| Abstract|| |
Cognitive impairment (CI) is common in patients with chronic kidney disease, and its prevalence increases in patients on hemodialysis (HD). Different factors were identified to be the cause of cognitive dysfunction, of which Vitamin D, which is known to have pleiotropic effects, has been implicated for the neurocognitive decline of functions. We assessed the prevalence of cognitive dysfunction in patients on HD in our center and also studied the deficiency of Vitamin D on CI.
|How to cite this article:|
Reddy BA, Yadla M. Assessment of cognitive impairment and its correlation with vitamin D levels patients on maintenance hemodialysis. Saudi J Kidney Dis Transpl 2020;31:431-9
|How to cite this URL:|
Reddy BA, Yadla M. Assessment of cognitive impairment and its correlation with vitamin D levels patients on maintenance hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Jul 3];31:431-9. Available from: http://www.sjkdt.org/text.asp?2020/31/2/431/284018
| Introduction|| |
Cognitive impairment (CI) is common in patients with chronic kidney disease (CKD) and in those on hemodialysis (HD). Although common in patients on dialysis, it is often underdiagnosed, unidentified, and thus not treated. Potential contributing factors for the high prevalence of CI in those on dialysis have metabolic abnormalities, vascular disease associated with increased morbidity.,, In addition, Kurella Tamura et al have shown an association between frequent HD and CI. Kurella Tamura et al have assessed the relation between retinopathy and CI. Prevalence of CI in HD patients was reported to be as high as 70% with much poorer performance in executive functions, as shown in the Boston study. The presence of cardiovascular disease was thought to be one of the significant contributing factors for CI. Few studies have shown an association between dementia and mortality. It was also suggested that periodic identification of dementia in patients on dialysis would help in the identification of such patients and thus curb the mortality in this group.,
Both hypovitaminosis D and CI are common in patients with CKD. Vitamin D is known to have neuroprotective role preventing neuro- degeneration. The association between CI and Vitamin D deficiency has been reported in a few studies., Vitamin D deficiency is common in patients with CKD and in those on dialysis. Pre-existent genetic background was thought to be one of the predisposing factors for development of CI in these patients. We undertook a study in our center to assess the prevalence of CI among patients on HD and its correlation with Vitamin D deficiency.
| Aim|| |
The aim of our study is to assess the CI in patients on maintenance HD and its correlation with Vitamin D levels.
| Patients and Methods|| |
This study was done at our center, tertiary care referral center over a period of 2 years. In our center, HD is given free of cost under the government funded cashless scheme. Under this scheme, patients are given twice or thrice weekly dialysis along with erythropoietin support.
We have included patients on maintenance HD of >6 months and those who consented to participate in the study.
Excluded in the study are those patients on maintenance HD <6 months, those who had dementia or cerebrovascular accidents causing higher mental function disturbance, those who did not consent to participate in the study.
Cognitive function was assessed using a detailed neurocognitive questionnaire during a dialysis session. All testing was completed within the 1st h of initiation of dialysis session to reduce the effects of fatigue.
The Addenbrooke’s Cognitive Examination- R cognitive test that assesses five cognitive domains: Attention and orientation, memory, verbal fluency, language and visuospatial abilities. The total score is 100 with higher scores indicating better cognitive functioning. Vitamin D levels were assessed using chemiluminiscence assay.
| Results|| |
A total of patients who satisfied the inclusion criteria were 100. The mean age of the study population was 42.8 ± 11.5 years. Men were 68 and women were 32 in number. The mean vintage of the dialysis was 2.4 ± 1.7 years. Diabetes was present in 13 patients. Hypertension (HTN) was present in 96 patients. Native kidney disease was presumed chronic interstitial nephritis (47), presumed this chronic glomerulonephritis (44), and diabetic nephropathy in nine patients. All the patients were on permanent access. HD sessions were twice weekly in 25 patients and thrice-weekly in 75 patients [Table 1].
CI using the questionnaire was assessed in all the patients. The factors that showed a statistically significant association with CI in dialysis population were age and gender (P <0.05). Older age group was associated with CI rather than the younger age group (46.35 years vs. 41.18 years). The female gender was associated with CI. Factors such as duration diabetes, HTN, vintage of dialysis, anemia, and native kidney disease, did not show a statistically significant association with CI P > 0.05) [Table 2].
|Table 2: Characteristics of patients with and without cognitive impairment.|
Click here to view
Among the two groups, levels of Vitamin D differed significantly. Vitamin D levels were preserved in those without CI and were very low in those with CI (P < 0.05) [Table 3].
