|Year : 2018 | Volume
| Issue : 4 | Page : 130-136
Cognitive disorders in chronic kidney disease and hemodialysis patients
Ahmed S El Belbessi1, Iman E El Gohary1, Hesham A Sheshtawi2, Mona M Abdulmoneim Mohamed3
1 Department of Internal Medicine, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Neuropsychiatry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
3 Department of Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||04-Sep-2018|
|Date of Acceptance||18-Oct-2018|
|Date of Web Publication||17-Dec-2018|
Dr. Mona M Abdulmoneim Mohamed
Source of Support: None, Conflict of Interest: None
Introduction Cognitive impairment (CI) is common in individuals with chronic kidney disease (CKD) and among those treated with hemodialysis (HD). It may jeopardize treatment adherence by affecting the efficiency of every-day tasks, including correct medication and dietary rules. The severity of CKD is associated with the severity of CI, independent of age, education, and other key confounders. It is important to identify those patients with CI to reduce the considerable morbidity associated with this condition and improve their quality of life.
Objectives The aim of the present study is to assess cognitive functions in patients with chronic renal diseases and patients on regular HD and to identify CI in these patients.
Patients and methods A total of 30 patients with CKD were recruited from the outpatient clinic of Alamerya General Hospital (group I), and 30 HD patients were enrolled in the dialysis unit of the Alamerya General Hospital (group II). Moreover, 30 sex-matched and age-matched patients were recruited as controls (group III). Montreal Cognitive Assessment (MoCA) and Depression Anxiety Stress scale-21 were used as cognitive and neurological tests.
Result The mean executive functions score was significantly lower in group II (2.37±0.67) in comparison with group I (3.33±0.48), with a P value less than 0.001, and it is also significantly lower in groups I and II in comparison with the control group (3.90±0.31), with a P value of 0.002 and less than 0.001, respectively.
The mean attention score was significantly lower in group I (4.20±0.81) and group II (4.23±0.94) in comparison with the control group (5.27±0.69), with a P value of less than 0.001.
The mean memory score was significantly lower in group I (3.10±0.40) and group II (2.57±0.90) in comparison with the control group (4.47±0.73), with a P value of less than 0.001.
The mean total MoCA test score was significantly lower in group II (22.87±1.68) in comparison with group I (24.27±1.26), with a P value of less than 0.017, and it is also significantly lower in groups I and II in comparison with the control group (28.33±1.47), with a P value of less than 0.001.
Conclusion Impaired renal function affects total MoCA score in the studied groups.
Keywords: chronic kidney disease, cognitive impairment, hemodialysis
|How to cite this article:|
El Belbessi AS, El Gohary IE, Sheshtawi HA, Mohamed MM. Cognitive disorders in chronic kidney disease and hemodialysis patients. J Egypt Soc Nephrol Transplant 2018;18:130-6
|How to cite this URL:|
El Belbessi AS, El Gohary IE, Sheshtawi HA, Mohamed MM. Cognitive disorders in chronic kidney disease and hemodialysis patients. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2019 May 26];18:130-6. Available from: http://www.jesnt.eg.net/text.asp?2018/18/4/130/247706
| Introduction|| |
Chronic kidney disease (CKD) is a world-wide public health problem, with increasing incidence and prevalence . It is currently defined as a creatinine-based estimated glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 or a urine albumin-to-creatinine ratio of 30 mg/g or higher for 3 months or more, irrespective of clinical diagnosis .
End-stage renal disease (ESRD) represents the end of the spectrum of CKD where GFR falls below 15 ml/min/1.73 m2 which is the level of renal function that is not compatible with life and requires treatment .
Hemodialysis (HD) is one of three renal replacement therapies methods (the other two being renal transplant and peritoneal dialysis) that are used to remove waste products when the kidneys are in a state of renal failure .
Patients with CKD are subjected to many complications that develop progressively as GFR declines below 60 ml/min/1.73 m2 and in particular below 30 ml/min/1.73 m2. Those include anemia, bone and mineral disease, metabolic acidosis, increased risk of infection, cardiovascular disease, and neurological complications .
