The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid (FA). We evaluated whether a ...high-dose L-folinic acid-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report.
We block-randomized 48 chronic, stable hemodialysis patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 24 subjects treated for 12 weeks with oral FA at 15 mg/day or an equimolar amount (20 mg/day) of oral L-folinic acid (FNA) L-5-formyltetrahydrofolate. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12.
The mean percentage (%) reductions (with 95% CIs) in predialysis tHcy were not significantly different FNA = 22.1% (11.8 to 31.4%), FA = 20.7% (11.7 to 30.5%), P = 0.950 by paired t test. Final on-treatment values (mean with 95% CI) were as follows: FNA, 15.9 micromol/L (14.0 to 18.0); FA, 16.9 micromol/L (14.8 to 18.8). Moreover, in those subjects with baseline tHcy levels >/=14 micromol/L, neither treatment resulted in "normalization" of tHcy levels (that is, final on-treatment values <12 micromol/L) among a significantly different or clinically meaningful number of patients FNA = 2 out of 22 (9.1%); FA = 2 out of 24 (8.3%); Fisher's exact test of between groups difference, P = 1.000.
Relative to high-dose FA, high-dose oral L-folinic acid-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (that is,> 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen.
Distribution of plasma folate forms in hemodialysis patients receiving high daily doses of l-folinic or folic acid.
We have previously reported that a daily oral high dose of l-folinic acid for the ...treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine (tHcy) levels than an equimolar dose of folic acid. The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid. This was done to investigate claims that renal insufficiency is associated with impaired folate interconversion, a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates, than folic acid.
Forty-eight chronic and stable hemodialysis patients were block-randomized, based on their screening predialysis tHcy levels, sex, and dialysis center, into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount (20 mg/day) of oral l-folinic acid. All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12. Folate distribution was determined in plasma of 46 participants (Folinic acid group, N = 22; Folic acid group, N = 24) by using the affinity/HPLC method, with electrochemical (coulometric) detection.
Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution. Following treatment, both groups demonstrated similar marked elevation in plasma total folate (geometric mean of the increase: Folinic acid group, +337 ng/mL; Folic acid group, +312 ng/mL; P = 0.796). In the folinic acid-treated group, practically all of the increase in total folate was due to 5-methyltetrahydrofolate. In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35% of the increase in total folate and the remainder was unmethylated folic acid.
Data from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients.
Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients.
Hyperhomocysteinemia, a putative atherothrombotic risk factor, is observed in at least 85% of patients ...undergoing maintenance hemodialysis (HD), as well as 65 to 70% of renal transplant recipients (RTRs). The hyperhomocysteinemia regularly found in HD patients is largely refractory to combined oral vitamin B supplementation featuring supraphysiological doses of folic acid (FA). Relative to their HD counterparts, the hyperhomocysteinemia of RTRs appears to be considerably less refractory to treatment with high-dose FA-based vitamin B supplementation regimens, although controlled comparison data are lacking. We evaluated whether improved total homocysteine (tHcy)-lowering efficacy could be achieved in chronic HD patients with a high-dose L-5-methyl-tetrahydrofolate (MTHF)-based regimen, as suggested by recent uncontrolled findings, and compared the relative responsiveness of RTRs and HD patients with equivalent baseline tHcy levels, to 12 weeks of tHcy lowering with combined folate-based vitamin B treatment.
First, we blocked randomized 50 chronic, stable HD patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 25 subjects treated for 12 weeks with oral FA at 15 mg/day, or an equimolar amount (17 mg/day) of oral MTHF. All 50 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12.
