Treatment of hyperhomocysteinemia in children on dialysis by folic acid

Adult patients with renal failure have a high total homocysteine concentration in plasma. Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Folic acid lowers the homocysteine concentrations in plasma in hyperhomocysteinemia. Whether this results in a reduced risk for cardiovascular diseases remains to be proven by intervention studies. In the present study we investigated: (1) if homocysteine concentrations are elevated in the plasma of children with renal failure and (2) the influence of folic acid administration on the plasma homocysteine concentration. The plasma homocysteine concentration was measured in 21 children, 9 on hemodialysis and 12 on peritoneal dialysis, before and 4 weeks after treatment with 2.5 mg folic acid daily. Healthy children (234) constituted the control group. In controls the median homocysteine concentration was 9.1 μmol/l (range 4.3–20.0 μmol/l). The median plasma homocysteine concentration in patients before folic acid treatment was 20.0 μmol/l (Q1-Q3 13.7–26.0; Q, quartile). After 4 weeks of folic acid treatment the median plasma homocysteine concentration was 12.0 μmol/l [Q1-Q3 9.8–14.3 (P<0.0001 Wilcoxon signed rank test)]. There was no significant difference between hemodialysis and peritoneal dialysis patients. Children with renal failure treated with hemodialysis or peritoneal dialysis have elevated plasma homocysteine concentrations, but this is significantly reduced after administration of 2.5 mg folic acid daily for 4 weeks. It is suggested that folic acid be added to the treatment of children with renal failure, although a beneficial effect still has to be proven. The required dose needs further study. Received: 16 February 1998 / Revised: 2 November 1998 / Accepted: 4 November 1998     

Creatine supplementation does not decrease total plasma homocysteine in chronic hemodialysis patients

BACKGROUND: Hyperhomocysteinemia is present in the majority of chronic hemodialysis patients. Treatment with folic acid, vitamin B12, and vitamin B6 cannot fully normalize plasma homocysteine concentrations (tHcy). Previously we have demonstrated the tHcy-lowering effect of creatine supplementation in an animal model of uremia (Kidney Int 64:1331-1337, 2003). The present study investigates the effects of creatine supplementation on tHcy in a vitamin-repleted chronic hemodialysis population. METHODS: Forty-five hemodialysis patients receiving folic acid and vitamin B6 and B12 were included. Patients were treated with creatine (2 g/day) or placebo during 2 treatment periods of 4 weeks, separated by a washout of 4 weeks. Plasma tHcy, creatine, Kt/V(urea), folic acid, vitamin B12, and routine biochemistry were determined, as well as the prognostic inflammatory and nutritional index. RESULTS: All patients had elevated tHcy concentrations (21.2 +/- 5.6 micromol/L). Creatine treatment resulted in increased plasma and red blood cell creatine levels, documenting uptake of creatine. Creatine did not affect tHcy concentrations. There was no relationship between plasma creatine concentrations and tHcy concentrations. No changes in body weight, routine biochemistry, nutritional status, folic acid, or vitamin B12 were observed during the study. CONCLUSION: Creatine supplementation at a rate of 2 g/day does not further decrease tHcy concentrations in chronic dialysis patients already treated with high dose folic acid, vitamin B6, and B12 supplementation.     

Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease

BACKGROUND: The pathogenesis of hyperhomocysteinemia in end-stage renal disease (ESRD) is unclear. Folic acid lowers, but does not normalize, the plasma homocysteine level in patients with ESRD, but its effect on whole body metabolism of homocysteine is unknown. METHODS: We studied the effect of 3 weeks of oral treatment with 5 mg folic acid per day on homocysteine metabolism in six chronic hemodialysis patients and six healthy controls. Primed, continuous infusions with [(2)H(3)-methyl-1-(13)C] methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation, and homocysteine transsulfuration. Metabolic homocysteine clearance was defined as the ratio of transsulfuration and plasma homocysteine level. RESULTS: Folic acid treatment lowered plasma homocysteine significantly by 39% (95% CI 5 to 73) in the ESRD group, but plasma homocysteine remained higher than baseline values in the control group. In ESRD patients, homocysteine remethylation and methionine transmethylation rate increased by 34% (95% CI 5 to 62) and 22% (95% CI 5 to 39), respectively (i.e., levels that were similar to the baseline values of the control group). Transsulfuration rate and metabolic homocysteine clearance were not significantly altered by folic acid treatment in both the ESRD and the control group. CONCLUSION: In ESRD patients, folic acid treatment lowers, but does not normalize plasma homocysteine, whereas homocysteine remethylation and methionine transmethylation increase to levels found in untreated healthy controls. These findings indicate a persistent, folate-independent, defect in metabolic homocysteine clearance in ESRD.     