Neurological complications are characterized by cognitive impairment (CI), anxiety, fatigue, apathy, clumsiness, irritability, sleep disturbances, verbal and nonverbal memory deficits, language, visuoconstructive deficits, and impaired concentration .
Cognitive disorders are common in individuals with CKD in close relation with decreased renal functions and among those treated with HD regardless of age and other potential confounding factors . CI is defined as a new deficit in at least two areas of cognitive functioning. These may include disturbances in memory, executive functioning, attention or speed of information processing, perceptual motor abilities, or language . It can be understood as a decline in patient baseline functions possibly at a level severe enough to interfere with the performance of daily living activities by the individual .
Diagnosis of CI is important as it is associated with an increased risk of death in dialysis patients , and interventions to slow progression of CI would likely have a major effect on public health . Furthermore, those with mild CI are 5–10 times more likely to develop dementia . CI has also been associated with a decreased quality of life in dialysis patients  and may affect decision making as well as the ability to adhere to dialysis recommendations and to understand the rationale and to provide informed consent for medical procedures .
Tests for evaluation of cognitive function
Two broad classes of tests can be used to assess cognitive function in the general population:
- Neurophysiological tests use electrophysiological methods, for example, electroencephalogram and cognitive evoked potentials .
- Neuropsychological tests consist of an array of tests, which may be divided into general screening tests for cognitive function versus comprehensive testing in a particular domain, for example, Mini-Mental State Examination , the 3MS , and the Montreal Cognitive Assessment (MoCA) .
The MoCA is a brief screening tool assessing visuospatial and executive functions, attention, short-term memory, language, and orientation, and has been translated and adapted into several languages. It includes tasks such as trail making test − part B, cube copying, clock drawing, naming, digit span backwards and forwards, serial subtraction, selective attention, sentence repetition, phonemic word fluency, verbal abstraction, a five-word learning and delayed recall task, and spatial and temporal orientation. Completion time is ∼10–15 min and a maximum of 30 points can be obtained. A maximum of 30 points is attainable, whereas a score of 26 is used as a cutoff value between normal and pathological patterns .
The MoCA is a screening test for CI that covers major cognitive domains including episodic memory, language, attention, orientation, visuospatial ability, and executive functions, while remaining brief and easy to administer. It is generally considered superior to the well-established Mini-Mental State Examination screening test , as the MoCA not only assesses executive functioning, which may be particularly important in the CKD population, but also presents a higher sensitivity for mild CI . Accordingly, the MoCA has been evaluated and found to be an adequate screening tool in various clinical populations . Recently, the MoCA was also recommended as a standardized approach to cognitive assessment in patients undergoing HD .
| Patients and methods|| |
After obtaining the approval of the ethics committee of the Faculty of Medicine of the Alexandria University, 30 patients with CKD (stage 3 and stage 4), 30 patients with ESRD on HD from Alamerya General Hospital, and 30 healthy controls were recruited. An informed consent from the patients was taken before conducting the study. Patients with heart failure, acute coronary syndrome or acute myocardial infarction within 3 months from the study, chronic obstructive pulmonary diseases, cerebrovascular diseases, degenerative neurological diseases, mental subnormality, previous psychotic or subcognitive diseases, and liver insufficiency were excluded.
Data including name, age, sex, past medical history, and data obtained from clinical examination were recorded at enrollment. Laboratory investigations included complete blood picture, lipid profile, renal function test, urinary albumin/urinary creatinine ratio, serum calcium, serum phosphorus, intact parathyroid hormone (PTH), and C-reactive protein, estimated sedimentation rate, and liver function test.
Cognitive and neurological tests included MoCA  and Depression Anxiety Stress Scale-21 .
