Claus Luley

Cardiac troponin T predicts mortality in patients with end-stage renal disease

BackgroundPatients with end-stage renal disease have a high risk of premature death, mainly as the result of cardiovascular disease (CVD), which is not sufficiently explained by the conventional risk factors. We therefore prospectively investigated total mortality and cardiovascular events in 102 patients on hemodialysis and assessed the prognostic value of baseline disease status and laboratory variables including total homocysteine and cardiac troponin T. Methods and ResultsPatients were followed for 2 years or until their first event of CVD (for outcome variable cardiovascular events, n=33) or death (for outcome variable total mortality, n=28). Survival was computed by the Kaplan-Meier method. Cox proportional hazards model was used to determine independent predictors of CVD events or total mortality. Cardiac troponin T emerged as the most powerful predictor of mortality, resulting in an almost 7-fold risk increase at concentrations >0.10 ng/mL (hazard ratio 6.85, 95% CI 3.04 to 15.45). Total homocysteine level greater than median was also associated with mortality (hazard ratio 2.44, 95% CI 1.10 to 5.40). These hazard ratios did not change substantially after adjustment for other risk factors. Significant predictors for CVD events were baseline diabetes, cerebrovascular disease, serum glucose, and triglycerides. After adjustment, only glucose and triglycerides remained significantly related to CVD events (hazard ratio with 95% CI 1.33 [1.12 to 1.57] and 1.14 [1.04 to 1.26], respectively, for a 1-mmol/L increase in concentration). ConclusionsWe conclude that total homocysteine and particularly cardiac troponin T are important predictors of mortality in patients with end-stage renal disease, whereas other laboratory variables and baseline disease status have less prognostic value.

B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease Results of a Randomized Controlled Trial

Background— In observational studies, hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease. These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B12. We conducted a randomized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality. Methods and Results— This randomized, double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008. We randomly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments: 5 mg folic acid, 50 &mgr;g vitamin B12, and 20 mg vitamin B6 (active treatment) or 0.2 mg folic acid, 4 &mgr;g vitamin B12, and 1.0 mg vitamin B6 (placebo) given 3 times per week for an average of 2 years. The primary outcome was total mortality; the secondary outcome was fatal and nonfatal cardiovascular events. The primary outcome occurred in 102 patients (31%) receiving the active treatment and in 92 (28%) receiving placebo (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50; P=0.51). The secondary outcome occurred in 83 patients (25%) receiving the active treatment and in 98 (30%) receiving placebo (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P=0.13). Conclusions— Increased intake of folic acid, vitamin B12, and vitamin B6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease. Clinical Trial Registration— URL: www.anzctr.org.au. Unique identifier: ACTRN12609000911291. URL: www.cochrane-renal.org. Unique identifier: CRG010600027.

Detection of Recent Ethanol Intake With New Markers: Comparison of Fatty Acid Ethyl Esters in Serum and of Ethyl Glucuronide and the Ratio of 5-Hydroxytryptophol to 5-Hydroxyindole Acetic Acid in Urine

BACKGROUND At present, recent ethanol consumption can be routinely detected with certainty only by direct measurement of ethanol concentration in blood or urine. Because ethanol is rapidly eliminated from the circulation, however, the time span for this detection is in the range of hours. Several new markers have been proposed to extend the detection interval, but their characteristics have not yet justified their use in routine clinical practice. We therefore investigated three new markers and compared their kinetics and sensitivities: (1) fatty acid ethyl esters (FAEEs) in serum, (2) ethyl glucuronide (EtG) in urine, and (3) the ratio of 5-hydroxytryptophol to 5-hydroxyindole acetic acid (5-HTOL/5-HIAA) in urine. METHODS Seventeen healthy men participated in a drinking experiment. Blood and urine samples were collected twice daily on three consecutive days and once daily on days 4 and 5. Ethanol concentration was determined by gas chromatography, FAEE levels, by gas chromatography with mass spectrometry, EtG concentration, by liquid chromatography-tandem mass spectrometry, and 5-HTOL/5-HIAA ratio, by high-performance liquid chromatography. RESULTS The peak serum ethanol concentrations of the subjects ranged from 5.4 to 44.7 mmol/liter (mean +/- SD, 30.1 +/- 9.1 mmol/liter). In the case of the serum ethanol determination, 100% sensitivity was reached only immediately after the end of the drinking experiment, and in the case of FAEE levels and 5-HTOL/5-HIAA ratio, it tested for 6.7 hr after the end of the ethanol intake. Thereafter, these latter parameters declined until 15.3 hr (FAEEs) and 29.4 hr (5-HTOL/5-HIAA), subsequently remaining in a stable range until 78.5 hr without further decrease. In contrast, EtG concentration showed 100% sensitivity until 39.3 hr and thereafter decreased, falling to below the limit of quantification of 0.1 mg/liter at 102.5 hr. CONCLUSION After moderate drinking, EtG in the urine proved to be a superior marker of recent ethanol consumption in healthy subjects. This is because EtG is a direct ethanol metabolite, it occurs in the urine only when ethanol has been consumed, and its sensitivity remains at the level of 100% for 39.3 hr.

