B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease

Abstract

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 B 12 . 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 g vitamin B 12 , and 20 mg vitamin B 6 (active treatment) or 0.2 mg folic acid, 4 g vitamin B 12 , and 1.0 mg vitamin B 6 (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; Pϭ0.51). 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; Pϭ0.13). Conclusions-Increased intake of folic acid, vitamin B 12 , and vitamin B 6 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.

Homocysteine-lowering therapy does not lead to reduction in cardiovascular outcomes in chronic kidney disease patients: a meta-analysis of randomised, controlled trials

“…Wrone et al (13) Righetti et al (14) Zoungas et al (12) House et al (21) Heinz et al (22) Overall 0·159537 One report demonstrated that endothelial cells can develop abnormal vasoreactivity and may adopt a prothrombotic phenotype and secrete leucocyte chemotactic factors, adhesion molecules and inflammatory cytokines when exposed to elevated Hcy (23) . Endothelial dysfunction is a key process in atherosclerosis, which independently predicts CVD events (24) ; and it becomes progressively more common as renal function declines (25) .…”

“…Also, to the best of our knowledge, there are no studies that have determined a threshold value for Hcy level for effective prevention of cardiovascular events in the general population or in patients with CKD. Observational data in a meta-analysis show that a 25 % reduction in Hcy was associated with a 32 % lower risk of CVD among Study Righetti et al (16) Wrone et al (13) Righetti et al (14) Zoungas et al (12) Jamison et al (20) Nanayakkara et al (18) Vianna et al (17) Mann et al (19) House et al (21) Heinz et al (22) Overall 0·074931 …”

“…Wrone et al (13) Zoungas et al (12) Righetti et al (14) Jamison et al (20) Heinz et al (22) House et al (21) Overall 0·021215 women and a 15 % lower risk among men (29) . However, the reported decreases in Hcy levels vary substantially; and the ten papers in our meta-analysis reported a wide range of Hcy-lowering from 8·9 % to 53·8 %, which is consistent with the observed range of decrease in patients without CKD.…”

“…It has been proposed that the mutant TT genotype at nucleotide 677 of the gene regulating methylenetetrahydrofolate reductase activity is associated with increased Hcy levels and increased mortality in general and CKD populations. In the methylenetetrahydrofolate reductase TT group, the greatest reductions of Hcy concentration after folate Study Wrone et al (13) Righetti et al (14) Zoungas et al (12) Jamison et al (20) Mann et al (19) House et al (21) Heinz et al (22) Overall 0·297827 Heterogeneity: t 2 = 0·02; c 2 = 5·50, df = 3 (P = 0·14); l 2 = 45% Test for overall effect: Z = 0·87 (P = 0·39) Heterogeneity: t 2 = 0·04; c 2 = 8·75, df = 5 (P = 0·12); l 2 = 43% Test for overall effect: Z = 0·49 (P = 0·62) Heterogeneity: t 2 = 0·01; c 2 = 7·24, df = 6 (P = 0·30); l 2 = 17% Test for overall effect: Z = 1·86 (P = 0·06) Heterogeneity: t 2 = 0·10; c 2 = 5·63, df = 2 (P = 0·06); l 2 = 64% Test for overall effect: Z = 0·83 (P = 0·41) Heterogeneity: t 2 = 0·00; c 2 = 3·47, df = 4 (P = 0·48); l 2 = 0% Test for overall effect: Z = 1·56 (P = 0·12)…”

Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis

“…[28] However, findings from trials on Hcy-lowering therapy with folic acid or B-vitamins (containing folic acid) in stroke prevention have been mostly negative. [29][30][31] A meta-analysis of relevant trials revealed that most previous trials were conducted in countries with high folic acid consumption [32,33] and that mandatory folate fortification of the grain supply in those countries may have reduced the Hcy levels in the total population and affected the power of the trials to detect a positive effect. Consistently, our recent meta-analysis found that lowering Hcy concentration by folic acid supplementation significantly reduced the progression of carotid intima-media thickness, [34] the risk of cardiovascular diseases in patients with chronic kidney disease, [35] and the risk of stroke, [36] particularly in those without dietary folic acid fortification.…”