Nicotinamide and acute kidney injury

Abstract

In a recent issue of ckj, Piedrafita et al. reported that urine tryptophan and kynurenine are reduced in cardiac bypass surgery patients that develop acute kidney injury (AKI), suggesting reduced activity of the kynurenine pathway of nicotinamide (NAM) adenine dinucleotide (NAD⁺) synthesis from tryptophan. However, NAM supplementation aiming at repleting NAD⁺ did not replete kidney NAD⁺ and did not improve glomerular filtration or reduce histological injury in ischaemic-reperfusion kidney injury in mice. The lack of improvement of kidney injury is partially at odds with prior reports that did not study kidney NAD⁺, glomerular filtration or histology in NAM-treated wild-type mice with AKI. We now present an overview of research on therapy with vitamin B3 vitamers and derivate molecules {niacin, Nicotinamide [NAM; niacinamide], NAM riboside [Nicotinamide riboside (NR)], Reduced nicotinamide riboside [NRH] and NAM mononucleotide} in kidney injury, including an overview of ongoing clinical trials, and discuss the potential explanations for diverging reports on the impact of these therapeutic approaches on pre-clinical acute and chronic kidney disease.

Keywords: NAD; acute kidney injury; chronic kidney disease; nicotinamide; treatment; vitamin B3.

FIGURE 1:

NAD⁺ metabolic pathways. NAD⁺ production from NAM or from NR consists of two steps, while production from niacin includes three enzymatic reactions and is known as the Preiss–Handler pathway. In contrast, NAD⁺ synthesis from tryptophan through the kynurenine pathway requires six enzymatic steps to yield quinolinic acid, which is then transformed to NAMN that, in turn, is the precursor of NAD⁺ in the Preiss–Handler pathway. NAD⁺ levels can be decreased by enzyme such as CD38, CD157 and SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1). CD38 also degrades NR and NMN [3]. Tryptophan may also be a source of uraemic toxins, which are either metabolites of the kynurenine pathway or of indole, which is generated by bacterial tryptophanase in the gut.

FIGURE 2:

Dietary sources of vitamin B3 vitamers and pharmacological dosing of niacin. Pharmacological doses of niacin are over 100-fold higher that the US recommended dietary allowance. The size of each square is proportional to the magnitude of the dose.

FIGURE 3:

Clinical trials of vitamin B3 vitamers, according to ClinicalTrials.gov (accessed on 10 July 2021). (A) Completed and ongoing clinical trials involving the vitamin B3 vitamers, NAM, niacin and NR. Note that most completed trials tested niacin, followed by NAM and NR. In contrast, most ongoing trials are testing NR. (B) Completed clinical trials involving persons with CKD or prevention or treatment of AKI. (C) Ongoing clinical trials involving persons with CKD or prevention or treatment of AKI. As is the case for other trials, a shift can be observed in kidney disease to testing of NR as well as an increasing interest in AKI.

FIGURE 4:

Dosing schedules and outcomes of pre-clinical studies in AKI. (A) Cisplatin AKI. (B) IRI AKI.