The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury

Background: Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD⁺) production was identified after acute kidney injury (AKI), leading to the hypothesis that supplementation with NAM may increase the kidney NAD⁺ content, rescuing tryptophan pathways and subsequently improving kidney outcomes.

Methods: Urinary measurement of tryptophan and kynurenin using liquid chromatography-mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia-reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used.

Results: We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve [AUC] 0.82 [95% confidence interval (CI) 0.75-0.88] and 0.75 [0.68-0.83], respectively} and severe KDIGO Stages 2-3 AKI [AUC 0.71 (95% CI 0.6-0.81) and 0.66 (0.55-0.77), respectively]. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin-fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid-Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD⁺ kidney content.

Conclusion: Notwithstanding the potential role of NAM supplementation in the setting of basal NAD⁺ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients.