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

Abstract

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.

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

“…Considerable evidence has, however, implied this biomarker to be responsive to multiple physiological and pathological factors [ 50 , 51 , 52 , 53 , 54 , 55 ], and most recently to renal function [ 30 ], and noted opposing shifts of 2Py excretion in parallel to N 1 -MN excretion [ 30 , 54 ]. Given the furthermore presumed presence of increased enzymatic conversion of N 1 -MN to 2Py in conditions of renal function impairment [ 30 , 55 , 56 ], additional interpretation of 2Py, rather than N 1 -MN alone, is indicated to address niacin status in KTR. Noteworthy, other conditions inherent to renal function decline, such as aging [ 57 , 58 ], may superimpose the latter proposition.…”

“…N 1 -MN and 2Py concentrations were measured with a validated liquid chromatography (Luna HILIC column; Phenomenex, Torrance, CA, USA) isotope dilution-tandem mass spectrometry (Quattro Premier; Waters, Milford, MA, USA) (LC-MS/MS) method, as reported previously [ 22 , 30 , 44 ]. The 24-h urinary excretion of N 1 -MN and 2Py (μmol/day) was calculated by multiplying concentrations (μmol/L) by total urine volume calculated from weight (L/day).…”

“…Further evidence on the potential of niacin nutrition for improvement of long-term outcome in KTR is unrevealed, as previous studies have only addressed pharmacological doses of niacin within the context of chronic kidney disease and renal transplantation [23][24][25][26][27][28], and dietary intake of niacin to reduce frailty and risk of mortality in elderly [29]. In a recent study, we have demonstrated lower N 1 -MN excretion to be paralleled by higher 2Py excretion in KTR, due to putative increased enzymatic conversion of N 1 -MN to 2Py in conditions of renal function impairment [30]. Accordingly, it has been suggested that interpretation of N 1 -MN excretion alone is of limited value, at least in conditions of renal function impairment, and 2Py should be additionally interpreted for assessment of niacin status [30].…”

“…In a recent study, we have demonstrated lower N 1 -MN excretion to be paralleled by higher 2Py excretion in KTR, due to putative increased enzymatic conversion of N 1 -MN to 2Py in conditions of renal function impairment [ 30 ]. Accordingly, it has been suggested that interpretation of N 1 -MN excretion alone is of limited value, at least in conditions of renal function impairment, and 2Py should be additionally interpreted for assessment of niacin status [ 30 ].…”

The Biochemical Pathways of Nicotinamide-Derived Pyridones

“…As waste products, these by-products of NAD(P)(H) metabolism associate with aging and nephrotic dysfunction as their levels associate with advanced kidney injuries (AKI) and kidney failure [ 4 , 6 , 10 , 11 , 12 ]. Liquid chromatography combined with mass spectrometry is the most common method used to detect nicotinamide-derived pyridones in biological samples [ 13 , 14 , 15 ].…”