Homocysteine and cardiovascular disease in renal disease

Elevated homocysteine (hyperhomocysteinaemia) in renal patients is a major concern for physicians. Although cause and effect between homocysteine and cardiovascular disease (CVD) has not been established in either the general population or renal patients, there is much evidence that this relationship does exist. Purported mechanisms that may explain this effect include increases in endothelial injury, smooth muscle cell proliferation, low-density lipoprotein oxidation and changes in haemostatic balance. Renal patients have a much greater incidence of hyperhomocysteinaemia and this may be explained by decreases in either the renal or extrarenal metabolism of the compound. We conclude that data from long-term placebo-controlled trials are urgently required to determine whether hyperhomocysteinaemia in renal patients is a cause of CVD events and requires therapeutic targeting.

Homocysteine-lowering therapy in renal disease

Hyperhomocysteinemia is a potential risk factor for vascular disease and is associated with endothelial dysfunction, a predictor of adverse cardiovascular events. Renal patients (end-stage renal failure (ESRF) and transplant recipients (RTR)) exhibit both hyperhomocysteinemia and endothelial dysfunction with increasing evidence of a causative link between the 2 conditions. The elevated homocysteine appears to be due to altered metabolism in the kidney (intrarenal) and in the uremic circulation ( extrarenal). This review will discuss 18 supplementation studies conducted in ESRF and 6 in RTR investigating the effects of nutritional therapy to lower homocysteine. The clinical significance of lowering homocysteine in renal patients will be discussed with data on the effects of B vitamin supplementation on cardiovascular outcomes such as endothelial function presented. Folic acid is the most effective nutritional therapy to lower homocysteine. In ESRF patients, supplementation with folic acid over a wide dose range ( 2 - 20 mg/day) either individually or in combination with other B vitamins will decrease but not normalize homocysteine. In contrast, in RTR similar doses of folic acid normalizes homocysteine. Folic acid improves endothelial function in ESRF patients, however this has yet to be investigated in RTR. Homocysteine-lowering therapy is more effective in ESRF patients than RTR.

Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy

To compare the incidence of foetal malformations (FMs) in pregnant women with epilepsy treated with different anti-epileptic drugs (AED) and doses, and the influence of seizures, family and personal history, and environmental factors. A prospective, observational, community-based cohort study. Methods. A voluntary, Australia-wide, telephone-interview-based register prospectively enrolling three groups of pregnant women: taking AEDs for epilepsy; with epilepsy not taking AEDs; taking AEDs for a non-epileptic indication. Four hundred and fifty eligible women were enrolled over 40 months. Three hundred and ninety six pregnancies had been completed, with 7 sets of twins, for a total of 403 pregnancy outcomes. Results. 354 (87.8%) pregnancy outcomes resulted in a healthy live birth, 26 (6.5%) had a FM, 4 (1%) a death in utero, 1 (0.2%) a premature labour with stillbirth, 14 (3.5%) a spontaneous abortion and 4 lost to follow-up. The FM rate was greater in pregnancies exposed to sodium valproate (VPA) in the first trimester (116.0%) compared with those exposed to all other AEDs (16.0% vs. 2.4%, P < 0.01) or no AEDs (16.0% vs. 3.1 %, P < 0.01). The mean daily dose of VPA taken in pregnancy with FMs was significantly greater than in those without (11975 vs: 1128 mg, P < 0.01). The incidence of FM with VPA doses greater than or equal to 1100 mg was 30.2% vs. 3.2% with doses < 1100 mg (P < 0.01). Conclusions. There is a dose-effect relationship for FM and exposure to VPA during the first trimester of pregnancy, with higher doses of VPA associated with a significantly greater risk than with lower doses or with other AEDs. These results highlight the need to limit, where possible, the dose of VPA in pregnancy. (C) 2004 Elsevier Ltd. All rights reserved.

