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Differential impact of age on verbal memory and
executive functioning in chronic kidney disease
WENDY LOKEN THORNTON,
1
R. JEAN SHAPIRO,
2
SIRAD DERIA,
1
SHANNON GELB,
1
and AMANDA HILL
2
1Department of Psychology, Simon Fraser University, Burnaby, British Columbia, Canada
2Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
(Received June 21, 2006; Final Revision October 16, 2006; Accepted October 20, 2006)
Abstract
We compared aspects of verbal memory and executive functioning in 51 community-dwelling persons with chronic
kidney disease (CKD) and 55 healthy controls matched on age and education. Depressive symptoms were assessed
with the Centre for Epidemiological Studies-Depression Scale (CES-D), and illness variables included glomerular
filtration rate (GFR) and hemoglobin. Findings indicate that persons with CKD exhibited poorer performance on
measures of memory (CVLT-II) and executive functioning (DKEFS Trailmaking Test B and Color-Word
Interference Tests) in comparison with healthy controls. Furthermore, per formance decrements were magnified in
older CKD participants on measures of verbal memory and inhibition. Nearly half of CKD participants aged 61 and
older exhibited significant impairments in verbal memory and inhibition in comparison to matched controls.
Cognitive per formance in CKD was not associated with measures of illness severity. The differences observed were
not accounted for by depressive symptoms, which were only weakly associated with cognitive per formance, and
negatively associated with age. Findings highlight the need for further exploration of the etiologies and functional
consequences of the neuropsychological presentation of CKD. ( JINS, 2007, 13, 344 –353.)
Keywords: Cerebrovascular disorders, Memory, Cognition, Kidney diseases, Aging, Neuropsychology, Dementia
INTRODUCTION
Chronic Kidney Disease (CKD) is an increasingly common
illness of mid to late adulthood, with an estimated 11% of
adults in the United States affected (Coresh et al., 2003).
The term CKD is used to describe a decrease in renal func-
tion caused by kidney damage, and this illness is typically
managed on an outpatient basis with strict dietary and med-
ication regimens (Levey et al., 2003). Left untreated, CKD
results in the gradual development of renal failure and ure-
mia secondary to the accumulation of neurotoxins and reduc-
tions in metabolic rates (Burn & Bates, 1998). Estimated
glomerular filtration rate (GFR) is considered the best over-
all indicator of level of kidney function, with lower GFR
levels indicating a decrease in the overall number and0or
filtration rate of the kidney nephrons (Levey et al., 2003).
Renal failure eventually results when GFR drops consis-
tently below 15 mL0min per 1.73 m
2
and requires replace-
ment therapy such as dialysis. It is well-documented that
persons with end stage renal disease (ESRD) undergoing
hemodialysis are at considerably higher risk for cognitive
impairment than their age peers, and this has been linked to
metabolic derangements and cerebrovascular diseases asso-
ciated with renal failure (Burn & Bates, 1998; Fazekas et al.,
1996; Fazekas et al., 1995; Kurella et al., 2004; Lass et al.,
1999; Pereira et al., 2005). Those studies that have not
reported cognitive declines in ESRD have likely been lim-
ited by reliance on cognitive screening instruments (Maugeri
et al., 1999), and small samples ( Pliskin et al., 1996; Umans
& Pliskin, 1998).
Despite the fact that the prevalence of the earlier stage of
CKD is more than 100 times greater then that of ESRD
(Collins et al., 2003; Levey et al., 2003), neuropsycholog-
ical functioning in CKD has been virtually ignored to date.
In fact, several factors lead to the prediction that CKD may
be associated with exceptionally high risk for cognitive
impairment even before the development of renal failure.
Diabetes mellitus (Type II adult onset) and hypertension
Correspondence and reprint requests to: Wendy Loken Thornton, Ph.D.,
Department of Psychology, Simon Fraser University, 8888 University Drive,
Burnaby, B.C. V5A 1S6, Canada. E-mail: wthornto@sfu.ca
Journal of the International Neuropsychological Society (2007), 13, 344–353.
Copyright © 2007 INS. Published by Cambridge University Press. Printed in the USA.
