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.

项目总结/摘要 肾性骨营养不良（ROD）是一种皮质骨质量和强度的复杂疾病。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的共同作用 因为肾衰竭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。目前的ROD治疗目标是， 由于肾性甲状旁腺功能亢进导致骨转换率高，在存在低转换率的情况下禁忌 缺乏确定低流动率状态的可靠方法。肾脏疾病改善全球结果 （KDIGO）指南建议治疗由生物标志物PTH和骨特异性碱性磷酸酶指导。 磷酸酶（BSAP），而不是治疗时，营业额低。然而，尽管有这些建议，皮质- 在过去的25年里，透析患者中的2型骨折发生率翻了一番， 部分原因是PTH和BSAP被开发用于识别小梁骨而不是皮质骨的周转。此外─ 此外，尽管KDIGO推荐四环素标记的骨活检来确定周转和指导治疗， 组织形态计量学也是基于对骨小梁而非皮质骨的分析，后者是主要的骨组织形态计量学。 PTH作用部位。我们发表的初步数据表明，骨小梁周转率是皮质骨周转率的一个很差的替代品。 转换，骨室之间只有中度相关性（R2 59%）。因此，存在未满足的需求 为了鉴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质转换， 在没有或没有小梁转换的情况下使用，以指导治疗决策并用于临床试验。在我们 根据已发表的数据，我们假设一个先验定义的调节成骨细胞的microRNA（miRNA）子集， （miRNA-30 c，30 b，125 b）和破骨细胞（miRNA-155）的发育将是低皮质骨发育的准确生物标志物。 周转在23例骨活检的CKD患者中，用于区分低与非低的曲线下面积， miRNAs-30 b、30 c、125 b和155的低周转率分别为0.866、0.813、0.813和0.723， 四种miRNA组合的一组，而PTH和BSAP单独和一起在这方面没有区别 这个人口。基于这些发现，我们的中心假设是循环中的miRNAs区分ROD 皮质骨亚型在90例低、正常和高转换的CKD患者（30例/组;目标1）中，我们 将使用miRNAseq来鉴定与ROD类型相关的新型miRNA，并确定它们与 初步小组加强了歧视。在40例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转换的变化是否 如果循环miRNA组反映了骨组织中的miRNA， 压力。然后，我们将确定面板是否与骨质和强度相关（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。