Uremic hyperhomocysteinemia: A randomized trial of folate treatment for the prevention of cardiovascular events

Abstract

Homocysteine is a risk factor for atherosclerosis in the general population, and serum homocysteine levels are almost universally elevated in chronic renal failure patients. When such patients are treated with dialysis, cardiovascular disease accounts for more than 50% of their mortality, which, in some proportion, may be pathophysiologically related to the elevated serum homocysteine levels. From April 2003 to March 2005, we conducted a 2-year, double-blind, randomized, placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause, who were older than 18 years and stable on hemodialysis. Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study. On admission, plasma total homocysteine (tHcy) levels were above 13.9 micromol/L in 96.7% of patients (median 25.0 micromol/L, range 9.3-104.0 micromol/L). In the placebo group, tHcy levels remained elevated at 6, 12, and 24 months, while oral folate significantly decreased tHcy to a median value of 10.5 (2.8-20.3) micromol/L, (p<0.01). During the study, 38 patients (folic acid group 17 vs. placebo group 21; p=0.47) died from cardiovascular disease. Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events, both fatal and nonfatal (myocardial infarction, arrhythmias, angina, heart failure, cerebrovascular accident), showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events (p=0.41; hazard ratio 1.24, 95% CI 0.74-2.10). However, the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 +/- 0.59 mm to 1.67 +/- 0.38 mm (p<0.01) after 2 years of folate therapy. In this short-term study of uremic patients, 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3% of patients but did not change the incidence of cardiovascular events compared with the control group. However, ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation. This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration.

Homocysteine: An Emerging Cardiovascular Risk Factor that Never Really Made it~!2009-10-29~!2009-12-27~!2010-04-08~!

“…In this population, there was a 3% increase in CAD mortality with each increase of 1 μmol/L of tHcy [43]. This is in agreement with previous findings showing an association between tHcy and CVD risk factors in uremic patients [44]. However, CAD patients with end-stage renal disease are a very different category of high risk patients.…”

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

“…For example, the plausibility of a link between the levels of Hcy and the risk of CVD was supported by a number of studies. (12) Folic acid: 5 mg/d or 5 mg, every other day 35·0 13·1 2 15·1 2 49·3 Righetti et al (14) Folic acid: 15 mg/d 27 13·0 2 2·4 2 8·9 Vianna et al (17) Folic acid: 10 mg, three times a week 23·5 15 2 10·5 2 44 Jamison et al (20) Folic Vit, vitamin.…”

“…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 …”

The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis

“…Among them, seven were excluded since no stroke risk was reported (16)(17)(18)(19)(20)(21)(22) , one was excluded due to small patient pool (23) , three were excluded due to no baseline report for folate and homocysteine (22,24,25) , one was excluded due to high dose of folate (1 mg/d) as control (26) and one was excluded due to duplicate study (27) . The final fourteen RCT enrolled 39 420 patients.…”