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

TLDR

High plasma homocysteine is an established risk factor for mortality and vascular disease in patients with chronic kidney disease, as shown in observational studies. This study aimed to determine whether daily high‑dose folic acid and B‑vitamin supplementation reduces mortality in advanced chronic kidney disease. In a double‑blind randomized controlled trial of 2,056 veterans with advanced CKD or end‑stage renal disease, participants received a daily capsule of 40 mg folic acid, 100 mg vitamin B6, and 2 mg vitamin B12 versus placebo over a median 3.2‑year follow‑up, with all‑cause mortality as the primary outcome. The intervention lowered homocysteine by 25.8 % but did not significantly affect mortality (HR 1.04, 95 % CI 0.91–1.18) or secondary vascular outcomes, and composite events, dialysis initiation, or access thrombosis rates were unchanged. ClinicalTrials.gov Identifier: NCT00032435.

Abstract

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.