Homocysteine as a Risk Factor for Cardiovascular Disease in Patients Treated by Dialysis: A Meta–analysis

BACKGROUND In the general population, increased homocysteine concentrations are a risk factor for cardiovascular disease and mortality. However, it is not known whether this also applies to patients with end-stage renal disease. STUDY DESIGN Meta-analysis of retrospective (11 studies including 1,506 individuals), prospective observational studies (12 studies including 1,975 individuals), and intervention trials (5 studies including 1,642 dialysis patients). Analyses were carried out separately, according to the study design. SETTING & POPULATION Studies of patients with end-stage renal disease treated by means of hemodialysis or peritoneal dialysis. SELECTION CRITERIA FOR STUDIES Studies investigating the association between total homocysteine level and cardiovascular disease or total mortality or the influence of vitamin supplementation on cardiovascular or mortality risk. INTERVENTION In intervention studies, vitamin preparations with folic acid alone or in combination with other vitamins, such as vitamin B(12) and B(6), were used. OUTCOMES In retrospective studies, cases are patients with cardiovascular diseases. Outcomes for prospective observational and intervention studies are cardiovascular events and total mortality. RESULTS In retrospective studies, there was no significant overall difference in homocysteine concentrations between cases and controls (weighted mean difference in homocysteine, 2.82 micromol/L; 95% confidence interval [CI], -2.22 to 7.86; P = 0.3). The pooled overall risk estimate for prospective observational studies suggests no association between homocysteine level (5-micromol/L increase) and total mortality (hazard ratio [HR], 1.02; 95% CI, 0.93 to 1.12; P = 0.7), but there was an association with cardiovascular events (HR, 1.09; 95% CI, 1.03 to 1.14; P = 0.001). In subgroup analysis of patients not receiving vitamins, an increase in homocysteine level was associated with increased mortality (HR, 1.07; 95% CI, 1.02 to 1.13; P = 0.01). For intervention trials with B vitamins, there was a significant risk reduction for cardiovascular disease (relative risk, 0.73; 95% CI, 0.56 to 0.94; P = 0.02), but no risk reduction for total mortality or the composite end point including total mortality (relative risk, 1.01; 95% CI, 0.88 to 1.15; P = 0.9). LIMITATIONS Many studies are small, which may lead to the observed heterogeneity. Some intervention trials are neither placebo controlled nor randomized. Separate analyses for specific end points and patients treated by means of hemodialysis or peritoneal dialysis were not possible. CONCLUSION Total homocysteine level may be a risk factor for cardiovascular events and total mortality in patients with end-stage renal disease not receiving vitamin supplementation or folic acid food fortification. There may be a potential for reducing cardiovascular disease in this population by folic acid supplementation.

Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease

Hyperhomocysteinemia is frequently found in patients with end-stage renal disease (ESRD). Plasma total homocysteine (tHcy) concentrations may be reduced by supplementation with folic acid or combinations of folic acid, vitamin B12, and vitamin B6. Supplementation studies with vitamin B12 alone in patients with ESRD have not yet been published. In this study, we investigated the effects of intravenous injection of cyanocobalamin (1 mg/wk for 4 weeks) in ESRD patients (N = 14) with low serum cobalamin concentrations (<180 pmol/L). All patients had elevated levels of plasma tHcy, methylmalonic acid (MMA), and cystathionine before supplementation. After supplementation, plasma tHcy and MMA decreased 35% and 48%, respectively; however, cystathionine levels were unchanged. The extent of the plasma tHcy reduction tended to be influenced by the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR). Serum cobalamin increased significantly upon supplementation, whereas serum folate levels were substantially reduced by 47%. In contrast, red blood cell (RBC) folate was unchanged. This study shows that vitamin B12 supplementation effectively decreases both MMA and plasma tHcy in ESRD patients with low B12 levels. Furthermore, it illustrates the close interrelation between vitamin B12 and folate metabolism.

