Nicotinamide Riboside for AKI in COVID-19 positive inpatients

项目概要/摘要 在重症监护室（ICU）收治的COVID-19患者中，急性肾损伤（阿基）高达68% 在纽约州纽约市的机械通气患者中为90%。此外，高达86%的死亡是 使用标准肾脏疾病：改善全球结局（KDIGO）定义与阿基相关。肾 含有丰富的线粒体和受损的线粒体功能，现在被公认为是一个主要的 阿基的易感性特征。基于组织病理学证据，通常认为， 阿基的起源是炎症或抑制PPAR-gamma-coactivator-1 α（PGC 1 α）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+的较低可用性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阿基的发生 和严重程度。最近使用口服烟酰胺（NAM）和 烟酰胺核苷（NR）作为NAD+供体已被发现是安全的，耐受性良好，并上调NAD+ 以剂量依赖的方式。此外，NAM在围手术期的使用， 心胸外科手术显示少数患者阿基的发生率降低， 事件已证明NR的口服生物利用度高于NAM，且无重大不良事件 在第一阶段的研究中。目前还没有针对阿基的标准医学治疗， 仍然是治疗的主要手段因此，应用药物安全地恢复线粒体功能 可能为降低阿基的发生率和严重程度以及潜在降低多器官衰竭提供主要益处 and mortality.我们特别假设，在入院时补充NR将改善 阿基包括SARS-CoV-2患者的线粒体功能指数，无显著不良事件。我们 我将在一项名为NIRVANA：SARS-CoV-2中的烟酰胺核苷的初步临床研究中检验这一假设 对病人进行肾保护。这项初步研究的主要目的是确定NR对减少 使用随机、双盲安慰剂，在新入院的SARS-CoV-2患者中评估阿基的严重程度， 口服烟酰胺核苷（NR）500 mg每日两次连续治疗10天的对照临床试验 （相对于安慰剂）。主要结局将是KDIGO指南定义的阿基发生率。共100 三大医学学术机构所属医院收治的≥18岁SARS-CoV-2患者 （德克萨斯大学健康圣安东尼奥分校（UTHSA），纽约州纽约西奈山伊坎医学院，以及 华盛顿大学西雅图分校（UW）将入组本项初步研究。评估次级和 探索性结果，我们将确定阿基的严重程度，NR对阿基生物标志物的影响， 线粒体功能，通过分析与肾脏受累、炎症和 从研究参与者收集的定时生物样品中的代谢组学。

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.