Nicotinamide Riboside for AKI in COVID-19 positive inpatients

烟酰胺核苷治疗 COVID-19 阳性住院患者的 AKI

基本信息

批准号：
10216107
负责人：
Kumar Sharma
金额：
$ 50.22万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216107
关键词：
18 year old 2019-nCoV Acute Renal Failure with Renal Papillary Necrosis Admission activity Adverse event Animal Model Bioavailable Biogenesis Biological Markers Blood COVID-19 Cardiac Output Cessation of life Clinical Research Clinical Trials Controlled Clinical Trials Dose Double-Blind Method Effectiveness Enrollment Exhibits Failure Functional disorder Guidelines Health Hematuria Hospitals Human Impairment Incidence Infection Inflammation Injury to Kidney Inpatients Institution Intensive Care Units Intervention Kidney Kidney Diseases Lead Life Liquid substance Measures Mechanical ventilation Medical Mitochondria Modeling Names New York New York City Niacinamide Nicotinamide adenine dinucleotide Obesity Operative Surgical Procedures Oral Organ Model Organ failure Outcome PPAR gamma Participant Pathway interactions Patients Perioperative Pharmaceutical Preparations Pilot Projects Placebos Pneumonia Pre-Clinical Model Predisposition Process Production Proteinuria Randomized Reperfusion Injury Reporting Research Role Septic Shock Severities Supplementation Supportive care Testing Texas Therapeutic Time Titrations Universities Urine Washington base blood pressure regulation cytokine release syndrome dietary supplements electron donor high risk human morbidity human mortality improved indexing medical schools metabolomics mortality nicotinamide-beta-riboside novel coronavirus pandemic disease phase 1 study prevent primary endpoint primary outcome pulmonary function targeted treatment

项目摘要

Project Summary / Abstract Acute kidney injury (AKI) has been as high as 68% in COVID-19 patients admitted to intensive care unit (ICU) and 90% in patients on mechanical ventilation in New York City, NY. Moreover, up to 86% of deaths were associated with AKI using standard Kidney Disease: Improving Global Outcomes (KDIGO) definition. Kidney contain abundance of mitochondria and impaired mitochondrial function is now well recognized as a major susceptibility feature for AKI. It is generally believed based on histopathological evidence that the underlying origin of AKI is inflammation or “cytokine storm” which suppresses PPAR-gamma-coactivator-1alpha (PGC1α) – the primary regulator of mitochondrial biogenesis and a regulator of nicotinamide adenine dinucleotide (NAD+). Lower availability of NAD+ limits existing mitochondrial function by reducing electron donors to the mitochondria. Stimulation of pathways that lead to enhancement of NAD+ appears to be beneficial in mitigating AKI occurrence and severity in both animal models and humans. Recent studies using oral Nicotinamide (NAM) and Nicotinamide Riboside (NR) as NAD+ donors have been found to be safe, well-tolerated, and upregulate NAD+ pathways in a dose-dependent manner. In addition, NAM use during perioperative period in patients undergoing cardiothoracic surgery showed reduced incidence of AKI in a small number of patients without any adverse events. It has been demonstrated that NR is more orally bioavailable than NAM and has no major adverse events in Phase I studies. At the present time no standard medical treatment for AKI is available and supportive care remains the mainstay of therapy. Therefore, the application of agents to safely restore mitochondrial function may provide a major benefit for reduced incidence and severity of AKI and potentially lower multi-organ failure and mortality. We specifically hypothesize that at admission supplementation with NR will improve markers of AKI including indices of mitochondrial function in SARS-CoV-2 patients without significant adverse events. We will test this hypothesis in a pilot clinical study named: NIRVANA: NIcotinamide Riboside in SARS-CoV-2 pAtients for reNAl protection. The primary aim of this pilot study is to determine the effects of NR to reduce severity of AKI in newly admitted patients with SARS-CoV-2 using a randomized, double-blinded placebo- controlled clinical trial of 10-day consecutive treatment with oral nicotinamide riboside (NR) 500 mg twice daily (versus placebo). The primary outcome will be incidence of AKI defined by the KDIGO guidelines. A total of 100 SARS-CoV-2 patients ≥18 years of age admitted to hospitals affiliated with 3 major medical academic institutions (University of Texas Health San Antonio (UTHSA), Icahn School of Medicine at Mount Sinai, New York, NY, and University of Washington at Seattle (UW) will be enrolled into this pilot study. To evaluate secondary and exploratory outcomes, we will determine severity of AKI, the effects of NR on biomarkers of AKI and mitochondrial function by analyzing putative markers related to renal involvement, inflammation, and metabolomics in timed biosamples collected from the study participants.

项目概要/摘要重症监护病房 (ICU) 收治的 COVID-19 患者中，急性肾损伤 (AKI) 率高达 68% 在纽约州纽约市，90% 的接受机械通气的患者死亡，高达 86%。使用标准肾脏疾病：改善全球结局 (KDIGO) 定义与 AKI 相关。含有丰富的线粒体，线粒体功能受损现在被公认为是一个主要的根据组织病理学证据，人们普遍认为 AKI 的易感性特征是潜在的。 AKI 的起源是炎症或抑制 PPAR-gamma-coactivator-1alpha (PGC1α) 的“细胞因子风暴” – 线粒体生物发生的主要调节剂和烟酰胺腺嘌呤二核苷酸 (NAD+) 的调节剂。 NAD+ 的可用性较低，通过减少线粒体的电子供体来限制现有的线粒体功能。刺激导致 NAD+ 增强的途径似乎有利于减轻 AKI 的发生最近使用口服烟酰胺（NAM）和人类的研究。烟酰胺核苷 (NR) 作为 NAD+ 供体已被发现是安全的、耐受性良好且上调 NAD+ 此外，NAM 在围术期患者中的使用呈剂量依赖性。心胸外科手术显示少数患者 AKI 发生率降低，且无任何不良反应已证明 NR 的口服生物利用度高于 NAM，并且没有重大不良事件。目前尚无 AKI 的标准治疗方法和支持性护理。因此，应用药物来安全地恢复线粒体功能仍然是治疗的支柱。可能为降低 AKI 的发生率和严重程度以及潜在地降低多器官衰竭提供重大益处我们特别指出，入院时补充 NR 将改善死亡率的指标。 AKI，包括 SARS-CoV-2 患者的线粒体功能指数，无明显不良事件。将在一项名为“NIRVANA：SARS-CoV-2 中的烟酰胺核苷”的试点临床研究中测试这一假设该试点研究的主要目的是确定 NR 对减少肾功能的影响。使用随机、双盲安慰剂对新入院的 SARS-CoV-2 患者中 AKI 的严重程度进行评估口服烟酰胺核苷 (NR) 500 mg 每天两次连续治疗 10 天的对照临床试验（与安慰剂相比）。主要结局是 KDIGO 指南定义的 AKI 发生率，总计 100。三大医学学术机构附属医院收治的≥18岁SARS-CoV-2患者（德克萨斯大学圣安东尼奥分校 (UTHSA)、纽约州西奈山伊坎医学院和西雅图华盛顿大学 (UW) 将参与这项试点研究，以评估中学和大学。探索性结果，我们将确定 AKI 的严重程度、NR 对 AKI 生物标志物的影响以及通过分析与肾脏受累、炎症和相关的假定标记物来确定线粒体功能从研究参与者收集的定时生物样本的代谢组学。