(1/2811) Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus.
BACKGROUND: The plasma concentrations of total homocysteine (tHcy) and total cysteine (tCys) are determined by intracellular metabolism and by renal plasma clearance, and we hypothesized that glomerular filtration is a major determinant of plasma tHcy and tCys. We studied the relationships between the glomerular filtration rate (GFR) and plasma tHcy and tCys in populations of diabetic patients with particularly wide ranges of GFR. METHODS: We measured GFR, urine albumin excretion rate (UAER), plasma tHcy, tCys, methionine, vitamin B12, folate, C-peptide, and routine parameters in 50 insulin-dependent diabetes mellitus (IDDM) and 30 non-insulin-dependent diabetes mellitus (NIDDM) patients. All patients underwent intensive insulin treatment and had a serum creatinine concentration below 115 micromol/liter. RESULTS: Mean plasma tHcy in diabetic patients (0.1 micromol/liter) was lower than in normal persons (11.1 micromol/liter, P = 0.0014). Mean plasma tCys in diabetic patients (266.1 micromol/liter) was also lower than in normal persons (281.9 micromol/liter, P = 0.0005). Seventy-three percent of the diabetic patients had relative hyperfiltration. Plasma tHcy and tCys were closely and independently associated with GFR, serum folate, and serum B12. However, plasma tHcy was not independently associated with any of the 22 other variables tested, including age, serum creatinine concentration, UAER, total daily insulin dose, and glycemic control. CONCLUSIONS: Glomerular filtration rate is an independent determinant of plasma tHcy and tCys concentrations, and GFR is rate limiting for renal clearance of both homocysteine and cysteine in diabetic patients without overt nephropathy. Declining GFR explains the age-related increase in plasma tHcy, and hyperfiltration explains the lower than normal mean plasma tHcy and tCys concentrations in populations of diabetic patients. (+info)
(2/2811) Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.
BACKGROUND: Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patients is unknown. METHODS: We screened 636 kidney graft recipients for the presence of the MTHFR C677T gene polymorphism. The major determinants of total homocysteine and folate plasma concentrations of 63 patients, who were identified to be homozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age, glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass index, time since transplantation, folate and vitamin B12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kidney donor MTHFR genotype on total homocysteine and folate plasma concentrations, a similar model was applied in 111 kidney graft recipients with stable graft function, in whom the kidney donor C677T MTHFR gene polymorphism was determined. RESULTS: The allele frequency of the C677T polymorphism in the MTHFR gene was 0.313 in the whole study population [wild-type (CC), 301; heterozygous (CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MTHFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 and P = 0.0002, respectively). Furthermore, a significant influence of the GFR (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass index (P = 0.0001), gender (P = 0.0005), and vitamin B12 levels (P = 0.004) on total homocysteine concentrations was observed. The donor MTHFR gene polymorphism had no influence on total homocysteine and folate levels. Geometric mean total homocysteine levels in patients homozygous for the mutant MTHFR allele were 18.6 micromol/liter compared with 14.6 micromol/liter and 14.9 micromol/liter in patients heterozygous for the MTHFR gene polymorphism and those with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean folate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) compared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). CONCLUSIONS: This study demonstrates that homozygosity for the C677T polymorphism in the MTHFR gene significantly increases total homocysteine concentrations and lowers folate levels in kidney graft recipients, even in patients with excellent renal function (GFR more than median). These findings have important implications for risk evaluation and vitamin intervention therapy in these patients who carry an increased risk for the development of cardiovascular disease. (+info)
(3/2811) Influence of haemodialysis on plasma total homocysteine concentration.