Evidence of altered homocysteine metabolism in chronic renal failure

The fasting serum concentrations of total homocysteine and metabolites of transsulfuration (cystathionine, cysteine, methylmalonic acid, 2-methylcitric acid) and remethylation (methionine) were determined by gas chromatography-mass spectrometry in 40 nondialyzed patients with chronic renal disease and in 50 patients with end-stage renal disease requiring chronic maintenance hemodialysis. The nondialyzed patients and 28 of the dialysis patients did not receive additional vitamin supplementations. Twenty-two of the dialysis patients received daily oral vitamin preparations containing 10 mg pyridoxine (vitamin B(6)), 6 microg cyanocobalamin (vitamin B(12)), and 1 mg folic acid. In the nondialyzed patients, linear regression analysis showed positive correlations between serum concentrations of creatinine and total homocysteine (r = 0.68, p < 0.0001), cystathionine (r = 0.73, p < 0. 0001), methylmalonic acid (r = 0.77, p < 0.0001), and 2-methylcitric acid (r = 0.81, p < 0.0001). Serum homocysteine was positively correlated with serum concentrations of cystathionine (r = 0.59, p < 0.0001), cysteine (r = 0.69, p = 0.004), methylmalonic acid (r = 0. 64, p = 0.0001), and 2-methylcitric acid (r = 0.64, p < 0.0001). There was no significant correlation between serum concentrations of homocysteine and methionine (r = -0.14, p = 0.63). In the hemodialysis patients receiving oral vitamin supplementation, serum homocysteine and cystathionine concentrations were significantly lower than in hemodialysis patients not receiving vitamins (homocysteine 21.8 +/- 1.1 vs. 33.2 +/- 3.7 micromol/l, p = 0.0004; cystathionine 2,075.9 +/- 387.1 vs. 3,171.3 +/- 680.2 nmol/l, p = 0. 02; mean +/- SEM). In summary, our results show increased intermediate products of the transsulfuration pathway, but no increase in remethylation of homocysteine in chronic renal disease, including end-stage renal disease requiring chronic maintenance dialysis. Copyright Copyright 1999 S. Karger AG, Basel     

Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia

BACKGROUND: Hyper-homocyst(e)inemia is an independent risk factor for atherosclerotic vascular disease in patients with end-stage renal disease (ESRD), although optimal treatment remains unknown. This randomized, double-blind, placebo-controlled study was designed to measure the effect of high-dose oral vitamin B(12) and folic acid on predialysis total homocyst(e)ine levels in patients with ESRD. METHODS: We studied 81 hemodialysis patients who had hyper-homocyst(e)inemia (>16 micromol/L) on varied doses of a multivitamin containing 1 mg of folic acid/day. After screening blood work, all patients were switched to daily multivitamin therapy, including 1 mg of folic acid for four weeks. For all patients, vitamin B(12), 1 mg/day, was added for an additional four weeks. Patients were then randomized to receive four weeks of 0, 5, or 20 mg of folic acid in addition to the multivitamin and vitamin B(12) (all given daily). RESULTS: Screening homocyst(e)ine levels (mean 27.7 micromol/L) decreased by 19.2% after four weeks of treatment with a daily multivitamin containing 1 mg of folic acid (P < 0.001). Homocyst(e)ine levels were reduced further from 22.3 to 18.6 micromol/L (mean reduction 16.7%, 95% CI 11.8 to 21.6%, P < 0.001) after four weeks of therapy with vitamin B(12) (1 mg/day). There was no significant difference in mean reduction of homocyst(e)ine levels after therapy with high-dose folic acid compared with placebo (P = 0.35). CONCLUSIONS: The optimal oral treatment of hyper-homocyst(e)inemia in hemodialysis patients consists of 1 mg of folic acid and 1 mg of oral vitamin B(12) daily. Whether this treatment will lower the risk of future atherosclerotic vascular events remains to be investigated.     

A controlled trial of the effect of folate supplements on homocysteine, lipids and hemorheology in end-stage renal disease

Elevated plasma homocysteine (Hcy), dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease (ESRD) and are recognized risk factors for arteriosclerosis. To study the effect of folate supplementation on these factors we conducted a randomized controlled trial. Thirteen hemodialysis (HD) and 8 continuous ambulatory peritoneal dialysis (CAPD) patients received either 5 mg folic acid daily or placebo for 3 months. After 1 and 3 months, fasting blood samples were taken for Hcy, lipid profile, blood and plasma viscosity, red blood cell (RBC) osmotic fragility, plasma fibrinogen concentration and in vivo platelet aggregability. At baseline, the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity. Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33%. Mean total cholesterol, LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate. Folate had no significant effect on hemorheology. In conclusion, folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles. In our patients, hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation.     

Sustained reduction of hyperhomocysteinaemia with folic acid supplementation in predialysis patients.

BACKGROUND: Moderate hyperhomocysteinaemia, as occurs in chronic renal failure patients, is an established independent risk factor for atherosclerotic arterial occlusive accidents, the incidence of which is abnormally high in such patients. Folic acid supplementation has been shown to reduce plasma homocysteine level in end-stage renal disease patients treated with haemodialysis or peritoneal dialysis, but its long-term effects in predialysis patients had not been assessed. METHODS: We prospectively treated a total of 78 predialysis patients with folic acid for at least 1 year (range 12-74 months) together with oral pyridoxine and vitamin B12 supplements. Of the patients, 67 received 5 mg folic acid three times per week, whereas the other 11 patients who were treated with recombinant erythropoietin received 5 mg/day. Plasma fasting total homocysteine concentration was determined at baseline, after 3 months and at the end of follow-up. RESULTS: Mean (+/-SD) plasma total homocysteine level decreased from 21.2+/-6.4 micromol/l at baseline to 14.2+/-4.6 at 3 months and remained at 12.8+/-3.7 micromol/l at the end of follow-up (average duration 2.8 years), whereas plasma creatinine rose from 268+/-129 to 399+/-234 micromol/l. Mean plasma folate concentration rose from 19+/-12 to 47+/-13 nmol/l and mean plasma vitamin B12 rose from 237+/-119 to 347+/-191 pmol/l from baseline to end of follow-up. CONCLUSIONS: Moderate folic acid supplementation (2.15 mg/day) allows a substantial (40% as a mean) and sustained (up to 6 years) reduction of plasma total homocysteine level in predialysis uraemic patients without any detectable side effect. Folic acid supplementation may thus contribute to lower the risk of accelerated atherosclerosis in such patients.     

Improvement of endothelial function in uraemic patients on peritoneal dialysis: a possible role for 5-MTHF administration.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. METHODS: We examined the effect of oral treatment with 15 mg/daily of 5-methyltetrahydrofolate (5-MTHF) for 12 weeks, on homocysteinaemia and endothelial function in 19 patients undergoing peritoneal dialysis and compared them, for the same period of time, to a control group of patients on peritoneal dialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by the inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after sublingual administration of glyceryl trinitrate. Finally, oxidative stress was assessed by evaluating the conjugated dienes plasma levels. RESULTS: Plasma homocysteine concentrations fell by 30% after oral treatment with 5-MTHF. Endothelial function improved significantly after oral 5-MTHF treatment (13.8 +/- 1.2% vs 11.4 +/- 1.4%; P < 0.02) while in the control group we observed a worsening of basal values from 12.1 +/- 2.66% to 8.7 +/- 2.90% (P < 0.02). The conjugated dienes plasma levels did not change either. CONCLUSIONS: Our study demonstrated that 5-MTHF administration improves endothelial dysfunction in patients undergoing peritoneal dialysis. This effect appears to be independent of the reduction in homocysteine plasma levels.     

Reduction of plasma homocysteine by folic acid in children with chronic renal failure

Hyperhomocysteinemia is a well-known independent risk factor for cardiovascular disease and is a prevalent abnormality in chronic renal failure. However, studies on this abnormality in children with chronic renal failure, before renal replacement therapy, are scarce. In this study, we measured the plasma homocysteine levels of 27 children (mean age 8.9+/-4.8 years) with predialytic chronic renal failure, and analyzed the effect of folic acid supplementation (1 mg daily for 4 weeks) on the homocysteine levels in 14 of these children. The baseline homocysteine concentration of the patients (12.5+/-6.0 micro mol/l) was higher than that of the control group (5.9+/-1.8 micro mol/l, P<0.001), and correlated positively with age and negatively with folic acid concentration. Folic acid and vitamin B(12) concentrations were not below normal in any patient. The homocysteine concentration was decreased from 13.2+/-6.6 micro mol/l (pretreatment) to 9.3+/-4.2 micro mol/l by folic acid supplementation in the 14 patients. Folic acid supplementation also lowered the prevalence of hyperhomocysteinemia from 64.3% to 42.9%. According to these results, we recommend that folic acid supplementation be started in children with chronic renal failure early in the disease course.     

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 (intra-renal) and in the uremic circulation (extra-renal). 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.     

5-methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. METHODS: We examined the effect of the active metabolite of folic acid, 5-methyltetrahydrofolate (5-MTHF), 45 mg/week i.v. for 10 weeks, combined during the last 2 weeks with vitamin B12, 500 microg s.c. twice weekly, on homocysteinaemia and endothelial function in 15 patients undergoing convective haemodialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after administration of isosorbide dinitrate. Finally, the presence of the thermolabile variant of methyltetrahydrofolate reductase (t-MTHFR) was assessed by genotype analysis. RESULTS: Plasma homocysteine concentrations fell by 47% after treatment with 5-MTHF alone and by a further 13.6% after the addition of vitamin B12. The reduction was more marked in homo- and heterozygous patients than in normal genotypes for t-MTHFR. Flow-mediated endothelial vasodilation, measured by ultrasonography of the brachial artery, improved after administration of 5-MTHF (12.52+/- 2.47% vs. 7.03+/-1.65%; P<0.05), but there were no further changes following the addition of vitamin B12. CONCLUSIONS: Our study demonstrated that 5-MTHF administration not only reduced plasma homocysteine but also improved endothelial function in uraemic patients undergoing convective haemodialysis.     

Reduction of the homocysteine plasma concentration by intravenously administered folinic acid and vitamin B(12) in uraemic patients on maintenance haemodialysis

BACKGROUND: Hyperhomocysteinaemia is an independent cardiovascular risk factor which can induce vascular lesions, thus contributing to the early development of atherosclerosis. Low-dose folic acid supplementation reduces the pretreatment homocysteine plasma levels by 25-35%. Recent studies report that higher intravenous or oral administration of the active form of folic acid reduces the homocysteine plasma concentration by nearly 70%. The reduction could also be influenced by the thermolabile variant of methylenetetrahydrofolate reductase (tMTHFR) and by the dialysis modality. METHODS: A cross-sectional clinical study was performed to evaluate the effect of a drug containing folinic acid and vitamin B(12) on the plasma homocysteine concentration and whether this variable could also be influenced by the presence of a genetic variant of the methionine pathway and the use of different dialysis modalities. The plasma homocysteine concentration was measured in 55 patients undergoing haemodialysis, 27 of whom have been treated intravenously for megaloblastic anaemia using a drug containing low concentrations of folinic acid and vitamin B(12) at the end of each dialysis session for 6 months. The presence of tMTHFR was sought by molecular analysis, and the role of the dialysis modality was also investigated. RESULTS: The patients given the folic acid treatment had lower homocysteine plasma levels than those not so treated. The plasma homocysteine concentration was significantly higher in the tMRHFR homozygotes than in the patients with a normal genotype, significantly lower in the treated than in the untreated homozygotes, and significantly higher in the untreated homozygotes than in the untreated subgroup with a normal genotype. The homocysteine level was also significantly lower in the patients who underwent convective haemodialysis than in those who received standard bicarbonate dialysis. CONCLUSIONS: A drug containing low concentrations of folinic acid combined with vitamin B(12) using an intermittent intravenous regimen is effective in reducing the homocysteine plasma concentration in uraemic patients. The homocysteine levels seem also to depend on genotype and dialysis modality.     

Study of the homocysteine status in children with chronic renal failure

BACKGROUND/AIMS: Vascular diseases are a major cause of morbidity and mortality in end-stage renal disease (ESRD) patients and they cannot be explained entirely by the prevalence of traditional risk factors for atherosclerosis. The role of hyperhomocysteinemia as an additional risk factor in the development of accelerated atherosclerosis and/or thrombosis in these patients has been suggested possibly due to homocysteine (Hcy) induced endothelial cell injury. This study was aimed at evaluation of the Hcy status in children with chronic renal failure (CRF) especially in those suffering from ESRD and the possible role of folic acid and vitamin B12 therapy in the correction of hyperhomocysteinemia if present. METHODS: This study included 40 patients with CRF, 30 on regular hemodialysis (HD) treatment (group I) and 10 on conservative (medical) treatment (group II) in comparison to 20 healthy age- and sex-matched controls (group III). The basal serum levels of Hcy, folic acid and vitamin B12 as well as plasma level of activated protein C resistance (APC-R) were measured in patients and controls. RESULTS: The mean serum Hcy was significantly higher in those on regular HD (17.9 +/- 10.07 micromol/l) in comparison to those on conservative treatment (8.05 +/- 2.99 micromol/l) (p < 0.001) and controls (7.07 +/- 2.24 micromol/l) (p < 0.001), while there was no significant variation between the latter two groups. The mean values of APC-R, folic acid and vitamin B12 failed to show any significant difference in the three studied groups. No significant difference in the basal Hcy level between patients with previous history of vaso-occlusive disease and those without was found. Half of the patients on regular HD (group Ia) (n = 15) were given folic acid as 50 mg of 5-formyl-tetrahydrofolate (the active form of folic acid) intravenously once weekly after the dialysis session for 4 weeks. The other half (group Ib) (n = 15) received in addition to folic acid therapy, vitamin B12 1,000 microg hydroxycobalamine once intramuscularly. After therapy the mean Hcy decreased significantly in those who received folic acid and vitamin B12 (7.80 +/- 3.77 micromol/l) (p < 0.001) to a level comparable to the basal levels in conservative and control groups, whereas a non-significant decrease was found in those who received folic acid only (13.3 +/- 11.47 micromol/l) (p > 0.05). CONCLUSIONS: Hcy is high in children with ESRD on regular HD and combined therapy of the active form of folic acid and vitamin B12 is of value in decreasing Hcy values comparable to that in controls.     

Concentrations of vitamin C, vitamin B12 and folic acid in patients treated with hemodialysis and on-line hemodiafiltration or hemofiltration

OBJECTIVE: Uncertainty has arisen as to whether vitamin supplements are needed by dialysis patients, in particular those treated by means of hemofiltration or hemodiafiltration using highly permeable (high-flux) filters. We therefore measured the concentrations of vitamin C, cobalamin (vitamin B12) and folic acid in conventional (low-flux) dialysis patients and in those receiving on-line treatment (hemofiltration or hemodiafiltration). MATERIAL AND METHODS: Plasma (P-)ascorbate, serum (S-)cobalamin and S-folate concentrations were measured before and after a treatment session in 15 patients treated with low-flux hemodialysis and in 14 treated with on-line hemofiltration or hemodiafiltration. The patients' vitamin supplementations were also recorded. RESULTS: P-ascorbate concentrations were lowered by 51% and 53% in the hemodialysis and on-line groups, respectively after treatment and this reduction was significant (p<0.001). Concentrations below the reference values were found in 12/14 patients not receiving vitamin C supplementation. S-cobalamin did not decrease in the hemodialysis or on-line groups. S-folates did not change significantly in the hemodialysis or filtration groups. Patients without folacin supplementation had low values. CONCLUSIONS: P-ascorbate was reduced by both dialysis and filtration treatments. Neither S-cobalamin nor S-folate were reduced by dialysis or filtration treatments.     

Hyperhomocysteinemia in hemodialysis patients: effects of 12-month supplementation with hydrosoluble vitamins

BACKGROUND: High-efficiency hemodialysis may induce a deficiency in hydrosoluble vitamins. Supplementation with B-complex vitamins has been shown to lower serum homocysteine concentrations in several groups, but relatively few studies have concerned hemodialysis patients. Our objectives were to determine the status in B-complex vitamins in a large cohort of unsupplemented hemodialysis patients and to assess the effects of supplementation with hydrosoluble vitamins on serum homocysteine over one year. METHODS: Serum total homocysteine (tHcy), vitamin B12, folate, pyridoxal-5'-phosphate (P-5'-P; the active moiety of vitamin B6), as well as red blood cell folate concentrations, were measured in 168 chronic dialysis patients on three times weekly high-efficiency hemodialysis and not supplemented with hydrosoluble vitamins. Their methylenetetrahydrofolate reductase C677T (MTHFR) genotypes were also determined (homozygotes TT, heterozygotes CT, without mutation CC). All involved patients were then supplemented with hydrosoluble vitamins (once daily by mouth, DiaVite; R&D Laboratories, Minneapolis, MN, USA), and half of them were randomized to receive in addition 10 mg intravenously of folic acid posthemodialysis (30 mg intravenously per week). Serum tHcy was monitored after 6 and 12 months of supplementation in the 140 and 128 patients available for follow-up. RESULTS: At baseline, serum and red blood cell folate concentrations were within normal limits in all patients except for two with borderline serum folate (mean values of 21 +/- 8 and 1195 +/- 454 nmol/L), whereas serum vitamin B12 and P-5'-P were below normal in 11 and 65 patients, respectively (mean values of 327 +/- 215 pmol/L and 19 +/- 16 nmol/L for the 168 patients). Initial tHcy levels were increased in all patients (mean 33.3 +/- 16.6 for a normal below 11.8 +/- 1.5 micromol/L); tHcy significantly decreased to 23.5 +/- 7.6 micromol/L after six months (P < 0.0001 vs. baseline) and to 21.7 +/- 6.1 micromol/L after 12 months (P < 0.0001 vs. baseline) for the entire group, but was normalized in only four patients at 12 months. After six months, the mean reduction in tHcy was slightly but significantly greater for patients receiving intravenous folic acid (12.2 +/- 18.5 micromol/L) compared with patients not receiving it (8.3 +/- 9.8 micromol/L, P < 0.05). However, at 12 months, no difference between both subgroups persisted. When considering the different genotypes, tHcy at baseline tended to be higher for TT than CT and CC (39.8 +/- 30.9 vs. 31.4 +/- 10.5 vs. 31.6 +/- 11.8 micromol/L) and decreased to respective values of 21.1 +/- 6.9 versus 21.4 +/- 6.1 versus 22.2 +/- 5.9 micromol/L at 12 months. The impact of the addition of folic acid to DiaVite appeared particularly significant in TT patients at six months. CONCLUSIONS: (1) Hyperhomocysteinemia was present in 100% of our hemodialysis patients. (2) Nearly 40% of our unsupplemented hemodialysis patients were deficient in vitamin B6. (3) Supplementation with DiaVite(R) has resulted in significant tHcy reductions for all three genotypes. (4) The impact of the proposed supplementation protocol was found after six months and was maintained, but did not increase further after 12 months of the same regimen. (5) The addition of intravenous folic acid has been associated with a more pronounced decrease in tHcy in TT patients.     

The effect of vitamin B12 on total plasma homocysteine concentration in folate-replete hemodialysis patients

AIM: Results from several studies indicate that the total homocysteine (tHcy) concentration in plasma is an independent risk factor for cardiovascular disease in hemodialysis patients. Folic acid is the established mainstay of homocysteine-lowering treatment, but since such treatment does not normalize plasma tHcy concentration in hemodialysis patients, it is of importance to search for additional therapy. METHODS: Twenty-eight folate-replete hemodialysis patients were randomized to 2 equally sized groups, a treatment group and a control group. The treatment group received vitamin B12 tablets at a dose of 2 mg 3 times a week for 6 weeks (after each dialysis session) while the control group received no such treatment. Blood samples were collected before and at the end of the treatment period for analysis of tHcy in plasma and vitamin B12, methylmalonic acid as well as folate in serum. RESULTS: At the end of the study period, serum vitamin B12 concentrations were significantly higher in the treatment group than in the control group. Plasma tHcy concentrations decreased significantly in both groups during the study period. However, there was no difference between the responses of the 2 groups. CONCLUSION: The results of this open, randomized controlled study did not support the hypothesis that treatment with oral vitamin B12 has considerable homocysteine-lowering effect in folate-replete hemodialysis patients.     

Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD

BACKGROUND: Hyperhomocysteinemia is seen in most hemodialysis (HD) patients and is an independent risk factor for cardiovascular disease. Homocysteine metabolism via remethylation requires activated folate and vitamin B12 and metabolism via transsulfuration requires serine and vitamin B6. Prior studies have shown highly variable effects of supplemental B vitamin and folate therapy for hyperhomocysteinemia. We undertook a fully controlled trial with abnormally high doses of folic acid alone or with supplemental vitamin B6 and B12 compared with active folate alone or with serine. METHODS: Two prospective studies were undertaken in hemodialysis patients. In the first study (protocol A), hyperhomocysteinemia was treated in 77 patients with 30 or 60 mg folic acid with or without vitamins B6 and B12 for eight weeks and compared with matching placebos. In the second study (protocol B), hyperhomocysteinemia was treated in 37 patients with intravenous folinic acid given alone or with serine and compared with matching placebos. All patients received the standard of care treatment with a multivitamin tablet before and throughout the protocol to test the hypothesis that additional therapy is required over and above the routine therapy for maximum reduction in total homocysteine (tHcy). RESULTS: Normal volunteers; The mean (SD) tHcy of 128 normal subjects was 6.5 (4) micromol/L. Protocol A; Plasma folate increased significantly in the groups given folic acid at both four and eight weeks (P = 0.0001 at both time points). Plasma vitamin B12 was significantly increased at four weeks (P = 0.0018) but not at eight weeks (P = 0.064) in those given Vitamin B12. However, tHcy did not differ between treatment groups at baseline (P = 0.63), four weeks (P = 0.79) or eight weeks (P = 0.74). Protocol B: Plasma folate increased significantly at four weeks in those receiving folinic acid (P = 0.0001) but tHcy was not significantly different between groups (P = 0.92). In neither study was there any significant change in tHcy comparing before and during any treatment intervention. CONCLUSIONS: In our studies high dose oral folic acid, intravenous folinic acid, vitamins B6 and B12 and oral serine were ineffective at lowering tHcy in patients on hemodialysis when given folic acid, folinic acid serine or B vitamins in addition to routine folic acid and B vitamin supplements.     

Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease

High serum total homocysteine (tHcy) is gaining scrutiny as a risk factor for cardiovascular disease in the general population. The relationship between tHcy and mortality and cardiovascular events in patients with end-stage renal disease (ESRD) is unsettled. This randomized trial evaluates the efficacy of high-dose folic acid in preventing events in ESRD. A total of 510 patients on chronic dialysis were randomized to 1, 5, or 15 mg of folic acid contained in a renal multivitamin with a median follow-up of 24 mo. Mortality, cardiovascular events, and homocysteine levels were assessed. There were 189 deaths, and 121 patients experienced at least one cardiovascular event. Composite rates of mortality and cardiovascular events among the folic acid groups did not differ (at 24 mo: 43.7% in 1 mg group, 38.6% in 5 mg group, 47.1% in 15 mg group; log-rank P = 0.47). Unexpectedly, high baseline tHcy was associated with lower event rates. From lowest to highest quartile, event rates at 24 mo were 54.5% for Q1, 41.8% for Q2, 41.2% for Q3, and 34.7% for Q4 (log-rank P = 0.033). In contrast to some studies describing tHcy as a risk factor for mortality and cardiovascular events, this study found a reverse relationship between tHcy and events in ESRD patients. Administration of high-dose folic acid did not affect event rates.     

Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of L-folinic or folic acid

BACKGROUND: We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid. METHODS: Forty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12. Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection. RESULTS: Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in total folate and the remainder was unmethylated folic acid. CONCLUSIONS: Data from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients.     

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. BACKGROUND: Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients. METHODS: In a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin. RESULTS: Folinic acid and pyridoxine i.v. supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse effects attributable to folinic acid treatment were observed during this time. CONCLUSIONS: Intravenous folinic acid therapy (50 mg) once per week associated with pyridoxine supplementation appears to be an effective and safe strategy to normalize plasma tHcy levels in the majority of chronic HD patients.