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NDT Advance Access originally published online on October 5, 2006
Nephrology Dialysis Transplantation 2007 22(2):440-444; doi:10.1093/ndt/gfl572
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cognitive impairment in chronic kidney disease

Pankaj Madan1, Om P. Kalra2, Sunil Agarwal2 and Om P. Tandon2

1Department of Medicine, Baylor College of Medicine, Houston, USA and 2Department of Medicine, University College of Medical Sciences and GTB Hospital, Delhi, India

Correspondence and offprint requests to: Pankaj Madan, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Email: pankajmadaan{at}rediffmail.com



   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Background. Although end-stage renal disease (ESRD) has been associated with cognitive impairment, the relation between lesser degrees of chronic kidney disease (CKD) and cognitive impairment is less well understood. The objective of this study was to assess the cognitive function in patients with varying severity of CKD using P3 event-related potentials (P3ERPs).

Methods. In this cross-sectional study, 15 neurologically asymptomatic (Mini Mental State Examination >24) patients each of CKD stage 3, 4 and 5 (undialysed) were enrolled. Besides this, 15 healthy controls were also studied. All groups were age and sex matched. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease equation. The P300 was studied in all subjects by using standard auditory ‘odd-ball’ paradigm and the data obtained were statistically analysed.

Results. We noted significant prolongation of P300 latencies as severity of CKD increased from stage 3 (318.8 ± 28.98 ms) to stage 4 (357 ± 24.65 ms) (P < 0.002) and from stage 4 to 5 (388.47 ± 31.67 ms) (P < 0.01). P300 latency in CKD stage 3 was not found to be significantly different from controls (308.4 ± 13.73 ms). Significant positive correlation was noted between serum creatinine, blood urea and uric acid with P3 latency. Significant negative correlation was noted between GFR, serum calcium and haemoglobin with P3 latency.

Conclusions. Increasing severity of CKD is associated with progressive cognitive decline and this may have important clinical consequences.

Keywords: chronic renal failure; cognitive function; event-related potentials



   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
Cognitive impairment is highly prevalent in end-stage renal disease (ESRD) patients when compared with the general population [1,2]. Deficits in a number of spheres of cognition, including concentration, memory and planning may impair a person's capability to participate in ESRD care, such as dietary modification and medication compliance, and to understand the rationale and to provide informed consent for medical procedures [2,3].

Two broad classes of tests can be used to assess cognitive function. Neuropsychological tests, e.g. Trail Making Tests A and B (TMTA and TMTB), Symbol Digit Modalities Test (SDMT), California Verbal Learning Trial (CVLT), etc. use validated questions and screening tests to evaluate cognition. Neurophysiological tests use electrophysiological methods, e.g. electroencephalogram and event-related potentials (ERPs) to assess cognitive dysfunction [4]. Performance on cognitive function is provided by assessment of cognitive ERP. In the prototypical ERP trace, the most prominent and most studied is the P3 (or P300, the third positive wave, or the wave with a 300 ms latency) (Figure 1). The P3 wave is evoked by a task known as the odd-ball paradigm. The latency of the P3 corresponds to the speed of cognitive processing and memory [5,6] and the amplitude of P3 varies with the attention, on the relevancy of the task or with stimulus novelty [7]. Prolongation of P3 latency has been shown to be the earliest sign of cognitive dysfunction in metabolic encephalopathies [8]. Thus, these ERPs may be a more sensitive and useful quantitative method than neuropsychological tests to assess cognitive function.


Figure 1
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  		Fig. 1. A prototypical ERP trace.

 
Cognitive decline in chronic kidney disease (CKD) can be caused by various factors such as uraemic encephalopathy, complications of dialysis procedure, high prevalence of clinical and subclinical cerebrovascular disease and various comorbidities (anaemia, hypertension, diabetes, malnutrition, etc.) afflicting these patients [9]. However, our study focuses on the cognitive dysfunction caused by uraemia per se. In order to study the effect of declining renal function on cognitive function, other potential causes of cognitive decline in CKD have been excluded.

ERPs have been used to study the effects of haemodialysis on ESRD patients [10–13]; however, on detailed search of relevant literature, we could not come across any study that has assessed the cognitive function by P3ERPs in earlier stages of CKD. The objective of this study was to assess the cognitive function in patients with varying severity of CKD by using P300 ERPs (P3ERPs).



   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
Subjects
The study population included 45 stable patients of CKD. Staging of CKD was done as per the criteria given by National Kidney Foundation, USA (K-DOQI), using Modification of Diet in Renal Disease (MDRD) equation [14] for calculation of glomerular filtration rate (GFR). Patients in the age group 21–50 years with CKD were recruited from the renal clinic and medical wards of our hospital for the study. Besides this, age- and sex-matched healthy controls were also studied. Age matching was done within every subgroup of 5 years. Informed consent was taken from all study subjects. The subjects were divided into four groups: group A (n = 15), age- and sex-matched healthy controls, group B (n = 15), CKD stage 3, group C (n = 15), CKD stage 4 and group D (n = 15), undialysed patients of CKD stage 5.

The various diseases causing CKD in the patients were chronic glomerulonephritis (n = 26), hypertensive nephrosclerosis (n = 9), chronic interstitial nephritis (n = 8) and autosomal dominant polycystic kidney disease (n = 2). It may be mentioned at this stage that patients with diabetic nephropathy as a cause of CKD were excluded from the present study. Besides this, patients were excluded from the study if they had primary neurological or psychiatric disorder, hepatic disease, dyselectrolytaemia, ingested alcohol during the preceding 1 month, consumed centrally acting drugs, overt cognitive dysfunction [Mini Mental State Examination (MMSE) ≤24], accelerated hypertension, severe anaemia (Hb <7 gm/dl), known myocardial infarction/unstable angina, hearing impairment, active collagen vascular disorders or vasculitis requiring use of cytotoxic drugs or steroids (at doses greater than 10 mg prednisone/day), evidence of protein malnutrition (serum albumin <3.5 g/dl) or were on treatment with recombinant human erythropoietin (to exclude its effects on P3ERPs).

An MMSE, allowing an estimate of cognitive function, was performed to exclude patients with significant impairment (scoring ≤24); however it was not used to monitor mental changes in patients due to its low sensitivity [15].

Testing procedure
The P3ERPs were measured in all subjects using the MEB-9100 Version 0.3-0.6 Neuropack µ (Nihon Kohden, Japan). The P300 was recorded with Ag/AgCl disc electrodes placed at standard scalp locations of 10–20 international system. The active electrodes were placed at Fz and Pz, with reference electrodes at A1 and A2 positions. The ground electrode was placed at Fpz site. The skin-electrode contact impedance was kept below 5 {Omega}. The P300 wave was elicited by delivering the standard auditory ‘odd-ball paradigm’ binaurally. The frequent tones (80%) and the rare tones (20%) were set at 1 and 2 kHz, respectively (Intensity 70 dB, rise fall time 10 ms, plateau 100 ms). Stimulus sequence was in random order, and the signals were in phase at the two ears. The patient was asked to respond to the rare tone by pressing the button. The recorder settings were properly selected and evoked responses to the frequent and rare stimuli, filtered with a band pass 0.1–50 Hz and averaged simultaneously for 30 responses. Data obtained were stored, analysed and averaged by the computer. The latency and amplitude of P300 from target stimulus (rare) was calculated. The latencies of N1, N2, P2 and P3 were recorded. In addition, amplitudes of waves N1-P2, P2-N2 and N2-P3 were also recorded.

Data analysis
The data were analysed by using SPSS 13 statistical software. The differences between the groups were compared by using one-way ANOVA (two tailed). For significant ANOVAs, Tukey post hoc test was applied to ascertain significance of each group with the other groups. We also performed correlation analysis using Pearson correlation coefficient between haemoglobin, serum creatinine, uric acid, calcium and blood urea levels with amplitude and latency of P3 wave. P-values <0.05 were considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
Demographic characteristics and mean laboratory values are presented in Table 1. By design, there were no significant differences in age and sex distribution between various groups. Each group had 10 males and 5 females.


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  		Table 1. Demographic and laboratory parameters amongst various stages of CKD

 
Auditory event-related potentials
Table 2 shows findings of auditory ERPs in the 60 subjects. There were no significant differences between all the groups as far as latencies of N1, P2 and N2 and amplitudes of N1-P2, P2-N2 and N2-P3 were concerned. The only significant differences were noted for P3 latencies.


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  		Table 2. Electrophysiological studies in patients of chronic kidney disease

 
Latency of P3 component
Table 2 shows an incremental trend in P3 latencies as the severity of CKD increases. However, the differences in P300 latency between the controls and CKD stage 3 were not found to be statistically significant (P = 0.69). The P300 latencies in CKD stage 4 (P < 0.001)) and CKD stage 5 (undialysed) (P < 0.001) were significantly prolonged when compared with the controls. The P300 latencies of CKD stage 4 (P < 0.002) and CKD stage 5 (undialysed) (P < 0.001) were also significantly higher than CKD stage 3. The P300 latency showed a significant increase from CKD stage 4 to CKD stage 5 (P < 0.01).

Correlations of P3ERPs with some laboratory parameters
Intercorrelations between P3 latencies and amplitudes and the values of haemoglobin, blood urea, serum creatinine, calcium and uric acid were assessed (Table 3). There was a significant positive correlation of serum creatinine, blood urea and uric acid with P3 latency. Significant negative correlation was noted between GFR, serum calcium and haemoglobin with P3 latency. There was no correlation of these laboratory parameters with amplitude of P3 wave.


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  		Table 3. Correlation of P3 latency and amplitude with laboratory parameters

 


   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
The subjects recruited in the present study had no overt cognitive dysfunction (by design those with MMSE score <24 had been excluded). However, on neurophysiological testing, P300 latency was significantly prolonged in CKD stage 4 and CKD stage 5 (undialysed) when compared with controls. These data indicate that there is a deficit in cerebral cognitive function in uraemic patients even in clinically asymptomatic stages, thus highlighting the sensitivity of ERPs in assessing cognitive dysfunction even when it is not clinically apparent. Prolongation of P300 wave latency was noted to be the earliest and most evident sign of cognitive dysfunction in chronic liver disease and chronic renal failure by Ruzicka et al. [8].

Our data indicate a graded decline in cognitive function associated with increasing severity of CKD from stage 3 to 4 and stage 4 to 5 (undialysed). In this study, many comorbid conditions common in CKD patients (such as coronary artery disease, stroke, diabetes, severe anaemia, malnutrition, uncontrolled hypertension, etc.), which could contribute to cognitive dysfunction, had been carefully excluded. Thus, we feel that there exists a real association between the decreased kidney function and cognition. Since the P300 latencies of CKD stage 3 patients were similar to those of controls, it may imply that patients with GFR >30 ml/min/1.73 m2 may be free of cognitive dysfunction provided they do not have other comorbidities. On searching the available literature, we found no study that has assessed cognitive function in earlier stages of CKD by electrophysiological methods. Kurella et al. [16] have evaluated cognitive function using neuropsychological tests (TMTB, CVLT and MMSE) in patients not requiring haemodialysis (CKD stages 3 and 4); however they did not conduct electrophysiological tests. The patients not requiring haemodialysis fared worse than controls in TMTB and CVLT. The patients of CKD stages 3 and 4 were taken as a single group in this study. The results of this study support our findings that decreased kidney function is associated with decreased cognition.

Although there was a significant positive correlation of serum creatinine, blood urea and uric acid with P3 latency, 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 haemodialysis patients despite having higher levels of serum creatinine [17]. Moreover, patients with uncomplicated gout do not have apparent cognitive dysfunction in spite of higher levels of uric acid [18]. We also know from previous studies that in patients on maintenance dialysis, no correlation has been seen between various biochemical values and electrophysiological indices [17]. We, therefore, hypothesize that blood urea and creatinine are non-specific indicators of renal failure and are surrogate markers of putative neurotoxin(s) accumulating in patients of CKD who are undialysed. We noted a significantly negative correlation between haemoglobin and P3 latency. Anaemia is an important risk factor for cognitive impairment in ESRD patients on haemodialysis. Cognitive function has shown improvement after an increase in haemoglobin level with erythropoietin therapy in haemodialysis patients [19,20]. It remains to be seen whether amelioration of anaemia can produce similar effects in earlier stages of CKD.

In summary, increasing severity of CKD is associated with graded decline in cognitive function. Additional large-scale studies are required to confirm the association described here, and to elucidate the various factors causing cognitive dysfunction in these patients. Various strategies need to be devised and evaluated for amelioration of cognitive dysfunction in CKD.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

  1. Fazekas G, Fazekas F, Schmidt R, et al. (1995) Brain MRI findings and cognitive impairment in patients undergoing chronic hemodialysis treatment. J Neurol Sci 134:83–88.[CrossRef][Web of Science][Medline]
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  8. Ruzicka E, Tesar V, Jelinkova E, Mmerta M, Nevsimalova S, Kucerova O. (1993) Event related potentials in evaluation of metabolic encephalopathies. Scheweiz Arch Neurol Psychiatr 144:378–384.
  9. Pereira AA, Weir DE, Scott T, Sarnak MJ. (2005) Cognitive function in dialysis patients. Am J Kidney Dis 45:448–462.[CrossRef][Web of Science][Medline]
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Received for publication: 10. 8.06
Accepted in revised form: 28. 8.06


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