| Aim and BackgroundsEnd-stage renal disease is a major health burden worldwide,and cognitive impairment is a common but poorly recognized problem among patients with end-stage renal disease.There are numerous links between kidney diseases and neurological diseases,suggesting that kidney diseases could lead to neurological damage.Recent studies showed that cognitive impairment was a potential risk factor for poor prognosis of end-stage renal disease patients,and had become one of the important causes of death in end-stage renal disease population.Therefore,the medical profession needs pay widespread attention to this issue.Currently,in patients with end-stage kidney disease,cognitive impairment can be identified by neurological symptoms,as well as by physical examination including Kidney Disease Quality of Life?KDQOL?,Mini-Mental Status Examination?MMSE?,Modified Mini-Mental State Exam?3M?,St Louis University Mental Test?SLUMS?,Montreal Cognitive Assessment?MoCA?and so on.With the rapid development of magnetic resonance imaging technology,functional magnetic resonance imagings?fMRIs?has been widely applied to the early diagnosis,differential diagnosis,treatment and prognosis tracking of neurological diseases,including cognitive impairment.Thiamine and folic acid belong to the family of water-soluble B vitamins.Thiamine is vitamin B1,which plays an important role in reducing the production of reactive oxygen species in the nervous system and alleviating oxidative stress as the cofactor of transketolase.Folic acid,is also called as vitamin B9,involved in the synthesis of purine and thymine,metabolism of amino acid,as well as hemoglobin production.Folic acid has a direct antioxidant effect,interacts with endothelial nitric oxide synthase,and affects the bioavailability of nitric oxide cofactors.Moreover,folic acid is essential for the metabolism of homocysteine into methionine,which can reduce homocysteine levels.In uremic environments,it is not clear whether the lack of thiamine and folic acid was related with cognitive impairment.Clinical studies have reported that the application of vitamins B can reduce blood homocysteine levels,thereby reducing oxidative stress,and bring benefits for the treatment of cardiovascular complications in patients with end-stage renal disease.However,it is not clear whether supplementation with vitamins B include thiamine and folic acid,can improve cognitive function in patients with end-stage kidney disease and what are the possible mechanisms?At first,we performed a cohort observational study of patients with end-stage renal disease undergoing maintenance hemodialysis?MHD?at Renji hospital affiliated to Shanghai Jiao Tong university School of Medicine.The aim of this study was to explore the epidemiological characteristics,risk factors and prognosis of cognitive impairment in patients with MHD.Next,we established the rat model of uremia and used Morris water maze to detect the cognitive function of these rats,and the changes of thiamine and folic acid in the environment of uremia were preliminarily explored,as well as their relationship with the cognitive function.At last,a prospective randomized controlled study was explored to identify the treatment of cognitive impairment in patients with MHD.Methods?1?Cohort observational study was conducted to analyze the risk factors and prognosis of cognitive impairment in patients with MHD.Patients who underwent MHD at Renji hospital affiliated to Shanghai Jiao Tong university school of medicine were enrolled.Patients were screened according to inclusion and exclusion criteria.Demographic data,previous history,hemodialysis data,laboratory examination data,functional magnetic resonance imaging,cognitive function score?MoCA score?,prognosis and major causes of death were collected.These data were used to analyze the epidemiological characteristics,risk factors and prognosis of cognitive impairment in patients with MHD.?2?Relationship between thiamine and folic acid and cognitive function in uremic rat model.24 SD rats were randomly divided into two groups:5/6nephrectomized group?n=12?and sham-operated group?n=12?.The body weight of rats was recorded before surgery,4 weeks and 8 weeks after surgery,respectively.Renal function was measured 4 weeks after surgery to estimate if the model was successfully constructed.Morris water maze was used to detect the cognitive function of rats 8 weeks after surgery.After