Among the patients with CI (31/100), 16 were women and 15 were men. Of the total number of women in the study, 16/32 (50%) had CI compared to 15/68 (22%) of men. On comparison of baseline characteristics based on gender, the presence of anemia showed a statistically significant difference between the two groups [Table 4].
Based on levels of Vitamin D, patients were grouped into Vitamin D sufficiency, Vitamin D insufficiency, and Vitamin D deficient [Table 5].
|Table 5: Clinical and demographic variables stratified by Vitamin D status.|
Click here to view
It was observed that Vitamin D deficiency was associated with a longer vintage of dialysis. The mean vintage of the group with Vitamin D deficiency was 3.15 ± 1.9 years. CI was present in those patients with Vitamin D deficiency (P < 0.05). Other factors such as age, gender, duration of diabetes, HTN, mean blood pressure, inter-dialytic weight gain, type of access, frequency of dialysis.
Correlation between Vitamin D status and the presence of CI was also assessed. It was observed that there was a significant positive correlation between deficient Vitamin D levels and the presence of CI [Table 6].
Sensitivity, the specificity of levels of Vitamin D with a cutoff value of 24.6 (best cutoff value of Vitamin D was 24.6) in predicting presence of CI was also analyzed [Table 7].
Sensitivity and positive predictive values with cutoff of 24.6 pg/mL were found to be 81.2% and 83.5%, respectively. ROC of the assessment shows that it is a highly sensitive marker for the assessment of Vitamin D [Figure 1].
A logistic regression was performed to ascertain the effects of age, gender, and Vitamin D status on the likely hood that participants have CI. The logistic regression model was statistically significant, x = 30.055, P <0.001. The model explained 36.6% (Nagelkerke R2) of the variance in CI and correctly classified 80% of the cases [Table 8].
By multivariate logistic regression analysis, it was found that female gender, old age, and Vitamin D deficiency showed a statistically significant association with CI.
It was observed that the female gender is 4.78 times at risk of the development of CI compared to the male gender.
| Discussion|| |
A diagnosis of CI is established by demonstrating a cognitive decline from a previously attained level of functioning. It can be a decline in any of the six principle domains including complex attention, executive attention, learning and memory, language, perceptual- motor function and social cognition.
Vitamin D was shown to play a role in neuroprotection through various factors such as glial cell-derived neurotrophic factor, nitric oxide synthase, and nerve growth factor. Evidence shows that Vitamin D promotes neuron survival, increases antioxidant activity, ameliorates oxidative stress-induced mito- chondrial dysfunction and decreases the effect of excitatory neurotoxins. Vitamin D also prevents amyloid-beta accumulation by reducing amyloid precursor transcription. Thus it is understood that due to Vitamin D deficiency neurofunction would decline and hence the CI.,
Few studies have shown an association between Vitamin D levels and global cognitive function, and the higher prevalence of cognitive decline in community-based populations without identified CKD and in patients with Alzheimer’s disease and stroke.,,, A meta- analysis by Balion et al showed that CI is associated with a low level of Vitamin D <20 ng/mL. Another study in Italian elderly group showed an increased risk of CI in those with Vitamin D <10 ng/mL compared to those with levels >30 ng/mL. The possibility of two APOE 4 alleles with the prevalence of CI had also been reported in literature.
Similarly, few studies were showed association between CI and Vitamin D deficiency in patients on HD.,, Prevalence of CI was reported to be as high as 70% in patients on HD. Factors that are identified to be contributing factors for the development of CI in patients on HD are: the presence of morbidities like diabetes, HTN, hyperlipidemia, high levels of pro-inflammatory markers enhancing atherogenesis, co-existing endothelial dysfunction.
Shaffl et al studied Vitamin D deficiency in relation with CI in 244 patients on dialysis, wherein it was found that lower Vitamin D level was associated with impaired executive function but not global function. Similar study was done by Liu et al in 273 Chinese patients on peritoneal dialysis and showed an association between low Vitamin D level of <10 ng/mL with lower global function but not executive function. In contrast to the above findings, Jovanovich et al had shown a negative association between Vitamin D and cognitive function. It was also observed that patients on HD show much severe cognitive deficits than patients not on HD, though fluctuation in CI were noted with inter- and intra-HD session.,
The mean age of the study group, vintage of dialysis, Vitamin D levels, number of patients with CI and Vitamin D deficiency are similar to the observations in Shaffl et al study [Table 9].
In the present study, the total number of patients is 100 in number, with 13% of them having DM. This is in contrast with Shaffi et al with 255 patients in number and 42% of them have DM. There is no statistically significant association between DM and CI.