DOI: 10.10170S1355617707070361
344
are the leading causes of CKD (Coresh et al., 2003; Levey
et al., 2003). Both of these illnesses have been indepen-
dently associated with development of cerebrovascular dis-
ease (Carmelli et al., 1999; Novak et al., 2006; Raz et al.,
2003), reductions in memory and executive functioning
(Knopman et al., 2001; MacKnight et al., 2002; Perlmuter
et al., 1984; Raz et al., 2003; Saxby et al., 2001), and accel-
erated cognitive decline in late middle-age and older adult-
hood (Hassing et al., 2004; MacKnight et al., 2002; Ott
et al., 1999; Posner et al., 2002). Thus, whereas underlying
cerebrovascular disease is recognized as contributing to the
cognitive presentation of ESRD (Pereira et al., 2005), it is
likely that these effects may emerge earlier in the disease
course as well. Other potential risks for cognitive dysfunc-
tion associated with CKD include elevated levels of homo-
cysteine ( Reutens & Sachdev, 2002), and anemia caused by
decreased production of erythropoietin (Pliskin et al., 2001).
To date, only a few studies have attempted to character-
ize cognitive functioning in persons with CKD. In a cross-
sectional comparison of persons with CKD and persons with
ESRD on hemodialysis, findings suggested a graded rela-
tion between cognitive function and severity of renal dis-
ease, with ESRD participants performing worse than those
with CKD, and persons with CKD performing worse than
published neuropsychological norms on measures of verbal
memory and executive functioning (Trails B; Kurella et al.,
2004). Nonetheless, the inclusion of participants with overt
CNS pathologies confounds the etiology and significance
of the findings. For example, 28% of the CKD sample had
a history of stroke, which may be independently associated
with significant and lasting neuropsychological impair-
ments (Desmond et al., 1999). Similarly, a recent study of
cognition in menopausal women with coronary artery dis-
ease and co-morbid CKD repor ted reductions in neuropsy-
chological performance associated with worsening renal
functioning (Kurella et al., 2005). Whereas these findings
may suggest that specific subgroups of persons with CKD
may be at risk for cognitive impairments, the significance
for the larger CKD population without overt neurological
co-morbidities remains unknown. Furthermore, the restricted
age ranges employed has limited the strength of the conclu-
sions that can be drawn to date. If cerebrovascular disease
contributes toward the cognitive presentation of this ill-
ness, one may expect that the reported reductions in mem-
ory and executive function in CKD may be differentially
exacerbated with increasing age (Hassing et al., 2004; Mac-
Knight et al., 2002).
To address these issues, we assessed cognitive function-
ing in a consecutive outpatient sample of persons with CKD,
and compared their performance with that of healthy con-
trols drawn from the same community. Given previous asso-
ciations between memory0executive functioning and renal
disease, we examined these functions in a CKD sample that
did not have overt CNS pathologies, such as stroke, that
may confound the cognitive presentation. Secondly, we
examined the roles of three potential variables predicted to
have a negative effect on cognitive performance in CKD,
increasing age, a higher number of depressive symptoms,
and increased metabolic derangement (i.e., estimated GFR
and hemoglobin). Toward these ends, we examined (a) the
bivariate associations between age, metabolic derange-
ment, and depressive symptoms in CKD participants, and
(b), the utility of age, health status, and their interaction in
predicting individual differences in verbal memory and exec-
utive functioning before and after controlling for depres-
sive symptoms.
METHODS
Subjects
We tested 51 consecutive outpatients (age 38–89), with a
current diagnosis of CKD who were referred to the Renal
Clinic at Vancouver General Hospital for treatment. Poten-
tial participants were considered to meet criteria for CKD if
they had an average estimated GFR ,60 mL0min 01.73 m
2
and were not receiving renal replacement therapy (i.e., hemo-
dialysis, peritoneal dialysis). Testing of CKD participants
was completed at the Renal Clinic between August 2003
and December 2005. Participants were considered eligible
for inclusion if they met the following criteria: (a) they
were fluent in the English language, (b) had completed a
minimum grade 6 education; and (c) had been followed by
the renal clinic for at least six months to ensure medical
stabilization of acute illness parameters. Participants were
ineligible if they had a history of other major illnesses with
known direct CNS effects (e.g., stroke, head injury, CNS
malignancies, and Parkinson’s disease), or had previously
identified cognitive impairments (e.g., diagnosis of demen-
tia). Additional exclusion criteria included diagnosi s of con-
current terminal illness, major psychiatric illness, or other
major organ failure (e.g., end stage liver disease). Because
of the visual nature of some tasks, we screened partici-
pants’ visual acuity, with the lower limit of corrected vision
set at 20050. Consecutive patients who met these criteria
were invited to participate during their regularly scheduled
clinic visit by a research coordinator. Recruitment success
was approximately 70%. Control participants were recruited
through local community centers and through university
staff union email lists, and were subject to the same exclu-
sion criteria. The study protocol was approved by both the
University of British Columbia and Simon Fraser Univer-
sity research ethics boards, and all participants signed
informed consents.