Data were fed to the computer and analyzed using IBM SPSS software package, version 20.0 (IBM Corp., Armonk, New York, USA) . Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level. F test (analysis of variance) was used to compare normally distributed data and Mann–Whitney test to compare abnormally distributed data. Kruskal–Wallis test was used to compare normally distributed data to compare between more than two studied groups, and post-hoc (Dunn’s multiple comparisons test) for pairwise comparisons. Spearman’s coefficient was used to correlate quantitative variables. Regression was used to detect the most independent/affecting factor for MoCA total .
| Results|| |
Demographic data of the studied groups as regard age ,sex and years of education are shown in [Table 1].
|Table 1 Comparison between the studied groups regarding sex, age, and education|
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In group I we found that there was statistically significant negative correlation between age of the patients, urea, creatinine, phosphorus, parathyroid hormone levels and category of CKD and total MoCA score. There was statistically significant positive correlation between calcium level and total MoCA score ([Table 2]).
|Table 2 The significant correlations between Montreal Cognitive Assessment and different parameters in group I|
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In group II we found that there was statistically significant negative correlation between durationof HD, urea and creatinine and total MoCA score ([Table 3]).
|Table 3 The significant correlations between Montreal Cognitive Assessment and different parameters in group II|
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In total patients of both groups we found that there was statistically significant negative correlation between urea, creatinine, parathyroid hormone levels and category of CKD and total MoCA score ([Table 4])
|Table 4 The significant correlation between total Montreal Cognitive Assessment score and different parameters for total cases|
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In group I, we found that the age of patients was the most significant parameter affecting the total MoCA score ([Table 5]).
|Table 5 Multivariate linear regression for the parameters that affect Montreal Cognitive Assessment total score in group I (N=30)|
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In group II, we found that creatinine level and duration of HD were the most significant parameters affecting total MoCA score ([Table 6]).
|Table 6 Multivariate linear regression for the parameters that affect Montreal Cognitive Assessment total score in group II (N=30)|
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For the total number of patients in both groups I and II, we did not find a specific significant parameter affecting total MoCA score more than other parameters ([Table 7]).
|Table 7 Multivariate linear regression for the parameters that affect Montreal Cognitive Assessment total score for total patients in groups I and II (N=60)|
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| Discussion|| |
Cognitive disorders are common in individuals with CKD in close relation with decreased renal functions and among those treated with HD . It is important to identify those patients with CI to reduce the considerable morbidity associated with this condition and improve their quality of life .
The MoCA is a brief screening tool assessing cognitive functions (visuospatial and executive functions, attention, short-term memory, language, and orientation) and has been translated and adapted into several languages .
In this study, the mean total MoCA score was significantly lower in group II in comparison with group I, and it is also significantly lower in the groups I and II in comparison with the control group.
The mean visuospatial, attention, and memory scores were significantly lower in groups I and II in comparison with the control group. The mean executive function score was significantly lower in group II in comparison with group I, and it is also significantly lower in the group I and II in comparison with the control group. There is no significant difference in the language score or orientation score among the three groups. This could be explained by the fact that dialysis processes directly contribute to cognitive involvement by inducing brain ischemia. Acute decreases in intravascular volumes and fluid exchanges occurring during dialysis sessions may cause edema and diminish cerebral perfusion .
In a study by Tiffin-Richards et al. , it was found that HD patients achieved lower mean total scores in the MoCA than the control group. The deficits were especially prominent in the areas of executive functions and short-term memory capacity. The most difficult tasks appeared to be digit span backward and forward, phonemic word fluency, verbal abstraction, and immediate and delayed word recall. No significant differences could be identified between groups with respect to naming and orientation.
Unlike our study, they found no significant differences between groups with respect to visuospatial tasks and level of attention, but there is a prominent deficit regarding language ability, especially sentence repetition. They suggest that this may be because of vascular disease as a potential cause of CI in HD patients, but this remains, nevertheless, a limitation for interpretation of correlation between tests, owing to a partial overlap between the tasks, which may affect association analysis.
In a study by Iyasere et al. , it was hypothesized that dialysis would be associated with a decline in cognitive function compared with patients with CKD. The results suggest that global cognitive function declines over time for patients on dialysis compared with patients with CKD. It is well recognized that the risk of CI increases as renal function declines . Dialysis potentially exerts an independent effect on cognitive function in patients with advanced CKD. This is supported by the improvement in cognitive function in dialysis patients following transplantation .
In this study, there was a statistically significant negative correlation between the age of the patients and total MoCA score in group I.
In accordance with our study, Paraizo Mde et al.  observe that there is an association between lower MoCA total score and older age. Age is the most relevant risk factor for loss of cognitive functions, a finding seen among individuals aged 35 years and older and more frequently in persons older than 65 years, in patients with CKD.
