Reduce Plasma Homocysteine Levels Research Articles

High Bioavailability of Spinach Folate Evaluated by Functional Biomarkers in a Folate Depletion-Repletion Mouse Model.

The bioavailability of natural folates is 50% lower than that of synthetic folic acid (FA); however, it remains unclear whether this value is universally applicable to all foods. Therefore, the present study investigated the bioavailability of folate from spinach using multiple biomarkers in a folate depletion-repletion mouse model. Mice were fed a folate-deficient diet for 4 wk and subsequently divided into three groups: folate-deficient, FA, and spinach folate. The folate repletion group received either FA or spinach folate at 2 mg/kg diet for 9 d. On the 7th day of repletion, half of each group underwent low-dose total body X-ray irradiation to induce chromosomal damage in bone marrow. Folate bioavailability biomarkers included measurements of folate levels in plasma, liver, and bone marrow along with an analysis of plasma homocysteine levels and chromosome damage, both of which are functional biomarkers of body folate. The consumption of a folate-deficient diet led to decreased tissue folate levels, increased plasma homocysteine levels, and chromosomal damage. Repletion with spinach folate restored folate levels in plasma, liver, and bone marrow to 69, 13, and 68%, respectively, of FA levels. Additionally, spinach folate repletion reduced plasma homocysteine levels and chromosome damage to 83% and 93-117%, respectively, of FA levels. Collectively, the present results demonstrated that the bioavailability of spinach folate exceeded 83% of FA, particularly when assessed using functional biomarkers.

Folic acid, but not folate, regulates different stages of neurogenesis in the ventral hippocampus of adult female rats.

Folate is an important regulator of hippocampal neurogenesis, and folic acid is needed prenatally to reduce the risk of neural tube defects. Both high levels of folic acid and low levels of folate can be harmful to health because low levels of folate have been linked to several diseases while high folic acid supplements can mask a vitamin B12 deficiency. Depressed patients exhibit folate deficiencies, lower levels of hippocampal neurogenesis, elevated levels of homocysteine and elevated levels of the stress hormone, cortisol, which may be inter-related. In the present study, we were interested in whether different doses of natural folate or synthetic folic acid diets can influence neurogenesis in the hippocampus, levels of plasma homocysteine and serum corticosterone in adult female rats. Adult female Sprague-Dawley rats underwent dietary interventions for 29days. Animals were randomly assigned to six different dietary groups: folate deficient+succinylsulphathiazole (SST), low 5-methyltetrahydrofolate (5-MTHF), low 5-MTHF+(SST), high 5-MTHF+SST, low folic acid and high folic acid. SST was added to a subset of the 5-MTHF diets to eliminate folic acid production in the gut. Before and after dietary treatment, blood samples were collected for corticosterone and homocysteine analysis, and brain tissue was collected for neurogenesis analysis. High folic acid and low 5-MTHF without SST increased the number of immature neurones (doublecortin-expressing cells) within the ventral hippocampus compared to folate deficient controls. Low 5-MTHF without SST significantly increased the number of immature neurones compared to low and high 5-MTHF+SST, indicating that SST interfered with elevations in neurogenesis. Low folic acid and high 5-MTHF+SST reduced plasma homocysteine levels compared to controls, although there was no significant effect of diet on serum corticosterone levels. In addition,low folic acid and high 5-MTHF+SST reduced the number of mature new neurones in the ventral hippocampus (bromodeoxyuridine/NeuN-positive cells) compared to folate deficient controls. Overall, folic acid dose-dependently influenced neurogenesis with low levels decreasing but high levels increasing neurogenesis in the ventral hippocampus, suggesting that this region, which is important for regulating stress, is particularly sensitive to folic acid in diets. Furthermore, the addition of SST negated the effects of 5-MTHF to increase neurogenesis in the ventral hippocampus.

Folic acid attenuates homocysteine and enhances antioxidative capacity in atherosclerotic rats.

Atherosclerosis is a chronic disease that can seriously endanger human life. Folic acid supplementation modulates several disorders, including atherosclerosis, via its antiapoptotic and antioxidative properties. This study investigated whether folic acid alleviates atherogenesis by restoring homocysteine levels and antioxidative capacity in atherosclerosis Wistar rats. To this end, 28 Wistar rats were randomly divided into 4 groups (7 rats/group) as follows: (i) wild-type group, fed only the AIN-93 semi-purified rodent diet (folic acid: 2.1 mg/kg); (ii) high-fat + folic acid-deficient group (HF+DEF) (folic acid: 0.2 mg/kg); (iii) high-fat + normal folic acid group (folic acid: 2.1 mg/kg); and (iv) high-fat + folic acid-supplemented group (folic acid: 4.2 mg/kg). After 12 weeks, histopathological changes in the atherosclerotic lesions of the aortic arch were determined. In addition, serum folate levels, plasma homocysteine levels, plasma S-adenosyl-homocysteine levels, antioxidant status, oxidant status, and lipid profiles were evaluated. The results show aggravated atherosclerotic lesions in the HF+DEF group. Folic acid supplementation increased concentrations of serum folate. Further, folic acid supplementation increased high-density lipoprotein-cholesterol, decreased plasma homocysteine levels, and improved antioxidant capacity in atherogenic rats. These findings are consistent with the hypothesis that folic acid alleviates atherogenesis by reducing plasma homocysteine levels and improving antioxidant capacity in rats fed a high-fat diet.

Reduced plasma homocysteine levels in elderly Australians following mandatory folic acid fortification – A comparison of two cross-sectional cohorts

ObjectiveIn 2009, Australia implemented mandatory folic acid fortification in wheat flour for bread-making. The primary aim was to improve folate status in reproductive-aged women to reduce neural tube defect incidence. However, folic acid consumption has consequently increased in all demographics. Blood folate is inversely associated with homocysteine levels, a risk factor for multiple diseases. Therefore, we assessed the impact of mandatory folic acid fortification on homocysteine levels in elderly Australians. MethodsHomocysteine and blood folate levels were compared between two elderly cross-sectional cohorts (pre-versus post-mandatory folic acid fortification). Importantly, dietary habits were assessed to evaluate the confounding influence of altered dietary patterns not related to fortification. ResultsPost-fortification, plasma homocysteine levels (10.6 vs. 14.5 μmol/L) and hyperhomocysteinemia incidence (27.2% vs 56.3%) were significantly reduced, relative to the pre-fortification subjects. This was associated with increased blood folate (red cell: 1243 vs 1066 nmol/L, serum 28.0 vs 23.9 nmol/L), and increased intake of synthetic folic acid (366.8 vs 231.0 DFE/day) but not natural folate (332.7 vs 323.6 DFE/day). Limited other differences were detected in dietary intake patterns between groups. The positive relationship between homocysteine levels and age was abrogated post-fortification (p = 0.3 vs p = 0.0003). ConclusionsA potential off-target benefit of mandatory folic acid fortification in Australia was demonstrated. With many countries still considering the merits and consequences of mandatory fortification policies, it is important to unravel the off-target effects including dietary context.

Inhibition of homocysteine-induced endoplasmic reticulum stress and endothelial cell damage by l-serine and glycine

Hyperhomocysteinemia is an independent risk factor for several cardiovascular diseases. The use of vitamins to modulate homocysteine metabolism substantially lowers the risk by reducing plasma homocysteine levels. In this study, we evaluated the effects of l-serine and related amino acids on homocysteine-induced endoplasmic reticulum (ER) stress and endothelial cell damage using EA.hy926 human endothelial cells. Homocysteine treatment decreased cell viability and increased apoptosis, which were reversed by cotreatment with l-serine. l-Serine inhibited homocysteine-induced ER stress as verified by decreased glucose-regulated protein 78kDa (GRP78) and C/EBP homologous protein (CHOP) expression as well as X-box binding protein 1 (xbp1) mRNA splicing. The effects of l-serine on homocysteine-induced ER stress are not attributed to intracellular homocysteine metabolism, but instead to decreased homocysteine uptake. Glycine exerted effects on homocysteine-induced ER stress, apoptosis, and cell viability that were comparable to those of l-serine. Although glycine did not affect homocysteine uptake or export, coincubation of homocysteine with glycine for 24h reduced the intracellular concentration of homocysteine. Taken together, l-serine and glycine cause homocysteine-induced endothelial cell damage by reducing the level of intracellular homocysteine. l-Serine acts by competitively inhibiting homocysteine uptake in the cells. However, the mechanism(s) by which glycine lowers homocysteine levels are unclear.

Effect of continuous positive airway pressure on homocysteine levels in patients with obstructive sleep apnea: a meta-analysis

Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea hypopnea syndrome (OSAHS), but previous studies assessing the effect of CPAP on homocysteine (HCY) in patients with OSAHS yielded conflicting results. In this study, we conducted a meta-analysis to determine whether CPAP therapy could reduce plasma HCY levels. Searches of PUBMED, SCI, and Elsevier databases were completed. Studies of adult patients with OSAHS who reported HCY levels pre- and post-CPAP treatment were collected by two independent reviewers. RevMan (version 5.2) and STATA (version 12.0) were used to perform data synthesis. A total of 6 studies involving 206 participants were included. Meta-analysis showed that the total weighted mean difference (WMD) for HCY levels was -0.62 units (95% confidence interval (CI) -1.21 to -0.04, P<0.05) post- and pre-CPAP therapy. Subgroup analysis showed that HCY was decreased nonsignificantly within 3 months after the therapy (WMD, -0.07, 95% CI -0.88 to 0.74, P>0.05), but it was significantly reduced after 3 months therapy (WMD, -1.22, 95% CI -2.07 to -0.38, P<0.05). This meta-analysis suggests that HCY levels were significantly reduced by CPAP therapy in patients with OSAHS and the HCY levels may be clinically recognized as a valuable indicator for OSAHS treatment, but the clinical significance of this finding as it relates to cardiovascular risk reduction in OSAHS patients warrants further study.

Role of Sulfur Containing Amino Acids as an Adjuvant Therapy in the Prevention of Diabetes and its Associated Complications

Amino acid supplementation is gaining acceptance as an important adjuvant therapy in the treatment of diabetes and its associated complications. Numerous studies in the literature report the impaired amino acid metabolism in diabetes and the beneficial effects of amino acids are positively correlated with the increase in plasma levels of those amino acids. Oxidative stress is known to play a major role in diabetic pathophysiology. Sulfur containing compounds are well known in the treatment of oxidative stress induced pathological disorders. Methionine, cysteine, and homocysteine are the three common sulfur containing amino acids. In addition, taurine, a sulfonic acid containing an amino group (amino sulfonic acid), is found in substantial amounts in mammalian tissues. Both experimental and clinical studies reported the modulatory effects of cysteine, N-acetyl cysteine, or compounds having cysteine moiety in the regulation of insulin secretion and plasma glucose levels. Taurine supplementation has been found to prevent the onset of diabetes mellitus in experimental models of both insulin dependent and insulin independent pathways. Recent reports suggest that the beneficial role of cysteine or taurine is mediated via their ability in reducing glycooxidation and preventing the generation of intracellular reactive intermediates. Studies with methionine or S-adinosyl methionine has been shown to increase mitochondrial DNA density in skeletal muscle, improve insulin sensitivity and prevent body weight gain. Homocysteine, on the other hand, is an emerging risk factor for cardiovascular disease and diabetic patients have higher levels of this sulfur containing amino acid. Supplementation with cysteine or taurine, however, was found to be effective in reducing plasma homocysteine levels. This review will discuss the role of sulfur containing amino acids in the regulation of hyperglycemia and in the development of its associated pathological dysfunctions.

Homocysteine, a Risk Factor for Cardiovascular Disease.

Fasting hyperhomocysteinemia is an independent risk factor for coronary artery disease, stroke, peripheral vascular atherosclerosis, and for arterial and venous thromboembolism. The risk for cardiovascular disease with homocysteine is similar to conventional risk factors. The interaction of hyperhomocysteinemia with hypertension and smoking is strong and the combined effect is more than multiplicative. The combined effect of homocysteine and cholesterol is additive. Homocysteine produces atherosclerosis, thromboembolism, and vascular endothelial cell injury. Vascular dysfunction produced by homocysteine may be due to endothelial cell damage. Homocysteinemia-induced atherosclerosis is probably due to various factors including endothelial cell injury, inability to sustain S-nitroso-homocysteine formation because of imbalance between production of nitric oxide by dysfunctional endothelium and homocysteine, smooth muscle cell proliferation, and thromboembolism. There is strong evidence that endothelial cell injury is associated with oxidative stress produced by homocysteine. Hyperhomocysteinemia is associated with numerous conditions, including coronary disease, stroke, peripheral vascular disease (carotid artery and cerebrovascular atherosclerosis), venous thrombosis, renal disease, diabetes mellitus, and organ transplant. Folic acid, vitamin B12 and B6 have been shown to be beneficial in reducing plasma homocysteine levels. Folic acid is specifically very effective, safe and inexpensive.

