Urinary Excretion of N1-Methylnicotinamide and N1-Methyl-2-Pyridone-5-Carboxamide and Mortality in Kidney Transplant Recipients.

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.

Urinary Excretion of 6-Sulfatoxymelatonin, the Main Metabolite of Melatonin, and Mortality in Stable Outpatient Renal Transplant Recipients.

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/24h, 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.