Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events.
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.
Vianna
Areuza C A
AC
Nephrology Section, Department of Internal Medicine, State University of Londrina, Parana, Brazil.
Mocelin
Altair J
AJ
Matsuo
Tiemi
T
Morais-Filho
Domingos
D
Largura
Alvaro
A
Delfino
Vinicius A
VA
Soares
Abel E
AE
Matni
Anuar M
AM
D000328:Adult; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D002423:Cause of Death; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D016896:Treatment Outcome; D014511:Uremia
D005492:Folic Acid