Therapeutic interventions and adjustments in the management of Parkinson disease: role of combined carbidopa/levodopa/entacapone (Stalevo).

Parkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3-0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa-induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing "on" time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/ levodopa/entacapone (Stalevo(®)) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDEPD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results.

The content of docosahexaenoic acid in serum phospholipid is inversely correlated with plasma homocysteine levels in patients with end-stage renal disease

Patients with end-stage renal disease (ESRD) have a high morbidity and mortality from cardiovascular disease. An elevated homocysteine level is an independent predictor of cardiovascular events in patients with ESRD. Interestingly, some studies have found an inverse relationship between the content of marine n-3 polyunsaturated fatty acids (PUFAs) and homocysteine levels, but data are ambiguous. In patients with ESRD, we hypothesized that serum phospholipid n-3 PUFA content would inversely correlate with homocysteine levels in plasma and that supplementation with n-3 PUFA would reduce plasma homocysteine levels. In a double-blind, randomized, controlled design, 206 patients with documented cardiovascular disease and treated with hemodialysis for a minimum of 6 months were randomized to treatment with daily supplement of 1.7 g n-3 PUFA or placebo (olive oil) for 3 months. The content of n-3 PUFA in serum phospholipids and homocysteine levels in plasma were measured at baseline and after 3 months of intervention. A dietary questionnaire was filled out at baseline, and study participants were divided into groups of low, intermediate, and high fish intake. Docosahexaenoic acid was inversely correlated with homocysteine at baseline (coefficient = -0.161; P = .03). Homocysteine was not related to self-reported fish intake. Supplementation with n-3 PUFA did not reduce homocysteine levels compared with placebo (mean ± SD difference, -0.3 ± 7.8 versus 0.3 ± 7.1; P = .58). The content of docosahexaenoic acid in serum phospholipids is inversely correlated with plasma homocysteine levels, and supplementation with n-3 PUFA does not reduce homocysteine levels in patients with ESRD.

ACE inhibitors and ??-blockers significantly reduce plasma homocysteine levels in patients with essential hypertension,

ACE inhibitors and ??-blockers significantly reduce plasma homocysteine levels in patients with essential hypertension,

Vitamins and Stroke

During the last years, many epidemiologic studies have identified homocysteine as an independent risk factor for cardiovascular diseases like coronary events, stroke, and venous thromboembolism. Supplementation with oral folate and vitamins B6 and B12 (mainly folate) reduce plasma homocysteine levels to a significant degree. Recent clinical trials showed that vitamin supplementation leads to slower progression or even regression of atherosclerotic lesions in the carotid arteries, as confirmed by ultrasonographic measurement of carotid intima media thickness. However, the recent Vitamin Intervention for Stroke Prevention (VISP) study failed to show any clinical effect on stroke prevention. It is unclear if homocysteine-lowering therapy really has a role in the prevention of cardiovascular diseases. Large trials, which are already conducted, will probably give the definitive answer. In this review, we try to keep pace with the data that make the homocysteine hypothesis still doubtful.

Folic acid therapy reduces plasma homocysteine levels and improves plasma antioxidant capacity in hemodialysis patients

Objective We evaluated the effects of folic acid on homocysteine levels and oxidative stress in 46 stable patients on hemodialysis. Methods This double-blind, placebo-controlled, randomized trial assessed the effects of 6 mo of 10 mg of folic acid (26 patients) or placebo (20 patients) given three times weekly after each dialysis under nurse supervision on homocysteine levels, total plasma antioxidant capacity, and hydroperoxide plasma levels. Results Folic acid treatment normalized plasma homocysteine levels in most patients, significantly increased total plasma antioxidant capacity levels, but had no significant effect on hydroperoxide levels. Placebo treatment had no statistically significant effect on the three parameters. Conclusion The folic acid therapy protocol effectively lowered plasma homocysteine levels and improved the total plasma antioxidant capacity in hemodialysis patients. Further studies are required to assess the usefulness of folic acid for decreasing cardiovascular mortality in patients with chronic kidney disease.

