Long-term reduction of plasma homocysteine levels by super-flux dialyzers in hemodialysis patients

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease in chronic hemodialysis (CHD) patients. Treatment with folic acid normalizes total homocysteine (tHcy) in only a minority of the patients. The present investigation has been conducted to study the influence of various dialyzers with different flux characteristics on the reduction of tHcy in the long term. METHODS: Total Hcy, folate, vitamin B6, vitamin B12, and albumin levels were assessed prospectively in 10 patients undergoing HD with high-flux polysulfon (PS; F 60) and 20 patients with super-flux dialyzers (N = 10 PS, F 500S; N = 10 CTA, Tricea 150G). Blood samples were collected before hemodialysis both at the beginning of the study and after 12 weeks. RESULTS: At baseline, all the groups showed similar tHcy levels. During high-flux dialysis, tHcy remained stable. In contrast, during dialysis with both super-flux modalities, tHcy decreased significantly (F 500S week 1, 29.6 +/- 9.9 micromol/L, and week 12, 21.5 +/- 8.5 micromol/L, P = 0.007; Tricea 150G week 1, 24.4 +/- 8.7 micromol/L, and week 12, 15.3 +/- 3.7 micromol/L, P = 0.008). The difference between high-flux and super-flux dialyzers was highly significant (mean: high-flux increase 15.6%, super-flux decrease 33. 3%, P = 0.001). Multivariate analysis showed a significant effect of super-flux dialysis on tHcy (P = 0.001), independently of the previously mentioned variables. CONCLUSIONS: Our findings clearly show that both types of super-flux dialyzers reduced tHcy significantly. As the molecular weight of free homocysteine is less than 268 D, the most likely explanation seems to be the removal of uremic toxins with inhibitory activities against enzymes involved in the extrarenal homocysteine metabolism.     

Anaesthesia for non-cardiac surgery in heart-transplanted patients

This review documents the anaesthetic management, haemodynamic function and outcome in 18 of 86 heart-transplanted recipients, who returned for 32 non-cardiac surgical procedures at the Toronto Hospital from 1985 to 1990. General anaesthesia was administered in eight of the 27 elective operations and four of the five emergency operations. Induction medications included thiopentone (2–4 mg· kg^?1), fentanyl (1–7 μg· kg^?1) and succinylcholine (1–1.5 mg· kg^?1). Anaesthesia was maintained with a combination of oxygen /nitrous oxide and isoflurane or enflurane. Muscle relaxation was maintained with vecuronium or pancuronium. No delayed awakening or unplanned postoperative ventilation was observed. Neuroleptanaesthesia was administered to 63.0% and 20.0% of the elective and emergency operations, respectively. The anaesthetics included fentanyl (25–100 ng) and midazolam (0.5–1.5 mg) or diazemuls (2.5–5.0 mg). Spinal anaesthesia (75 mg lidocaine) was administered to only two of the 27 elective operations. No important haemodynamic changes were observed in any anaesthetic group, but lower systolic BP was found after induction and during maintenance periods in the patients who received general anaesthesia than in those who received neurolept-anaesthesia. However, no anaesthesia-related morbidity or mortality was noted. This suggests that general, neurolept- and spinal anaesthesia do not affect haemodynamic function or postoperative outcome in heart-transplanted recipients undergoing subsequent non-cardiac surgery.     

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.     

