Comparative Safety and Efficacy of Low-dose Vitamin D in Kidney Failure

小剂量维生素 D 治疗肾衰竭的安全性和疗效比较

• 批准号: 10721791
• 负责人: Simon Hsu
• 金额: $ 18.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721791
• 关键词: Acceleration; Adherence; Agonist; Alkaline Phosphatase; Animals; Benefits and Risks; Blood Vessels; Bone Diseases; Calcitriol; Calcium; Cardiovascular Diseases; Cardiovascular system; Caring; Chronic Kidney Failure; Clinical; Clinical Trials; Complement; Complex; Databases; Deposition; Development Plans; Dialysis procedure; Discipline of Nursing; Disease; Dose; Electronic Health Record; Enrollment; Epidemiology; Event; Foundations; Future; Goals; Harm Reduction; Health Benefit; Hemodialysis; Hydroxyapatites; Hypercalcemia; Hyperparathyroidism; In Vitro; Interruption; Intervention; Intervention Trial; Intravenous; Kidney; Kidney Failure; Left Ventricular Hypertrophy; Maintenance; Measures; Mentors; Metabolic; Metabolism; Minerals; Normal Range; Oral; Osteogenesis; Outcome; PTH gene; Participant; Pathologic; Patients; Pharmaceutical Preparations; Physicians; Positioning Attribute; Process; Provider; Research; Research Design; Research Personnel; Retrospective cohort study; Risk; Safety; Scientist; Serum; Smooth Muscle Myocytes; Structure; Testing; Titrations; Training; Treatment Cost; Vascular Smooth Muscle; Vascular calcification; Vitamin D; Vitamin D3 Receptor; acceptability and feasibility; arterial stiffness; biomarker panel; bone; bone turnover; calcification; cardiovascular disorder risk; cardiovascular risk factor; career development; cinacalcet; clinical epidemiology; clinical practice; comparative efficacy; comparative safety; coronary perfusion; cost; design; epidemiologic data; experience; fibroblast growth factor 23; hospitalization rates; improved; inorganic phosphate; intravenous administration; meetings; mortality risk; multidisciplinary; osteogenic; patient oriented; practice setting; pragmatic trial; prevent; primary outcome; promoter; public health research; randomized, clinical trials; safety testing; skills; symposium; synergism; translational health science; treatment as usual; treatment strategy; trial design

PROJECT SUMMARY/ABSTRACT The components of chronic kidney disease-mineral and bone disorder (CKD-MBD) include calcitriol deficiency, hyperphosphatemia, and excesses of fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH), all of which consistently and strongly associate with cardiovascular disease (CVD) in patients with kidney failure on dialysis. Vascular calcifications are present in >80% of these patients and may be a mechanism through which CKD-MBD increases CVD risk. Intravenously-administered (IV) vitamin D receptor agonists (VDRA) are routinely used as first-line therapy for CKD-MBD in kidney failure, supported by experimental and epidemiological evidence that suggest VDRAs improve CVD and survival. However, the long-term risks and benefits of the current treatment approach, which encourages escalating VDRA doses to reduce PTH concentrations towards the normal range, have never been tested by clinical outcomes trials. This approach often leads to high VDRA doses which incur several risks: (1) a dose-dependent rise in FGF-23, a major risk factor for CVD that is associated with monotonically increasing risk of death in kidney failure; (2) hypercalcemia, a key promoter of vascular calcification; (3) low turnover bone disease, which drive calcium and phosphate into the vasculature because they cannot deposit into bone; (4) held doses of VDRA as a result of (2) and (3), which interrupts therapy and deprives patients of its likely health benefits. The goal of this project is to evaluate the safety, efficacy, and feasibility of a low fixed-dose vitamin D strategy to treat CKD-MBD in kidney failure to move the field towards identifying an optimal strategy that balances the risks and benefits of VDRA use. The two Aims proposed will leverage a unique partnership with Northwest Kidney Centers (NKC), the largest provider of dialysis in Seattle, WA. Aim 1 is a 12-month pragmatic randomized clinical trial of 90 NKC patients on hemodialysis that will compare the effects of a low fixed-dose oral calcitriol strategy (intervention) with the current usual care of PTH-titrated IV VDRAs (control) on a comprehensive panel of biomarkers assessing mineral metabolism, bone turnover, and serum calcification propensity, as well as measures of feasibility and acceptability. Aim 2 is a complementary retrospective cohort study using the NKC electronic health records database that will test associations between mean VDRA dose and variability in VDRA doses with CVD event and hospitalization rates. These Aims test whether a low fixed- dose vitamin D strategy has causal effects that improve intermediate outcomes (Aim 1) and associate with improved clinical outcomes (Aim 2), building a foundation for future large-scale clinical outcomes trials. Integrated with this research agenda is a career development plan designed to position me to become a successful independent investigator in the field of disordered mineral metabolism in CKD. This mentored approach to training includes regular meetings with co-mentors who are established leaders in multi- disciplinary fields, structured didactics, attendance at local and national conferences, and experiential training.