Measures
Measures were individually administered and scored by
trained research assistants according to standardized proce-
dures. Healthy controls were tested at community testing
sites (i.e., local libraries or community centers) or at the
Simon Fraser University Human Neuropsychology Labora-
tory. Participants received monetary compensation for their
time and travel expenses. Measures included:
Cognition in CKD 345
1. Vocabulary: An untimed multiple choice vocabulary test
was created by combining Vocabulary (V2) and Extended
Vocabulary (V3) from the ETS kit (Ekstrom et al., 1976).
2. Verbal Learning and memory functioning were mea-
sured with the California Verbal Learning Test-2 (CVLT-
II). The CVLT-II assesses learning over repeated trials,
susceptibility to memory interference, and delayed ver-
bal memory. The sum of performance across Trials 1–5
represents the total number of items learned across five
repetitions. Delayed recall on the CVLT-II provides an
estimate of information retained after a 20-minute delay
(Delis et al., 2000).
3. Executive functions were assessed with the Trailmaking
and Color-Word Interference subtests of the Delis-
Kaplan Executive Functioning System ( DKEFS; Delis
et al., 2001). For the Trailmaking test, Trails Test B (letter-
number sequencing) was used as an index of mental set
shifting. In addition to the commonly used versions of
this task, we also utilized the Motor Speed Trails task
(Delis et al., 2001), which requires participants to trace
a dotted line over the Trails path without the numbers or
letters present. We computed a “mental set shifting”
variable by subtracting an individual’s difference in psy-
chomotor speed from the Trails B total score. For the
Color-Word Interference test, we used the difference
between the Inhibition trial and the Color Naming trial
(aka “Stroop effect”) to assess cognitive inhibition abil-
ities while controlling for differences in reading speed.
4. Depressive symptoms were assessed with the Centre for
Epidemiological Studies-Depression Scale (CES-D; Rad-
loff, 1977).
5. A measure of Instrumental Activities of Daily Living
(IADL’s) was included (Lawton & Brody, 1969) to assess
to what extent participants could complete various tasks
(i.e. financial, housekeeping) autonomously, or with assis-
tance. A maximum score of eight reflects autonomy on
all items.
6. All CKD and healthy control par ticipants completed a
health questionnaire to evaluate general medical his-
tory. In persons with CKD, information confirming spe-
cific medical diagnoses, medication regimens, and
duration of illness was obtained from their medical
records. Medical diagnoses (e.g., hypertension, diabetes)
were made by the treating nephrologists. For controls
we followed published recommendations for obtaining
valid and reliable prevalence estimates of target ill-
nesses (Campbell et al., 2005) (i.e., to be considered
hypertensive, participants must report a diagnosis of
“high blood pressure” and currently be prescribed anti-
hypertensive medication).
The state of metabolic compensation was determined by
examining blood test results obtained during the most recent
clinic visit, and testing was scheduled to ensure that blood
work was obtained within two weeks of neuropsychologi-
cal testing.The following parameters were considered: hemo-
globin concentration to assess the degree of anemia and
estimated glomerular filtration rate (GFR) to assess clear-
ance capacity of nitrogenous wastes. Estimated GFR was
calculated with the widely used 4-variable equation (Levey
et al., 1999).
