| Abstract|| |
Cognitive impairment is a common entity in patients with chronic kidney disease (CKD), which plays an important role in increasing the morbidity in these patients. This study was performed to evaluate cognitive dysfunction and its severity in different stages of CKD and identify the correlation with factors affecting this dysfunction. A cross-sectional design study was conducted on 100 patients with CKD Stage III to V-D fulfilling the eligibility criteria. Cognitive status was assessed using the mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) tests. The patients were divided into four groups according to their estimated glomerular filtration rate (eGFR); Group A with eGFR ranging between 30 and 59 mL/min/1.73 m2, Group B with eGFR between 15 and 29 mL/min/1.73 m2, Group C with eGFR <15 mL/min/1.73 m2 not on hemodialysis (HD), and Group D with eGFR <15 mL/min/1.73 m2 and on HD for the past six months. Factors affecting MMSE and MoCA scores were assessed using univariate and multivariate linear regression analysis. Mean MMSE score was 28.72 ± 1.37 in Group A, 26.00 ± 3.67 in Group B, 20.76 ± 4.84 in Group C, and 17.28 ± 3.32 in Group D, which showed a statistically significant difference. The mean MoCA score also showed a statistically significant decline from Group A to Group D with values being 26.36 ± 1.91, 24.56 ± 1.94, 22.08 ± 2.12 and 20.12 ± 1.81, respectively (P < 0.05). The MMSE and MoCA scores were found to have a statistically significant positive correlation with hemoglobin; serum corrected calcium and eGFR (P < 0.01) and statistically significant negative correlation with blood urea, serum creatinine, serum uric acid, serum phosphate, serum potassium and stage of CKD (P < 0.01). By raising the clinician’s awareness about cognitive dysfunction in CKD patients and its potential effects on medication, fluid and, dietary compliance improved quality of care is expected. Early intervention will improve the patient’s quality of life.
|How to cite this article:|
Aggarwal H K, Jain D, Bhavikatti A. Cognitive Dysfunction in Patients with Chronic Kidney Disease. Saudi J Kidney Dis Transpl 2020;31:796-804
|How to cite this URL:|
Aggarwal H K, Jain D, Bhavikatti A. Cognitive Dysfunction in Patients with Chronic Kidney Disease. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Sep 27];31:796-804. Available from: http://www.sjkdt.org/text.asp?2020/31/4/796/292313
| Introduction|| |
The incidence of chronic kidney disease (CKD) is on the rampant increase and problematic in the global scenario due to the demo-graphical trend of an aging population. The increase in the number of CKD patients can be partially attributed to the epidemic of chronic diseases such as hypertension and diabetes. Increasing aging population as a result of increased longevity because of better availability of health-care facilities also resulted in an increased prevalence of chronic diseases. It has been estimated that 7% of the population worldwide have a CKD diagnosis, but it is likely that the “true” percentage of CKD is much higher in developing countries like India.
Cognition is the mental process of acquiring knowledge by the use of reasoning or perception and underlies all daily activities from the most basic to the most complex. Cognitive dysfunction includes reduced mental alertness, intellectual impairment, decreased attention and concentration, memory deficits and diminished perceptual motor coordination. It is well established that patients with CKD commonly have some degree of cognitive impairment and kidney dysfunction is associated with a more rapid decline in mental function in these patients than in age-matched comparisons.
Although the cause of death in CKD patients is mostly due to cerebrovascular disease, cognitive dysfunction also plays an important role in increasing the morbidity in these patients. Cognitive impairment in CKD is mediated by the retention of putative neuro- toxins, including products of nitrogen metabolism and parathyroid hormone and also influenced by chronic inflammation. Cognitive impairment in these patients results in various neuropsychiatric manifestations such as delirium, dementia, anxiety, depression, withdrawal from dialysis, sleep disorders and suicidal tendency. The severity of CKD is associated with the severity of cognitive impairment, independent of age, education, and even after adjustment for several potential confounders, including demographic characteristics, and relevant comorbidities. Executive function and attention are most affected in mild CKD patients, while in severe CKD patients, cognitive impairment is more severe and involves major domains of cognition such as general cognitive abilities, executive function, and episodic memory.
The cognitive dysfunction can be assessed by using various tests such as mini-mental state examination (MMSE), modified mini-mental state, six items cognitive screen test, Montreal cognitive assessment (MoCA), and the cognitive screening interview for dementia, and Trials making test and digit symbol substitution task., MMSE can be used in estimating the severity and progression of cognitive impairment in an individual over a time thus, making it an effective way to document an individual’s response to treat- ment. The MoCA is capable of discriminating CKD patients with and without cognitive impair-ment, especially those on hemo- dialysis (HD). Cognitive impairment by MoCA test is defined by performance on a comprehensive neuropsychological test battery, presenting good sensitivity and specificity levels, as well as a good concurrent validity.