维持性血液透析患者血浆同型半胱氨酸与骨密度的相关性研究

目的 探讨维持性血液透析（MHD）患者血浆同型半胱氨酸（Hcy）与指骨骨密度（BMD）的关系.方法 选择2006年2月至2010年2月在我院住院的MHD患者94例,分别将男性和女性患者分为3组,骨质疏松组：T值＜-2;骨量减少组：T值-2～-1;正常骨量组：T值＞-1.分别比较3组男性和3组女性患者年龄、血钙、血磷、碱性磷酸酶（ALP）、血浆Hcy.对血浆Hcy水平与指骨BMD进行相关性分析,用逐步回归法以指骨BMD为自变量建立多元线性回归方程以分析指骨BMD的影响因素.结果 骨质疏松组年龄均大于骨量减少组和正常骨量组（P＜0.05）,骨量减少组年龄大于正常骨量组（P＜0.05）.3组血钙、血磷、ALP、Hcy差异无统计学意义（P＞0.05）.男性血浆Hcy水平与指骨BMD无相关性（r=0.267,P＞0.05）.年龄是指骨BMD的影响因素（回归系数b1=-0.002,P=0.022）.骨质疏松组血浆Hcy水平均高于骨量减少组和正常骨量组（P＜0.05）,而骨量减少组和正常骨量组Hcy差异无统计学意义（P＞0.05）.3组血钙、血磷、ALP差异无统计学意义（P＞0.05）.女性血浆Hcy水平与指骨BMD呈负相关（r=-0.527,P＜0.05）.年龄和Hcy是指骨BMD的影响因素（回归系数b1=-0.002,P=0.011;回归系数b4=-0.003,P=0.048）.结论 女性MHD患者高血浆Hcy水平可能与指骨BMD降低有关,男性MHD患者血浆Hcy水平与指骨BMD无相关性.血浆Hcy升高可能是女性MHD患者骨质疏松潜在的危险因素.     

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.     

Effect of dialyser membrane pore size on plasma homocysteine levels in haemodialysis patients.

BACKGROUND: Hyperhomocysteinaemia is a putative risk factor for atherothrombotic cardiovascular disease in the haemodialysis population. High-dose vitamin B therapy does not entirely normalize elevated plasma total homocysteine (tHcy) levels in haemodialysis patients. Alternative therapies to reduce tHcy further are therefore required. Modifications of the dialysis regimen may result in a better removal of Hcy. We examined the effect of dialyser membrane pore size on tHcy levels in vitamin-replete chronic haemodialysis patients. METHODS: Forty-five haemodialysis patients were dialysed during 4 weeks with a low-flux, a high-flux and a super-flux membrane, in random order. Pre-dialysis tHcy was determined at baseline and every 4 weeks. In 18 patients, plasma tHcy before and after dialysis and dialysate tHcy concentrations were measured. RESULTS: Pre-dialysis tHcy decreased significantly during 4 weeks super-flux dialysis (-14.6 +/- 2.8%), whereas it remained stable during high-flux (+0.5 +/- 2.4%) and low-flux dialysis (+1.7 +/- 3.2%). The homocysteine reduction ratio was not different for the three membranes: 0.39 +/- 0.03 for the super-flux, 0.47 +/- 0.02 for the high-flux and 0.39 +/- 0.02 for the low-flux dialyser. The amount of Hcy recovered in the dialysate during a single dialysis session was also similar: 117.5 +/- 3.6 micro mol during super-flux, 95.3 +/- 11.5 micro mol during high-flux and 116.5 +/- 11.6 micro mol during low-flux dialysis. CONCLUSION: Super-flux dialysis significantly lowers tHcy in chronic haemodialysis patients. Improved removal of middle-molecule uraemic toxins with inhibitory effects on Hcy-metabolizing enzymes, rather than better dialytic clearance of Hcy itself, may explain the beneficial effect of the super-flux membrane.     

Folate supplementation in peritoneal dialysis patients with normal erythrocyte folate: effect on plasma homocysteine

The possible role of folate supplementation in reducing hyperhomocysteinemia in dialysis patients has been reported in several recent papers. However, scant data are available for peritoneal dialysis patients; besides, none of these studies investigated either the role of intraerythrocyte folate concentration or the presence of side effects caused by folate administration. Sixty-six peritoneal dialysis patients with hyperhomocysteinemia (>15 micromol/l) and normal folate status (as assessed by erythrocyte folate level >600 nmol/l) were randomly allocated to receive either oral folate (5 mg/day) or no vitamin supplementation. After 2 months of therapy, patients were requested to answer a questionnaire investigating the occurrence of symptoms possibly related to folate supplementation. Twenty-nine treated patients and 30 untreated controls completed the study. In the treated patients, serum and erythrocyte folate increased significantly (p < 0.0001) (respectively from 10.6 +/- 4.9 to 237 +/- 231 nmol/l and from 1,201 +/- 297 to 2,881 +/- 294 nmol/l) to levels at the uppermost limit of detection by laboratory methods. Serum vitamin B(12) levels did not change. Plasma homocysteine levels decreased from 54 +/- 32 to 23 +/- 14 micromol/l after folate supplementation and remained unchanged in the control group. After 4 months of folate therapy, homocysteine concentration was within the normal range in 5 patients (17%) and below 30 micromol/l in the other 21 (72%). Folate therapy resulted in a decrease in homocysteine of more than 50% in 45% of the patients and decrease of more than 20% in a further 38%. No significant symptoms were reported. Thus, serum and erythrocyte folate increase confirms that normal folate levels are inadequate in dialysis patients, even if serum and erythrocyte levels before folate supplementation cannot predict the effect on homocysteine plasma levels.     

