Reiner Riezler

Acetylcysteine Reduces Plasma Homocysteine Concentration and Improves Pulse Pressure and Endothelial Function in Patients With End-Stage Renal Failure

Background—Increased oxidative stress, elevated plasma homocysteine concentration, increased pulse pressure, and impaired endothelial function constitute risk factors for increased mortality in patients with end-stage renal failure. Methods and Results—We investigated the metabolic and hemodynamic effects of intravenous administration of acetylcysteine, a thiol-containing antioxidant, during a hemodialysis session in a prospective, randomized, placebo-controlled crossover study in 20 patients with end-stage renal failure. Under control conditions, a hemodialysis session reduced plasma homocysteine concentration to 58±22% predialysis (mean±SD), whereas in the presence of acetylcysteine, the plasma homocysteine concentration was significantly more reduced to 12±7% predialysis (P <0.01). The reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure. A 10% decrease in plasma homocysteine concentration was associated with a decrease of pulse pressure by 2.5 mm Hg. Analysis of the second derivative of photoplethysmogram waveform showed changes of arterial wave reflectance during hemodialysis in the presence of acetylcysteine, indicating improved endothelial function. Conclusions—Acetylcysteine-dependent increase of homocysteine removal during a hemodialysis session improves plasma homocysteine concentration, pulse pressure, and endothelial function in patients with end-stage renal failure.

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 B6), 6 µg cyanocobalamin (vitamin B12), 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 µmol/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.

Long-Term Effects of Vitamin B12, Folate, and Vitamin B6 Supplements in Elderly People with Normal Serum Vitamin B12 Concentrations

Background: In the elderly, deficiencies of folate, cobalamin (vitamin B12) and pyridoxal phosphate (vitamin B6) are common. The metabolites homocysteine, methylmalonic acid, 2-methylcitric acid and cystathionine have been reported to be sensitive markers of these vitamin deficiencies. Objective: The long-term (269 days) effect of an intramuscular vitamin supplement containing 1 mg vitamin B12, 1.1 mg folate, and 5 mg vitamin B6 on serum concentrations of homocysteine (tHcy), methylmalonic acid (MMA), 2-methylcitric acid (2-MCA), and cystathionine (Cysta) was studied in 49 elderly subjects with normal levels of vitamin B12. Methods: Vitamin supplement was administered 8 times over a 21-day period, metabolite concentrations were measured until day 269 (e.g. 248 days after the end of vitamin supplementation). Results: From day 0 to 21, the serum levels of the 3 vitamins increased significantly, after cessation of supplementation the levels returned to baseline within the follow-up period. The MMA, 2-MCA and tHcy levels decreased during the treatment period significantly and did not reach baseline values within the 248-day period. Cysta levels did not differ significantly from baseline, either during or after treatment. Conclusion: MMA and 2-MCA levels rather reflect the availability of vitamins, especially cobalamin, than the actual serum levels. Since deficiencies of folate, cobalamin and pyridoxal phosphate in the elderly may cause hyerhomocysteinemia and hence may have unfavorable effects on mental performance, determination of MMA and 2-MCA levels in elderly patients with mental disturbances may be a cost-effective measure to improve or maintain mental performance.

Variability of post-methionine load plasma homocysteine assays.

BACKGROUND Numerous variations of the methionine load test are frequently used as dynamic function tests to assess homocysteine metabolism. Lack of standardization impedes inter-laboratory comparisons. Criteria based on biological variation are suggested to standardize the methionine load test. METHODS Weekly methionine load tests (n=5) with blood sampling at 0, 4, 6 and 8 h were performed on 15 young men. For both basal and post-methionine load homocysteine measurements, total variance (sigma(S)(2)), within-subject variance (sigma(I)(2)), between-subject variance (sigma(G)(2)) and analytical variance (sigma(A)(2)) were calculated from an appropriate analysis of variance (ANOVA). RESULTS Plasma homocysteine concentrations measured 6 h after methionine loading had analytical, within-subject and between-subject coefficients of variation of 5.2%, 17.5% and 9.7%, respectively. Measurements at 4 h had a higher within-subject coefficient of variation. Adjustment of post-methionine load homocysteine concentrations for basal levels resulted in considerable increases of all the measures of variation. CONCLUSIONS Adjustment of post-methionine load plasma homocysteine concentrations for basal levels does not improve the interpretation of changes in serial results due to the higher analytical and biological variance of adjusted concentrations. It is suggested that the methionine load test is standardized to a single, unadjusted homocysteine measurement at 6 h.

Does a single vitamin B-supplementation induce functional vitamin B-deficiency?

Abstract In a pilot study we measured the effect of three different combinations of the vitamins B6, folate and B12 on the serum concentrations of homocysteine, cystathionine and methylmalonic acid in five healthy young men without hyperhomocysteinemia. The results indicate that there are still undescribed interactions between vitamin B6 and folate, suggesting that these two vitamins should be given together to avoid depletion of the one not given. With regard to the well known metabolic pathways of methionine and cysteine, this confirms the hypothesis that a combined supplementation with the vitamins B6 and folate (and B12) is superior to folate alone in order to lower homocysteine.