In the present pilot study, we found that the MoCA score of treatment group was significantly improved, implicating that supplementation with thiamine and folic acid may improve the cognitive function of patients undergoing MHD with CI. The survival of patients in treatment group was significantly improved compared with that in control group. The proportion of adverse events in the control group was significantly higher than that in the treatment group, especially in cardiovascular and cerebrovascular events.
The present study pointed out that after 96 weeks of thiamine (90mg/day) and folic acid (30mg/day) supplementation, the MoCA score of the treatment group were significantly higher than that of control group, implicating the improvement of cognitive function. Recently, an animal study in mice demonstrated that thiamine deficiency decreased activity of antioxidants and increased activity of malondialdehyde (MAD), protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide (NO) in the cerebral cortex and hippocampus, leading to oxidative stress and cognitive impairment [12]. Meanwhile, an experimental mouse model simulating the effects of exposure to methotrexate on behavior and cognitive function found acute decrease in serum and CSF levels of folate acid, leading to oxidative stress and displayed cognitive [13]. This may be due to thiamine, as a cofactor of ketolase, can act as an oxygen free radical scavenger and play an important role in reducing the production of reactive oxygen species (ROS) in the nervous system and alleviating oxidative stress [12]. Another reason is the direct antioxidant effect of folic acid, which interacts with endothelial nitric oxide synthase (eNOS) to affect the bioavailability of NO cofactors. Moreover, folic acid is essential for the metabolism of homocysteine into methionine, which can reduce the homocysteine level of MHD patients, thus relieving oxidative stress [8]. However, there is insufficient evidence to support supplementation with thiamine or folic acid alone can improve cognitive functioning in healthy older people or non-chronic kidney diseases (CKD) older adults [14, 15]. Therefore, we designed this pilot study to explore whether the combination of these two vitamin B can improve cognitive function in MHD patients with CI.
Homocysteine is not only a uremia toxin but a biomarker of oxidative stress in patients with MHD. Many observational studies have suggested that elevated blood homocysteine levels are strongly associated with CI [16]. Moreover, previous studies have found that there are many mechanisms that cause elevated homocysteine levels in MHD patients including deficiency of vitamins B, especially thiamine and folate acid [17]. In the present study, blood homocysteine levels were significantly higher than the normal range in both groups at baseline, suggesting the presence of oxidative stress in patients of MHD with CI [18]. Compared with baseline, homocysteine didn’t decrease significantly (p=0.063) at week 96. Although, serum homocysteine level at week 96 in treatment group was lower than that in control group, we can’t conclude thiamine combined with folic acid treatment improve MoCA scores dependent on decreasing homocysteine. A new study with larger sample size and longer follow-up time should be performed to clarify the role of serum homocysteine.
It is worth mentioning that the survival rate of MHD patients with CI was significantly lower than that of patients with normal cognitive function, suggesting that CI is a risk factor for death of MHD patients [4]. Recent COGNITIVE-HD studies have also confirmed this phenomenon [19], therefore, it is urgent to find effective methods or measures to treat or improve the concurrent CI of MHD. In this study, Kaplan-Meier survival curve analysis indicated that the survival rate in treatment group was significantly higher than that in control group. The main cause of death in the two groups is cardiovascular and cerebrovascular events (9 cases, accounting for 75%), including 8 cases (88.9%) in the control group and 1 case (33.3%) in the treatment group. We believe that thiamine combined with folic acid treatment doesn’t only improve MoCA scores but also decrease the risk of cardiovascular and cerebrovascular disease in patients undergoing hemodialysis.
Several limitations of our study should be considered. First, this study was not designed to use a blind method and placebo control. It may lead to the generation of psychological bias and influence the MoCA scores. Furthermore, the sample size is small, which will lead to insufficient grasp in statistics and may cause false negative results. Moreover, we only used MoCA score as the basis for judging cognitive functions, which was highly subjective and could not cover all the assessments of cognitive functions. Future studies need to include more scoring criteria such as neuropsychological battery of 10 tests [20], and even imaging tests such as functional magnetic resonance imaging [21], to accurately judge cognitive function. Finally, patients in treatment group were given two medicines, it was difficult to identify which one played a key role.