Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study

Abstract

Background: Individuals with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) have high plasma total homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown.

Study design: Randomized controlled trial.

Setting & participants: A substudy of 659 patients (mean age, 67.3 +/- 11.7 years) who participated in a randomized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level. 236 (35.8%) were treated by using dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less (advanced CKD). All had high tHcy levels (> or =15 micromol/L) at baseline. Cognitive assessments began during the follow-up period of the main trial 3 years after treatment began; participants subsequently were retested 1 year later to assess cognitive change.

Intervention: Daily high-dose B vitamin capsule (40 mg of folic acid, 100 mg of vitamin B(6), and 2 mg of vitamin B(12)) or placebo.

Outcomes: Cognitive function at initial assessment and 1 year later.

Measurements: Telephone Interview of Cognitive Status-modified, supplemented with attention, working memory, and executive function tests.

Results: Initial cognitive function was impaired in approximately 19% of patients regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment decreased tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later.

Limitations: Cognitive assessments began after treatment was initiated; cognitive assessment was limited.

Conclusion: Treatment with high daily doses of B vitamins, which decreased tHcy levels, did not affect cognitive outcomes in patients with advanced CKD and ESRD.

Trial registration: ClinicalTrials.gov NCT00032435.

Figure 1

Veterans affairs (VA) Homocysteine Study (HOST) and VA Homocysteine Study Cognitive Function Substudy (HOSTCOG) enrollment and follow-up timelines.

Figure 2

Flow of participants into the Veterans Affairs Homocysteine Study (HOST) Cognitive Function Substudy. Abbreviations: ESRD, end stage renal disease; ACKD, advanced chronic kidney disease.