Urinary Excretion of N1-Methylnicotinamide, as a Biomarker of Niacin Status, and Mortality in Renal Transplant Recipients

Abstract

Renal transplant recipients (RTR) commonly suffer from vitamin B6 deficiency and its functional consequences add to an association with poor long-term outcome. It is unknown whether niacin status is affected in RTR and, if so, whether this affects clinical outcomes, as vitamin B6 is a cofactor in nicotinamide biosynthesis. We compared 24-h urinary excretion of N1-methylnicotinamide (N1-MN) as a biomarker of niacin status in RTR with that in healthy controls, in relation to dietary intake of tryptophan and niacin as well as vitamin B6 status, and investigated whether niacin status is associated with the risk of premature all-cause mortality in RTR. In a prospective cohort of 660 stable RTR with a median follow-up of 5.4 (4.7–6.1) years and 275 healthy kidney donors, 24-h urinary excretion of N1-MN was measured with liquid chromatography-tandem mass spectrometry LC-MS/MS. Dietary intake was assessed by food frequency questionnaires. Prospective associations of N1-MN excretion with mortality were investigated by Cox regression analyses. Median N1-MN excretion was 22.0 (15.8–31.8) μmol/day in RTR, compared to 41.1 (31.6–57.2) μmol/day in healthy kidney donors (p < 0.001). This difference was independent of dietary intake of tryptophan (1059 ± 271 and 1089 ± 308 mg/day; p = 0.19), niacin (17.9 ± 5.2 and 19.2 ± 6.2 mg/day; p < 0.001), plasma vitamin B6 (29.0 (17.5–49.5), and 42.0 (29.8–60.3) nmol/L; p < 0.001), respectively. N1-MN excretion was inversely associated with the risk of all-cause mortality in RTR (HR 0.57; 95% CI 0.45–0.71; p < 0.001), independent of potential confounders. RTR excrete less N1-MN in 24-h urine than healthy controls, and our data suggest that this difference cannot be attributed to lower dietary intake of tryptophan and niacin, nor vitamin B6 status. Importantly, lower 24-h urinary excretion of N1-MN is independently associated with a higher risk of premature all-cause mortality in RTR.

Urinary Excretion of N1-methyl-2-pyridone-5-carboxamide and N1-methylnicotinamide in Renal Transplant Recipients and Donors

“…The WHO and the EFSA recommend the 24-h urinary excretion of N 1 -MN for laboratory assessment of niacin nutritional status accordingly [3,4]. In a previous study, we found that N 1 -MN excretion is clearly reduced in RTR compared to healthy kidney donors [12]. The fact that this is paralleled by a significant elevation of 2Py excretion in the present study, raises speculation that enhanced enzymatic conversion of N 1 -MN to 2Py by AOX1 may be present in RTR.…”

“…Baseline characteristics of RTR and the total cohort of kidney donors were compared by means of t, Mann-Whitney, and Chi-Square tests, of which age, sex, body surface area, N 1 -MN excretion and eGFR have been reported previously [12]. Crude associations of 2Py and N 1 -MN excretion with intake of niacin equivalents were investigated with linear regression analyses.…”

“…Signed informed consent was obtained from all participating subjects and the study protocol was approved by the institutional review board (METc 2008/186) adhering to the Declaration of Helsinki. This study included the same cohort of 660 RTR and 275 kidney donors for data collection as reported previously [12]. In a recent study, we found that N 1 -MN excretion is lower in renal transplant recipients (RTR) than in healthy controls [12].…”

“…This study included the same cohort of 660 RTR and 275 kidney donors for data collection as reported previously [12]. In a recent study, we found that N 1 -MN excretion is lower in renal transplant recipients (RTR) than in healthy controls [12]. As this discrepancy could not be explained by lower dietary intake of niacin equivalents, enhanced enzymatic conversion of N 1 -MN to 2Py by AOX1 might be present in this population due to the suggested contribution of AOX1 to N 1 -MN clearance with lower kidney function [13,14].…”

“…Although the 24-h urinary excretion of N 1 -MN has shown the most sensitive response to oral test doses of niacin equivalents [3,7], excretion of 2Py, whether or not combined with that of N 1 -MN, has also been implicated for the assessment of niacin status [8][9][10][11]. In a recent study, we found that N 1 -MN excretion is lower in renal transplant recipients (RTR) than in healthy controls [12]. As this discrepancy could not be explained by lower dietary intake of niacin equivalents, enhanced enzymatic conversion of N 1 -MN to 2Py by AOX1 might be present in this population due to the suggested contribution of AOX1 to N 1 -MN clearance with lower kidney function [13,14].…”