Cognitive impairment in CKD is associated with poor quality of life, increase in healthcare resource utilization and medical cost, more frequent hospitalizations, finally resulting in sub-optimal medical care. It also has a major implication for informed consent in relation to dialysis initiation, maintenance, and ultimately, transplantation. Therefore, the identi-fication of cognitive impairment in CKD patients is an important step to mitigate the morbidities associated with this condition. Only a few studies have examined cognitive dysfunction in various stages of CKD. The focus of this study was to evaluate cognitive dysfunction and its severity in different stages of CKD and correlation with factors affecting this dysfunction.
| Materials and Methods|| |
This was a cross-sectional study conducted on 100 adult patients with CKD on regular follow-up at the kidney and dialysis clinic in Pt. B. D. Sharma PGIMS, Rohtak, India. Patients between 18 and 75 years of age with at least a primary level of education were included in the study. Patients with preexisting psychiatric illness, pregnancy, chronic liver disease, malignancy, cerebrovascular disease and neuro-degenerative disorder, chronic infectious and inflammatory diseases such as chronic glomerulonephritis, amyloi- dosis and obstructive uropathy were excluded. All participants had given their informed consent. The study was approved by the ethical committee of the University of Health Sciences, Rohtak.
A detailed history and clinical examination were obtained in all subjects included in the study. The patients were divided into four groups according to their estimated glomerular filtration rate (eGFR), with each group consisting of 25 patients.
Group A: patients with eGFR between 30 and 59 mL/min/1.73 m2 (Stage III).
Group B: patients with eGFR between 15 and 29 mL/min/1.73 m2 (Stage IV).
Group C: patients with eGFR <15 mL/min/ 1.73 m2, not on HD (Stage V).
Group D: patients with eGFR <15 mL/min/ 1.73 m2, on HD for the last 6 months (Stage V- D).
All patients underwent routine biochemical laboratory investigations including complete hemogram and renal parameters, radiographic evaluation, including chest X-ray, ultrasound of abdomen for bilateral kidneys, and noncontrast computerized tomography scan of Head to exclude organic causes of cognitive dysfunction. GFR was estimated using the Modification of Diet in Renal Disease formula in all participants. Cognitive status of each patient was assessed using MMSE and MoCA tests. Patients were divided on the basis of their performance in these tests as per standard values. The MMSE is a 30-point questionnaire with maximum score of 30, which is a widely used, well-validated screening tool for cognitive impairment. It tests five areas of cognitive function such as orientation, registration, attention and calculation, recall, and language. MMSE score between 26 and 28 was considered as mild cognitive impairment, score between 18 and 25, and score <18 were considered as moderate and severe cognitive impairment. The MoCA test is a one-page 30- point validated test; Hindi and English version of this test was used to assess following cognitive domains such as Alternating Trail Making, Visuoconstructional Skills (Cube), Visuoconstructional Skills (Clock), Naming, Memory, Attention, Sentence repetition Verbal fluency, Abstraction, Delayed recall, and Orientation. A final total score of 26 and above of 30 was considered normal.
| Statistical Analysis|| |
The statistical analysis was performed using the IBM SPSS Statistics for Windows version 21.0 (IBM Corp., Armonk, NY, USA). Categorical variables were presented in number and percentage (%), and continuous variables were presented as mean ± standard deviation. Quantitative variables were compared using the ANOVA test between the groups. Qualitative variables were correlated using the Chi-square test. Pearson correlation coefficient was used to assess the association of various parameters with each other. Univariate and multivariate linear regression was used to assess the factors affecting the MOCA score and MMSE score. Inter-rater kappa agreement was used to assess the strength of agreement between MOCA and MMSE findings. A value of P < 0.05 was considered statistically significant.
| Results|| |
Out of a total of 100 patients, 59 were male and 41 were female, with the mean age of study population being 50.34 years with a range of 37–64 years. The most common etiology of kidney disease in our study was hypertension (48%), followed by diabetes mellitus (37%) and autosomal dominant polycystic kidney disease (15%). The demographic and laboratory characteristics of patients are presented in [Table 1]. As expected, a statistically significant steady rise in the mean values of blood urea, serum creatinine, serum uric acid, serum phosphate, and serum potassium was noticed from Group A to Group D (P < 0.05). Mean MMSE score in Group A was 28.72 ± 1.37, 26.00 ± 3.67, in Group B, 20.76 ± 4.84, in Group C, and 17.28 ± 3.32 in Group D, which showed statistically significant difference. Mean MoCA score also showed a statistically significant decline from Group A to Group D with the value being 26.36 ± 1.91, 24.56 ± 1.94, 22.08 ± 2.12 and 20.12 ± 1.81, respectively (P < 0.05).