Efficacy of twice-weekly multiple micronutrient supplementation for improving the hemoglobin and micronutrient status of anemic adolescent schoolgirls in Bangladesh

Background: Although iron deficiency is a major cause of anemia, other micronutrient deficiencies may also play a role. Objective: We examined whether multiple micronutrient supplementation is more efficacious than is supplementation with iron and folic acid alone for improving the hemoglobin and iron status of anemic adolescent girls in Bangladesh. Design: Anemic (hemoglobin < 12.0 g/dL) girls (n = 197) aged 14-18 y from rural schools in Dhaka District were entered into a randomized double-blind trial and received twice-weekly supplements of iron and folic acid (IFA group) or multiple micronutrients (15 micronutrients, including iron and folic acid; MMN group) for 12 wk. Results: At recruitment, the characteristics of the girls in the 2 groups were not significantly different, except for family size and body mass index. At the end of the study, although both groups benefited significantly from supplementation, mean changes in hemoglobin and serum ferritin concentrations were not significantly different between groups. Compared with the IFA group, girls in the MMN group had significantly greater increases in mean serum vitamin A, plasma vitamin C, red blood cell folic acid, and riboflavin concentrations (assessed as erythrocyte glutathione reductase activation coefficient). After 12 wk of supplementation, only the prevalence of vitamins A and C and riboflavin deficiencies decreased more significantly in the MMN group than in the IFA group. Conclusions: Twice-weekly MMN supplementation for 12 wk significantly improved the status of the micronutrients assessed but was not more efficacious than was supplementation with iron and folic acid alone in improving the hematologic status of anemic adolescent girls. More frequent doses may be needed to achieve full benefit.

A rapid dietary assessment tool to determine intake of folate was developed and validated

Background and Objective: Estimates of dietary folate intake are currently of considerable interest, but no rapid tools are available to assess dietary intake of folate that are well suited to everyday health promotion activities, We developed and tested the reliability and validity of two prototypes of a rapid dietary assessment tool (a folate intake tool, FIT) to determine dietary intake of folate. Study Design and Setting: Five hundred and sixty eight men and women aged 33-93 years from Perth, Western Australia. Completed one of the two prototypes of the tool and gave a fasting blood sample for measurement of serum folate. A subset (n - 277) of participants completed the same tool on a second occasion 3-6 weeks later. Results: The Pearson correlations (r) between folate score from the tool and serum folate were moderately high for both prototypes (FIT-A r = 0.54-, FIT-B r = 0.49). The folate scores for the two prototypes were similar on repeat testing and correlated strongly (FIT-A r = 0.75; FIT-B r = 0.68). Conclusions: The rapid dietary assessment tool described here, FIT, provides a valid and reliable measurement of dietary intake of folate for both men and women. (c) 2005 Elsevier Inc. All rights reserved.

Folate: Methods of analysis

Folates and its derivatives occur as polyglutamates in nature. The multiplicity of forms and the generally low levels in foods makes quantitative analysis of folate a difficult task. The assay of folates from foods generally involves three steps: liberation of folates from the cellular matrix; deconjugation from the polyglutamate to the mono and di-glutamate forms; and the detection of the biological activity or chemical concentration of the resulting folates. The detection methods used are the microbiological assay relying on the turbidimetric bacterial growth of Lactobacillus rhamnosus which is by far the most commonly used method; the HPLC and LC/MS techniques and bio-specific procedures. This review attempts to describe the methods along with the merits and demerits of using each of these methods.

Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry

The Australian Pregnancy Registry, affiliated European Register of Antiepileptic drugs in Pregnancy (EURAP), recruits informed consenting women with epilepsy on treatment with antiepileptic drugs (AEDs), those untreated, and women on AEDs for other indications. Enrolment is considered prospective if it has occurred before presence or absence of major foetal malformations (FMs) are known, or retrospective, if they had occurred after the birth of infant or detection of major FM. Telephone Interviews are conducted to ascertain pregnancy outcome and collect data about seizures. To date 630 women have been enrolled, with 565 known pregnancy outcomes. Valproate (VPA) above 1100 mg/day was associated with a significantly higher incidence of FMs than other AEDs (P < 0.05). This was independent of other AED use or potentially confounding factors on multivariate analysis (OR = 7.3, P < 0.0001). Lamotrigine (LTG) monotherapy (n = 65), has so far been free of malformations. Although seizure control was not a primary outcome, we noted that more patients on LTG than on VPA required dose adjustments to control seizures. Data indicate an increased risk of FM in women taking VPA in doses > 1100 mg/day compared with other AEDs. The choice of AED for pregnant women with epilepsy requires assessment of balance of risks between teratogenicity and seizure control.