项目概要/摘要 慢性肾病-矿物质和骨骼疾病（CKD-MBD）的组成部分包括骨化三醇缺乏、 高磷血症以及成纤维细胞生长因子 23 (FGF-23) 和甲状旁腺激素 (PTH) 过量，所有这些 其中与肾衰竭患者的心血管疾病 (CVD) 始终密切相关 进行透析。超过 80% 的患者存在血管钙化，这可能是一种机制 CKD-MBD 会增加 CVD 风险。静脉注射 (IV) 维生素 D 受体激动剂 (VDRA) 是 常规用作肾衰竭 CKD-MBD 的一线治疗，并得到实验和研究的支持 流行病学证据表明 VDRAs 可以改善 CVD 和生存率。然而，长期风险和 当前治疗方法的好处，鼓励增加 VDRA 剂量以减少 PTH 浓度接近正常范围，从未经过临床结果试验测试。这种做法 通常会导致高 VDRA 剂量，从而引发多种风险：(1) FGF-23 剂量依赖性升高，这是一个主要风险 与肾衰竭死亡风险单调增加相关的 CVD 因素； (2) 高钙血症，血管钙化的关键促进因素； (3)低周转性骨病，导致钙的流失 磷酸盐进入脉管系统，因为它们不能沉积到骨骼中； (4) 因此持有 VDRA 剂量 (2) 和 (3)，这会中断治疗并剥夺患者可能的健康益处。 该项目的目标是评估低固定剂量维生素 D 策略的安全性、有效性和可行性 治疗肾衰竭中的 CKD-MBD 推动该领域确定平衡的最佳策略 使用 VDRA 的风险和好处。拟议的两个目标将利用与西北航空的独特合作伙伴关系 肾脏中心 (NKC) 是华盛顿州西雅图最大的透析提供商。目标1是为期12个月的务实 对 90 名接受血液透析的 NKC 患者进行的随机临床试验，比较低固定剂量的效果 口服骨化三醇策略（干预）与目前 PTH 滴定 IV VDRAs 的常规护理（对照） 评估矿物质代谢、骨转换和血清钙化的综合生物标志物组 倾向以及可行性和可接受性的衡量标准。目标 2 是一个互补的回顾性队列 使用 NKC 电子健康记录数据库进行的研究将测试平均 VDRA 剂量之间的关联 VDRA 剂量随 CVD 事件和住院率的变化。这些目标测试是否低固定 维生素 D 剂量策略具有改善中间结果（目标 1）的因果效应，并与 改善临床结果（目标 2），为未来大规模临床结果试验奠定基础。 与该研究议程相结合的是一个职业发展计划，旨在使我成为一名 CKD 矿物质代谢紊乱领域的成功独立研究者。此次辅导的 培训方法包括与共同导师定期举行会议，这些导师是多领域公认的领导者 学科领域、结构化教学、参加地方和国家会议以及体验式培训。