Nicotinamide Riboside for AKI in COVID-19 positive inpatients

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 wereassociated with AKI using standard Kidney Disease: Improving Global Outcomes (KDIGO) definition. Kidneycontain abundance of mitochondria and impaired mitochondrial function is now well recognized as a majorsusceptibility feature for AKI. It is generally believed based on histopathological evidence that the underlyingorigin 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 occurrenceand severity in both animal models and humans. Recent studies using oral Nicotinamide (NAM) andNicotinamide 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 undergoingcardiothoracic surgery showed reduced incidence of AKI in a small number of patients without any adverseevents. It has been demonstrated that NR is more orally bioavailable than NAM and has no major adverse eventsin Phase I studies. At the present time no standard medical treatment for AKI is available and supportive careremains the mainstay of therapy. Therefore, the application of agents to safely restore mitochondrial functionmay provide a major benefit for reduced incidence and severity of AKI and potentially lower multi-organ failureand mortality. We specifically hypothesize that at admission supplementation with NR will improve markers ofAKI including indices of mitochondrial function in SARS-CoV-2 patients without significant adverse events. Wewill test this hypothesis in a pilot clinical study named: NIRVANA: NIcotinamide Riboside in SARS-CoV-2pAtients for reNAl protection. The primary aim of this pilot study is to determine the effects of NR to reduceseverity 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 100SARS-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, andUniversity of Washington at Seattle (UW) will be enrolled into this pilot study. To evaluate secondary andexploratory outcomes, we will determine severity of AKI, the effects of NR on biomarkers of AKI andmitochondrial function by analyzing putative markers related to renal involvement, inflammation, andmetabolomics in timed biosamples collected from the study participants.