Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m2) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.

Whole-body synthesis of L-homoarginine in pigs and rats supplemented with L-arginine.

Recent studies suggest an important role for L-homoarginine in cardiovascular, hepatic and neurological functions, as well as the regulation of glucose metabolism. However, little is known about whole-body L-homoarginine synthesis or its response to dietary L-arginine intake in animals. Four series of experiments were conducted to determine L-homoarginine synthesis and catabolism in pigs and rats. In Experiment 1, male and female pigs were fed a corn- and soybean meal-based diet supplemented with 0.0-2.42 % L-arginine-HCl. In Experiment 2, male and female rats were fed a casein-based diet, while receiving drinking water containing supplemental L-arginine-HCl to provide 0.0-3.6 g L-arginine/kg body-weight/day. In both experiments, urine collected from the animals for 24 h was analyzed for L-homoarginine and related metabolites. In Experiment 3, pigs and rats received a single oral dose of 1 or 10 mg L-homoarginine/kg body-weight, respectively, and their urine was collected for 24 h for analyses of L-homoarginine and related substances. In Experiment 4, slices of pig and rat tissues (including liver, brain, kidney, heart, and skeletal-muscle) were incubated for 1 h in Krebs-bicarbonate buffer containing 5 or 50 µM L-homoarginine. Our results indicated that: (a) animal tissues did not degrade L-homoarginine in the presence of physiological concentrations of other amino-acids; (b) 95-96 % of orally administered L-homoarginine was recovered in urine; (c) L-homoarginine was quantitatively a minor product of L-arginineg catabolism in the body; and (d) dietary L-arginine supplementation dose-dependently increased whole-body L-homoarginine synthesis. These novel findings provide a new framework for future studies of L-homoarginine metabolism and physiology in animals and humans.

The low nanomolar levels of N G-monomethylarginine in serum and urine of patients with chronic renal insufficiency are not significantly different from control levels.

There are no reliable mean values of N(G)-monomethylarginine (NMMA) in blood and urine of patients with renal insufficiency available in the literature. Therefore we investigate whether the NMMA levels are changed in blood and urinary excretion of nondialysed and dialysed patients with chronic renal insufficiency to evaluate whether NMMA may reach sufficiently increased concentrations in blood of the patients to exert toxic biological activity. In nondialysed as well as in dialysed patients we find no significant difference in serum concentration of NMMA between patients and controls. In nondialysed patients (all with a residual creatinine clearance lower than 15 ml/min), we find 94.5 +/- 26.1 nM (mean +/- SD) versus 94.6 +/- 19.5 nM in controls. Similar levels are found in serum of haemodialysed patients (each with serum creatinine levels >700 micro M): 83.0 +/- 20.2 nM. The urinary excretion of NMMA in nondialysed patients is also not significantly different from the excretion of controls: 123 +/- 110 in patients versus 157 +/- 117 nmol/24 hrs in controls. Furthermore, the clearance of NMMA is much lower compared to the clearance of the dimethylarginine derivatives. Based on the literature, the low nanomolar levels of NMMA found in blood of patients with renal insufficiency do not support the statement that NMMA proper may act as a uremic toxin.