It is unclear whether niacin nutritional status is a target for improvement of long-term outcome after renal transplantation. The 24-h urinary excretion of N¹-methylnicotinamide (N¹-MN), as a biomarker of niacin status, has previously been shown to be negatively associated with premature mortality in kidney transplant recipients (KTR). However, recent evidence implies higher enzymatic conversion of N¹-MN to N¹-methyl-2-pyridone-5-carboxamide (2Py) in KTR, therefore the need exists for interpretation of both N¹-MN and 2Py excretion for niacin status assessment. We assessed niacin status by means of the 24-h urinary excretion of the sum of N¹-MN and 2Py (N¹-MN + 2Py), and its associations with risk of premature mortality in KTR. N¹-MN + 2Py excretion was measured in a longitudinal cohort of 660 KTR with LS-MS/MS. Prospective associations of N¹-MN + 2Py excretion were investigated with Cox regression analyses. Median N¹-MN + 2Py excretion was 198.3 (155.9–269.4) µmol/day. During follow-up of 5.4 (4.7–6.1) years, 143 KTR died, of whom 40 due to an infectious disease. N¹-MN + 2Py excretion was negatively associated with risk of all-cause mortality (HR 0.61; 95% CI 0.47–0.79; p < 0.001), and infectious mortality specifically (HR 0.47; 95% CI 0.29–0.75; p = 0.002), independent of potential confounders. Secondary analyses showed effect modification of hs-CRP on the negative prospective association of N¹-MN + 2Py excretion, and sensitivity analyses showed negative and independent associations of N¹-MN and 2Py excretion with risk of all-cause mortality separately. These findings add further evidence to niacin status as a target for nutritional strategies for improvement of long-term outcome in KTR.

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.

N¹-methylnicotinamide (N¹-MN) and N¹-methyl-2-pyridone-5-carboxamide (2Py) are successive end products of NAD⁺ catabolism. N¹-MN excretion in 24-h urine is the established biomarker of niacin nutritional status, and recently shown to be reduced in renal transplant recipients (RTR). However, it is unclear whether 2Py excretion is increased in this population, and, if so, whether a shift in excretion of N¹-MN to 2Py can be attributed to kidney function. Hence, we assessed the 24-h urinary excretion of 2Py and N¹-MN in RTR and kidney donors before and after kidney donation, and investigated associations of the urinary ratio of 2Py to N¹-MN (2Py/N¹-MN) with kidney function, and independent determinants of urinary 2Py/N¹-MN in RTR. The urinary excretion of 2Py and N¹-MN was measured in a cross-sectional cohort of 660 RTR and 275 healthy kidney donors with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear regression analyses were used to investigate associations and determinants of urinary 2Py/N¹-MN. Median 2Py excretion was 178.1 (130.3–242.8) μmol/day in RTR, compared to 155.6 (119.6–217.6) μmol/day in kidney donors (p < 0.001). In kidney donors, urinary 2Py/N¹-MN increased significantly after kidney donation (4.0 ± 1.4 to 5.2 ± 1.5, respectively; p < 0.001). Smoking, alcohol consumption, diabetes, high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) were identified as independent determinants of urinary 2Py/N¹-MN in RTR. In conclusion, the 24-h urinary excretion of 2Py is higher in RTR than in kidney donors, and urinary 2Py/N¹-MN increases after kidney donation. As our data furthermore reveal strong associations of urinary 2Py/N¹-MN with kidney function, interpretation of both N¹-MN and 2Py excretion may be recommended for assessment of niacin nutritional status in conditions of impaired kidney function.

Melatonin is a multifaceted hormone which rises upon the onset of darkness. Pineal synthesis of melatonin is known to be disturbed in patients with end-stage renal disease, but it is not known if its production is restored to normal after successful renal transplantation. We hypothesized that urinary excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin, is lower in renal transplant recipients (RTRs) compared to healthy controls and that this is associated with excess mortality. Urinary 6-sulfatoxymelatonin was measured via LC-MS/MS in 701 stable outpatient RTRs and 285 healthy controls. Median urinary 6-sulfatoxymelatonin in RTR was 13.2 nmol/24 h, which was 47% lower than in healthy controls. Urinary 6-sufatoxymelatonin appeared undetectable in the majority of 36 RTRs with diabetic nephropathy as primary renal disease. Therefore, this subgroup was excluded from further analyses. Of the remaining 665 RTRs, during 5.4 years of follow-up, 110 RTRs died, of whom 38 died due to a cardiovascular cause. In Cox-regression analyses, urinary 6-sulfatoxymelatonin was significantly associated with all-cause mortality (0.60 (0.44–0.81), p = 0.001) and cardiovascular mortality (0.49 (0.29–0.84), p = 0.009), independent of conventional risk factors and kidney function parameters. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTRs.