The effect of vitamin B6 and folate supplements on plasma homocysteine and serum lipids levels in patients on regular hemodialysis

Background: Hyperhomocysteinemia is anindependent risk factor for cardiovascularevents. The aim of this study was to show theresults of the reduction of homocysteine in endstage renal failure patients on hemodialysis,as it is known, have higher levels ofhomocysteine than other groups of subjects.Methods: Plasma homocysteineconcentration was determined before and afterthe administration of vitamin B₆ and folicacid in 12 patients (males : 6) on regulardialysis therapy. Mean monthly fasting serumconcentrations of total cholesterol (TCHOL),HDL-chol, LDL-chol and triglycerides (TRG) weredetermined for a period 68 months (12–120months) before and 26 months after theadministration of vitamin B₆ and folicacid. Results: Mean serum concentrations forfolic acid and vitamin B₁₂ before andafter the administration were: folic acid:5.03 ± 4.9 and 18.0 ± 19.2 ng/ml,(p < 0.0001) and B₁₂ : 456 ± 257 and514.38 ± 307 pg/mL respectively). Plasmahomocysteine was reduced significantly afterthe administration of above drugs (from47 ± 14 to 29 ± 9 µmol/mL, p < 0.001).This reduction of homocysteine resulted in amodification of the patients' lipidemicprofile: Serum LDL-chol was decreasedsignificantly (119 ± 38 mg/dL to110 ± 35 mg/dL, p<0.005). TCHOL and TRG werealso decreased but not significantly(190 ± 45 mg/dL to 187 ± 43 mg/dL and116 ± 63 mg/dL to 108 ± 47 mg/dLrespectively)). Serum concentrations HDL-cholwere increased significantly (from42 ± 10 mg/dL to 47 ± 10 mg/dL, p < 0.001).The atherogenic index for cholesterol, LDL/HDL,was 1.6 times lower after the drugs receiving(before: LDL/HDL = 3.1 and after: LDL/HDL = 2.5,p < 0.001).Conclusions: These results indicate thatthe folate and vitamin B₆ supplementationresulted in reduction of homocysteine levelsand improvement of lipidemic profile in regulardialysis patients.     

Methylenetetrahydrofolate reductase gene C677T polymorphism,plasma homocysteine and folate in end-stage renal disease dialysis and non-dialysis patients

BACKGROUND: It has been recently suggested that the presence of the methylenetetrahydrofolate reductase gene 677TT genotype is associated with younger age at initiation of dialysis, thus raising a hypothesis that younger renal patients carrying the TT genotype are at higher risk to develop end-stage renal disease. The aim of this study was to test the association between the C677T polymorphism and the presence of end-stage renal disease using a family-based study design. MATERIAL AND METHOD: C677T polymorphism was genotyped in a group of 247 family trios (offspring affected with end-stage renal disease, dialysed or conservatively treated, and both parents). Transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: The TDT analysis revealed no significant deviation in the transmission of the MTHFR C677T alleles to CRF patients (51 vs. 49% for the C allele and T allele transmission, respectively). We observed a significant relationship between MTHFR genotypes and total plasma homocysteine (tHcy), as well as folate concentration. Also, plasma tHcy and folate were negatively correlated. CONCLUSION: Our results did not show any association between the MTHFR reductase C677T polymorphism and the increased risk of the development of end-stage renal disease. Whether this polymorphism contributes to the faster rate of decline of renal function in renal patients, must be evaluated further.     

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.     

Plasma reduced homocysteine concentrations are increased in end-stage renal disease

BACKGROUND: Plasma total homocysteine (tHcy) concentrations> 15 micromol/L are associated with an increased risk of cardiovascular disease. This is especially the case in end-stage renal disease (ESRD), in which tHcy concentrations commonly range between 20 and 30 micromol/L. Adverse vascular or prothrombotic effects associated with hyperhomocysteinemia are assumed to be mediated by the free sulfhydryl (reduced) form of the molecule (rHcy), but data based on fluorescence high-pressure liquid chromatography (HPLC) indicate that rHcy concentrations are not increased in ESRD despite two- to threefold elevations in tHcy. METHODS: We developed a sensitive method for measuring plasma rHcy concentrations in which freshly drawn blood is incubated with sodium iodoacetate, and the resulting S-carboxymethylhomocysteine is analyzed by gas chromatography mass spectrometry. RESULTS: Unlike with the earlier methodology, we found plasma rHcy concentrations two to four times higher than normal in ESRD. These concentrations were lowered by hemodialysis and were proportional to plasma tHcy over the range of tHcy concentrations that has been associated with increased cardiovascular risk (r2 = 0.39, P < 0.0001). CONCLUSIONS: These results support the hypothesis that homocysteine could directly mediate vascular disease through mechanisms related to the reactivity of its free sulfhydryl group. It remains to be determined how much of the variability between plasma tHcy and rHcy is due to analytical variation and how much is due to biologic factors that separately influence concentrations of the disease marker, tHcy, and its presumed mediator, rHcy.     

Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease

Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis in patients with normal renal function. Plasma homocysteine (Hcy) is increased in patients with chronic renal failure (CRF) and could be linked to their high cardiovascular (CV) morbidity and mortality. We prospectively studied 77 patients (47 males and 30 females aged 62.85 +/- 1.53 yrs) who had been on maintenance hemodialysis (HD) (4 hr/x3/week) for 65.5 +/- 7.23 months. Patients were followed-up for 44 months. At baseline, blood samples were taken for hemoglobin (Hb), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, serum calcium, serum phosphates, parathyroid hormone (PTH), Hcy, vitamin B12, serum and erythrocyte folate and methylentetrahydrofolate-reductase (t-MTH-FR) genotype determination. Plasma Hcy levels of patients were divided into four quartiles. The univariate analysis demonstrated a significant relationship between Hcy and diastolic blood pressure (BP) (r=0.45; p=0.003), and both plasma (r=-0.30; p=0.03) and erythrocyte (r=-0.48; p=0.01) folate levels and CV score (r=0.39; p=0.007). Kaplan-Meier analysis showed that the mortality rate due to CV events was statistically significantly higher in the 4th Hcy quartile (68%; 12 patients) vs. the 3rd quartile (12%; two patients), the 2nd quartile (28%; four patients) and the 1st quartile (14%; two patients) (log-rank test p=0.02). Cox's regression analysis for CV survival showed that Hcy was a positive CV mortality predictor (beta=0.02; hazard ratio=1.031; 95% confidence interval (95% CI): 1.013-1.050; p=0.001), while LDL cholesterol and albumin related negatively to CV mortality (LDL cholesterol: beta=-0.02; hazard ratio=0.095; 95% CI: 0.0957-0.0997; p=0.035; albumin: beta=-2.35; hazard ratio=0.097; 95% CI: 0.011-0.847; p=0.026). Our results show that Hcy is a strong independent mortality predictor in HD patients with a 3% increase in mortality for each 1 micromol/L increase in plasma Hcy concentration. This agrees with previous findings confirming the role of Hcy in predicting CV risk factors in uremic patients.     

Testing the homocysteine hypothesis in end-stage renal disease: Problems and a possible solution

The homocysteine hypothesis states that circulating homocysteine is a vascular toxin in concentrations that occur in the general population and in renal failure. This hypothesis is currently being tested in the Kidney and End State Renal Disease Study (HOST), but data have emerged since the HOST began that suggest its results will be inconclusive. The crucial treatment component in the HOST is folic acid, but its effect is likely to be lost because the American food supply is now fortified with folic acid. A second concern is that the very high doses of folic acid and pyridoxine being used in the HOST may confound the results. Finally, confounding due to 'reverse epidemiology' was not considered when the HOST was designed. Parenteral vitamin B(12) is a highly promising therapy for homocysteine reduction in end-stage renal disease that merits careful investigation. Clinical trials using it to test the homocysteine hypothesis will avoid the problems inherent in the HOST.     

Association between plasma homocysteine concentrations and cardiac hypertrophy in end-stage renal disease.

In patients with end-stage renal disease, plasma homocysteine and cardiac mass are both increased and considered independent risk predictors for cardiovascular-specific morbidity and mortality. In order to establish a relationship between these two parameters, we determined cardiac mass and plasma homocysteine in 75 patients with end-stage renal disease undergoing chronic hemodialysis. We observed a statistically significant positive association between plasma homocysteine and cardiac mass index or either of its components. This was observed even after adjustment for age, sex, systolic blood pressure and hematocrit (p = 0.0027). The adjusted odds ratio for left ventricular hypertrophy was 6.6 (95% confidence interval 1.3-32.8) for subjects with the highest versus the lowest plasma homocysteine concentrations. This cross-sectional study is the first to show a statistical link between plasma homocysteine and cardiac structure, independently of mechanical factors. High plasma homocysteine concentrations are associated with an increased adjusted risk of left ventricular hypertrophy in end-stage renal disease patients.     

Randomized trial of methylcobalamin and folate effects on homocysteine in hemodialysis patients

Experimental evidence indicates that uraemic patients undergoing haemodialysis are subject to increased oxidative stress. Plasmalogens are a phospholipid subclass found in cell membranes and plasma lipoproteins, which may work as an endogenous antioxidant. Using gas chromatography, we measured reduced portions of fatty aldehyde dimethyl acetals (16:0 DMA and 18:0 DMA, representing derivatives of plasmalogens) in fatty acid patterns of fasting serum phospholipids from 30 patients with chronic renal failure (CRF) receiving repeated ambulatory haemodialysis, as compared to 99 normal control subjects (CS). The highly significant difference of mean 16:0 DMA and 18:0 DMA values between CRF patients and CS (0.53 +/- 0.15 vs. 0.67 +/- 0.13, p < 0.001 and 0.33 +/- 0.11 vs. 0.40 +/- 0.11, p < 0.01, respectively) was lost when the patients were compared to subjects older than 85 (16:0 DMA) or 75 years (18:0 DMA). Weak, but significant inverse correlations with age or triglycerides were observed in blood serum of CS for 16:0 DMA and 18:0 DMA, respectively, but not of the patients. Partial correlation analysis indicated a mutually independent association of age and triglyceride values with serum plasmalogens in CS, but not in CRF patients. In conclusion, the reduced content of serum plasmalogen phospholipids of uraemic patients undergoing haemodialysis suggests an increased oxidative stress.     

Omega-3 fatty acid supplementation and total homocysteine levels in end-stage renal disease patients

Aim: Elevated total homocysteine (tHcy) levels are commonplace among end‐stage renal disease (ESRD) patients increasing risk for poor cardiovascular outcomes. Specifically, when plasma levels become significantly elevated, tHcy levels appear to contribute to vascular damage and premature atherosclerosis. The purpose of this study was to examine the effect of an over‐the‐counter omega‐3 (n‐3) fatty acid supplementation on tHcy levels in ESRD patients undergoing chronic haemodialysis. Methods: The present study was conducted using a double‐blind, permuted‐randomized and placebo‐controlled experimental protocol. ESRD patients were followed prospectively while supplementing n‐3 or corn oil (n‐6) prospectively for 6 months. Patients: Sixty‐nine patients were recruited that had previously demonstrated compliance with dialysis and medication. Following a 12 h fast, participants donated 12 mL of blood for analysis of tHcy at baseline and at 6 months. Results: The results of this study using regression models revealed no differences in age and gender regarding homocysteine levels at the post‐test with P‐values of 0.6818, 0.6709 and 0.3331 for each regression model. The study findings also revealed that daily administration of 6 g of n‐3 fatty acids containing 160 mg of eicosapentaenic acid (0.96 g/day) and 100 mg of docosahexaenoic acid (0.6 g/day) had no effect on tHcy levels when compared with control. Conclusion: Potential reasons for this non‐significant result may be found in a dose–response relationship, advancement of disease progression in our sample population, or potentially the lack of a significant relationship between fish oil and tHcy. Future studies should address whether a dose–response relationship between n‐3 fatty acid supplementation and tHcy levels exists, and how stage of disease progression affects intervention success or failure.     

A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease

Patients with anemia of end-stage renal disease were studied for 36 weeks to determine efficacy, safety, and long-term benefits of epoetin beta administration. A total of 131 patients participated in the 12-week, double-blind, placebo-controlled portion of the multicenter study. For the first 6 weeks (fixed-dose period), patients were randomized to receive 100 U/kg of epoetin beta or placebo thrice weekly; in the second 6 weeks (dose-adjustment period), the dose of epoetin beta ranged from 50 to 150 U/kg thrice weekly. Of the 131 patients who entered the placebo-controlled period, 122 crossed over to a 24-week open-label period, where all patients received active drug and doses of epoetin beta could be individually titrated after the first 6 weeks. One hundred patients completed the 36-week study. In all phases of the study, epoetin beta was shown to produce a consistent, sustained increase in hemoglobin (baseline, 7.1 +/- 0.1 to 10.5 +/- 0.2 g/dL) and hematocrit (baseline, 21.5 to 32.7%), which virtually eliminated the need for packed red blood cell transfusions. Reticulocyte counts rose initially in response to epoetin beta and stabilized at levels higher than baseline throughout the remainder of the study period (baseline, 1.7 to 2.5%). The placebo group showed no change in these parameters during the double-blind period. Similar patterns of response were seen in the original placebo group after crossover to active drug (mean hemoglobin increase, 2.6 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Riboflavin is a determinant of total homocysteine plasma concentrations in end-stage renal disease patients

The effect of thiamine (vitamin B(1)) or riboflavin (vitamin B(2)) availability on fasting total homocysteine (tHcy) plasma levels in end-stage renal disease patients is unknown. A cross-sectional study was performed in a population of non-vitamin supplemented patients maintained on continuous ambulatory peritoneal dialysis. Red blood cell availability of thiamine (alpha-ETK) and of riboflavin (alpha-EGR), along with other predictors of tHcy plasma levels, was considered in the analysis. There was a linear association of alpha-EGR with tHcy plasma concentrations (P = 0.009), which was not observed for alpha-ETK. Among red blood cell vitamins, alpha-EGR was the only predictor of tHcy levels (P = 0.035), whereas alpha-ETK, red blood cell pyridoxal-5-phosphate supply (alpha-EGOT) and red blood cell folate levels had no effect. The risk for having a high tHcy plasma levels within the fourth quartile (plasma tHcy >38.3 micromol/L) was increased by an alpha-EGR > median (odds ratio, 4.706; 95% confidence interval, 1.124 to 19.704; P = 0.026). By way of contrast, alpha-ETK had no effect in these analyses. Independent predictors of tHcy plasma levels were serum albumin, alpha-EGR, red blood cell folate, and certain MTHFR genotypes. A logistic regression analysis showed that the MTHFR genotype is a predictor for having a tHcy plasma concentration within the fourth quartile. In summary, riboflavin availability, as measured by alpha-EGR, is a determinant of fasting tHcy plasma levels in peritoneal dialysis patients. This finding may have implications for tHcy lowering therapy in individuals with end-stage renal disease.     

The effect of intradialytic combined exercise on hemodialysis efficiency in end-stage renal disease patients: a randomized-controlled trial

Purpose

Insufficient dialysis is a difficult problem for patients undergoing hemodialysis, and causes cardiovascular complications and increases mortality. Increasing aerobic exercise and resistance exercise have been shown to be beneficial to physical fitness of patients undergoing hemodialysis, but a few studies have focused on combined exercise (combination of aerobic and resistance exercise training) and the interaction effect of combined exercise and intervention duration on hemodialysis efficiency. This study aimed to investigate the effects of 24-week combined exercise on hemodialysis efficiency, blood pressure, exercise capacity, and quality of life in patients undergoing hemodialysis.

Methods

In total, 47 eligible subjects were randomly allocated to exercise group and control group. The intervention group performed a 24-week, three times weekly, and moderate-intensity intradialytic combined exercise. Patients in the control group received usual care. The primary outcome was hemodialysis efficiency, which recorded every 4 weeks. Secondary outcomes included blood pressure, exercise capacity, and quality of life, measured at baseline and after 24 weeks of intervention.

Results

In intervention group, sp Kt/V significantly improved by 13.2%, and systolic blood pressure and diastolic blood pressure significantly decreased by 8.5 mmHg and 6.5 mmHg, respectively. The 6-min walking distance increased significantly by 43 m (9.8%), but there was no significant change in quality of life.

Conclusion

Combined exercise and intervention duration had an interaction effect on hemodialysis efficiency. Combined exercise improved blood pressure and physical fitness for patients undergoing hemodialysis, but did not affect quality of life. The extensive benefits of combined exercise provide evidence for the exercise development for patients undergoing hemodialysis.

     

Propionyl-L-carnitine therapy: effects on endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage renal disease

BACKGROUND/AIMS: Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months. RESULTS: In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group. CONCLUSIONS: Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.     

Comparison of lipids, apoproteins and associated enzyme activities between diabetic and nondiabetic end-stage renal disease.