|Table 1: Baseline demographic and renal parameters of the study participants.|
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As per MMSE, of 100 patients, 32 patients had normal cognition and 68 patients had cognitive impairment. Of them, 18 patients had mild cognitive impairment, 24 patients had moderate and 26 patients had severe cognitive impairment. Out of 41 females, 14 had a normal cognitive function, while five, 15, and seven had mild, moderate, and severe cognitive impairment, respectively. Out of 59 males, 18 had normal cognition, 13 had mild, nine had moderate and, 19 had severe cognitive impairment.
With the MoCA score, 75 out of the 100 study patients had cognitive impairment. Out of 59 males, 47 had impaired cognition and out of 41 females, 28 had impaired cognition. The difference in cognitive impairment between males and females was not statistically significant (P > 0.05).
A Pearson’s correlation was applied to determine the association between various parameters and MMSE and MoCA scores. As depicted in [Table 2], there was a statistically significant positive correlation of hemoglobin, serum corrected calcium, and eGFR with MMSE and MoCA scores, implying an increase in severity of cognitive impairment as these values decrease (P < 0.01). There was a statistically significant negative correlation of blood urea, serum creatinine, serum uric acid, serum phosphate, serum potassium, and stage of CKD with MMSE and MoCA scores indicating an increase in the severity of impairment in cognition as these parameters increases (P < 0.01). As the CKD stage increased, there was an increase in cognitive impairment. Correlation of other parameters such as age, systolic and diastolic blood pressure, fasting blood sugar, and serum sodium with MMSE and MoCA scores was also assessed in the study. However, the results were not statistically significant (P > 0.05).
|Table 2: Correlation between parameters, mini-mental state examination, and Montreal cognitive assessment scores.|
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MMSE score and MoCA score were signi ficantly associated with the stage of CKD, hemoglobin, blood urea, serum creatinine, serum uric acid, serum corrected calcium, serum phosphate, serum potassium, eGFR using univariate linear regression [Table 3]. Serum creatinine and eGFR were found to be significant factors affecting MMSE and MoCA score, while hemoglobin and serum potassium were found to be significant factors affecting MMSE after adjusting for the confounding factors using multivariate linear regression [Table 4]. Good agreement was found between MOCA and MMSE findings (P < 0.05), which was assessed using inter-rater kappa agreement (κ = 0.78).
|Table 3: Univariate linear regression between parameters, mini-mental state examination, and Montreal cognitive assessment scores.|
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|Table 4: Multivariate linear regression between parameters, mini-mental state examination, and Montreal cognitive assessment scores.|
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| Discussion|| |
CKD is becoming a major public health problem worldwide. The current burden of the disease might be due to a change in the underlying pathogenicity of CKD. Like all other chronic diseases, CKD might be an independent risk factor for cognitive impairment. Multiple factors can affect cognition including demographic factors such as older age, low education, female sex, Hispanic and
African American ethnicity and psychosocial factors such as depression, anxiety, fatigue, loss of identity, and insomnia., Cognitive impairment is associated with an increased risk of death in CKD patients, which is mostly due to cerebrovascular and cardiovascular events, since these patients have more endothelial dysfunction, abnormal vascular reactivity and atherosclerosis risk. CKD patients are exposed to traditional and nontraditional vascular risk factors including chronic inflammation due to uremic toxins and oxidative stress; creatinine levels and cystatin C levels also influence neurocognitive performance decline by increasing the risk of cerebrovascular disease.,
Cognitive dysfunction is associated with poor quality of life and invariably leads to difficulties in effective treatment of the primary disease due to various factors such as poor compliance or withdrawal from treatment and will have major impact on overall morbidity associated with the disease. By getting an early diagnosis and finding various factors influencing these conditions along with early intervention, the treating team can help the patients in a better way to improve their physical, mental, and social well-being.
