Nicotinamide Riboside for AKI in COVID-19 positive inpatients

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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.