Statistical Analysis
Sample differences across the demographic, affective, and
cognitive variables were examined with independent sam-
ple t-tests or nonparametric tests ( Pearson x
2
) where appro-
priate. For purposes of sample description and presentation,
age 60 was determined as a cut-off for middle-aged (30–
60), and older (61–89) age groups. To assess learning and
memory abilities, two measures were selected from the
CVLT-II, the total number of words remembered across the
5 trials, and the number of words correctly recalled after a
20-minute delay. The mean performances on these mea-
sures are presented in Table 2. Because these two measures
were highly correlated within the full sample (r5.78), a
composite “verbal memory” T-score combining these mea-
sures was generated based on the control sample means,
and used in all subsequent analyses to reduce the number of
dependent variables. The two measures of executive func-
tioning (inhibition and mental set shifting) were treated inde-
pendently for the following reasons. First, because executive
functioning has received little previous attention in CKD,
we wished to expand our assessment to include two aspects
of executive functions, mental set shifting and inhibition
(Miyake et al., 2000). Secondly, these measures exhibited
only a modest relationship ( r5.55), and were thus not
considered redundant.
For the regression analyses, results of evaluation of
assumptions led to logarithmic transformation of the CES-D
variable to reduce skewness and improve the normality of
the distribution. For all participants, distributions were exam-
ined for extreme values and departures from normality. Data
from 2 participants (1 CKD and 1 control) were identified
as extreme values for the Mental Set Shifting variable, and
two (both CKD) were identified as extreme values for the
Inhibition variable. Consequently, the data was evaluated
after adjusting these extreme values to make them contig-
uous with the next closest value while maintaining the rank
ordering of the distribution (see Tabachnick & Fidell, 2007).
As this adjustment did not significantly impact the regres-
sion findings, the results are presented on the non-adjusted
values. The continuous independent variable (Age) was cen-
tered to reduce multicollinearity in examination of the inter-
action term. To facilitate presentation of the relevant findings
in the Figures, T-scores (mean of 50, SD of 10) were cal-
culated for the dependent variables to place these scores on
a consistent metric. Analyses were conducted using SPSS
14 software (SPSS Inc. Chicago, Il).
346 W.L. Thornton et al.
RESULTS
Subject Characteristics
Information regarding demographic and illness characteris-
tics is presented in Table 1. The 51 CKD and 55 control
participants were well matched on age and education, and
they did not significantly differ in their gender composi-
tion, or on a measure of verbal knowledge (Vocabulary). As
expected, persons with CKD had significantly higher rates
of diabetes, hypertension, and hypercholesterolemia than
controls (see Table 1). All CKD participants scored 7 or 8
on a measure of IADL’s (Lawton & Brody, 1969; mean
7.89, SD 5.37), and all controls obtained a maximal score
of 8 on this measure. Thus, all participants can be consid-
ered functionally independent for daily living skills.
Severity and Moderators of Cognitive
Impairment in CKD
The percentage of CKD participants considered to meet
criteria for cognitive impairment was calculated using the
recommended cut-off score of performance at least 1.5 SD’s
below matched controls ( Tuokko et al., 2001). As can be
seen in Table 2, the estimates of cognitive impairment in
CKD varied with age. In younger CKD participants (ages
38– 60), estimates of cognitive impairments ranged from
0% to 16%, with the largest performance differences noted
on the delayed recall measure. In older CKD par ticipants
(ages 61–89), estimates of cognitive impairment ranged from
27% to 46%, with largest performance differences again
noted on the delayed recall measure. Overall, CKD partici-
pants reported a higher number of depressive symptoms
than healthy controls, although when stratified by age group,
these differences only reached significance in younger par-
ticipants (see Table 2). As can be seen in Table 3, increasing
age was associated with worse performance on all of the
cognitive tasks in CKD participants. Importantly, age was
not significantly associated with increased severity of ill-
ness as indexed by either estimated GFR (Pearson r5 2.04)
or hemoglobin (Pearson r5.05). Furthermore, neither hemo-
globin nor estimated GFR were significantly correlated with
cognitive performance.
To examine the predictive utility of age, health status,
and their interaction in accounting for individual differ-
ences in verbal memory and executive functioning, we con-
ducted a series of two-step hierarchical regression analyses,
the results of which are presented in Table 4. The first step
of the model included participant’s age (centered), group
(CKD vs. controls) and the interaction of these variables. In
addition, because persons with CKD reported a higher level
of depressive symptoms than controls, we wanted to deter-
mine whether this variable improved prediction of perfor-
mance on the cognitive measures. Therefore, scores on the
CES-D (log) were entered into the second step of the model.
As can be seen in Table 4, increasing age, CKD, and their
interaction were each significant predictors of poorer per-
formance on measures of verbal memory and inhibition.