In the present study, 96% of the patients had HTN with mean body mass index (BMI) of 21.21 kg/m2, intra-dialytic weight gain of 2.2 ± 1.1 kg This finding is in concordance with the study by Shaffi et al with HTN in 90.6%, mean BMI of 28.6kg/m2 and intra-dialytic weight gain of 2.7 ± 1.1 kg, respectively. There is no statistically significant association between HTN, mean BMI, and intradialytic weight gain with respect to CI.
Mean Vitamin D levels in the present study were 17 ± 12.5 ng/mL, which is in concordance with Vitamin D levels (17 ± 7 ng/mL) by Shaffi et al.
In the present study, CI is present in 31% of patients which is in concordance with CI (45%) in the study by Shaffi et al. There is a statistically significant association between CI and Vitamin D levels (P <0.001) in the present study which is in concordance with the study by Shaffi et al (P <0.01).
In a study by Wolf et al, it was observed that patients on HD were three times more likely to have severe CI than a comparison group of nonCKD patients. In a study of CKD and HD patients by Kurella et al, among 80 HD patients (mean age 61.2 years), 38% had severe impairment in executive function and 33% severe memory impairment. Using a detailed 45 min neuro-psychological battery, 37% of patients had severe, 36% moderate, and 14% mild cognitive impairment; only 13% had a normal cognitive function. In the Dialysis Outcomes and Practice Patterns Study (DOPPS), only 4% of the HD population carried a medical record diagnosis of dementia. Thus, many cases may go unrecognized, raising the specter of a massive occult burden of CI in CKD and HD patients.
In the DOPPS, only 4% of the HD population carried a medical record diagnosis of dementia. Thus, many cases may go unrecognized, raising the specter of a massive occult burden of CI in CKD and HD patients. In Sehgal’s study of 336 HD patients, only 15% of the cognitively impaired patients (Mini-Mental State Examination <24) had a medical record diagnosis of cognitive problems.
In a recent review, Bugnicourt et al proposed a detailed model of the complex pathophysiology of CI in CKD that emphasizes three primary pathways to CI: traditional cardiovascular risk factors, nontraditional factors such as inflammation, oxidative stress, and hypercoagulable state, and uremic toxins including cystatin C. which cause either primarily vascular CI or neurodegenerative CI.
Gesualdo et al studied CI in 99 HD patients and found a positive correlation exists with the vintage of dialysis and a negative correlation with education status and age. In our study, 80% of the patients are uneducated, but the correlation of education status with CI could not be analyzed. In the meta-analysis of 42 studies done by O’Lone et al, it was observed that patients on HD had impaired cognitive function compared to general population in the domains of attention and executive function.
Studies show a high prevalence of white matter disease in the brain in patients on HD, which explains the high prevalence of CI in these patients., Though the relation of the adequacy of dialysis as measured by Kt/V with CI could not be studied; certain retained uremic solutes were thought to be associated with CI. In Frequent Hemodialysis Network trials, it was shown that an increase in the frequency of dialysis is not associated with improved neurocognition though the duration of dialysis may have an impact on cognitive dysfunction.
Although there are studies which did not show a significant association of CI with Vitamin D, few studies have definitely shown a positive association with Vitamin D.
| Conclusion|| |
Points of interest in our study are: 31% of the study population had CI; factors associated with CI were old age, female gender and Vitamin D deficiency. The best cutoff value of Vitamin D level of 24.6 ng/mL has high sensitivity and specificity. It is essential to assess the CI in patients on HD for early diagnosis and an apt management, and it is prudent to assess periodically Vitamin D levels in patients on HD.
| Limitations|| |
Small sample size of the study group.
Parameters such as serum calcium, phosphorus, uric acid, and intact parathyroid hormone could not be done. Duration of exposure to sunlight and its effect on the Vitamin D levels could not be assessed.
Although we excluded patients who were receiving oral 25(OH) Vitamin D2 or D3 replacement at the time of the study, it is possible that ascertainment of use was not 100% accurate or that individuals had received it in the past.
Patients with lower 25 (OH)D levels are generally sicker than the patients with higher levels, and, although we adjusted analyses for several comorbid conditions, unmeasured or residual confounding remains a possibility.