Vitamin A supplementation for breastfeeding mothers (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of vitamin A supplementation, alone or in combination with other micronutrients (e.g. iron, folic acid, vitamin E), in mothers during the postpartum period, on maternal and infant health. Specific objectives are to compare the effects of vitamin A supplementation (alone or in combination with other micronutrients) with placebo or no supplementation on: 1. the duration and occurrence of maternal morbidity (xerophthalmia, infection) or illness symptoms (night blindness, fever, nausea, vomiting); 2. the duration and occurrence of neonatal or infant morbidity (respiratory tract infection, diarrhea, measles) or illness symptoms (fever, nausea, vomiting); 3. maternal serum retinol concentration; 4. infant serum retinol concentration; 5. breast milk retinol concentration; and 6. maternal satisfaction.

Efficacy of B vitamins in lowering homocysteine in older men - Maximal effects for those with B-12 deficiency and hyperhomocysteinemia

Background and Purpose - A higher plasma concentration of total homocysteine (tHcy) is associated with a greater risk of cardiovascular events. Previous studies, largely in younger individuals, have shown that B vitamins lowered tHcy by substantial amounts and that this effect is greater in people with higher tHcy and lower folate levels. Methods - We undertook a 2-year, double-blind, placebo-controlled, randomized trial in 299 men aged >= 75 years, comparing treatment with a daily tablet containing 2 mg of folate, 25 mg of B-6, and 400 mu g of B-12 or placebo. The study groups were balanced regarding age (mean +/- SD, 78.9 +/- 2.8 years), B vitamins, and tHcy at baseline. Results - Among the 13% with B12 deficiency, the difference in mean changes in treatment and control groups for tHcy was 6.74 mu mol/L (95% CI, 3.94 to 9.55 mu mol/L) compared with 2.88 mu mol/L (95% CI, 0.07 to 5.69 mu mol/L) for all others. Among the 20% with hyperhomocysteinaemia, the difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 mu mol/L (95% CI, 0.6 to 4.9 mu mol/L). Baseline vitamin B12, serum folate, and tHcy were significantly associated with changes in plasma tHcy at follow-up (r = 0.252, r = 0.522, and r = -0.903, respectively; P = 0.003, <0.001, and <0.001, respectively) in the vitamin group. Conclusions - The tHcy-lowering effect of B vitamins was maximal in those who had low B12 or high tHcy levels. Community-dwelling older men, who are likely to be deficient in B12 or have hyperhomocysteinemia, may be most likely to benefit from treatment with B vitamins.

Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients

Background: Cyclosporin A (CsA)-treated renal transplant recipients (RTR) exhibit relative hyperhomocystinemia and vascular dysfunction. Folate supplementation lowers homocysteine and has been shown to improve vascular function in healthy subjects and patients with coronary artery disease. The aim of this study was to assess the effects of 3 months of folate supplementation (5 mg/day) on vascular function and structure in RTR. Methods: A double-blind, placebo-controlled crossover study was conducted in 10 CsA-treated RTR. Vascular structure was measured as carotid artery intima media thickness (IMT) and function was assessed as changes in brachial artery diameter during reactive hyperemia (RE) and in response to glyceryl trinitrate (GTN). Function data were analyzed as absolute and percent change from baseline and area under the diameter/time curve. Blood samples were collected before and after supplementation and analyzed for total plasma homocysteine, folate, vitamin B-12 and asymmetric dimethyl arginine (ADMA) in addition to regular measures of hemoglobin, hematocrit, mean corpuscular volume (MCV) and serum creatinine. Results: Folate supplementation significantly increased plasma folate by 687% (p < 0.005) and decreased homocysteine by 37% (p < 0.05) with no changes (p > 0.05) in vitamin B 12 or ADMA. There were no significant (p > 0.05) changes in vascular structure or function during the placebo or the folate supplementation phases; IMT; placebo pre mean +/- SD, 0.52 +/- 0.12, post 0.50 +/- 0.11; folate pre 0.55 +/- 0.17, post 0.49 +/- 10.20 mm 5% change in brachial artery diameter (RH, placebo pre 10 +/- 8, post 6 +/- 5; folate pre 9 +/- 7, post 7 +/- 5; GTN, placebo pre 18 +/- 10, post 17 +/- 9, folate pre 16 +/- 9, post-supplementation 18 +/- 8). Conclusion: Three months of folate supplementation decreases plasma homocysteine but has no effect on endothelial function or carotid artery IMT in RTR.