Attention and information processing in end stage renal disease and effect of hemodialysis: a bedside study

Abstract

The neurobehavioral syndrome of uremia in chronic kidney disease affects the functioning of the central nervous system. Cognitive impairment is one of the most important manifestations of this dysfunction. The process of hemodialysis is known to bring about conflicting changes in the cognitive status of patients. In the present study an assessment of cognitive status of patients with end stage renal disease was done in comparison to controls before and after a session of hemodialysis using simple bedside paper-pencil tests. Thirty patients of end stage renal disease on maintenance dialysis for at least one month with MMSE score >24 were assessed one hour before and one hour after hemodialysis using Digit Symbol Substitution Test, One Letter and Three Letter Cancellations tasks. Their results were compared to age and sex matched healthy controls. The patients with end stage renal disease had significantly lower performance in cognitive tests in comparison to controls. The performance improved 1 hour after hemodialysis in comparison to pre-dialysis values. However, the values after dialysis were significantly lower than in controls, thereby indicating that though the cognitive functions improved after hemodialysis, they did not reach the control levels. There was also a significant change in the biochemical parameters after dialysis. We conclude that patients with end stage renal disease suffered from cognitive impairment which improved on hemodialysis due to removal of metabolic waste products.

• Attention
• cognition
• end stage renal disease
• hemodialysis
• information processing

Introduction

Chronic kidney disease (CKD) is a public health problem varying in severity from asymptomatic to end stage renal disease (ESRD) requiring hemodialysis. Patients with ESRD are known to have intellectual impairment, reduced attention, deficits in memory and other cognitive functions.1,2 Various mechanisms have been proposed for the decline in cognitive abilities in ESRD. Hypertension, diabetes, cardiovascular diseases are believed to be the major category of vascular risk factors contributing towards cognitive impairment.3–5 Anemia is considered to be an important contributing factor and its treatment has shown improvement in cognitive functions.6 Depression and sleep disturbances are common in patients with CKD and affect cognitive testing.7,8

Diagnosis of cognitive impairment is important as patients suffering from it are unable to adhere to medications or dialysis regimes, require more specialized care and hence increase the burden on health resources. Also cognitive impairment and dementia are associated with increased risk of death in dialysis patients.9

Cognitive functions can be assessed using computerized and paper-pencil neuropsychological tests and electrophysiological tools like evoked potentials. The advantage of computerized neuropsychological tasks is that, they can be easily programmed and pick up even subtle changes in performance. However, they are expensive and difficult to administer in hospital settings. The paper-pencil tasks are not only economical methods of evaluating the cognitive changes, but also have the advantage of easy administration that can be done even at patient bedside.

Previous studies done on ESRD patients have reported a decline in cognitive abilities. Madan et al. evaluated the cognitive functions in patients with varying severity of CKD using P300.10 They found that cognitive functions declined progressively with increasing severity of CKD. In another study they assessed the effect of hemodialysis on cognitive functions using P300 event related potential and found a prolongation of latency of P300 in patients with ESRD in comparison to controls, thereby indicating a decline in cognitive functions in patients.11 However, hemodialysis failed to bring about any significant change in the latencies of P300, thereby indicating that it did not improve cognitive functions.

Murray et al. assessed the cognitive functions in patients on hemodialysis for at least 2 months.12 Out of their 338 hemodialysis patients, 37% were in a state of severe cognitive impairment. They found that duration of hemodialysis for more than two years, Hb <11.0 gm/dL and history of stroke were more likely to be associated with severe cognitive impairment. The authors did not find association with age, depression and time of testing during dialysis cycles.

Vos et al. used a battery of tests to assess speed of information processing, memory, executive functions and attention in patients on short daily hemodialysis and on conventional thrice weekly hemodialysis.13 They found that there was difference in the performance of both groups across the four domains of cognitive functions.

Pliskin et al., in their study, used a battery of neuropsychological tests to assess intelligence, memory, mental, processing speed, language, motor abilities, complex problem solving and depression in hemodialysis patients.14 They found a reduced mental processing speed in the cases compared to that observed in controls. All the other cognitive abilities showed similar results in cases and controls.

Jassal et al. evaluated attention and working memory, psychomotor efficiency and processing speed and learning efficiency of patients with CKD and observed15 that psychomotor efficiency and processing speed were affected more than attention or working memory. In their study, Figueiredo et al. assessed 28 patients on chronic hemodialysis and found decreased cognitive and psychomotor performance with a reduced ability to learn novel procedures.16 Williams et al. in their study found that patients on hemodialysis had fluctuations in cognitive performance.17 They used a neuropsychological battery at 1, 24 and 67 h after hemodialysis to assess cognitive performance and reported maximum impairment at 67 h after hemodialysis session.

A thorough literature search revealed conflicting evidence regarding the cognitive changes following hemodialysis. In this study we assessed the cognitive functions using paper-pencil tasks, before and after a session of hemodialysis. Paper-pencil tasks were used instead of the computerized versions as the subject population was unfamiliar with the use of computers and was not comfortable using them.

Materials and methods

Thirty patients (age group 18–60 years) of end stage renal disease on maintenance hemodialysis for at least one month were recruited for the study. Thirty age- and sex-matched controls were also recruited. The study was approved by the Institute Ethical Committee and written informed consent was taken from all the participants. The exclusion criteria of the patients included neurological or psychiatric disease, electrolyte imbalance, severe anemia (<7 g%), history of myocardial infarction, diabetes mellitus, accelerated hypertension, chronic alcoholism, any evidence of infection, for example, urinary tract infection etc. and any history of narcotic abuse.

The causative factors for ESRD in patients were chronic glomerulonephritis (n = 19) and chronic interstitial nephritis (n = 11). The patients were subjected to Hamilton Rating Scale for Depression and those found depressed, were excluded from the study. The patients abstained from nicotine and caffeine for at least 12 h before the test.

Tests

The following tests were done on all the patients one hour before and an hour after a single session of hemodialysis.

1. Mini Mental State Examination: Both patients and controls were assessed by MMSE. Only those patients who had a MMSE score of >24 were recruited for the study.

2. Neuropsychological tests:

   1. Digit symbol substitution test

   2. Letter cancellation task

3. Digit symbol substitution test: Digit symbol substitution task18,19 was used to assess the speed of information processing wherein the subjects had to replace number with symbols. Along with mental processing speed, it evaluated the visuomotor coordination and motor persistence.

The test consisted of numbers (1–9) arranged randomly in 4 rows of 25 squares each. The subjects substituted each number with a symbol using a number-symbol key given on each page. The time taken to complete the test along with the number of correct responses, errors and omissions was noted.

1. Letter cancellation tasks: Letter cancellation tasks19,20 were used to assess the attention of the subjects and involved cancelling out one or more letters printed amongst a matrix of other letters. A one and three letter cancellation task was used to assess attention. In the One letter cancellation task (1-LCT), the subjects were asked to cancel out Letter “A”. In the Three letter cancellation task (3-LCT), the subject cancelled out “A”, “Q” and “T”. In both the cancellation tasks, the time taken to complete the test along with the number of correct responses, errors and omissions was noted. In one letter cancellation task, 240 “A” were to be cancelled out, whereas in the three letter task, 80 each of “A”, “Q” and “T” (with total of 240) were to be cancelled. The three letter cancellation task exerted an additional load on the attentional resources of the brain and hence we also evaluated the effect of task complexity on cognitive functions.

Data analysis

The data obtained was analyzed using SPSS 17. Unpaired t test with Bonnferroni correction was applied to compare the data between controls & pre-dialysis state and controls & post-dialysis state. The pre- and post-dialysis states were analyzed using paired t test.

Results

There was no significant difference in the age group of controls (30.7 ± 8.8 years) and patients (31.2 ± 9.5 years).

Mini mental state examination

The controls had MMSE score of 29.6 ± 0.5, which was significantly more (p < 0.025 using Bonnferroni correction) than that of patients in pre-dialysis (score of 25.8 ± 2.2) and post dialysis (26.5 ± 1.6) state. Hemodialysis led to a significant improvement (p < 0.01) in patients in post-dialysis state compared to the pre-dialysis state.

Digit symbol substitution task (Table 1)

The time taken to complete the DDST was significantly more for pre-dialysis (p < 0.025 using Bonnferroni correction) and post-dialysis (p < 0.025 using Bonnferroni correction) in comparison to controls. However, in the post-dialysis state, the time taken was significantly less (p < 0.001) in comparison to pre dialysis state. There was no significant difference in the number of correct responses, errors and omissions between the controls and the patients.

Table 1. Digit symbol substitution task.

		Patients
	Controls	Pre-dialysis	Post-dialysis
Time for completion (in s)	272.9 ± 35.8	353.0 ± 71.5#	339.6 ± 71.2*,^
Correct responses	99.8 ± 0.6	98.9 ± 2.7	99.3 ± 1.6
Errors	0.2 ± 0.6	1.0 ± 2.7	0.7 ± 1.6
Omissions	0	0.13 ± .34	0.03 ± .18

Notes: #p < 0.025 (using Bonnferroni correction) for analysis between controls and pre-dialysis.

*p < 0.001 for analysis between pre and post dialysis.

^p < 0.025 (using Bonnferroni correction) for analysis between controls and post-dialysis.

One letter cancellation task (Table 2)

Analysis of data revealed that the controls took significantly shorter time (p < 0.025 using Bonnferroni correction) than the pre-dialysis state to complete the 1-LCT. However, after dialysis there was no significant difference in the performance of controls and patients. In the post-dialysis state the time taken to complete the 1LCT was significantly less than in the pre-dialysis state (p < 0.001). There was no significant difference in the number of correct and error responses between the controls, pre-dialysis and post-dialysis states. However, the controls had significantly less number of omissions when compared to pre-dialysis and post-dialysis states (p < 0.025 using Bonnferroni correction).

Table 2. One letter cancellation task.

		Patients
	Controls	Pre-dialysis	Post-dialysis
Time for completion (in s)	301.0 ± 28.4	372.7 ± 85.4#	329.0 ± 63.0*
Correct responses	251.5 ± 3.5	247.1 ± 11.5	249.4 ± 11.5
Errors	0.4 ± 1.1	2.5 ± 7.0	0.5 ± 1.2
Omissions	2.0 ± 2.3	8.8 ± 11.3#	5.8 ± 6.0^

Notes: #p < 0.025 (using Bonnferroni correction) for analysis between controls and pre-dialysis.

*p < 0.001 for analysis between pre and post dialysis.

^p < 0.025 (using Bonnferroni correction) for analysis between controls and post-dialysis.

Three letter cancellation task (Table 3)

The patients in both pre-dialysis and post-dialysis states took significantly (p < 0.025 using Bonnferroni correction) more time than the controls to complete the task. The time taken in the post-dialysis state was significantly shorter (p < 0.001) than in the pre-dialysis state. An analysis of the number of correct responses and omissions revealed significantly (p < 0.025 using Bonnferroni correction) more correct and less omissions for the controls in comparison to the patients in pre-dialysis and post-dialysis. The patients did not have a significant difference in the number of correct responses, errors and omissions.

Table 3. Three letter cancellation task.

		Patients
	Controls	Pre-dialysis	Post-dialysis
Time for completion (in s)	266.0 ± 32.6	437.4 ± 79.4#	414.6 ± 73.5*,^
Correct responses	253.3 ± 2.6	237.6 ± 12.2#	241.3 ± 7.0^
Errors	1.1 ± 1.3	2.4 ± 6.4	1.2 ± 1.2
Omissions	1.6 ± 1.9	11.2 ± 10.5#	8.0 ± 6.9^

Notes: #p < 0.025 (using Bonnferroni correction) for analysis between controls and pre-dialysis.

*p < 0.001 for analysis between pre and post dialysis.

^p < 0.025 (using Bonnferroni correction) for analysis between controls and post-dialysis.

The biochemical parameters showed a significant change in the post dialysis state in comparison to the pre-dialysis state (Table 4).

Table 4. Biochemical parameters.