Conflict of interest: None declared.
| References|| |
Weiner DE, Scott TM, Giang LM, et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011;58:773-81
Yaffe K, Lindquist K, Penninx BW, et al. Inflammatory markers and cognition in well- functioning African-American and white elders. Neurology 2003;61:76-80
Kurella Tamura M, Xie D, Yaffe K, et al. Vascular risk factors and cognitive impairment in chronic kidney disease: The Chronic Renal Insufficiency Cohort (CRIC) study. Clin J Am Soc Nephrol 2011;6:248-56. '
Kurella Tamura M, Wadley V, Yaffe K, et al. Kidney function and cognitive impairment in US adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am J Kidney Dis 2008;52:227-34
Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006;67:216-23
Sarnak MJ, Tighiouart H, Scott TM, et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013;80:471-80
Rakowski DA, Caillard S, Agodoa LY, Abbott KC. Dementia as a predictor of mortality in dialysis patients. Clin J Am Soc Nephrol 2006;1:1000-5
Kurella M, Mapes DL, Port FK, Chertow GM. Correlates and outcomes of dementia among dialysis patients: The Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant 2006;21:2543-8
Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognition, and dementia: A systematic review and meta-analysis. Neurology 2012; 79:1397-405
Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170:1135-41
Shea MK, Benjamin EJ, Dupuis J, et al. Genetic and non-genetic correlates of Vitamins K and D. Eur J Clin Nutr 2009;63:458-64
Weiner DE, Scott TM, Giang LM, et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011;58:773-81
Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: An occult burden. Adv Chronic Kidney Dis 2008;15:123-32
Sehgal AR, Grey SF, DeOreo PB, Whitehouse PJ. Prevalence, recognition, and implications of mental impairment among hemodialysis patients. Am J Kidney Dis 1997;30:41-9
Kurella M, Chertow GM, Fried LF, et al. Chronic kidney disease and cognitive impairment in the elderly: The health, aging, and body composition study. J Am Soc Nephrol 2005;16:2127-33
Shaffi K, Tighiouart H, Scott T, et al. Low 25- hydroxyvitamin D levels and cognitive impairment in hemodialysis patients. Clin J Am Soc Nephrol 2013;8:979-86
Liu GL, Pi HC, Hao L, Li DD, Wu YG, Dong J. Vitamin D status is an independent risk factor for global cognitive impairment in peritoneal dialysis patients. PLoS One 2015; 10:e0143782
Jovanovich AJ, Chonchol M, Brady CB, et al. 25-vitamin D, 1,25-vitamin D, parathyroid hormone, fibroblast growth factor-23 and cognitive function in men with advanced CKD: A veteran population. Clin Nephrol 2014;82:S1-4
Buell JS, Dawson-Hughes B, Scott TM, et al. 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010;74:18-26
Coen G. Vitamin D: An old prohormone with an emergent role in chronic kidney disease. J Nephrol 2008;21:313-23
Ibi M, Sawada H, Nakanishi M, et al. Protective effects of 1alpha, 25-(OH)(2)D(3) against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology 2001;40:761-71
Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72: 1004-13
Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in ESRD: Diagnostic and therapeutic strategies. Kidney Int 2011 ;79:14- 22
Wechsler D. Wechsler Adult Intelligence Scale. (WAIS-III). 3rd ed. San Antonio, Texas: Pearson; 1997
Heaton R, Grant I, Matthews C. Comprehensive Norms for an Expanded Halstead-Reitan Battery. Odessa, Florida: Psychological Assessment Resources Inc.; 1991
Mapes DL, Lopes AA, Satayathum S, et al. Health-related quality of life as a predictor of mortality and hospitalization: The Dialysis Outcomes and Practice Patterns Study (DOPPS). Kidney Int 2003;64:339-49. '
Griva K, Stygall J, Hankins M, Davenport A, Harrison M, Newman SP. Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 2010;56:693-703
Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: The neglected kidney- brain axis. J Am Soc Nephrol 2013;24:353-63
Gesualdo GD, Duarte JG, Zazzetta MS, et al. Cognitive impairment of patients with chronic renal disease on hemodialysis and its relation ship with socio demographic and clinical characteristics. Dement Neuropsychol 2017; 11:221-6
O’Lone E, Connors M, Masson P, et al. Cognition in people with end-stage kidney disease treated withhemodialysis: A systematic review and meta-analysis. Am J Kidney Dis 2016;67:925-35.
Drew DA, Bhadelia R, Tighiouart H et al. Anatomic brain disease in hemodialysis patients: A cross-sectional study. Am J Kidney Dis 2013;61:271-8
Kim CD, Lee HJ, Kim DJ, et al. High prevalence of leukoaraiosis in cerebral magnetic resonance images of patients on peritoneal dialysis. Am J Kidney Dis 2007; 50:98-107
FHN Trial Group, Chertow GM, Levin NW, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med 2010;363:2287-300.
Department of Nephrology, Gandhi Medical College, Hyderabad, Telangana
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]