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 肾性骨营养不良(Rod)是一种复杂的皮质骨质量和强度障碍。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的结果 是肾衰竭的结果。Rod影响几乎所有慢性肾脏疾病(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- 由于肾性甲状旁腺机能亢进症导致的高骨转换，在低转换的情况下是禁忌症。 缺乏可靠的方法来确定低周转率状态。肾脏疾病改善全球预后 (KDIGO)指南建议治疗应以生物标记物甲状旁腺素和骨特异性碱性为指导。 磷酸酶(BSAP)和不治疗时，营业额低。然而，尽管有这些建议，皮质- 在过去的25年中，透析患者的类型性骨折发生率翻了一番，这是由于骨折复位失败 部分原因是甲状旁腺激素和BSAP被开发用来识别骨小梁而不是皮质骨的转换。进一步- 此外，尽管KDIGO建议用四环素标记的骨活检来确定周转和指导治疗， 组织形态计量学也基于对骨小梁的分析，而不是皮质骨，后者是主要的 PTH操作的位置。我们已发表的初步数据表明，骨小梁周转率不能很好地替代皮质骨 周转率，只有中等相关的骨室(R2 59%)。因此，有一种未得到满足的需求。 为了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转换率， 在没有或没有骨小梁翻转的情况下使用，用于指导治疗决定和用于临床试验。在我们的 在已发表的数据中，我们假设了一个先验定义的、调节成骨细胞的microRNAs(MiRNA)子集 (miRNA-30c、30b、125b)和破骨细胞(miRNA-155)发育可能是低皮质的准确生物标志物 营业额。在23例CKD患者的骨活检中，曲线下面积区分低与非低 成交量低的miRNA-30b、30c、125b和155b分别为0.866、0.813、0.813和0.723，a为0.925 四个miRNAs组合的小组，而PTH和BSAP单独和一起没有歧视 这群人。基于这些发现，我们的中心假设是循环中的miRNAs区别于杆状 皮质骨亚型。在90名低周转率、正常周转率和高周转率的CKD患者中(30例/组；目标1) 将使用miRNAseq来识别与Rod类型相关的新miRNAs，并确定它们是否与 预审小组加强了歧视。在40名采用改变周转策略的ROD患者中 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营业额变化是否 反映在优化的面板中的变化，以及循环miRNA面板是否反映了骨组织miRNA ex. 压迫感。然后，我们将确定该面板是否与骨骼质量和强度有关(目标3)。我们的结果将 确定循环板是否可以作为指导棒管理的生物标志物。如此高的冲击力 该提议有可能导致Rod的非侵入性诊断和管理的范式转变。