Morris water maze experiment,all rats were sacrificed,and blood samples were collected for the determination of serum thiamine,folic acid and homocysteine levels.Brain and kidney tissue samples were collected for pathological examination.Immunochemistry staining was used to exam the8-OHdG expression.?3?A prospective,randomized,single-center study of the effects of thiamine and folic acid on oxidative stress and cognitive function in MHD patients.Patients undergoing MHD in Renji hospital affiliated to Shanghai Jiao Tong university school of medicine were selected and screened according to inclusion and exclusion criteria.Patients were randomly divided into control group?n=25?and treatment group?thiamine 90mg/day and folic acid 30mg/day,n=25?at 1:1.Demographic data and medical history of subjects at baseline were collected.Hemodialysis data and laboratory examination data of subjects at baseline,follow-up 24 and 48 weeks were recorded.Functional magnetic resonance imaging and MoCA score at baseline and 48weeks of follow-up were collected.The primary outcome was the MoCA score comparison between the treatment group and the control group at the follow-up period of 48 weeks.Secondary outcome were changes of thiamine,folic acid,homocysteine,functional magnetic resonance imaging and survival at 48 weeks of follow-up between the treatment group and the control group.Safety index is the change of laboratory examination and the incidence of adverse events during the study period.Results?1?In a Cohort observational study,a total of 219 patients with MHD patients completed MoCA score and met the inclusion criteria.There were 113 patients with MoCA score less than 26,and the incidence of cognitive impairment with MHD patients was about 51.6%.Compared with the non-cognitive impairment group?MoCA?26,n=106?,the cognitive impairment group had a higher mean age,less education history of 12 years or more diabetes history,less urine volume and lower MoCA score and there were significant statistical differences?P<0.05?.Functional magnetic resonance imaging showed that,compared with the non-cognitive impairment group,the brain regional homogeneity decreased were mainly concentrated in right inferior temporal gyrus,left caudate nucleus,right parahippocampal gyrus,right superior temporal gyrus and the left cingulate gyrus.Amplitude ratio of low frequency fluctuation of left brainstem and left caudate nucleus decreased significantly.Amplitude of low frequency fluctuation of left middle temporal gyrus,left middle occipital gyrus,left caudate nucleus and right middle frontal gyrus decreased significantly in the cognitive impairment group.Multivariate Logistic regression analysis suggested that education<12 years?OR=3.428?,diastolic blood pressure<73mmHg?OR=2.234?and spKt/V<1.72?OR=1.982?were independent risk factors for cognitive impairment in patients with MHD.Kaplan-Meier survival curve analysis indicated that the survival rate of patients with cognitive impairment associated with MHD was lower than that of patients with non-cognitive impairment?P=0.046?.?2?In animal experiments,SD rats were selected for 5/6 nephrectomy to prepare an animal model of chronic renal insufficiency.At week 4 and 8 after modeling of rat,the weight of 5/6 nephrectomy group?n=12?was significantly lower than that of sham operation group?n=12??384.75±37.50g vs 428.0±1.41g,p=0.002;444.25±27.67g vs 525.5±33.23g,p=0.025?.In 5/6 nephrectomy group,the total average amount of kidney tissue resected was 2.10±0.46g,accounting for 1.04%of the body weight of the rats.Four weeks after surgery,the creatinine and urea nitrogen in 5/6nephrectomy group were significantly higher than those in sham operation group?104.25±28.85umol/L vs 37.50±2.12umol/L,p=0.000;25.68±3.90mmol/L vs 8.00±0.00mmol/L,p=0.000?.Eight weeks after surgery,in Morris water maze experiment,the incubation period on day 1 and day 2 was significantly longer in 5/6nephrectomy group than in sham group?71.89±15.21s vs 52.86±13.05s,p=0.030;49.86±28.03s vs 33.02±17.98s,p=0.046?.On day 6,the fourth quadrant residence time and the percentage of residence time in 5/6 nephrectomy group were significantly lower than those in sham operation group?20.00±7.91s vs 28.75±5.85s,p=0.005;22.23±8.78%vs 31.95±6.50%,p=0.006?.After Morris water maze experiment,serum thiamine and folic acid levels in 5/6 nephrectomy group were significantly lower than those in sham operation group?59.49±4.09nmol/L vs 