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.     

Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation.

BACKGROUND: Hydroxymethylglutaryl CoA reductase inhibitors (statins) have been demonstrated to reduce the risk of developing coronary allograft vasculopathy (CAV) following heart transplantation in adults and are used routinely in many centers. CAV and lipid abnormalities have been reported to be less prevalent in pediatric heart transplant recipients. It is not known whether statins reduce the risk of CAV in this population METHODS: A retrospective review was performed to analyze the risk factors for developing CAV following pediatric heart transplantation with particular attention to the impact of pravastatin therapy. The study population was comprised of 129 pediatric patients who underwent 142 heart transplants at our institution from 1988 to 2003. The outcome variable was freedom from CAV, CAV being determined by coronary angiography or autopsy. RESULTS: CAV was identified in 25 recipients at a median of 3.7 years after transplantation. There were 331 patient-years of pravastatin therapy. Pravastatin therapy resulted in a reduction in total cholesterol levels, 162 +/- 29 to 137 +/- 20 mg/dl, p = 0.01. In multivariate analysis the use of pravastatin was associated with a lower incidence of CAV (p = 0.03), whereas an increased frequency of late rejection (p = 0.003) and earlier year of transplantation (p = 0.04) were associated with increased risk of CAV. CONCLUSIONS: The routine use of pravastatin was associated with a lower risk following pediatric heart transplantation. Further studies into the relationship between lipid abnormalities, inflammation and rejection, and the development of CAV in children are warranted.     

血浆同型半胱氨酸对糖尿病肾损伤的影响

目的观察血浆同型半胱氨酸水平与糖尿病肾脏病大鼠肾损伤的关系及替米沙坦对其影响。方法用链佐菌素（STZ）诱导糖尿病大鼠模型,成模18只后随机分为替米沙坦治疗组（A组）和实验对照组（B组）,每组各9只;另设空白对照组（C组）10只。于12周末收集24h尿,测定尿白蛋白排泄率（UAER）,并处死大鼠,心脏采血,ELISA法测血浆同型半胱氨酸（Hcy）水平,生化分析仪测血糖、血肌酐等生化指标。取肾脏称重,免疫组化法测。肾组织中纤溶酶原激活物抑制物-1（PAI-1）的表达水平。结果①与C组相比,B组肾肥大指数（肾质量／体质量）、UAER显著增加（P〈0．05）,血浆Hcy浓度明显升高（P〈0．01）,肾组织表达PAI-1明显增强（P〈0．05）。②与B组相比,A组血浆Hcy水平明显下降（P〈0．05）,肾组织表达PAI-1显著减少（P〈0．01）,肾肥大指数、UAER显著降低（P〈0．01,P％0．05）。③相关性分析显示,血浆Hcy浓度与肾组织表达PAI-1水平呈显著正相关（r=0．641,P〈0．01）,与UAER呈显著正相关（r=0．684,P〈0．01）。结论血浆Hcy参与糖尿病肾损伤的发生、发展,其机制可能与其引起纤溶系统失衡等因素有关;替米沙坦可通过减少PAI-1表达水平而降低血浆Hcy水平,恢复纤溶系统平衡,降低蛋白尿,保护肾功能。     

Pravastatin treatment before coronary artery bypass grafting for reduction of postoperative atrial fibrillation

Purpose  

The aim of this observational study was to determine the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) in patients with or without preoperative pravastatin treatment.     