BACKGROUND: The high prevalence of hyperhomocysteinaemia in uraemic patients is of interest because of the cardiovascular risk associated with increased plasma total homocysteine (tHcy) concentration. Treatment with folic acid lowers tHcy in haemodialysis patients, however, in most patients not to normohomocysteinaemic levels. With possible tHcy-lowering modifications in mind, we studied the influence of standard haemodialysis on tHcy. METHODS: In 56 folate-loaded haemodialysis patients, tHcy and parameters of dialysis adequacy were measured. In six patients, interdialytic curves of tHcy and serum creatinine concentrations were obtained and in five patients, the amount of homocysteine (Hcy) in dialysate was determined. RESULTS: tHcy (21.8+/-14.4 micromol/l) correlated significantly with Kt/V (r=0.32, P<0.05), total Kt/V (r=0.29, P<0.05), nPCR (r=0.30, P<0.05) and serum concentrations of albumin (r=0.28, P<0.05) and cobalamines (r=-0.27, P<0.05). In a multiple linear regression analysis, only serum albumin concentrations significantly predicted tHcy (r=0.34, P < 0.05). During dialysis, tHcy decreased by 28% and remained constant for at least 8 h after treatment. The amount of Hcy recovered in dialysate was 63 micromol (12-158 micromol). There was no difference in tHcy between those who had residual renal function and those who had not. CONCLUSIONS: The direct relationship between tHcy and Kt/V seemed to be mediated by the serum albumin concentration. The shape of the interdialytic tHcy curve suggested facilitated Hcy removal for at least 8 h after dialysis possibly due to reduced levels of inhibitory activities against relevant enzyme(s). The dialysed amount of Hcy did not seem to contribute significantly to Hcy removal. Thus, modifications of standard dialytic regimens are not likely to be effective from a tHcy-lowering point of view whereas convective procedures such as haemofiltration or haemodiafiltration might be more effective. (+info)
(4/2811) The impact of an amino acid-based peritoneal dialysis fluid on plasma total homocysteine levels, lipid profile and body fat mass.
BACKGROUND: The caloric load from glucose-based peritoneal dialysis (PD) fluids contributes to hypertriglyceridaemia, adiposity and, as result of anorexia, protein malnutrition in PD patients. It has been suggested that replacement of a glucose-based by an amino acids-based PD fluid (AA-PDF) for one exchange per day might improve the nutritional status and lipid profile. Due to the uptake of methionine from the dialysate, however, exposure to AA-PDF might aggravate hyperhomocysteinaemia, a frequently occurring risk factor for atherosclerosis in uraemic patients. METHODS: We studied the impact of a once daily exchange with 1.1% AA-PDF instead of glucose-based PD fluid for 2 months on plasma methionine and total homocysteine (tHcy) levels, lipid profile, butyrylcholinesterase (BChE) and body fat mass of seven stable PD patients. Results are expressed as mean+/-SEM. RESULTS: Methionine levels did not increase significantly during therapy, but tHcy levels increased substantially from 60+/-12 to 84+/-19 micromol/l after 1 month (P=0.039), and to 85+/-22 micromol/l after 2 months of AA-PDF treatment. Serum triglyceride concentration decreased from 3.0+/-0.4 mmol/l at entry to 2.6+/-0.5 mmol/l (at 1 month, P=0.041 vs baseline). Serum BChE also decreased from 6.9+/-0.4 U/ml at entry to 6.3+/-0.4 U/ml after 2 months (P=0.014). Total cholesterol concentration and cholesterol fractions did not change. The reduced exposure to glucose-based PD fluid for 2 months resulted in a 0.5 kg reduction in fat mass which was due mainly to a reduction in fat mass of the trunk region (0.3 kg, P=0.031). CONCLUSIONS: It is concluded that methionine-containing AA-PDF induces an increase in the plasma tHcy level. This might, potentially, offset the beneficial effects of an improved serum lipid profile and reduced fat mass on the risk of cardiovascular disease in PD patients. Lowering the methionine content of the fluid, therefore, may be required to overcome this adverse effect. (+info)
(5/2811) Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats In vivo.
