Dataset Information

Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

ABSTRACT: BACKGROUND:Preclinical studies have identified both NAD+ and sirtuin augmentation as potential strategies for the prevention and treatment of AKI. Nicotinamide riboside (NR) is a NAD+ precursor vitamin and pterostilbene (PT) is potent sirtuin activator found in blueberries. Here, we tested the effect of combined NR and PT (NRPT) on whole blood NAD+ levels and safety parameters in patients with AKI. METHODS:We conducted a randomized, double-blind, placebo-controlled study of escalating doses of NRPT in 24 hospitalized patients with AKI. The study was comprised of four Steps during which NRPT (5 subjects) or placebo (1 subject) was given twice a day for 2 days. NRPT dosing was increased in each Step: Step 1250/50?mg, Step 2500/100?mg, Step 3750/150?mg and Step 41,000/200?mg. Blood NAD+ levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. RESULTS:AKI resulted in a 50% reduction in whole blood NAD+ levels at 48?h compared to 0?h in patients receiving placebo (p?=?0.05). There was a trend for increase in NAD+ levels in all NRPT Steps individually at 48?h compared to 0?h, but only the change in Step 2 reached statistical significance (47%, p?=?0.04), and there was considerable interindividual variability in the NAD+ response to treatment. Considering all Steps together, NRPT treatment increased NAD+ levels by 37% at 48?h compared to 0?h (p?=?0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. CONCLUSION:NRPT increases whole blood NAD+ levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000?mg/200?mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. TRIAL REGISTRATION:NCT03176628 , date of registration June 5th, 2017.

SUBMITTER: Simic P

PROVIDER: S-EPMC7427083 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nicotinamide riboside with pterostilbene (NRPT) increases NAD<sup>+</sup> in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

Simic Petra P Vela Parada Xavier Fernando XF Parikh Samir M SM Dellinger Ryan R Guarente Leonard P LP Rhee Eugene P EP

BMC nephrology 20200813 1

<h4>Background</h4>Preclinical studies have identified both NAD<sup>+</sup> and sirtuin augmentation as potential strategies for the prevention and treatment of AKI. Nicotinamide riboside (NR) is a NAD<sup>+</sup> precursor vitamin and pterostilbene (PT) is potent sirtuin activator found in blueberries. Here, we tested the effect of combined NR and PT (NRPT) on whole blood NAD<sup>+</sup> levels and safety parameters in patients with AKI.<h4>Methods</h4>We conducted a randomized, double-blind, p ...[more]

PMID: 32791973

Similar Datasets

Project description:BACKGROUND:Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11?-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. METHODS:We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. RESULTS:H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability. CONCLUSIONS:These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.

Dataset Information

Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

Publications

Nicotinamide riboside with pterostilbene (NRPT) increases NAD<sup>+</sup> in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets