Treatment with high daily doses of folic acid and vitamins B6
reduced tHcy levels by 26.7%, and the reduction was maintained for over three years21
. However, in this subset of participants, treatment did not influence cognitive outcomes at initial testing or change in cognition over a 1-year interval. These findings do not support the administration of B-vitamin therapy to improve cognitive outcomes in persons with advanced CKD and ESRD.
Our findings confirm the null findings of other clinical trials of the effects of B-vitamin therapy or tHcy reduction on cognitive outcomes in other populations 19, 37-41
, and extend these findings to advanced CKD and ESRD patients with higher baseline tHcy values receiving a higher dose B-vitamin intervention than those in previous studies. In contrast, the Folic Acid and Carotid Intima-Media Thickness (FACIT) trial cognitive substudy 42
, found that tHcy reduction via daily administration of 800 μg of folic acid improved cognitive outcomes in a large sample of community-dwelling older adults. It is unclear why the FACIT study found a beneficial effect of tHcy reduction on cognition whereas other similarly designed studies 38, 39
Two other notable findings were that the advanced CKD and ESRD groups had similar rates (approximately 19%) of cognitive impairment on the TICSm, and that cognitive impairment was present in nearly a third of patients aged 70 and older. In comparison, previous studies found that the prevalence of cognitive impairment was between 15-20% in advanced CKD 1-3, 43
. The prevalence of cognitive impairment in our ESRD sample was lower than the 27-87% prevalence seen in similar studies 1, 5, 44-46
, and may be due to differences in sample composition (e.g., age, comorbid conditions) or the cognitive measures used. The higher cognitive impairment prevalence in older members of our sample confirms recent findings about cognitive impairment in an aging CKD population 8, 47
There are several explanations for the failure to find a treatment effect on cognitive outcomes in our study. First, our participants had a high comorbidity burden of hypertension, diabetes and vascular disease. These comorbidities affect cognition 48-51
, and may have obscured any treatment effect on cognition. Second, although tHcy levels were reduced by 26.7%, only a third of the participants had their tHcy levels reduced to normal levels of 8 - 10 μmol/L21
. The results of the FACIT trial42
suggested that tHcy may need to be lowered into the normal range to produce beneficial effects on cognition; however, McMahon et al.39
reduced tHcy to normal levels in their trial and found no cognitive effect of this reduction.
Several limitations of this study may have contributed to the failure to demonstrate a treatment effect on cognition. The lack of baseline measurement of cognitive function at initial randomization in the parent study is an important limitation. However, two other trials examining cognitive function decline also enrolled a cohort during the follow up period of the main study; one found treatment effects on cognition52
whereas another did not53
. Because of this design limitation, we assumed that baseline cognitive function was similar in the two treatment groups at randomization, and any differences at the initial cognitive function assessment at 3 years after randomization would be due to treatment effects. It is likely that cognitive function was similar across the treatment groups at baseline because the groups did not differ in risk factors for cognitive dysfunction, such as age or hypertension, but it cannot be known for certain.
Moreover, we could not determine whether cognitive decline occurred in the 3-year interval between enrollment into HOST and the cognitive substudy. Thus, we may not have detected a treatment effect because our sample may have been cognitively stable during this interval. There are two reasons why this latter possibility is unlikely. First, although longitudinal data about cognitive function in CKD are limited, a significant decline has been demonstrated over 2-4 year intervals in both CKD54
patients. For example, Kurella-Tamura54
showed that those with moderate to advanced CKD (i.e., estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73 m2
) were nearly 2.5 times more likely to decline over 4 years on the Modified Mini Mental State Exam (3MS; decline defined as either a decline of > 5 points, or 1 standard deviation, or a score that decreased to < 80) compared with those without CKD (i.e., eGFR ≥ 60 mL/min/1.73 m2
). Second, cognitive decline over a similar interval is related to increasing age56-58
and vascular disease risk factors such as those present in our sample59
in relatively healthier community-dwelling samples. Therefore, it is likely that cognitive decline would have occurred in the participants after initial randomization and before enrollment into the substudy. The participants enrolled in the cognitive function substudy represent a survivor cohort, since sicker patients would have died prior to initiation of the substudy. This possibility is reflected in the younger age and lower rates of vascular disease in the substudy participants. Nevertheless, risk factors for cognitive decline were balanced by treatment group in the substudy participants and the burden of vascular comorbidities was still high.
Telephone assessment of cognition may not be as sensitive as an in-person interview to detect effects of treatment, but in-person assessments have also failed to disclose cognitive benefits of tHcy reduction39
. The early discontinuation of the parent HOST trial may have contributed to our not finding treatment effects over a one-year duration; however, since there were no differences in initial cognitive assessment after 3 years of treatment, it is unclear why discontinuing treatment would effect a change over one year. We were not able to conduct 1-year retests on 169 participants. Although the loss of follow-up data from these participants could have introduced bias into our 1-year retest results, it is unlikely that this affected the treatment effect results because the proportion of those who were not retested was similar in the placebo (25%) and vitamin (27%) groups. Finally, this trial was conducted in the United States after folic acid fortification of the food supply was completed in 1998, which may have reduced the power to detect the effect of folic acid intervention on cognition60, 61
In summary, we found a high prevalence of cognitive impairment in a large cohort of patients with advanced CKD and ESRD. The prevalence of cognitive dysfunction increased with age, with 28% of those over the age of 70 years having cognitive impairment. Treatment with high daily doses of B-vitamins, which reduced tHcy levels, did not improve cognitive outcomes compared to placebo and should not be recommended for treatment or prevention of cognitive dysfunction in patients with advanced CKD or ESRD.