In our study, there was a statistically significant negative correlation between renal functions tests (urea and creatinine) and executive functions, attention, language, and total MoCA scores in group I. There was a statistically significant negative correlation between renal functions tests (urea and creatinine) and executive functions, memory, and total MoCA scores in group II. There was a statistically significant negative correlation between duration of HD and executive functions, attention, memory, and total MoCA scores in group II.
This may be owing to the accumulation of uremic toxins, which may cause cerebral endothelial dysfunction and contribute to cognitive disorders in CKD. Various uremic toxins have been implicated in the pathogenesis of CI .
De Deyn et al.  reported that cerebrospinal fluid and brain levels of some guanidine compounds, such as creatinine, guanidine, guanidinosuccinic acid, and methylguanidine, are substantially elevated in uremic patients. Interestingly, these high toxin concentrations were found in brain regions that play a determinant role in cognition, such as the thalamus, the mammillary bodies, and the cerebral cortex. However, it is still not clear whether uremic toxins are directly responsible for CI.
Kurella et al.  demonstrated significant differences in cognitive scores in persons with CKD and ESRD from age-matched and education-matched published norms. The severity of kidney disease was directly related to the severity of CI. Mean scores on all cognitive tests and self-assessed cognitive function were lower, and the percentages of patients with impairment were higher among those with lower estimated GFR. These associations were independent of age, education, race/ethnicity, and other confounding factors. Moreover, the association between kidney function and cognitive function was present across several domains of cognitive function in addition to self-assessed cognitive function, with the most striking differences in executive, or frontal-lobe, function. Moreover, performance on tests of executive function and verbal memory in patients with CKD was significantly different from published norms, suggesting that executive function may be especially affected, possibly owing to disruptions in frontal-subcortical circuits that may be observed with white-matter disease or subcortical strokes.
Owolabi et al.  found that besides cerebrovascular changes, a direct uremic neuronal toxicity supports additional neurodegenerative pathways. In their study, urea, creatinine, and duration on dialysis were also found to be significantly associated with cognitive dysfunction in the patients but were not strong enough to predict impairment in the study.
In our study, there was a statistically significant positive correlation between serum calcium and memory score, and there was a statistically significant negative correlation between serum phosphorus and attention and total MoCA scores in group I.
In a study by Rossom et al. , a significant association was found between increased plasma calcium levels and higher cognitive function scores. They also identified plasma phosphorus level as a factor associated with lower cognitive scores.
The mechanism for calcium impact on brain function is hypothesized to be that, increased calcium level enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions.
The association between plasma phosphorus level and cognitive score is consistent with previous findings, where the mechanism for phosphorus and its effect on cognition is believed to be its interaction with calcification in the basal ganglia, thalamus, and cerebral white matter, which is associated with CI. In another study, it was observed that decreased serum phosphorus reduced arterial stiffness and improved cognitive function and renal disease .In this study, there was a statistically significant negative correlation between PTH level and attention and total MoCA scores in group I.
A study by Björkman et al.  stated that renal dysfunction inducing microvascular disease of the cerebral vasculature together with hypercalcemia has been proposed to result in disruption of the blood–brain barrier and accumulation of calcium deposits in brain tissue, leading to CI associated with hyperparathyroidism. However, the predictive value of PTH was consistent in patients with different levels of renal insufficiency and Ca2+ concentrations in the present study. It is possible, however, that other mechanisms, preceding and/or associated with the elevation of PTH and cognitive decline, for example, immobilization, poor nutrition, and vitamin D deficiency, leading to negative calcium balance, may explain our observations. Although the design of this study does not shed light on the possible atherogenetic role of PTH, some mechanisms can be suggested. Although PTH does not cross the undamaged blood–brain barrier, in conjunction with other mediators, leading to disturbed blood–brain barrier permeability, PTH may be involved in brain cell damage.
Another study by Chou et al.  mentioned that markedly increased serum intact PTH levels may facilitate the entry of calcium into brain tissues and thereby influence cognitive function.
| Conclusion|| |
People with CKD and those treated with HD have impaired cognitive function compared with the general population. This impairment is more prominent in HD patients, particularly in the domains of executive function.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]