Introduction

 

Chronic kidney disease (CKD) is a worldwide public health problem¹. The prevalence of CKD, which was approximately 11% in both the United States and Taiwan, has increased dramatically during recent decades and may rise even further in the future^2,3.

The association between end-stage renal disease and cognitive impairment has long been well recognized^4,5.

Because CKD is considered treatable and preventable during its early stages⁶, recent studies have focused on patients with less advanced CKD. In one of these studies, moderate renal impairment, which is defined by elevated serum creatinine, was found to be associated with an increased risk of dementia⁷.

Other studies have suggested that general cognitive dysfunction or specific cognitive impairments are already present during the early stages of CKD^8,9. However, most of these studies were conducted in elderly cohorts or in patients with co-morbid conditions^8,10.

Furthermore, it is likely that there will be an increased burden of cognitive impairment in the future as the end-stage renal disease (ESRD) population ages and the prevalence of diabetes and vascular disease increases in incident dialysis patients. Evaluation of cognitive impairment in dialysis patients should include several potentially reversible neurological disorders that may acutely affect mental status and that occur with increased frequency in this population¹¹.

It is unknown, however, how commonly cognitive impairment occurs in hemodialysis patients. Common occurrence would raise question about the ability of hemodialysis patients to comply with dialysis schedules and complex medication regiments or make informed decisions regarding initiating and continuing hemodialysis. Moderate to severe cognitive impairment is common and undiagnosed in hemodialysis patients.

This study was aiming to shed more light on severity and pattern of cognitive impairment in hemodialysis patients.

 

Methods

 

This study was conducted on 50 hemodialysis patients (Group I) recruited from hemodialysis unit in Beni Suef Hospital and 50 age and sex matched control subjects (Group II) during the period from April 2009 to August 2010.

The patient group included 25 males and 25 females ranging in age from 40 to 55 with a mean age of 48.2±4.8.

 

Inclusion criteria: Age ≤ 55 years, maintenance on hemodialysis for at least 1 year and normal brain-imaging (CT brain and or MRI brain).

 

Exclusion criteria: Age older than 55 years, disturbed conscious level, systemic diseases that affect cognitive function rather than renal disease (e.g. HTN and DM) and medications that could affect cognitive function.

 

Methods:

1.        Thorough history taking and complete general examination.

2.        Full neurological examination according to standard neurological sheet.

3.        Routine laboratory investigations including complete blood count, calcium, phosphorous, and liver function tests, kidney function tests.

4.        Neuropsychological battery including: Mini-mental state examination (MMSE)¹², The Trail Making Test¹³, The controlled oral word association test (COWA)¹⁴, The logical memory¹⁵, Beck Depression Inventory (BDI)¹⁶.

 

Statistical Methods

Descriptive analysis of the results in the form of percentage distribution for qualitative data (minimum, maximum, mean and standard deviation) calculation for quantitative data. The following tests were used: cross tabulation test, student t-test , chi-square test. Statistical package for social science (SPSS v 15) was used.

 

Results

 

1.            Laboratory results:

All patients (100%) of group (I) were suffering from anemia with HB level ranged from 8 to 11.5 mg\dl with a mean 9.9±1.

Regarding kidney functions of group (I),blood urea ranged from 50 to 100 with a mean 69.9±14.8 and serum creatinine ranged from 3 to 9 with a mean 5.8±1.6.

 

2.            Neuropsychological results:

As regards MMSE, 66% of patients had abnormal results (score<24). While 68% , 70% , 72%, 74% , 76% and 77% had abnormal results in Trail A, Trail B, COWA, logical memory A and B and BDI respectively.

A statistically highly significant impairment was observed in Group I when compared to Group II regarding the results of all used psychometric tests (Table 1).

A positive correlation was found between HB level and scores in MMSE, COWA and Logical memory A, B and a negative correlation was found between HB level and scores in Color trail A, B. However, such correlations did not reach statistical significance.

A positive correlation was found between blood urea level and scores in Color trail B and BDI and a negative correlation was found between blood urea level and scores in MMSE and Logical memory A. However such correlations also did not reach statistical significance (Table 2).

Furthermore, a positive correlation was found between serum creatinine level and scores in BDI. However, such correlations did not reach statistical significance (Table 3).

Table 1. Results of neuropsychological tests in both groups.

 

Parameter	Group I		Group II		P-Value
	Range	Mean ± SD	Range	Mean ± SD
MMSE	(16-30)	22.4±3.7	(26-30)	29.1±1.2	0.001*
Color trail A	(75-128)	104.2±15.8	(39-85)	63.4±12.1	0.000*
Color trail B	(219-257)	239.2±9.9	(109-220)	165.8±33.5	0.001*
COWA	(3.4-8.9)	6.1±1.5	(7.9-15.9)	12.6±2.2	0.002*
Logical memory A	(2-8)	4.5±1.4	(6-12)	9.2±1.7	0.000*
Logical memory B	(2-8)	3.8±1.5	(6-11)	8.3±1.5	0.001*
BDI	(43-65)	52.4±4.6	(13-59)	33.8±11.9	0.000*

* significant at p<0.01

 

Table 2. Correlation between blood urea level and results of neuropsychological tests.