Together, these variables explained 38% of the variance in
verbal memory performance with 95% confidence limits
from .21 to .51 (Steiger & Fouladi, 1992), and 37% of the
variance in Stroop (inhibition) performance (95% confi-
Table 1. Demographic and clinical variables
Participant characteristics
CKD
(n551)
Controls
(n555) p-value*
Age (mean 6SD) 63.24 613.57 60.53 615.15 ns
Female % 27 (53%) 34 (62%) ns
Education (mean years 6SD) 13.41 63.16 14.13 62.29 ns
Vocabulary 21.69 69.98 24.92 67.26 ns
Hypertension % 46 (90%) 16 (29%) ,.001
Diabetes mellitus % 16 (31%) 0 (0%) ,.001
Benzodiazepines % 5 (10%) 1 (2%) ns
Opiates % 3 (6%) 0 (0%) ns
CKD participants
Duration of renal disease (yrs.) 5.56 66.68
Stage of renal disease† (%)
Stage 3 (GFR 30–59) 12 (24%) Age range 540–83
Stage 4 (GFR 15–29) 28 (55%) Age range 540–84
Stage 5 (GFR ,14) 11 (22%) Age range 538–89
GFR 24.11 611.05
Hemoglobin (g0L) 124.06 612.61
*: p-value obtained from independent sample t-tests of group means; Vocabulary 5ETS V2 1
V3; †—5 stage model of kidney disease recommended by the Kidney Disease Outcome Quality
Initiative Practice Guidelines; GFR 5glomerular filtration rate (mL 0min 01.73m2).
Cognition in CKD 347
dence limits from .20 to .50; Steiger & Fouladi, 1992).
Both older age and CKD were associated with worse per-
formance on these measures. Furthermore, examination of
the regression slopes revealed that age-related performance
decrements were differentially exacerbated in CKD partici-
pants. These relationships can be observed in Figures 1
and 2. Whereas older age and diagnosis of CKD were pre-
dictive of worse performance on the mental set shifting
task (R
2
5.35; confidence limits from .18 to .48; Steiger &
Fouladi, 1992), the interaction of these variables was non-
contributory (see Fig. 3).
Depressive symptoms were not a significant predictor of
either verbal memory or mental set shifting performance
(R
2
change 5.000, and .001, respectively). However, de-
pressive symptoms were a significant predictor of Stroop
performance, resulting in an additional 3% of variance
explained. Interestingly, the direction of this relationship
was negative, as a lesser number of depressive symptoms
predicted greater inter ference on the Stroop task. To eluci-
date this relationship, the “age by depressive symptoms”
and “group by depressive symptoms” interaction terms were
entered into two hierarchical regression models along with
Table 2. Verbal memory, executive functioning, and depressive symptoms by age and group
Measures (mean 6SD) CKD Healthy controls Effect size* p-value** CKD impaired†
CVLT-II Trial 1–5 Total
All 40.69 69.63 48.38 69.90 .79 ,.001
Younger 46.20 66.67 49.53 610.05 .38 ns n50
Older 35.39 69.12 47.00 69.73 1.23 ,.001 n511 (42%)
CVLT-II delayed recall
All 8.26 63.52 11.33 63.20 .91 ,.001
Younger 9.96 62.35 11.50 63.18 .54 ,.05 n54 (16%)
Older 6.62 63.71 11.12 63.28 1.28 ,.001 n512 (46%)
Mental set shifting
All 80.39 645.43 61.55 633.98 .47 ,.05
Younger 55.04 626.66 49.37 623.04 .23 ns n53 (12%)
Older 104.77 646.75 76.16 639.34 .66 ,.05 n57 (27%)
Inhibition
All 34.53 615.38 27.05 610.35 .57 ,.01
Younger 25.68 67.86 24.17 68.57 .18 ns n53 (12%)
Older 43.04 616.14 30.52 611.41 .89 ,.005 n511 (42%)
CES-D
All 10.59 66.71 6.06 66.06 .70 ,.001
Younger 12.56 67.50 6.13 65.63 .97 ,.005
Older 8.69 65.33 5.96 66.66 .45 ns
Note. For comparisons of all participants, n551 for CKD and 55 for Controls groups, for Younger group comparisons,
n525 for CKD and 30 for Controls, for older group comparisons, n526 for CKD and 25 for Controls; CVLT-II items: more
words r etained 5better performance; mental set shifting (Trails B-Motor Speed ) 5time to completion (lowe r scores 5better
performance); inhibition (aka “Stroop effect”) 5difference between inhibition trial and color naming trial ( lower scores 5
better per formance); *: Effect size 5Cohen’s d(mean 1 2mean 2 0pooled SD), and all effects favor controls; **: p-value
obtained from independent sample t-tests o f group mea ns, †: % I mpaired 5percentage falling 1.5 or more SD below the mean
of the controls, CES-D 5Centre for Epidemiological Studies-Depression Scale.
