Nicotinamide Riboside for AKI in COVID-19 positive inpatients

项目摘要/摘要 在住进重症监护病房的新冠肺炎患者中，急性肾损伤的比例高达68%。 在纽约州纽约市，90%的患者接受机械通气。此外，高达86%的死亡是 与使用标准肾脏疾病的AKI相关：改善全球结局(KDIGO)定义。肾 含有丰富的线粒体和线粒体功能受损现在被公认为主要的 AKI的敏感性特征。人们普遍认为，根据组织病理学证据，潜在的 AKI的起源是炎症或抑制PPAR-γ-辅活化子-1α(Pgc1α)的“细胞因子风暴” -线粒体生物发生的主要调节者和烟酰胺腺嘌呤二核苷酸(NAD+)的调节者。 较低的NAD+可利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+增强的通路似乎有利于减轻AKI的发生 在动物模型和人类中都是如此。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+ 以一种剂量依赖的方式影响通路。此外，在接受手术的患者围手术期使用NAM 心胸外科手术显示，在少数患者中AKI的发生率降低，没有任何不良反应 事件。已经证明，与NAM相比，NR的口服生物利用度更高，并且没有重大不良事件 在第一阶段研究中。目前，AKI尚无标准的医疗治疗和支持性护理。 仍然是治疗的主力军。因此，应用药物安全恢复线粒体功能 可能为降低急性肾损伤的发生率和严重程度以及潜在的降低多器官衰竭提供重大益处 和死亡率。我们特别假设，在入院时补充NR将改善 AKI包括无明显不良反应的SARS-CoV-2患者的线粒体功能指标。我们 我将在一项名为：涅槃：SARS-CoV-2中的烟酰胺核苷的先导性临床研究中验证这一假设 患者要求肾脏保护。这项初步研究的主要目的是确定天然橡胶对降低 使用随机、双盲安慰剂对新入院的SARS-CoV-2患者AKI严重程度的影响 每日两次口服烟酰胺核苷500 mg连续治疗10天的临床对照试验 (与安慰剂相比)。主要结果将是KDIGO指南定义的AKI的发生率。总共有100个 SARS-CoV-2患者≥18岁住进三大医学学术机构附属医院 (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，以及 华盛顿大学西雅图分校(UW)将加入这项试点研究。评估第二级和第二级 探索性结果，我们将确定AKI的严重性，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 从研究参与者收集的定时生物样本中的代谢组学。

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.