Precision Medicine Approach to Vitamin D3 Administration in Critical Illness

项目总结 急性呼吸窘迫综合征(ARDS)是危重病的常见和破坏性并发症。 疾病，以及预防ARDS的有效治疗方法有限。维生素D代谢物有很强的效力 免疫调节作用和减轻动物模型中的急性器官损伤。随机对照试验 (RCT)正在进行以测试给予维生素D3(VitD3)是否能改善危重病人的预后 有患急性呼吸窘迫综合征的风险。然而，由于危重疾病的异质性，患者特有的因素可能起作用。 在决定对维生素D3的反应中起主要作用。我们将使用精确医学的方法来调查 临床、遗传和生化因素决定危重病患者对维生素D3治疗的反应。 这项建议是对NHLBI资助的维生素D的辅助研究，旨在通过利用 早期治疗(紫罗兰)试验，这是一项正在进行的多中心随机对照试验，招募了3000名危重患者。 有急性呼吸窘迫综合征和死亡的风险。患者被随机分配接受单剂54万国际单位的维生素T D3或安慰剂，以测试维生素D3是否减少90天的死亡率和急性器官损伤。紫罗兰正在存档 所有3000名患者在第0天采集血浆和DNA，前300名患者在第3天采集血浆。我们 建议在第三天收集额外500名患者的血浆(目标1)，并利用现有样本 (目标2和3)检验以下假设。 在目标1中，我们将使用第0天和第3天的配对血浆样本(n=400)来研究临床因素。 在危重疾病中影响维生素D3给药的药代动力学反应。我们将测试更大的 病情严重程度(SOFA评分较高)、肥胖、急性或慢性肝或肾脏疾病减轻 血浆25-羟基维生素D(25D)和1，25-二羟基维生素D(1，25D)水平从第0天增加到第3天 接受维生素D3治疗的患者。在目标2中，我们将调查预先指定的常见多态在 影响维生素D代谢的基因或维生素D靶基因确定的患者群体更有可能 受益于维生素D3治疗，通过90天死亡率(主要终点)和急性器官损伤进行评估 (次端点)。在目标3中，我们将调查较低的血浆成纤维细胞生长因子-23水平， 一种骨细胞衍生的激素，可以抑制25D到125D的转换，更多地识别患者群体 可能受益于维生素D3治疗，通过90天死亡率(主要终点)和急性器官评估 伤害(次要终点)。 开发一种用于危重疾病维生素D3给药的精确医学方法可能会 通过帮助为临床决策和设计提供信息，立即产生可操作的临床影响 未来维生素D代谢物在危重疾病中的试验。

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a common and devastating complication of critical illness, and effective therapies to prevent ARDS are limited. Vitamin D metabolites have potent immunomodulatory effects and attenuate acute organ injury in animal models. Randomized controlled trials (RCTs) are ongoing to test whether vitamin D3 (vit D3) administration improves outcomes in critically ill patients at risk of ARDS. However, due to the heterogeneous nature of critical illness, patient-specific factors likely play a major role in determining response to vit D3. We will use a precision medicine approach to investigate the clinical, genetic, and biochemical factors that determine response to vit D3 administration in critical illness. This proposal is an ancillary study to the NHLBI-funded Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, an ongoing, multicenter RCT that is enrolling 3000 critically ill patients at high risk of ARDS and death. Patients are randomly assigned to receive a single enteral dose of 540,000 I.U. of vit D3 or placebo to test whether vit D3 reduces 90-day mortality and acute organ injury. VIOLET is archiving plasma and DNA from all 3000 patients on day 0, and plasma on day 3 from the first 300 patients. We propose to collect plasma on day 3 from an additional 500 patients (Aim 1) and to leverage existing samples (Aims 2 and 3) to test the following hypotheses. In Aim 1 we will use paired plasma samples (n=400) from days 0 and 3 to investigate the clinical factors that affect the pharmacokinetic response to vit D3 administration in critical illness. We will test whether greater severity-of-illness (higher SOFA score), obesity, and acute or chronic liver or kidney disease attenuate increases in plasma 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) levels from day 0 to 3 in patients who receive vit D3. In Aim 2 we will investigate whether pre-specified common polymorphisms in genes affecting vitamin D metabolism or in vitamin D target genes identify a patient population more likely to benefit from vit D3 administration, assessed by 90-day mortality (primary endpoint) and acute organ injury (secondary endpoint). In Aim 3, we will investigate whether lower plasma levels of fibroblast growth factor-23, an osteocyte-derived hormone that inhibits the conversion of 25D to 1,25D, identify a patient population more likely to benefit from vit D3 administration, assessed by 90-day mortality (primary endpoint) and acute organ injury (secondary endpoint). Development of a precision medicine approach to vit D3 administration in critical illness could have immediate and actionable clinical impact by helping to inform both clinical decision making and the design of future trials of vitamin D metabolites in critical illness.