Effect of Homocysteine Lowering on Mortality and Vascular Disease in Advanced Chronic Kidney Disease and End-stage Renal Disease

Veterans Affairs Palo Alto Health Care Systems and Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94304, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 09/2007; 298(10):1163-70. DOI: 10.1001/jama.298.10.1163
Source: PubMed


High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease. Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown.
To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease.
Double-blind randomized controlled trial (2001-2006) in 36 US Department of Veterans Affairs medical centers. Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease (estimated creatinine clearance < or =30 mL/min) (n = 1305) or end-stage renal disease (n = 751) and high homocysteine levels (> or = 15 micromol/L).
Participants received a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or a placebo.
The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), stroke, amputation of all or part of a lower extremity, a composite of these 3 plus all-cause mortality, time to initiation of dialysis, and time to thrombosis of arteriovenous access in hemodialysis patients.
Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group. It was lowered 6.3 micromol/L (25.8%; P < .001) in the vitamin group and 0.4 micromol/L (1.7%; P = .14) in the placebo group at 3 months, but there was no significant effect on mortality (448 vitamin group deaths vs 436 placebo group deaths) (hazard ratio [HR], 1.04; 95% CI, 0.91-1.18). No significant effects were demonstrated for secondary outcomes or adverse events: there were 129 MIs in the vitamin group vs 150 for placebo (HR, 0.86; 95% CI, 0.67-1.08), 37 strokes in the vitamin group vs 41 for placebo (HR, 0.90; 95% CI, 0.58-1.40), and 60 amputations in the vitamin group vs 53 for placebo (HR, 1.14; 95% CI, 0.79-1.64). In addition, the composite of MI, stroke, and amputations plus mortality (P = .85), time to dialysis (P = .38), and time to thrombosis in hemodialysis patients (P = .97) did not differ between the vitamin and placebo groups.
Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease.
clinicaltrials.gov Identifier: NCT00032435.

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    • "The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review. Clinical chemistry and laboratory medicine : CCLM / FESCC 2007;45(12):1621-32 [114] Jamison RL, Hartigan P, Kaufman JS et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. "
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    Giornale italiano di nefrologia: organo ufficiale della Societa italiana di nefrologia 12/2014; 30(3).
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    • "In the intervention groups, the dose of folic acid ranged from 0.5 to 40 mg/day, the dose of vitamin B6 ranged from 3 to 250 mg/day, and the dose of vitamin B12 ranged from 6 to 2000 µg/day. In the meta-analysis, the trial outcome was MACE in 23 trials [20]–[36], [38]–[43], total mortality in 20 trials [21]–[31], [33], [35], [37]–[43], cardiac death in 15 trials [21]–[23], [25]–[27], [29]–[31], [34]–[36], [39], [42], [43], MI in 19 trials [21]–[31], [33], [35], [37]–[39], [41]–[43], and stroke in 18 trials [22], [23], [25]–[31], [33]–[35], [37]–[39], [41]–[43]. We restricted the inclusion criteria to RCTs with a minimum follow-up of 6 months to ensure a reliable conclusion. "
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    PLoS ONE 09/2014; 9(9):e107060. DOI:10.1371/journal.pone.0107060 · 3.23 Impact Factor
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    • "The follow-up period for participants ranged from 2.0 to 7.3 years, and the number of individuals included in each trial ranged from 114 to 12,064. Seven trials [7-9,11,17,18,20] included patients with chronic kidney disease. Eight trials [12-14,16,19,21,22,24] included patients with cardiovascular disease or stroke. "
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    PLoS ONE 11/2013; 8(11):e81577. DOI:10.1371/journal.pone.0081577 · 3.23 Impact Factor
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