Table 3. Correlations between illness variables, and cognitive variables in CKD par ticipants
Variable Age 2 3 4 5 6 7 8
1Age
2Education 2.22
3CVLT 1–5 2.63** .33*
4CVLT LD 2.55** .54** .77**
5Inhibition .59** 2.19 2.46** 2.44**
6Mental set shifting .54** 2.42** 2.56** 2.62** .54**
7CES-D 2.26 .23 .11 .13 2.32* 2.06
8GFR 2.04 .04 .21 .21 2.14 .01 2.17 —
9Hemoglobin .05 .03 2.17 .03 2.02 2.01 2.08 .30*
*p52-tailed correlation ,.05, **p,.01; GFR 5glomerular filtration rate (mL 0min01.73m2; higher 5better renal func-
tioning).
348 W.L. Thornton et al.
Table 4. Hierarchical regression results predicting verbal
memory, mental set shifting, and inhibition in persons
with CKD and healthy controls
Predictors B SE bp R
2
Verbal memory
Age 2.19 .073 2.27 ,.05
Group (CKD0Controls) 27.65 1.60 2.38 ,.001
Age by group 2.25 .11 2.23 ,.05
R
2
* .38
Mental set shifting
Age .32 .07 .46 ,.001
Group (CKD0Controls) 3.58 1.60 .18 ,.05
Age by group .12 .11 .11 ns
R
2
* .35
Inhibition: Step 1
Age .25 .07 .36 ,.005
Group (CKD0Controls) 4.52 1.58 .23 ,.01
Age by group .24 .11 .23 ,.05
R
2
.37
Inhibition: Step 2
Age .25 .07 .35 ,.005
Group (CKD0Controls) 5.85 1.68 .29 ,.005
Age by group .22 .11 .21 ,.05
Depressive symptoms 24.42 2.12 2.18 ,.05
R
2
.39
DR
2
.02
*Step 2 did not result in a significant increase in R2
Fig. 1. Regression slopes and scatter plot showing the effects of
Age, Group (CKD and Controls), and their interaction on the ver-
bal memory measure.
Fig. 2. Regression slopes and scatter plot showing the effects of
Age, Group (CKD and Controls), and their interaction on the Inhi-
bition measure.
Fig. 3. Regression slopes and scatter plot showing the effects of
Age and Group (CKD and Controls) on the Mental Set Shifting
task.
Cognition in CKD 349
the appropriate main effects, and were non-contributory.
Examination of the intercorrelations revealed that in CKD
participants, a higher number of depressive symptoms were
significantly associated with better performance on the Inhi-
bition task ( Pearson r5 2.32; see Table 3). Furthermore, it
was noted that this might reflect the fact that increasing age
was marginally associated with a reduction in depression
symptoms ( Pearson r5 2.26, p5.07). In fact, after con-
trolling for the effects of age through partial correlation, the
relationship between depressive symptoms and inhibition
was reduced to non-significance ( pr 5 2.22).
Finally, in CKD participants only, we conducted a series
of hierarchical regression analyses to determine the predic-
tive utility of metabolic factors (estimated GFR and hemo-
globin) after adjusting for the effects of age, which is
embedded in the MDRD GFR estimate. As expected, increas-
ing age emerged as a significant predictor of worse perfor-
mance on each of the cognitive dependent measures, whereas
the inclusion of the metabolic factors added no further pre-
diction over and above the effects of age.
