行治疗 磷酸酶（BSAP），并且在周转率低时不进行治疗。然而，尽管有这些建议，皮质- 过去25年里，透析患者的骨折发生率翻了一番，骨折复位失败是由于 部分原因是 PTH 和 BSAP 的开发是为了识别小梁骨而不是皮质骨的更新。更远- 此外，尽管 KDIGO 建议进行四环素标记的骨活检来确定周转率并指导治疗， 组织形态计量学也基于小梁骨而不是皮质骨的分析，后者是主要的 PTH 作用位点。我们发表的初步数据表明，小梁周转率不能很好地替代皮质周转率。 周转率，骨区之间只有中等相关性（R2 59%）。因此，存在未满足的需求 识别具有高诊断准确性和临床实用性的生物标志物，以识别低皮质周转率， 在有或没有小梁周转的情况下使用，以指导治疗决策并用于临床试验。在我们的 发表的数据中，我们假设先验定义的调节成骨细胞的 microRNA (miRNA) 子集 (miRNA-30c、30b、125b) 和破骨细胞 (miRNA-155) 发育将是低皮质的准确生物标志物 周转。在 23 名进行骨活检的 CKD 患者中，区分低骨和非骨的曲线下面积 miRNA-30b、30c、125b 和 155 的低周转率分别为 0.866、0.813、0.813 和 0.723，a 的低周转率分别为 0.925。 4 个 miRNA 的组合组合，而 PTH 和 BSAP，单独和一起，在 这个人口。基于这些发现，我们的中心假设是循环 miRNA 区分 ROD 皮质骨亚型。在 90 名具有低周转率、正常周转率和高周转率的 CKD 患者（30 人/组；目标 1）组成的队列中，我们 将使用 miRNAseq 来识别与 ROD 类型相关的新 miRNA，并确定它们是否与 初步小组加剧了歧视。 40 名 ROD 患者采用改变营业额的策略进行治疗 从高到低或从低到高（n=20/组；目标 2），我们将确定基于组织学的周转率的变化是否 通过优化面板的变化以及循环 miRNA 面板是否反映了骨组织 miRNA 的变化来反映 压力。然后，我们将确定该面板是否与骨质量和强度相关（目标 3）。我们的结果将 确定循环面板是否可以作为指导 ROD 管理的生物标志物。这种高冲击力 该提案有可能导致 ROD 非侵入性诊断和管理的范式转变。