Lipids, apoproteins and associated enzyme activities in type 2 diabetic end-stage renal disease (ESRD) were compared with that in nondiabetic ESRD and normal controls. Of the 40 uremic patients with non-insulin-dependent diabetes mellitus, 20 patients were receiving stable continuous hemodialysis treatment (CHT). Of the 39 patients with nondiabetic ESRD, 21 were undergoing CHT. Patients with nondiabetic ESRD exhibited elevated levels of serum triglyceride and a marked reduction in high-density-lipoprotein (HDL) cholesterol. Concentrations of serum apolipoprotein (Apo) C-3 were higher than in controls, whereas mean levels of serum Apo E were lower. The concentrations of serum Apo A-1 and Apo A-2 decreased with diminished lecithin: cholesterol acyltransferase activity. Lipoprotein lipase activity decreased in undialysed patients, and hepatic triglyceride lipase activity decreased significantly throughout the observation. Patients with diabetic ESRD exhibited elevated serum Apo B and normal serum Apo E levels, besides the lipid and Apo abnormalities observed in nondiabetic ESRD. Moreover, a prominent reduction in serum Apo A-1 was found in dialysed diabetic patients. The Apo B/Apo A-1 ratio was significantly higher in diabetic ESRD than in nondiabetic patients undergoing CHT. These results indicate that lipid abnormalities are accelerated in diabetic ESRD and may constitute a serious risk for the development of atherosclerosis.     

A randomized trial of intermittent versus continuous oral alfacalcidol treatment of hyperparathyroidism in end-stage renal disease

BACKGROUND: Secondary hyperparathyroidism, a major clinical problem in patients with chronic renal failure, develops in response to phosphate retention and impaired calcitriol [1,25-dihydroxyvitamin D3] synthesis. Vitamin D therapy, particularly alfacalcidol [1 alpha-hydroxyvitamin D3], has been shown to be effective in the treatment of secondary hyperparathyroidism. The aim of this study was to compare the effect of a 12-week course of continuous versus intermittent oral alfacalcidol therapy on parathyroid hormone suppression. PATIENTS AND METHODS: 34 patients were selected and randomly divided into 2 groups to receive either intermittent or continuous oral alfacalcidol. Baseline data were obtained on serum calcium, phosphorus, alkaline phosphatase and PTH. All but the PTH were monitored monthly. PTH levels were measured again until the end of the protocol. The intervention was 2 microg of alfacalcidol given after each dialysis session (intermittent group) or 1 microg given 6 days/week (continuous group). RESULTS: Serum calcium and phosphorus showed a tendency to increase from baseline levels in both groups. Mean PTH levels for both groups showed a progressive reduction over time during the study period. This decrement showed no significant difference with regard to the schedule of alfacalcidol administration when comparing the 2 groups. There also was no difference in the incidence of side effects--hypercalcemia and hyperphosphatemia--between the intermittent and continuous intervention. CONCLUSION: Feedback regulation of PTH with oral alfacalcidol therapy is efficient in the treatment of hyperparathyroidism. However, intermittent and continuous oral administration are equally effective in suppressing an elevated PTH level in hemodialysis patients, with similar safety margins.     

Exercise in the end-stage renal disease population

Many of the known benefits of exercise in the general population are of particular relevance to the ESRD population. In addition, the poor physical functioning that is experienced by patients who are on dialysis is potentially addressable through exercise interventions. The study of exercise in the ESRD population dates back almost 30 yr, and numerous interventions, including aerobic training, resistance exercise training, and combined training programs, have reported beneficial effects. Recently, interventions during hemodialysis sessions have become more popular and have been shown to be safe. The risks of exercise in this population have not been rigorously studied, but there have been no reports of serious injury as a result of participation in an exercise training program. It is time that we incorporate exercise into the routine care of patients who are on dialysis, but identification of an optimal training regimen or regimens, according to patient characteristics or needs, is still needed to facilitate implementation of exercise programs.     

Sexual and reproductive function in end-stage renal disease and effect of kidney transplantation

Advanced chronic kidney disease is associated with impaired spermatogenesis and testicular damage. Semen analysis typically shows a decreased volume of ejaculate, oligo-or complete azoospermia, and a low percentage of motile sperm. Erectile dysfunction （ED） is also common in patients with chronic renal failure （CRF） and is observed in excess of 50% of these patients. There have been ongoing improvements in survival and quality of life after renal transplantation. One of the most impressive aspects of successful renal transplantation in the young people is the ability of the male patient to father a child. In this article we first review pathophysiology of reproductive failure in end-stage renal disease （ESRD）, then ED in ESRD and its management are discussed, finally sexual function in renal transplant patients and management of ED in these patients are reviewed.