Washout of water‐soluble vitamins and of homocysteine during haemodialysis: Effect of high‐flux and low‐flux dialyser membranes

Aim:  Vitamin deficiencies are common in patients with end‐stage renal disease (ESRD) owing to dietary restrictions, drug–nutrient interactions, changes in metabolism, and vitamin losses during dialysis. The present study investigated the levels of serum and red blood cell (RBC) folate, plasma pyridoxal‐5′‐phosphate (PLP), serum cobalamin, blood thiamine, blood riboflavin, and plasma homocysteine (tHcy) before and after haemodialysis treatment.

Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate

Elevated homocysteine concentrations are a risk factor for atherosclerotic disease. Recently it was reported that lipid lowering with fibrates increases homocysteine by up to 40%. Since elevated homocysteine concentrations can readily be lowered by vitamin supplementation, a randomized, double-blind crossover study was performed to investigate the effect of fenofibrate plus folic acid, vitamin B6 and B12 versus fenofibrate plus placebo in hyperlipidemic men. The crossover study comprised a run-in period of 6 weeks, a first treatment phase of 6 weeks, a washout phase of 8 weeks and a second treatment phase of 6 weeks. Vitamins were given at doses of 650 microg folic acid, 50 microg vitamin B12 and 5 mg vitamin B6 per day for a period of 6 weeks. After fenofibrate plus placebo the increase in homocysteine concentration was 44+/-47%. After fenofibrate plus vitamins it was 13+/-25%, being significantly lower than without vitamins. The increase in homocysteine in response to fenofibrate may counteract the cardioprotective effect of lipid lowering. The addition of vitamins involved in homocysteine metabolism can prevent most of the homocysteine increase seen after fenofibrate plus placebo. Addition of these vitamins to fenofibrate may therefore be warranted for routine use.

Serum Lipoproteins Improve After Successful Pharmacologic Antidepressant Treatment: A Randomized Open-Label Prospective Trial

OBJECTIVE Despite reports of lower plasma cholesterol in depressed patients, major depressive disorder has been shown to increase cardiovascular risk. Our objective was to study the composition of lipoproteins in depressed patients and controls and to examine the effects of pharmacologic treatment and treatment response on lipoprotein composition. METHOD Lipoprotein composition was analyzed in 65 adult inpatients at a university psychiatric hospital in Germany with DSM-IV major depressive disorder and 33 healthy controls (recruited via newspaper and radio ads) matched for age and sex. After the cross-sectional study phase, the patients were randomized in an open-label prospective trial to treatment with either mirtazapine or venlafaxine. Lipoproteins were reanalyzed after 4 weeks of treatment. Main outcome measures were total cholesterol, the low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol ratio, and the LDL triglycerides to apolipoprotein B ratio. Secondary outcome measures were total triglycerides, HDL and LDL cholesterol levels, and apolipoproteins A1 and B levels. Comparisons were made between the 2 drug groups and between remitters and nonremitters as measured by the 21-item Hamilton Depression Rating Scale. The study was conducted from April 2003 through December 2007. RESULTS Total cholesterol at baseline was lower in patients than in controls (mean ± SD = 4.99 ± 0.98 mmol/L vs 5.63 ± 1.01 mmol/L; P = .003), with significantly lower HDL cholesterol (P < .001) and LDL cholesterol (P = .03) in patients. However, the ratio of LDL triglycerides to apolipoprotein B, an index of size and atherogenic potential of LDL particles, was higher in depressed subjects (mean ± SD = 0.46 ± 0.14 mmol/g vs 0.38 ± 0.09 mmol/g; P = .002). Irrespective of treatment allocation, we found significant improvement of cardiovascular risk parameters in remitters but found deterioration in nonresponders. The LDL cholesterol mean change from baseline (remitters vs partial responders vs nonresponders) was -0.06 mmol/L versus +0.39 mmol/L versus +0.56 mmol/L (P = .014); the mean change in LDL/HDL cholesterol ratio was -0.50 versus +0.14 versus +0.80 (P = .002); and the mean change in the LDL triglycerides per apolipoprotein B ratio was -0.01 versus -0.01 versus +0.08 (P = .045). No drug-specific changes in lipid concentrations during treatment were observed except for total cholesterol (venlafaxine group mean = -0.02 mmol/L and mirtazapine group mean = +0.37 mmol/L; P = .033). CONCLUSIONS In depressed patients, lipoprotein structure is changed toward LDL particles with a higher atherogenic potential. Remission from depression is associated with an improvement of the LDL/HDL cholesterol ratio, shifting lipoproteins toward a less atherogenic composition. Our findings should be confirmed in a larger study, as they have relevance for both researchers and clinicians. TRIAL REGISTRATION German Clinical Trial Registry Identifier: DRKS00000008.