DISCUSSION
Little attention to date has been directed toward cognitive
functioning in persons with CKD in the years prior to the
initiation of dialysis. We examined the pattern of cognitive
performance in a Canadian CKD sample with a broad range
of age and illness severity. In addition, we examined the
roles of three potential variables predicted to have a nega-
tive effect on cognitive performance in CKD, increasing
age, a higher number of depressive symptoms, and increased
illness severity (as indexed by estimated GFR and hemo-
globin). The current evidence extends previous findings
(Kurella et al., 2004) by demonstrating that even persons
with CKD who do not present with overt evidence of cere-
brovascular pathology (e.g., stroke) are at high risk for cog-
nitive impairments in comparison with age peers. In addition,
our findings suggest that age is an important moderator of
the cognitive presentation in CKD. Whereas cer tain aspects
of executive functioning and learning may be relatively pre-
served in younger CKD participants, older CKD partici-
pants exhibited worse per formance than matched controls
on all aspects of memory and executive functioning assessed
in the current study. Furthermore, examination of the effect
size estimates indicates that the magnitude of the cognitive
differences observed is moderate to large (see Table 2) with
very large differences noted in verbal memory in older CKD
participants (Cohen, 1992).
An important question remains, what may be underlying
these significant cognitive impairments in persons with
CKD? The current findings allow us to first approach this
question by ruling out some potentially important vari-
ables. Whereas CKD participants exhibited more self-
reported depressive symptoms than controls, these were only
weakly associated with cognitive performance after con-
trolling for the effects of age. Furthermore, we could find
no evidence for an association between cognitive perfor-
mance and illness progression in persons with CKD. Regard-
ing the effects of age, it is important to note that there was
no indication in the current sample of a direct association
between increasing age and our indices of severity of renal
disease. Specifically, whereas increasing age was associ-
ated with greater extent and severity of impairments in ver-
bal memory and inhibition, age was not significantly
associated with either estimated GFR (Pearson r5 2.04)
or hemoglobin (Pearson r5.05). Fur thermore, age was
evenly distributed across the stages of renal disease repre-
sented in the current sample (see Table 1).
To understand the age effects in this study, it is important
to note that we excluded participants with a previous diag-
nosis of dementia, and all participants were considered inde-
pendent for activities of daily living based on their IADL
performance. Nonetheless, the fact that older CKD partici-
pants exhibited such high rates of cognitive impairments
suggests that these results may reflect emergent cerebrovas-
cular disease that may exert a negative effect on cognition
even in the absence of overt symptoms such as stroke. As
reported previously and observed in the current sample,
hypertension is nearly ubiquitous in CKD (Levey et al.,
2003). Furthermore, hypertension and diabetes together form
the leading causes of renal disease (Collins et al., 2003;
Coresh et al., 2003), and both have been associated with
accelerated cognitive decline in late mid-age and late-life
(Abate et al., 2001; Gunning-Dixon & Raz, 2000; Hassing
et al., 2004; Knopman et al., 2001; MacKnight et al., 2002).
Whereas there has been little direct neuroradiological exam-
ination to date in persons with CKD, it has recently been
argued that cerebrovascular disease may be an important
cause of cognitive impairment in persons with the more
severe form of renal failure known as ESRD (Pereira et al.,
2005). Recent brain imaging studies have reported high
rates of cerebrovascular disease in persons with ESRD, with
50% to 80% exhibiting white matter hyperintensities (WMH)
and other evidence of ischemic brain lesions (Fazekas et al.,
1996; Fazekas et al., 1995; Lass et al., 1999). The presence
of WMH’s has been associated with cerebrovascular dis-
ease (Stewar t, 1999) and with impairments in executive
functioning and memory in elderly populations (Gunning-
Dixon & Raz, 2000). In addition, CKD is associated with
several other cerebrovascular risk factors, such as athero-
sclerosis, hyperhomocysteinemia, and oxidative stress (Leon-
cini et al., 2003; Pereira et al., 2005). Thus, the pattern of
memory and executive functioning impairments we observe
in older CKD par ticipants may in part reflect what has pre-
viously been deemed “vascular cognitive impairment”
(Hachinski, 1994), in patient populations with known
cerebrovascular risks. Such an explanation may underlie
previously reported associations between moderate renal
impairment and vascular dementia in older samples (Seliger
et al., 2004). An important direction for future research will
be to further elucidate the relative contributions of these
and other potential cognitive risk factors in CKD. Further-
more, it will be important to track cognitive performance
longitudinally in persons with CKD to determine how declin-
350 W.L. Thornton et al.
ing cognitive status may influence treatment decisions and
outcomes.