	Pre-dialysis	Post-dialysis
Serum Na^+ (meq/L)	133.8 ± 1.85	136.27 ± 2.20***
Serum K^+ (meq/L)	4.78 ± 0.98	3.45 ± 0.22***
Blood urea (mg/dL)	170.10 ± 8.12	117.89 ± 20.65***
Serum creatinine (mg/dL)	8.24 ± 0.85	6.88 ± 0.87***
Serum HCO3^− (mg/dL)	24.51 ± 1.80	28.14 ± 1.81***

Note: ***p < 0.001.

Discussion

The present study evaluated the cognitive functions in end stage renal disease patients before and after a session of hemodialysis. The results revealed that on general assessment of cognition, the patients had lower scores of cognitive functions in both pre and post-dialysis states in comparison to controls. Hemodialysis led to an overall improvement in cognitive functions as was revealed by the significant change in MMSE score after dialysis. Since the aim of the present study was not to find the percentage of patients with ESRD having dementia, we had excluded patients with MMSE score of ≤24.

The results revealed that the patients had significantly slower speed of information processing in comparison to controls, as was evident from the time taken to complete the Digit Symbol Substitution task. Hemodialysis led to an improvement in the mental processing speed as the patients took significantly less time to complete the task after a session of hemodialysis in comparison to pre-dialysis. However, the time was significantly more than that of controls, thereby indicating that patients on hemodialysis have cognitive impairment that persists even after a session of hemodialysis.

The data showed that the patients in pre-dialysis state had significantly less attention in comparison to controls as was revealed by the time taken to complete the letter cancellation tasks. Hemodialysis led to a significant improvement in the attention of patients. In the post dialysis state, the attention was affected by task complexity as the time taken to complete three letter cancellation task was significantly more in post dialysis in comparison to controls but the same was not the case with one letter cancellation task.

Our findings of decreased MMSE scores in ESRD patients is similar to that of Nulsen et al., who reported a mean MMSE score of 26.8 in patients.21 Kurella et al. also reported lower scores of patients with CKD using modified Mini Mental State Examination.22 Murray et al. found that out of 338 patients on hemodialysis, 37% had cognitive impairment.12 Folstein et al. used MMSE and reported that 30% of patients on hemodialysis had mild to severe cognitive impairment.23 Thus our findings of decreased cognitive abilities using MMSE are in agreement with known literature.

Jassal et al. in their study found that CKD was associated with decline in psychomotor efficiency, a finding similar to ours.15 However, they did not report any change in attention in patients with CKD. They used DSST to assess psychomotor speed and Digit Span and Spatial span tests for attention. The probable reason for difference of results in their study and ours is the presence of comorbidities like depression in their sample.

Madan et al. evaluated the cognitive functions in patients on hemodialysis using event related potentials.11 They found an increase in P3 latencies (an indicator of speed of information processing) in pre-dialysis state when compared to controls. However, 2 h after dialysis, there was no significant difference between the latencies of patients and controls. They did not comment on the changes in latencies between pre and post-dialysis. Madan et al. believed that the improvement in latencies and hence cognition was probably due to removal of uremic toxins following dialysis.

Vos et al. in their study used Digit Symbol test as one of the tests for assessing speed of information processing and cancellation test for evaluating attention in patients on short-term hemodialysis and conventional hemodialysis.13 They found no significant difference in speed of information processing and attention and inferred that the type of hemodialysis had no effect on cognitive functions.

Some studies have, however, shown that dialysis led to acute intravascular volume loss and fluid shifts thereby causing edema and decreased intracerebral blood pressure and cerebral perfusion.24,25 This in turn could contribute to cognitive impairment seen in hemodialysis.

We believe that the improvement in cognitive functions in our patients on hemodialysis was probably due to removal of toxic substances. The improvement was evident as early as 1 h after hemodialysis session. Another factor that may have contributed to the improvement was the fact that most of our patients were recently started on hemodialysis, with the possibility of less impact altered cerebral perfusion on cognition. We also tried to exclude patients with co-morbid conditions, thereby removing the contribution of these conditions to cognitive impairment.

Declaration of interest

The authors thank Indian Council of Medical Research (ICMR) STS programme for funding this work. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

The authors also thank Dr. Vijaya Lakshmi, Dept. of Physiology, UCMS for valuable help during the course of this study.