 

Blood Urea Level	R	P-Value
MMSE	-0.14	0.333
Color trail A	-0.18	0.901
Color trail B	0.02	0.896
COWA	0.17	0.234
Logical memory A	-0.19	0.174
Logical memory	0.01	0.928
BDI	0.28	0.051

Table 3. Correlation between serum creatinine and results of neuropsychological tests.

 

Serum Creatinine Level	R	P-Value
MMSE	0.28	0.049*
Color trail A	-0.19	0.192
Color trail B	-0.09	0.530
COWA	0.36	0.011
Logical memory A	0.01	0.937
Logical memory B	0.03	0.817
BDI	0.14	0.348

* significant at p<0.05

 

 

Discussion

 

Whether  cognitive dysfunction in CKD is a result of renal disease factors (i.e. metabolic disturbances) or due to the effects of other co-morbid conditions associated with this illness is poorly understood^7,8,17. The aim of the current study was to characterize the pattern of cognitive functioning of adults with CKD and comparing it to age and education matched healthy controls.

In the present study all subjects were less than 55 years old to minimize the effect of aging on cognition.

In the current study, nearly 70% of participants in the CKD group had global cognitive impairment. This ratio was higher than that reported by another who reported (15%) cognitive impairment¹⁸. The discrepancy could be explained by differences in the sensitivity of the measures employed and differences in the demographic characteristics of participants between studies.

In our study, 68% of our patients had impairment of executive functions as measured by trail making test. The same study found that 38% of patients had impairment of executive functions¹⁸.

Furthermore, significant memory impairment was confirmed in our hemodialysis patients when compared to control subjects as measured by logical memory test (76%) while the other study reported 33% of memory impairment as measured by verbal learning memory test. The discrepancy could be explained by differences of the measures employed¹⁸.

Overall, in our study on verbal learning and memory extend previous findings by suggesting that the pattern of memory impairment observed in patients with CKD does not appear to be consistent with an amnesic presentation characterized by rapid forgetting, but rather that memory problems in this population may be related to deficits in attention and executive functioning, such as the ability to organize information in ways that enhance learning and recall. In terms of executive functioning, patients with CKD demonstrated significant deficits in these abilities as indicated by worse performance on color trail A, B.⁸ As maintained above in this study, approximately 68% of adults with CKD met criteria for cognitive impairment on this measure.

One previous study using the mini mental state examination found that 30% of 336 hemodialysis patients aged 23 to 93 years had cognitive impairment⁸.Our study reported that 66% of patients had cognitive impairment using the MMSE.

Anemia has been linked with cognitive impairment in the general population and in persons with ESRD.¹⁹ Furthermore, in uncontrolled studies of patients receiving hemodialysis, amelioration of severe anemia with erythropoietin is associated with improvement in cognitive function^20,21. In addition, neurophysiological testing has shown improvement with the treatment of anemia in CKD.²² In this study, low hemoglobin levels were significantly correlated with cognitive impairment. Thus, it remains unclear whether anemia is a mediator or marker of other conditions, such as inflammation or nutritional deficiencies, which may contribute to cognitive impairment²³.

In our study, although there was a correlation of serum creatinine and blood urea with neuropsychological performance, we do not believe that these substances are neurotoxins per se. In a previous study comparing modality of dialysis delivery, patients on continuous ambulatory peritoneal dialysis (CAPD) had better cognitive function then hemodialysis patients despite having higher levels of serum creatinine²⁴. We, therefore, hypothesize that blood urea and creatinine are non-specific indicators of renal failure.

On the other hand, Seliger et al.⁷ suggested that CKD illness factors (i.e. metabolic disturbances) are linked to increased risk for developing dementia. Other findings suggest that metabolic disturbances may not be uniformly associated with deficits across cognitive domains. Decreased GFR was a significant predictor of poor performance in global cognition and delayed memory, but not of executive dysfunction¹⁸. However GFR was not included in our study due to technical difficulties.

The dialysis process may directly contribute to cognitive impairment by inducing cerebral ischemia²⁵.

Patients with CKD have a higher prevalence of subclinical cerebrovascular and traditional vascular risk factors including hypertension, diabetes mellitus and dyslipidemia than the general population²⁶. Non-traditional vascular risk factors including haemostatic abnormalities, hypercoaguable states, inflammation and oxidative stress may also be associated with cognitive impairment⁵.

The association of cognitive impairment or dementia and CKD may reflect long-term vascular disease burden manifested in two end organs, kidney and brain. This hypothesis is supported by two new cross-sectional studies demonstrating that albuminuria is associated with worse cognitive performance as well as increased white matter hyperintensity volume^27,28.

The fact that the CKD sample in this study consisted of participants with no histories of neurological impairments (e. g. stroke), major psychiatric illnesses, sensory impairments (e. g. visual), etc., can be considered a limitation as this may limit the generalizability of findings to the larger population of adults with CKD. However, this possibility would only suggest that the current findings underestimate the extent of cognitive difficulties in a larger population with a higher risk burden for cognitive impairment.

 

Conclusion

Cognitive impairment, in the form of executive dysfunction, memory and verbal learning impairment, is common and under-diagnosed in chronic kidney disease. Cognitive testing in hemodialysis patients before dialysis initiation and periodically are recommended.

 

[Disclosure: Authors report no conflict of interest]

 

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