Despite intense investigation, mechanisms linking the development of occlusive vascular disease with elevated levels of homocysteine (HCY) are still unclear. The vascular endothelium plays a key role in regulating thrombogenesis and thrombolysis. We hypothesized that vascular lesions in individuals with elevated plasma HCY may be related to a dysfunction of the endothelium triggered by HCY. We investigated the effect of HCY on human neutrophil adhesion to and migration through endothelial monolayers. We also examined the effect of HCY on leukocyte adhesion and migration in mesenteric venules of anesthetized rats. We found that pathophysiological concentrations of HCY in vitro induce increased adhesion between neutrophils and endothelial cells. This contact results in neutrophil migration across the endothelial layer, with concurrent damage and detachment of endothelial cells. In vivo, HCY infused in anesthetized rats caused parallel effects, increasing leukocyte adhesion to and extravasation from mesenteric venules. Our results suggest that extracellular H2O2, generated by adherent neutrophils and/or endothelial cells, is involved in the in vitro endothelial cell damage. The possibility exists that leukocyte-mediated changes in endothelial integrity and function may lead to the vascular disease seen in individuals with elevated plasma HCY. (+info)
(6/2811) Hyperhomocyst(e)inaemia in children with chronic renal failure.
BACKGROUND: Hyperhomocyst(e)inaemia has been identified as a significant risk factor for the occurrence of atherosclerosis in adults with chronic renal failure. Because of its presumed direct toxic effect on the vascular wall, long-standing hyperhomocyst(e)inaemia in children with chronic renal failure might have an important influence on their risk of future development of atherosclerosis. Hitherto no data on hyperhomocyst(e)inaemia in children with renal failure have been published. METHODS: We investigated 16 children with chronic renal failure on conservative management, 12 children on haemodialysis and 17 children with a renal transplant. Age-matched controls were used for comparison. Plasma homocyst(e)ine levels after an overnight fast were determined by HPLC. Glomerular filtration rate was estimated by the Schwartz formula. RESULTS: Mean plasma homocyst(e)ine levels were 12.6 +/- 5.2 micromol/l in the conservatively managed group, 22.2 +/- 13.5 micromol/l in the haemodialysed group, 14.2 +/- 2.1 micromol/l in transplanted children with an estimated GFR > 60 ml/min/1.73 m2 and 17.5 +/- 5.1 micromol/l in transplanted children with a lower estimated GFR. In all groups homocyst(e)ine levels were significantly elevated as compared to controls. Homocyst(e)ine levels were significantly correlated with age and negatively correlated with estimated GFR and serum folate levels. CONCLUSIONS: Hyperhomocyst(e)inaemia is a feature of chronic renal failure in children as well as in adults. Elevated homocyst(e)ine levels can already be demonstrated in children with renal failure before end-stage renal disease has developed and persist after renal transplantation. Whether treatment of hyperhomocyst(e)inaemia in children with renal failure decreases the risk for future atherosclerosis remains to be proven. (+info)
(7/2811) Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy.
BACKGROUND: Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C. METHODS AND RESULTS: We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C. CONCLUSIONS: We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms. (+info)
(8/2811) Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells.
BACKGROUND: Elevated plasma homocysteine levels have been reported to be an independent risk factor for vascular disease. However, there have been no reports concerning the effects of homocysteine on the production of nitric oxide (NO), another modulator of vascular function and proliferation, by the vascular smooth muscle. METHODS AND RESULTS: We investigated the effects of homocysteine on NO synthesis by measuring the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells (VSMCs). Incubation of cultures with interleukin (IL)-1beta 10 ng/mL for 24 hours caused a significant increase in nitrite generation. The IL-1beta-induced nitrite production by VSMCs was significantly increased by homocysteine in a dose-dependent manner. This effect of homocysteine was significantly inhibited in the presence of NG-monomethyl-L-arginine or actinomycin D. The homocysteine-induced nitrite production was accompanied by increased inducible NO synthase mRNA and protein accumulation. Cysteine, glutathione, or hydrogen peroxide also increased nitrite accumulation in IL-1beta-stimulated VSMCs. Coincubation with the radical scavenger catalase or superoxide dismutase markedly reduced homocysteine-induced nitrite accumulation. CONCLUSIONS: Homocysteine enhances NO synthesis in IL-1beta-stimulated VSMCs, and oxidative products are involved in the effect of homocysteine. (+info)