Effects of catechin on homocysteine metabolism in hyperhomocysteinemic mice

We have recently focused on the interaction between hyperhomocysteinemia, defined by high plasma homocysteine levels, and paraoxonase-1 expression and found a reduced activity of paraoxonase-1 associated with a reduced gene expression in the liver of cystathionine beta synthase (CBS) deficient mice, a murine model of hyperhomocysteinemia. As it has been demonstrated that polyphenolic compounds could modulate the expression level of the paraoxonase-1 gene in vitro, we have investigated the possible effect of flavonoid supplementation on the impaired paraoxonase-1 gene expression and activity induced by hyperhomocysteinemia and have evaluated the link with homocysteine metabolism. High-methionine diet significantly increased serum homocysteine levels, decreased hepatic CBS activity, and down-regulated paraoxonase-1 mRNA and its activity. However, chronic administration of catechin but not quercetin significantly reduced plasma homocysteine levels, attenuated the reduction of the hepatic CBS activity, and restored the decreased paraoxonase-1 gene expression and activity induced by chronic hyperhomocysteinemia. These data suggest that catechin could act on the homocysteine levels by increasing the rate of catabolism of homocysteine.

Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B 6 and B 12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial

Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial--the Heart Outcomes Prevention Evaluation (HOPE)-2 study--is being conducted to evaluate this therapy in patients at high risk for CV events. To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke. A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005. The patients' baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.

Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients

Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol- O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B 12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone ( P=0.001) or in the control group ( P=0.0001). Concentrations of serum vitamin B 12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B 12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.

Plasma homocysteine and cognitive function in elderly patients with diabetes mellitus

Background: The purpose of the present paper was to investigate a possible contribution of plasma homocysteine to cognitive impairment. To this end the relationship between plasma homocysteine levels and cognitive performance test results were investigated in elderly patients with diabetes.Methods: A total of 144 elderly patients (39 men and 105 women) with diabetes mellitus, who were free of clinical stroke, were studied. Plasma levels of homocysteine, folate, vitamin B12, vitamin B6, and the C677T polymorphism of methylene tetrahydrofolate reductase were determined. Cognitive function was assessed with the Wechsler Adult Intelligence Scale, Revised (digit symbol substitution, backward digit span, similarities, picture arrangement), Stroop test, Benton Visual Retention Test, and Mini‐Mental State Examination (MMSE).Results: In elderly women with diabetes, elevated homocysteine levels in the plasma were significantly associated with impairment of cognitive performance assessed with the MMSE, digit symbol substitution test, similarities, Stroop test, and Benton visual retention test, but not the backward digit span test. Multiple logistic regression analyses revealed that the associations between the log‐transformed plasma homocysteine level and low scores of the MMSE and digit symbol substitution test remained significant after adjustment for age, education, hemoglobin (Hb)A1c, systolic blood pressures, insulin treatment, serum levels of folate, vitamin B12, and vitamin B6, and the presence of asymptomatic cerebral infarction on brain magnetic resonance images.Conclusions: Elevated plasma homocysteine level was independently associated with cognitive impairment in elderly diabetic women. Because the cause of the association between homocysteine and cognitive impairment remains unclear, future intervention studies are necessary to examine whether reducing plasma homocysteine levels prevents cognitive decline in elderly patients with diabetes mellitus.

Variations in the lipid profile of patients with chronic renal failure, treated with folic acid.