The mean percentage (%) reductions (± 95% confidence intervals) in predialysis tHcy were not significantly different MTHF 17.0% (12.0 to 22.0%), FA 14.8% (9.6 to 20.1%),P = 0.444 by matched analysis of covariance adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% confidence interval) were: MTHF, 20.0 μmol/L (18.8 to 21.2); and FA, 19.5 μmol/L (18.3 to 20.7). Moreover, neither treatment resulted in “normalization” of tHcy levels (that is, final on-treatment values <12 μmol/L) among a significantly different or clinically meaningful number of patients MTHF, 2 out of 25 (8%); FA, 0 out of 25 (0%); Fisher's exact test of between groups difference,P = 0.490. Second, we compared the relative responsiveness of (N = 10) RTRs and (N = 39) HD patients with equivalent baseline tHcy levels (RTR range of 14.2 to 23.6 μmol/L, and HD range of 14.4 to 24.9 μmol/L) to 12 weeks of tHcy-lowering treatment. The RTRs received 2.4 mg/day of FA, 50.0 mg/day of vitamin B6, and 0.4 mg/day of vitamin B12, while the HD patients received 15 mg/day of FA or an equmolar amount (17 mg/day) of the reduced folate, MTHF, in addition to 50.0 mg/day of vitamin B12. The mean percentage (%) reductions (± 95% confidence interval) in tHcy were as follows: RTR 28.1% (16.2 to 40.0%); HD 12.1% (6.6 to 17.7%,P = 0.027 for comparison of between groups differences by analysis of covariance adjusted for baseline tHcy levels). Moreover, 5 out of 10 (50.0%) of the RTR versus only 2 out of 39 (5.1%) of the HD patients had final on-treatment tHcy levels <12 μmol/L <12 μmol/L (P = 0.002 for comparison of between groups differences by Fisher's exact test).
First, in comparison to hgh-dose FA, high-dose oral MTHF-based supplementation does not afford improved tHcy-lowering efficacy among HD patients. The preponderance of HD patients (that is, > 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absoprption or circulating plasma and tissue distribution. Second, relative to RTR with comparable baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering vitamin B treatment regimens featuring suprahysiological amounts of FA or the reduced folate MTHF. Accordingly, RTRs are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering vitamin B intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease.
Serum creatinine, a surrogate for both renal function and homocysteine generation, is an important determinant of fasting plasma total homocysteine levels in stable renal transplant recipients. In ...this study, it is hypothesized that among stable renal transplant recipients with normal creatinine levels (i.e., < or = 1.5 mg/dl), serum cystatin C, a more sensitive indicator of GFR, would better predict fasting total homocysteine levels compared with serum creatinine. Fasting plasma total homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate levels, along with serum cystatin C, creatinine, and albumin levels, were determined in 28 consecutive renal transplant recipients (mean age 47 +/- 14 yr; 60.7% men) with stable allograft function, whose serum creatinine was < or = 1.5 mg/dl. General linear modeling with analysis of covariance revealed that serum cystatin C was independently predictive (partial R = 0.494; P = 0.023) of fasting total homocysteine levels after adjustment for age, gender, vitamin status, albumin, and creatinine levels. In contrast, creatinine levels were not predictive of fasting total homocysteine levels in this model (P = 0.110) or an identical model that excluded cystatin C (P = 0.131). Serum cystatin C levels may reflect subtle decreases in renal function that independently predict fasting total homocysteine levels among stable renal transplant recipients with a normal serum creatinine.
Mild hyperhomocysteinemia is common among maintenance hemodialysis (HD) patients and renal transplant recipients (RTR) and may contribute to the excess incidence of arteriosclerotic outcomes ...experienced by both patient groups. Relative to their RTR counterparts, the hyperhomocysteinemia of HD patients seems to be considerably more refractory to treatment with high-dose folic acid (FA)-based B-vitamin supplementation regimens, although controlled comparison data are lacking.
We compared the relative responsiveness of (n=10) RTR and (n=39) HD patients with equivalent baseline total homocysteine (tHcy) levels (i.e., RTR range=14.2-23.6 micromol/L; HD range=14.4-24.9 micromol/L) to 12 weeks of tHcy-lowering treatment. The RTR received 2.4 mg/day of FA, 50.0 mg/day of vitamin B6, and 0.4 mg/day of vitamin B12, while the HD patients received 15 mg/day of FA or an equimolar amount (17 mg/day) of the reduced folate, L-5-methyltetrahydrofolate, in addition to 50.0 mg/day of vitamin B6, and 1.0 mg/day of vitamin B12.
The mean percent (%) reductions (+/-95% confidence interval) in tHcy were: RTR=28.1% (16.2-40.0%); HD=12.1% (6.6-17.7%), P=0.027 for comparison of between-groups differences by analysis of covariance adjusted for baseline tHcy levels. Moreover, (50.0%) of 10 of the RTR versus only (5.1%) of 39 of the HD patients had final on-treatment tHcy levels <12 micromol/L; P=0.002 for comparison of between-groups differences by Fisher's exact test.
Relative to RTR with comparable baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering B-vitamin treatment regimens featuring supraphysiological amounts of FA or the reduced folate, L-5-methyltetrahydrofolate. Accordingly, RTR are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering B-vitamin intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease.
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