Factors associated with increased plasma homocysteine in patients using an amino acid peritoneal dialysis fluid.

BACKGROUND: Although amino acid peritoneal dialysate (AAPD) substitution is thought to improve protein-energy malnutrition in patients undergoing peritoneal dialysis (PD), it may also increase plasma homocysteine (Hcy) levels due to the methionine load in the dialysate. However, it is still unclear which factors are important for elevating Hcy in patients treated with AAPD. METHODS: Sixteen malnourished PD patients (age 48+/-18 years) were treated daily with one exchange of 1.1% AAPD for 3 months. The effects of AAPD on nutrition, Hcy, methionine, leptin and insulin resistance were studied. We also analysed factors that influenced plasma Hcy levels. RESULTS: We found a transient increase in serum albumin (P<0.01) after 1 month treatment, especially in patients with serum albumin < or = 3.5 g/dl. Total plasma Hcy increased markedly after AAPD (the peak at month 2, P<0.001) and returned to baseline after ceasing AAPD, despite no changes in dietary methionine intake and serum methionine levels. Eight patients with Hcy increments >5.65 microM (the median) had lesser dietary intakes of protein (P = 0.01) and methionine (P = 0.028), lower body fat mass (P = 0.05) and lower aspartate transaminase (AST) (P = 0.008) before AAPD treatment than patients with lower increments. DeltaHcy was inversely correlated with baseline dietary methionine intake (r = -0.61), protein intake (r = -0.54) and AST (r = -0.51) (all P<0.05). There was no change in leptin or insulin resistance. AAPD treatment significantly increased Kt/Vurea (P<0.001), weekly creatinine clearance (P<0.05) and peritoneal glucose transport (P<0.05). CONCLUSIONS: Treatment with 1.1% AAPD transiently increased serum albumin in malnourished PD patients. However, the methionine load from the dialysate in this study significantly elevated plasma Hcy levels, especially in patients with lower protein and methionine intakes, and lower AST levels. Further long-term studies will be needed to clarify potential nutritional benefits and adverse effects of AAPD.     

Levels of plasma homocysteine in persons with spinal cord injury

BACKGROUND: Premature coronary vascular disease is a leading cause of morbidity and mortality in persons with chronic spinal cord injury (SCI). Evidence indicates that an elevated plasma homocysteine level is an independent risk factor for vascular disease. METHODS: Plasma homocysteine levels were collected in 845 subjects with SCI and compared to those in a reference population. Differences in plasma homocysteine were determined for sex, race/ethnicity, neurological deficit, and age, as well as for serum creatinine concentration. RESULTS: Plasma homocysteine was significantly higher in men than in women. Men were more likely to have moderately or severely elevated plasma homocysteine levels. Stratifying by male sex, greater percentages of whites and African Americans had severely elevated plasma homocysteine levels (>20 micromol/L) compared with Latinos (12% and 14% versus 8%; P > .01). For the total group with SCI, plasma homocysteine levels were not significantly different by race/ethnicity or neurological deficit subgroup. For the total group (P < .05) and within each sex (men, P < .05; women, P < .01), the older age group with SCI (>50 years) had significantly higher mean plasma homocysteine levels than the younger age group. Age was positively related to plasma homocysteine levels in men (P < .05) and women (P < .01). Plasma homocysteine levels were higher among men for any given age than among women (P < .0001) by an average of 3.19 +/- 0.51 micromol/L. Regardless of age or sex, persons with SCI tended to have higher levels of plasma homocysteine than able-bodied persons matched for age and sex. CONCLUSION: Because the risk of a vascular event increases with age, elevated levels of plasma homocysteine place older persons with SCI at further increased risk for a vaso-occlusive event. Of note, there was a stepwise increase in plasma homocysteine concentration for each quartile of higher serum creatinine concentration. Patients who have elevated levels of plasma homocysteine should receive a trial course of daily supplementation with oral folic acid and vitamin B12. If that is ineffective, they should receive vitamin B6 supplementation to lower their plasma homocysteine levels.