|Year : 2009 | Volume
| Issue : 5 | Page : 779-788
|Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients
Nassim Azadibakhsh1, Rahebeh Shaker Hosseini1, Shahnaz Atabak2, Navid Nateghiyan3, Banafsheh Golestan4, Anahita Hooshyar Rad1
1 Department of Human Nutrition, National Nutrition and Food Technology Research Institute, Tehran, Iran
2 Department of Nephrology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Department of Research and Development, Hakim Pharmaceutical Company, Tehran, Iran
4 Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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|Date of Web Publication||2-Sep-2009|
| Abstract|| |
To evaluate the efficacy of supplementation with high dose folic acid with and without vitamin B 12 in lowering plasma total homocysteine (tHcy) concentrations in hemodialysis (HD) patients, we studied 36 HD patients randomized into four groups according to the received therapeutic regimen: group I (only folic acid (FA), 5 mg/day), group II (FA, 5 mg/day + vitamin B 12 , 1 mg/day) group III (only FA, 15 mg/day), group IV (FA, 15 mg/day, vitamin B 12 , 1 mg/day) for a period of 8 weeks. Plasma tHcy and serum FA and vitamin B 12 levels were measured at baseline and after the supplementation period. Dietary intakes were assessed during the study period. At baseline, 27.8% of the patients had normal levels of tHcy and 72.2% had hyperhomocysteinemia. After supplementation, plasma tHcy increased by 1.35% in group I and decreased by 6.99%, 14.54% and 30.09% in groups II, III and IV respectively, which was only significant in group IV (P= 0.014). The patients did not show any significant changes in serum folic acid, but a significant change in serum vitamin B 12 in group IV (P= 0.006). Percentage of patients reaching normal levels of plasma tHcy was 5.6 fold higher in group IV than in the reference group (group I). No correlations were found between changes of plasma tHcy levels and dietary intakes. We conclude that oral supplementation with 15 mg/day folic acid together with 1 mg/day of vitamin B 12 is effective in reducing tHcy levels in HD patients. These supplements also have a desirable effect on serum folic acid and vitamin B12.
|How to cite this article:|
Azadibakhsh N, Hosseini RS, Atabak S, Nateghiyan N, Golestan B, Rad AH. Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients. Saudi J Kidney Dis Transpl 2009;20:779-88
|How to cite this URL:|
Azadibakhsh N, Hosseini RS, Atabak S, Nateghiyan N, Golestan B, Rad AH. Efficacy of folate and vitamin B12 in lowering homocysteine concentrations in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Mar 20];20:779-88. Available from: http://www.sjkdt.org/text.asp?2009/20/5/779/55361
| Introduction|| |
Hyperhomocysteinemia is present in 80 to 100 percent of hemodialysis (HD) patients. , It is a common manifestation of chronic kidney disease (CKD) as the glomerular filtration rate declines, and dialysis does not usually normalize its levels. ,
Retrospective, observational studies have shown that hyperhomocysteinemia is an independent risk factor for CVD and especially atherosclerosis and atherotrombosis. ,,,,,,,, However, large prospective studies have been inconsistent and suggest that tHcy could be a marker of nutritional status and not a cause of vascular diseases. ,,, However, lowering tHcy concentrations in HD patients is desirable since tHcy levels may partially account for thrombotic disease in dialysis patients and the correlation is confounded by malnutrition, inflammation, and atherosclerosis syndrome,  which may result in cardiovascular events. 
Homocysteine (Hcy) is metabolized by two pathways: remethylation and transsulfuration. Both pathways involve tetrahydrofolate, the active form of folic acid, and vitamin B 12 , as the cofactor. ,, Based on these metabolic path ways, different studies have been designed to normalize plasma tHcy levels in HD patients. Most of these studies supplemented HD patients with different doses of folic acid (FA) in order to achieve a considerable reduction in plasma tHcy or even normalize its levels. ,., .Some others evaluated the effect of supplementation with vitamin B 12 , vitamin B 6 , folinic acid, betaine, serine, and taurine, alone or in combination on tHcy concentrations in HD patients ,,,,,, and showed variable results. In none of these studies, the impact of dietary intake was considered on the outcome of the patients.
Most HD patients receive oral FA 5 mg/day by the time they are initiated on HD treatment; however, this strategy is inadequate to control hyperhomocysteinemia in them. ,
The aim of this study is to compare the efficacy of low and high doses of FA, with and without vitamin B 12 supplements in lowering tHcy concentrations in HD patients in addition to understanding of the impact of diet control on these levels.
| Patients and Methods|| |
We studied 40 HD patients who had been receiving 5 mg/d FA supplements for at least 3 months in a prospectively randomized doubleblind clinical trial. We excluded from the study patients under 18 years of age, having dialysis duration less than 3 months, being dialyzed other than 12 hours/week (3 sessions each lasting 4 hours, using bicarbonate based dialysate and polysulfone dialyzers), receiving supplementation history of more than 5 mg/d FA or any vitamin B, using Hcy interacting drugs, , having indication or contraindication for any of the study supplements or study procedure, being malnourished (Alb < 2 mg/dL) or vitamin B12 deficient (serum vitamin B 12 < 100 pg/mL), having a history of graft rejection in the last 6 months, or having a history of liver disease.
Before the supplementation period, the study patients were interviewed to determine their baseline characteristics including age, sex, height, dialysis duration, cigarette smoking (defined as smoking minimum 1 cigarette/d), consumption of tea (as there was not any coffee consumer among subjects), use of oral contraceptives (OCPs) and antacids (as Hcy interacting drugs), menopausal status, and etiology of CKD.
Fasting pre-dialysis blood samples were analyzed for plasma tHcy and serum FA, vitamin B 12 , albumin (Alb), creatinine (Cr) and blood urea nitrogen (BUN). Post-dialysis BUN was also determined to calculate urea reduction ratio (URR) as an indicator of dialysis efficiency, by dividing it to pre-dialysis BUN.  Baseline characteristics of patients are shown in [Table 1].
The study patients were divided randomly into four equal groups according to the received therapeutic regimen: group I (only folic acid (FA), 5 mg/day), group II (FA, 5 mg/day + vitamin B 12 , 1 mg/day) group III (only FA, 15 mg/day), group IV (FA, 15 mg/day, vitamin B 12 , 1 mg/day) for a period of 8 weeks.
At the end of the supplementation period, plasma concentrations of tHcy and serum concentrations of FA and vitamin B 12 were measured again. All patients were monitored for Kt/V (dialysis efficiency index) during the study procedure, with the goal of Kt/V > 1.2. 
The ethical committee of Shahid Beheshti University of Medical Sciences approved the whole procedure.
For biochemical assessments, fasting blood samples were drawn in the beginning and at the end of the study period. Whole blood samples were immediately cooled on ice packs and separated for plasma and serum within one hour using a refrigerated centrifuge.
Plasma samples were analyzed for tHcy concentrations by a rapid, isocratic, high performance liquid chromatography (HPLC) assay.  We adopted the described normal range for tHcy (5-12 µmol/L) and the borderline range (12-16 µmol/L) in our study. We also considered tHcy levels above 16 µmol/L as hyperhomocysteinemia. 
The measurement of serum FA and vitamin B 12 were performed using competitive immunoassay and an automated chemiluminescence system.  We adopted in our study the described normal ranges for serum FA and vitamin B 12 (316 ng/mL and 110-800 pg/mL, respectively). 
Alb, Cr and BUN concentrations were measured by Brom cresol green chemical method, chemical method based on reaction with alkaline picrate and enzymatic method based on hydrolysis of urea with urease relatively. , We adopted in our study the described normal ranges for these parameters (3.5-5 g/dL, 10-15 mg/dL and < 100 mg/dL, respectively). 
All fasting blood samples were collected before the dialysis session. Patients always received the FA and vitamin B 12 supplements 23-24 hours before the blood sampling.
Dietary intakes of energy, macronutrients (carbohydrate, protein and fat) and vitamins involving Hcy metabolism (FA and vitamins B12, B6 and B 2 ) were assessed during the supplementation period, using 24-hour recall method. The patients were interviewed, consecutively, for 3 days at the beginning, 2 days at week 4 and 3 days at the end of the supplementation period (8 days for each patient). 24-hour recall sheets were analyzed with the food processor (FP) software. To minimize measurement errors, the dietary assessment procedure (interviewing and analyzing) was done by a trained dietitian.
| Statistical Analysis|| |
All the statistical analysis was performed using the statistical software, SPSS (version 11.5). Descriptive statistics are reported in the form of mean values ± standard deviation (SD) together with 95% confidence intervals (CI). Since Kolmogorov-Smirnov test  showed that all the variables were normally distributed, we used parametric tests for the analysis. In order to compare the means of plasma tHcy and serum FA and vitamin B 12 levels within the groups before and after supplementation, the Student's "t" test  for paired samples was used. The effect of treatment and baseline measurements on post values of the main study variables was analyzed using linear regression. 
To determine the correlations between plasma tHcy concentrations and objective confounding factors, the Pearson's correlation coefficient  was used, while to compare the means of tHcy levels and subjective confounders, "t" test  for independent samples was used.
To monitor dietary intakes during the study period, we used ANOVA for repeated measurements.  In case of significant changes in these variables, linear regression  was used to assess the relationship between changes in tHcy concentrations and changes in dietary intakes. The significance level in this study was set at P= 0.05.
| Results|| |
From the 40 study patients, 2 died and 2 were eliminated due to injection of blood and vitamin B 12 . Only 36 finished the study period (n=9 in group I, n= 9 in group II, n= 10 in group III, and n= 8 in group IV). [Table 1] shows the main characteristics of the study patients.
Pearson's test revealed a statistically significant correlation between the mean of the initial plasma tHcy levels and the mean of the initial serum FA levels (r = -0.331, P= 0.048), height (r = -0.35, P= 0.036), and creatinine (r = -0.351, P= 0.88).
The mean of the initial plasma tHcy levels was significantly higher in women than in men (26.08 ± 9.39 µmo/L vs 19.58 ± 7.74 µmol/L, P= 0.032).
Effect of supplementation on plasma tHcy levels
At baseline, 72.2% of our study patients revealed hyperhomocysteinemia. Percentage of reduction in mean plasma tHcy level was only significant in group IV (-30.09 ± 22.55 %, P= 0.014) in comparison to group I [Table 2]. The percentage of reduction has been increased from group I to group IV [Figure 1].
Calculating the odds ratio to compare the percentage of patients with the normal range of plasma tHcy levels after the supplementation period, showed that the patients in group IV were 5.6 times more likely to enter the normal range than those in group I (OR= 5.6, 95% CI: 0.03 - 3.13). Compared to group I, reaching the normal range was 90% and 66% less likely in group II (OR= 0.1, 95%CI: 0 - 1.53) and group III (OR= 0.34, 95%CI: 0.03 - 3.13), respectively.
The linear regression analysis showed that in case of a constant initial mean of plasma tHcy levels, supplementation with 15 mg/day FA + vitamin B 12 might reduce plasma tHcy levels by 5.27 µmol/L ((3= -5.27, SE(R)= 2.28, P= 0.027) in comparison to group I.
Effect of supplementation on serum FA levels
The changes of serum FA levels were not significant in any of the 4 study groups [Table 2]. Supplementation with 5 mg/d FA + vitamin B12 did not result in a significant decrease in the mean serum FA levels [Table 2].
Changes of serum FA levels were the highest in the group receiving 15 mg/d FA + vitamin B 12 and negative in the group receiving 5 mg/d FA + vitamin B 12 [Figure 2].
Linear regression analysis showed that in case of a constant initial mean serum FA level, supplementation with 15 mg/day FA + vitamin B 12 might increase the mean serum FA levels by 130 ng/mL (R = 130, SE(13) = 50.9, P= 0.015) in comparison to group I.
Effect of supplementation on serum vitamin B 12 levels
The changes of serum vitamin B 12 levels were only significant in group IV (2150± 1539 pg/mL, P= 0.006) in comparison to group I [Table 2]. Supplementation with 5 mg/day FA + placebo for vitamin B 12 resulted in an insignificant decrease in serum vitamin B 12 concentration [Table 2].
The changes of serum vitamin B 12 levels increased from group I to IV, which exhibited the greatest increase [Figure 3].
Linear regression analysis showed that supplementation with 15 mg/day FA + vitamin B 12 may increase serum vitamin B 12 level by 1642 pg/mL β= 1642, SEβ = 505, P= 0.003) in comparison to group I. This increase is independent of the initial mean of the serum vitamin B 12 levels.
Effect of changes in dietary intake on main study variables
The dietary intake of energy, macronutrients and vitamins related to Hcy metabolism, during the study period is shown in [Table 3]. Based on ANOVA for repeated measurements, the changes in dietary intake of energy (P= 0.05), protein (P= 0.001) and fat (P= 0.031) were significant during the study period. Linear regression analysis showed no correlation between the changes of plasma tHcy levels and the changes in dietary intake of energy including protein and fat. The changes in the dietary intake of other nutrients assessed in the study were not significant.
| Discussion|| |
The results of our study demonstrate that supplementation with 15 mg/day of FA + 1 mg/day of vitamin B 12 resulted in a 30 percent (statistically significant) reduction in plasma tHcy concentrations. This finding supports the findings of the studies by Koyama et al and Manns et al, , but is different from the results of studies conducted by Billion et al and Trimarchi et al. ,
Billion et al could normalize plasma tHcy levels by 15 mg/d FA FA and vitamin B 12 supplements for two months.  This and previous studies have shown that the baseline plasma tHcy level is the major predictor of the response to therapy; the higher the tHcy level the better the response, and patients with normal levels of tHcy may show insignificant response. , This finding has been confirmed by our study too.
Trimarchi et al supplemented 62 HD patients in 4 groups receiving 10 mg/day oral FA and 500 µg i.v. vitamin B 12 treatments twice per week, alone or together. The changes in plasma tHcy concentrations were not significantly different in the co-supplemented group in comparison to the group that received only FA.  This result is probably due to the low dose of the FA supplements used, which is the same as the results obtained in group II of our study population (5 mg/day FA + 1 mg/day vitamin B12).
We evaluated the percentage of patients reaching the normal range in each group, as in some studies it was recommended to investigate the changes of this percentage in place of the changes of plasma tHcy levels, which is highly dependent on the baseline tHcy concentrations.
This evaluation showed that the greatest proportion of shifts to the normal range occurred in the group IV.
The dietary intakes of the patients revealed no change in dietary intakes of carbohydrates and vitamin B related to Hcy metabolism, during the study period. The changes in dietary intakes of energy, protein and fat were statistically significant in this period but these changes had no effects on the changes of plasma tHcy concentrations in our study groups.
Comparing serum FA concentrations, before and after the supplementation period, showed no significant change, whereas the analysis between groups showed a statistically significant change in the group IV in comparison to the reference group. These findings are in accordance with those of the studies by Manns et al and Arnadottir et al, who suggested that supplementation with increased dose of FA increases the amount of FA in cells and does not result in significant increase in serum FA. ,
We also found out that supplementation with 5 mg/d FA + 1 mg/d vitamin B 12 leads to a decrease in serum FA concentrations in comparison to the other groups that exhibited elevated levels of FA, and this is proportional to the amount of FA required within the cells. 5methyltetrahydrofolate is essential for Hcy methylation using vitamin B 12 dependent methionine syntase. Supplementation with vitamin B12 increases the intracellular demand for 5-methyltetrahydrofolate, which results in a decrease in serum FA levels and an increase in 5 methyltetrahydrofolate in the serum. Because serum folate counts for only 1-2% of extracellular folate, the distribution of folate between the intra and extracellular compartments severely influences the serum FA levels. The decrease in serum FA is highly dependent on the baseline FA; the higher the baseline levels, the lower are the eventual levels. , This decrease was not obvious in the group IV in our study, maybe because in these patients the intracellular FA levels were sufficient to satisfy the cell demands, which rendered the tHcy methylation pathway less dependent on the serum FA levels.
Comparing serum vitamin B 12 changes within and between groups revealed the significant changes in group IV, which was independent of the baseline levels of serum vitamin B 12 . This finding is in accordance with the results of Elian et al. 
The changes of serum vitamin B 12 concentrations show a strong relationship between the metabolism of FA and vitamin B 12 ; increasing FA consumption results in an increase in serum vitamin B 12 levels. The low dose of FA supplementation results in substitution of vitamin B12 in some metabolic pathways, but increasing the dose decreases the utilization of vitamin B12 and thus inhibits the decrease of this vitamin levels in serum.  This mechanism explains why increasing the dose of FA in both groups receiving placebo or 1 mg/day vitamin B 12 inhibits the decline in the serum vitamin B12 levels.
We conclude that oral supplementation with 15 mg/d FA + 1 mg/d vitamin B 12 is effective in reducing tHcy levels in HD patients. The next step is to design randomized, prospective, interventional studies to determine the effect of tHcy reduction on cardiovascular events.
| Acknowledgement|| |
This work was financially supported by Shahid Beheshti University of Medical Sciences. We thank Massoud Laboratory ( www.massoudlab. com ) for biochemical assessments; staff of the dialysis ward in Imam Hossein hospital for their technical assistance; library and computer section in nutrition faculty of Shahid Beheshti University of medical sciences and most of all, the dialysis patients who took part in this clinical trial, in spite of all their complications.
Nassim Azadibakhsh designed the study, collected and analyzed the data and wrote the manuscript. Rahebeh Shaker Hosseini gave significant advice and supervised the study in nutritional aspects. Shahnaz Atabak advised and monitored the study and analyzed the adverse events. Navid Nateghiyan formulated and manufactured vitamin B 12 supplements. Banafsheh Golestan supervised the statistical analysis.Anahita Hooshyar Rad gave consultation in the dietary assessment.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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