Homocysteine as a Risk Factor for Cardiovascular Disease in Patients Treated by Dialysis: A Meta-analysis

Background: In the general population, increased homocysteine concentrations are a risk factor for cardiovascular disease and mortality. However, it is not known whether this also applies to patients with end-stage renal disease. Study Design: Meta-analysis of retrospective (11 studies including 1,506 individuals), prospective observational studies (12 studies including 1,975 individuals), and intervention trials (5 studies including 1,642 dialysis patients). Analyses were carried out separately, according to the study design. Setting & Population: Studies of patients with end-stage renal disease treated by means of hemodialysis or peritoneal dialysis. Selection Criteria for Studies: Studies investigating the association between total homocysteine level and cardiovascular disease or total mortality or the influence of vitamin supplementation on cardiovascular or mortality risk. Intervention: In intervention studies, vitamin preparations with folic acid alone or in combination with other vitamins, such as vitamin B-12 and B-6, were used. Outcomes: In retrospective studies, cases are patients with cardiovascular diseases. Outcomes for prospective observational and intervention studies are cardiovascular events and total mortality. Results: In retrospective studies, there was no significant overall difference in homocysteine concentrations between cases and controls (weighted mean difference in homocysteine, 2.82 mu mol/L; 95% confidence interval [CI], -2.22 to 7.86; P = 0.3). The pooled overall risk estimate for prospective observational studies suggests no association between homocysteine level (5-mu mol/L increase) and total mortality (hazard ratio [HR], 1.02; 95% Cl, 0.93 to 1.12; P = 0.7), but there was an association with cardiovascular events (HR, 1.09; 95% Cl, 1.03 to 1.14; P = 0.001). in subgroup analysis of patients not receiving vitamins, an increase in homocysteine level was associated with increased mortality (HR, 1.07; 95% Cl, 1.02 to 1.13; P = 0.01). For intervention trials with B vitamins, there was a significant risk reduction for cardiovascular disease (relative risk, 0.73; 95% Cl, 0.56 to 0.94; P = 0.02), but no risk reduction for total mortality or the composite end point including total mortality (relative risk, 1.01; 95% Cl, 0.88 to 1.15; P = 0.9). Limitations: Many studies are small, which may lead to the observed heterogeneity. Some intervention trials are neither placebo controlled nor randomized. Separate analyses for specific end points and patients treated by means of hemodialysis or peritoneal dialysis were not possible. Conclusion: Total homocysteine level may be a risk factor for cardiovascular events and total mortality in patients with end-stage renal disease not receiving vitamin supplementation or folic acid food fortification. There may be a potential for reducing cardiovascular disease in this population by folic acid supplementation. Am J Kidney Dis 54:478-489. (C) 2009 by the National Kidney Foundation, Inc.