In our study, out of 100 patients, 68 and 75 patients, respectively, had cognitive impairment according to MMSE and MoCA scores. Results of this study revealed a steady decline in the mean values of MMSE, MoCA scores, and statistically significant increase in the number of patients with cognitive impairment as the CKD stage progresses (P < 0.05). As expected, with the progression of CKD stage, the eGFR decreases and serum creatinine increases, and that was associated with a decreasing trend of MMSE and MoCA scores. These findings are well correlated with findings of a study by Kurella et al, who have shown that the severity of kidney disease was directly related to the severity of cognitive impairment. These associations were independent of age, education, race or ethnicity, and other confounding factors. Berger et al in their meta-analysis, also demonstrated the progression of cognitive changes at different rates for different cognitive domains as CKD progressed, and eGFR declined. These results are consistent with Heart Estrogen/Progestin Replacement study, where women with an eGFR <30 mL/min/1.73 m2 were independently five times more likely to experience global cognitive impairment than women with an eGFR ≤ 60 mL/min/1.73 m2. Similar results were also observed in various other studies.
In our study, statistically significant positive correlation of hemoglobin, serum corrected calcium and eGFR and statistically significant negative correlation of blood urea, serum creatinine, serum uric acid, serum phosphate, serum potassium, stage of CKD with MMSE and MoCA scores was seen, which was assessed using Pearson correlation., implying an increase in severity of cognitive impairment as the CKD stage progresses. Multivariate linear regression revealed that serum creatinine and eGFR were found to be significant factors affecting MMSE and MoCA score, while hemoglobin was found to be a significant factor affecting MMSE after adjusting for the confounding factors. Similar findings were observed in a study, where the cognitive decline was associated with high serum phosphate levels. Liu observed that lower serum calcium level was associated with cognitive impairment in patients with Parkinson’s disease.
Anemia is common among patients with CKD, due in part to reduced erythropoietin production as kidney function declines. Some, but not all studies, have identified a cross- sectional association between anemia and cognitive function in patients with ESRD., Our results revealed a significant association between low hemoglobin levels and more severe impairment of cognitive functions. A strong positive correlation was seen between hemoglobin and MMSE, MoCA scores. These findings are in agree-ment with a cross- sectional study of CKD patients in Chronic Renal Insufficiency Cohort (CRIC) and in a study conducted by Chang Hyung Hong who observed 41% higher risk of developing dementia in patients with anemia than those without anemia after adjusting for age, race, sex, and education. Madero et al found that anemia, both in CKD patients and in older adults without CKD, has been associated with cognitive impairment, and neuropsychological and neurophysiological tests have shown improvement with the treatment of anemia in CKD. It remains unknown whether this is solely due to an improvement in the blood count or an independent effect of supplementation with erythropoietin. These findings are contrary to those seen by Tamura et al, who did not find an independent association between anemia and baseline cognitive function or the rate of cognitive decline.
The MoCA was chosen as a cognitive testing instrument in this study for feasibility reasons and because it explicitly covers executive functions, which appear to be impaired early in HD patients. Other tests, for example, the MMSE, do not include evaluation of this cognitive domain. Our findings are in consistent with previous research, where the MoCA’s sensitivity in detecting cognitive impairment ranged from 56% to 100%, while specificity varied between 29% and 87%, depending on the study population, and good agreement was found between MOCA and MMSE findings (P < 0.05), which was assessed by using inter-rater kappa agreement (κ = 0.78).
The results of this study should be interpreted with the limitation in mind that, since it was a cross-sectional study, it did not allow for a comparison to assess the benefit of different treatment modalities and their impact on cognitive function.
| Conclusion|| |
With increased longevity and prevalence of ESRD and diagnosis of CKD in earlier stages, cognitive dysfunction-related issues are gaining its importance in the management of CKD. Severe cognitive impairment among HD patients is associated with an approximately 2fold increased risk of both mortality and dialysis withdrawal. Therefore, awareness of cognitive dysfunction in dialysis patients improves the quality of care and outcomes by raising clinician’s awareness about the potential effects of cognitive impairment on medication, fluid, and dietary compliance. In view of the high percentage of cognitive impairment, reduced quality of life and depression even in stable CKD patients, psychological screening should get integrated in clinical routine for CKD treatment. Patients with CKD progression have to be treated in a multi- disciplinary care setting, including dietary counseling, advice about different renal replacement therapies and cardiovascular risks, as well as psychological and social support along with behavioral therapy. Further long-term studies with more number of patients are needed to better evaluate cognitive dysfunction and psychiatric disturbances.
Conflict of interest: None declared.
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Department of Medicine, Division of Nephrology, Pt. B. D. Sharma University of Health Sciences, Rohtak - 124 001, Haryana
[Table 1], [Table 2], [Table 3], [Table 4]