Association of two MTHFR polymorphisms with total homocysteine plasma levels in dialysis patients.

The effect of the combined 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C genotype on total homocysteine (tHcy), folate, and vitamin B(12) plasma levels was investigated in 983 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, and 389 healthy individuals. Mean tHcy plasma concentrations were 27.2 +/- 15.8 micromol/L in hemodialysis patients, 25.4 +/- 19.1 micromol/L in peritoneal dialysis patients, and 8.9 +/- 3.5 micromol/L in healthy individuals. Hyperhomocysteinemia (tHcy > 15 micromol/L) was detected in 81.6% of patients and 2.6% of controls. Multiple stepwise regression analysis showed that the MTHFR 677C-->T/1298A-->C genotype (CC/AA, CC/AC, CC/CC, CT/AA, CT/AC, TT/AA), vitamin use, age, folate and vitamin B(12) plasma level were significant predictors of tHcy plasma levels. Analysis of variance showed that this effect of MTHFR genotypes on tHcy level was caused by significantly greater tHcy levels in 677TT/1298AA hemodialysis and peritoneal dialysis patients versus other genotypes. Compound heterozygous controls (677CT/1298AC genotype) had significantly greater tHcy levels compared with 677CC/1298AA controls. There was no major effect of MTHFR polymorphisms on folate and vitamin B(12) plasma concentrations. This study shows that the MTHFR 677TT/1298AA genotype, but not the 677CT/1298AC genotype, is a significant predictor of tHcy plasma levels in dialysis patients.

Efficacy of folinic versus folic acid for the correction of hyperhomocysteinemia in hemodialysis patients.

The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown. In a randomized, controlled, double-blind trial, 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount (16.1 mg) of folinic acid intravenously three times weekly. Normalization of total homocysteine (tHcy) plasma levels after 4 weeks of treatment was achieved in 10 patients (30.3%) in the folic-acid group and 6 patients (18.2%; P: = 0.389) in the folinic-acid group (normalization at any time during the study period in 39.4% and 33.3% of the patients; P: = 0.798). The relative reduction in tHcy plasma levels at week 4 was 32.2% in the folic-acid group and 34.1% in the folinic-acid group. A high baseline tHcy plasma concentration (P: = 0.00001), methylenetetrahydrofolate reductase (MTHFR) 677TT/1298AA genotype (P: = 0.03540), and low red blood cell folate concentrations (P: = 0.02285) were associated with a better relative response to treatment. Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level (P: = 0.01976), younger age (P: = 0.00896), and MTHFR 677TT/1298AA or 677CT/1298AC genotypes (P: = 0.00208 and P: = 0.02320, respectively). A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients. The response to treatment is predicted by tHcy plasma level, red blood cell folate content, and MTHFR genotype.

Peritoneal elimination of homocysteine moieties in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: The amount of total homocysteine eliminated by peritoneal dialysis and its relationship to peritoneal transport characteristics in continuous ambulatory peritoneal dialysis (CAPD) patients are unknown. METHODS: The influence of total homocysteine, folate, and vitamin B12 plasma concentrations, serum albumin levels, age, sex, dialysate to plasma ratio (D/P) creatinine, D/D0 glucose, D/P albumin, dialysate effluent volume, and effluent albumin on the daily peritoneal excretion of total homocysteine was investigated in 39 CAPD patients. The relationship of D/P creatinine to D/P total homocysteine, D/P free homocysteine, and D/P protein-bound homocysteine was analyzed additionally in a subgroup of 25 patients. RESULTS: We observed a significant influence of plasma total homocysteine concentrations (P = 0.0001) of the daily dialysate effluent volume (P = 0.0221) and of the D/P creatinine (P = 0.0132) on peritoneal elimination of total homocysteine. The daily peritoneal excretion of total homocysteine was 38.94 +/- 20.82 mumol (5.27 +/- 2.81 mg). There was a positive linear association of the daily total homocysteine elimination with plasma total homocysteine concentrations (P = 0.0001). A significant linear correlation was observed between D/P creatinine and D/P total homocysteine (P = 0.0001), D/P free homocysteine (P = 0.0001), as well as D/P protein-bound homocysteine (P = 0.0001). CONCLUSIONS: The peritoneal elimination of total homocysteine primarily depends on the plasma total homocysteine concentration. Elevated total homocysteine plasma levels cannot be reduced efficiently by peritoneal dialysis.

Homocysteine levels in polycythaemia vera and essential thrombocythaemia.

Patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) have an increased risk of arterial and venous thromboembolic complications. Since hyperhomocysteinaemia (HHC) is a risk factor for vascular disease, we investigated the frequency of HHC in these disorders and analysed a possible association of elevated plasma homocysteine levels with vascular complications. In the cohort of 134 patients from Vienna (69 female, 65 male, median age 65.5 years, range 21-91 years) with PV (n = 74) or ET (n = 60), plasma homocysteine levels were significantly higher compared to 134 healthy controls. Median homocysteine level was 12.3 micromol/l (range 3.5-48.4 micromol/l) in patients with PV or ET and 8.9 micromol/l (range 4.8-30.5 micromol/l) in normal controls (P < 0. 0001). In addition to the 134 patients from Vienna, 48 patients (28 female, 20 male; median age 66.5 years, range 24-82) from Vicenza with PV (n = 25) or ET (n = 23) were included to evaluate the impact of HHC on the risk of thrombosis. Of 59 patients with HHC (44 from Vienna and 15 from Vicenza) 18 (31%) had a history of arterial and 10 (17%) of venous thrombosis. Of 123 patients with normal homocysteine levels, 30 (24%) had arterial and 16 (13%) had venous thromboses. The difference between the two groups was statistically not significant. Even though mild to moderate HHC occurred in a larger number of patients with PV or ET and thrombosis, it can presently not be regarded as an additional risk factor for thrombosis.

No evidence for an increased risk of venous thrombosis in patients with factor V Leiden by the homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase gene.

Hyperhomocysteinemia is an established risk factor for arterial and venous thrombosis. Recently, it has been shown that a C to T mutation at nt position 677 in the methylenetetrahydrofolate-reductase (MTHFR) gene is a common cause of moderately elevated levels of plasma homocysteine in adults. In order to investigate whether the newly recognized genetic alteration in the MTHFR gene potentiates the thrombotic tendency in patients with factor V Leiden, we studied 81 unrelated patients with a history of venous thrombosis and a heterozygous factor V Leiden mutation. In addition, we analyzed 111 family members of 34 families in which the proband had a heterozygous factor V Leiden mutation. In all individuals, factor V Leiden and the MTHFR mutation were tested and the occurrence of venous thrombotic events was evaluated retrospectively. Seventy-seven healthy subjects without the factor V Leiden mutation or any other known thrombotic risk factor served as a control group. The prevalence of the homozygous MTHFR mutation was similar in index patients (10 of 81, 12%) and in the control group (10 of 77, 13%). The median age at first thrombosis in index patients was 32 years (range 22-69 years) in 10 patients with heterozygous factor V Leiden and T/T MTHFR mutation, and 34 years (range 6-72 years) in 71 patients with the factor V Leiden mutation only. In the family members, the prevalence of thrombosis was not higher in patients with factor V Leiden and +/+ MTHFR genotype than in those with only the heterozygous factor V Leiden mutation. We conclude from these data that the 677 C to T mutation in the MTHFR gene does not represent a significant additional risk factor for venous thrombosis in patients with factor V Leiden mutation.