Limitations
These findings should be considered in light of certain lim-
itations. It is possible that our decision to exclude individ-
uals with other illnesses with CNS effects (i.e., stroke and
dementia) may reduce the generalizability of our findings
to the broader CKD population. In fact, it is likely that more
liberal inclusion would have led to even higher rates of
significant impairment observed. Nonetheless, we felt our
criteria allowed more precise elucidation of the cognitive
presentation of CKD. In addition, because we did not have
access to laboratory blood work on our control participants,
it is it possible that some of our “healthy controls” may
have had undetected renal disease (i.e., reduced GFR). In
any case, the inclusion of such individuals in the control
group would be expected to reduce the magnitude of the
differences observed and would not serve to confound inter-
pretation of the current results.
Regarding the dependent measures employed, we elected
to specifically examine verbal memory and aspects of exec-
utive functioning. The reasons for this were threefold. First,
a decline in these functions has previously been reported in
CKD samples with a large percentage of participants with a
history of stroke. We wished to extend these findings to
CKD participants without a history of stroke to better char-
acterize the pervasiveness and nature of the impairments.
Secondly, it is important to note that our measures of exec-
utive functioning were derived after controlling for the effects
of both psychomotor speed and reading speed. Thus, we
believe we have reported a more accurate and nuanced pic-
ture of the true nature of the deficits associated with CKD.
Thirdly, these functions have been shown to be particularly
sensitive to cerebrovascular risks that are highly prevalent
in this population. We acknowledge that postulating that
cerebrovascular disease may underlie at least some of the
deficits observed is speculative, but consistent with previ-
ous findings indicating high rates of cerebrovascular pathol-
ogy in renal disease (for a review, see Pereira et al., 2005).
Developing a direct link between cerebral integrity and func-
tion in CKD remains an important question for future
research.
Summary and Conclusions
In summary, our findings suggest that community-dwelling
adults with CKD display high rates of cognitive impair-
ments relative to matched controls. Furthermore, these
impairments are most pronounced in persons aged 61 and
older and are not associated with metabolic illness param-
eters such as estimated GFR or hemoglobin. The differ-
ences observed were not accounted for by depressive
symptoms, which were only weakly associated with cogni-
tive performance, and negatively associated with age. With
more than half of persons with renal disease over age 60
(Coresh et al., 2003), the current findings have important
implications for medical management of CKD, and high-
light the need for further neuropsychological investigation
of this highly prevalent and costly illness. Developing a
better understanding of the factors underlying neuropsycho-
logical per formance in CKD is crucial to detect persons
that may be at risk for cognitive compromise years before
the initiation of dialysis, to assist in treatment planning, to
identify and treat potentially reversible causes of cognitive
impairment, and to provide essential support to patients
required to manage increasingly complex medication and
dietary regimens.
ACKNOWLEDGMENTS
The authors thank Heike Dumke, Stacey Kesten, and Sarah
Meachen for their help in data collection, Teri Pentland for her
efforts in subject recruitment and study coordination, Dr. Ray Koop-
man for statistical consultation, and Dr. Allen E. Thornton for his
helpful comments on an earlier version of this manuscript. The
authors also address special thanks to those who agreed to partici-
pate in this study. This work was supported in part by a Simon
Fraser University0Social Sciences and Humanities Research Coun-
cil (SFU0SSHRC) Institutional Grant and an SFU0Institute of
Health Research and Education (SFU0IHRE) Seed Grant awarded
to Dr. Wendy Loken Thornton, and by a University of British
Columbia ( UBC) Division of Geriatric Medicine Grant awarded
to Dr.’s Thornton and Hill. Sirad Deria was supported by the For-
mation de Chercheurs et l’Aide a la Recherche - Fonds de la
recherche en santé du Québec Master’s Scholarship ( FCAR-
FRSQ), and by a Canadian Institute of Health Research (CIHR)
Professional Student Research Award. Shannon Gelb was sup-
ported by a SSHRC Canada Graduate Master’s Scholarship and
by a CIHR 0Michael Smith Foundation for Health Research
(MSFRH) Transplant Research Training Award. Portions of this
work were presented in abstract form at the 2nd Annual Congress
of the International Society for Vascular, Cognitive, and Behav-
ioural Disorders, and at the Gerontological Society of America’s
56th Annual Scientific Meeting.
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