Dyslipidemia and increases in plasma homocysteine usually occur at end-stage renal disease; both are recognized as risk factors for atherosclerosis. Folate administration reduces homocysteine concentration. In this study we determined the effect of a high dose of folic acid (40 mg intravenous injection three times a week) on plasma and red blood cell lipid profiles in twelve chronic renal failure patients on regular hemodialysis. Fasting blood samples were taken at the beginning of the study (baseline) and after 21, 42, and 64 days of treatment. Folic acid supplementation decreased plasma homocysteine. Plasma triglyceride levels decreased whereas polyunsaturated fatty acid values increased after 21 days; then they returned to baseline levels at the end of treatment. Total cholesterol and low-density lipoprotein (LDL) cholesterol were higher than those of the baseline during all the study, whereas high-density lipoprotein (HDL) cholesterol was reduced. In erythrocyte membranes, folic acid therapy enhanced cholesterol/phospholipid ratios and the fluorescence anisotropy of diphenyl-hexatriene. We conclude that large doses of folic acid produce a favorable effect, reducing plasma homocysteine levels and protecting patients from atherosclerosis. However, as this therapy induces significant alterations in both plasma and erythrocyte membrane lipid profiles, plasma lipid values should be controlled throughout the treatment of patients with renal failure.

Folate metabolism in renal failure.

In most patients with chronic kidney disease, provision of sufficient human recombinant erythropoietin (rHuEPO) and iron replacement therapy will effectively correct renal anaemia. Folate deficiency has been implicated as a contributory factor in renal anaemia and hyporesponsiveness to rHuEPO treatment. As such, the necessity of regular folate supplementation has been debated over the last decade. Although folate loss through dialysis is greater than by urinary excretion, these losses are easily balanced by a normal mixed diet containing 60 g protein/day. Thus, unless patients show significant folate depletion, additional supplementation of folic acid does not appear to have a beneficial effect on erythropoiesis or on responsiveness to rHuEPO therapy. However, a diagnosis of folate deficiency should be considered in patients with chronic renal insufficiency and significant elevation in mean cell volume or hypersegmented polymorphonuclear leucocytes; in patients with malnutrition or a history of alcohol abuse, or in patients hyporesponsive to rHuEPO treatment, especially when accompanied by macrocytosis. Measurements of serum folate are not necessarily indicative of tissue folate stores and red blood cell (RBC) folate measures provide a more accurate picture. Low RBC folate concentrations in these patients indicate the need for folate supplementation. Folate supplementation can also reduce elevated levels of homocysteine in dialysis patients, which may contribute to the high cardiovascular morbidity prevalent in these individuals. High-dose folate therapy (5-15 mg/day) has been shown to reduce plasma homocysteine levels by 25-30% and appears to be well tolerated provided the patient has adequate vitamin B(12) stores. Although long-term benefits of this intervention for cardiovascular protection and patient survival have yet to be established, folic acid is considered a relatively non-toxic and well-tolerated vitamin.

Association of endothelial dysfunction with sulfur amino acid metabolism in chronic renal failure

Moderate hyperhomocysteinemia and endothelial dysfunction are consistent findings in uremic patients. Although an exceedingly high incidence of cardiovascular disease and stroke has been shown in dialysis patients, several traditional risk factors are relatively limited predictors. Hyperhomocysteinemia could be a principal candidate for endothelial dysfunction. Recent findings suggest that hyperhomocysteinemia may impair endothelial function by the generation of oxygen species and decreased nitric oxide (NO) bioavailability. However, the precise mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function in chronic renal failure remain unclear. Endothelial function was evaluated by the response to reactive hyperemia and donor of NO. We observed impairment in both endothelium-dependent and endothelium-independent vasodilation in dialysis patients. These data suggest that patients with chronic renal failure may have defective NO-mediated function in the endothelium and smooth muscle of vessels. Most reports have shown only impairment of endothelium-dependent vasodilation, whereas another report observed impaired smooth muscle function and intact endothelial function. Only a few previous observations included a full set of vascular function data, such as baseline vessel diameter, reactive hyperemia, and responses of endothelium to hyperemia and NO donor, although all these observations could be essential for comparison with other reports. Treatment with folic acid was reported to reduce plasma homocysteine levels, but not to normal levels, and failed to improve impaired endothelial function in patients in a predialysis phase and on maintenance dialysis therapy. Another investigation, directed at reducing homocysteine levels in earlier stages of renal failure, may be necessary to clarify the link between hyperhomocysteinemia and endothelial function. © 2001 by the National Kidney Foundation, Inc.