66.03±5.63nmol/L,p=0.008;97.53±32.36ng/mL vs 169.29±26.37ng/mL,p=0.000?,while blood homocysteine levels in sham operation group was significantly lower than those in 5/6 nephrectomy group?11.63±1.43umol/L vs 12.99±1.28umol/L,p=0.044?.The higher the body weight at week 4,the blood thiamine and folic acid levels were,the longer the rats stayed in the fourth quadrant during Morris water maze experiment.However,the higher blood urea nitrogen level,the percentage of8-OHdG staining positive cells and the IOD value,the shorter the residence time in the fourth quadrant of Morris water maze experiment.The number of neurons in hippocampal area of brain tissue was significantly reduced,and 8-OHdG staining was found to be positive in 5/6 nephrectomy group.?3?A total of 50 patients with MHD met the inclusion criteria and were randomly divided into treatment group?n=25?and control group?n=25?in prospective,randomized controlled studies.In the baseline,except for the mean ultrafiltration volume,PH,HCO3-concentration,iron metabolism and blood phosphorus,the demographic data,previous medical history,hemodialysis data,laboratory examination data and MoCA score were matched well in two groups.There were statistically significant differences in serum thiamine,folate and homocysteine levels between 0 weeks and 48 weeks in the treatment group[53.29±7.12nmol/L vs 57.66±6.02nmol/L,p=0.048;8.18?6.58,9.14?ng/ml vs 2530.0?759.38,3475.0?ng/ml,p=0.000;43.92±21.05umol/L vs 33.27±11.63umol/L,p=0.035].There were statistically significant differences in serum thiamine,folate and homocysteine levels at 48 weeks between the treatment group and the control group[57.66±6.02nmol/L vs 53.77±6.06nmol/L,p=0.040;2530.0?759.38,3475.0?ng/ml vs 6.76?5.49,8.26?ng/ml,p=0.000;33.27±11.63umol/L vs 42.58±13.0umol/L,p=0.017].At 48 weeks of follow-up,MoCA score in the treatment group were significantly higher than those in the baseline?25.60±2.42 vs 22.08±3.59,p=0.000?and control groups?25.60±2.42 vs 19.00±5.01,p=0.000?.A total of 14 cases?28%?of adverse events occurred,of which 4 cases?16%?in the treatment group were significantly lower than 11 cases?44%?in the control group?p=0.031?.Kaplan-Meier survival curve analysis indicated that the survival rate of patients in the treatment group was higher than that in the control group,but there was no statistical difference?p=0.077?.Functional magnetic resonance imaging showed improvements in brain activity in the treatment group compared with the baseline period.Conclusion?1?Cognitive impairment is one of the most common complications of MHD patients,The MoCA score indicated that the incidence was about 51.6%.Education<12 years,diastolic blood pressure<73mmHg and spKt/V<1.72 wwere independent risk factors for cognitive impairment in patients with MHD.The survival rate of patients with cognitive impairment associated with MHD was lower than that of patients without cognitive impairment.fMRI examination revealed the imaging features of cognitive impairment in MHD patients.?2?5/6 nephrectomy is a reliable method for the preparation of uremic rat model.The levels of thiamine and folic acid in the 5/6 nephrectomy group were significantly lower than those in the sham operation group,while the levels of homocysteine were significantly higher than those in the sham operation group.The cognitive function of the 5/6 nephrectomy group was significantly lower than that of the sham operation group.Body weight at week 4,serum thiamine and folic acid levels were positively correlated with the cognitive function of rats,while blood urea nitrogen level,the percentage of positive cells stained with 8-OHdG and IOD value were negatively correlated with the cognitive function of rats.The number of neurons in hippocampal area of brain tissue was significantly reduced,and 8-OHdG overexpression was found in 5/6 nephrectomy rats.?3?In patients with MHD with MoCA score less than 26,after 48 weeks of supplementation with thiamine and folic acid,the blood levels of thiamine and folic acid in the treatment group were significantly higher than those in the baseline and control groups.Supplementation with thiamine and folic acid improved MoCA scores for MHD complicated with cognitive impairment.fMRI examination revealed the imaging features of MHD complicated with cognitive impairment after treatment.Supplementation with thiamine?90mg/day?and folic acid?30mg/day?are safely for patients with MHD. |
PDF Full Text Request