B Vitamin Plasma Levels and the Risk of Ischemic Stroke and Transient Ischemic Attack in a German Cohort

Background and Purpose— Data from prospective studies on the associations between B vitamin plasma levels and the risk of stroke are limited. We investigated the individual and combined effects of plasma folate, vitamin B12, and pyridoxal 5-phophate (PLP) levels on the risk of ischemic stroke and transient ischemic attack (TIA) in a large, prospective German cohort. Methods— Incident cases of ischemic stroke or TIA were identified among 25 770 participants (age 35 to 65 years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam Study during 6.0±1.5 years of follow-up. The present analysis is based on a case-cohort study comprising 779 subjects free from cardiovascular disease and 188 incident cases of cerebral ischemia (ischemic stroke or TIA). Multivariable Cox proportional-hazard models were applied to evaluate the association between B vitamin levels and risk of cerebral ischemia. Results— Participants in the lowest tertile of vitamin B12 values were at increased risk of cerebral ischemia compared with subjects in the highest tertile; this was not observed, however, for either folate or PLP. In subgroup analyses, the relative risks were similar in magnitude for stroke and TIA. When various combinations of B vitamin tertile levels were analyzed, only combined low folate and vitamin B12 levels (relative risk, 2.24; 95% CI, 1.10 to 4.54) were significantly related to an increased risk of cerebrovascular ischemia. Conclusions— Our data suggest that low vitamin B12 plasma levels, particularly in combination with low folate levels, increase the risk of cerebral ischemia. This effect may be mediated at least partly through elevations of homocysteine levels.

Effects of a Frequent Apolipoprotein E Isoform, ApoE4Freiburg (Leu28→Pro), on Lipoproteins and the Prevalence of Coronary Artery Disease in Whites

Different isoforms of apoE modulate the concentrations of plasma lipoproteins and the risk for atherosclerosis. A novel apoE isoform, apoE4Freiburg, was detected in plasma by isoelectric focusing because its isoelectric point is slightly more acidic than that of apoE4. ApoE4Freiburg results from a base exchange in the APOE4 gene that causes the replacement of a leucine by a proline at position 28. Analysis of the allelic frequencies in whites in southwestern Germany revealed that this isoform is frequent among control subjects (10:4264 alleles) and is even more frequent in patients with coronary artery disease (21:2874 alleles; P=0.004; adjusted odds ratio, 3.09; 95% confidence interval, 1.20 to 7.97). ApoE4Freiburg affects serum lipoproteins by lowering cholesterol, apoB, and apoA-I compared with apoE4 (P<0.05). Our 4 apoE4Freiburg homozygotes suffered from various phenotypes of hyperlipoproteinemia (types IIa, IIb, IV, and V). In vitro binding studies excluded a binding defect of apoE4Freiburg, and in vivo studies excluded an abnormal accumulation of chylomicron remnants. ApoE4Freiburg and apoE4 accumulated to a similar extent in triglyceride-rich lipoproteins. HDLs, however, contained about 40% less apoE4Freiburg than apoE4. In conclusion, our data indicate that apoE4Freiburg exerts its possible atherogenic properties by affecting the metabolism of triglyceride-rich lipoproteins and HDL.