In this prospective study, we examined mortality in a cohort of 145 prevalent dialysis patients and

performed a risk-factor analysis. After a 7-year observation period, 38.6% of patients had died. The
observed mortality rate in this patient cohort was lower than that reported in other registries and study
populations in the United States and Europe50- 51 and may reflect sample differences. The mean age and
percentage of patients with diabetes was lower in this study than in equivalent cohorts. 50,51 Cardiovascular
causes accounted for the largest percentage of deaths in accordance with previous research. 52,53 Despite
excluding frank dementia in the recruiting of this dialysis cohort, a very high proportion of participants had
at least mild cognitive impairment, in line with reports in older dialysis cohorts. 54 Rates of cognitive
impairment contrast unfavorably with reported rates in the general older population. 55 Cognitive
functioning emerged as a unique prognostic factor in predicting survival in the dialysis cohort, extending
previous findings on dialysis patients with diagnosed dementia 28,29 and studies in other clinical
populations24,56 and community cohorts.26 Cognitive impairment in 2 or more tests at baseline was
associated with nearly 3 times greater risk of death 7 years later, even after extensive case-mix
adjustments. This is the first report of higher mortality rates in dialysis patients with cognitive impairments
in the absence of dementia. Several possible explanations may account for this finding. One possibility is
that cognitive impairments may lead to increased mortality by impeding treatment adherence. 18,57 Optimal
selfmanagement for dialysis patients is complex and requires patients to understand, remember, and reason
to follow treatment advice and modify behavior (eg, in relation to diet, fluid intake, or medication).
Cognitive deficits may result in suboptimal care because of difficulty following treatment
recommendations and adhering to and managing multiple medications, as evidenced in other clinical
populations.22,58 An alternative explanation is that impaired cognition may be a surrogate marker of
global decline in health or disease progression. Population- based studies have shown that general ill health
is associated with cognitive deficits.59 It therefore is plausible that poor cognitive ability in dialysis patients
is related to mortality because cognitive function is a sensitive indicator of general physical deterioration.
It is possible that cognitive deterioration may reflect a specific disease process. Patients with chronic
kidney disease show high levels of vascular disease and related processes. 60 Vascular stiffness has been
shown to start at early stages of chronic kidney disease with morphologic alterations and structural changes
manifested even in pediatric patients with much lower exposure to “classical” risk factors for
atherosclerosis, such as diabetes or hyperlipidemia.61 Cognitive dysfunction may reflect this vascular
pathologic state.62,63 This is consistent with evidence showing that impaired neuropsychological scores are
associated with measures of cerebrovascular damage, such as white matter hyperintensities, in both
hemodialysis64- 66 and peritoneal dialysis patients67 and predict incident cardiovascular disease.68,69 It
therefore is conceivable that the reported associations between cognition and mortality are the result of
subclinical atherosclerosis or ischemic changes caused by vascular disease and/or smallvessel disease not
fully accounted for in these analyses. In the analyses, adjustments for severity of ESRD and comorbid
conditions, including established vascular risk factors and physical QoL, did not attenuate the mortality
risk associated with poor cognition. The expected multivariate associations of age, serum albumin level,
hemoglobin concentration, dose of dialysis administered, and depression with mortality were not
statistically significant in this study, although the trends and observed univariate associations were similar
to those in previous studies.4-7 The lack of association between the clinical indices (Kt/V and albumin and
hemoglobin levels) and survival may reflect the marked reduction in variability and improved care for
anemia and adequacy of dialysis in our sample because all patients in this dialysis cohort achieved clinical
targets. For instance, Lowrie and Lew70 showed that the risk of death increases exponentially as serum
albumin concentration decreases from 4.0 to 2.5 g/dL. Therefore, the notion that these clinical markers are
independent predictors may be more likely to be true at lower serum levels that do not meet clinical
targets. In this sample, we did not confirm previous findings of an increased risk of death associated with
depression.7,71,72 This may relate to differences in follow-up duration and assessment procedures. In this
study, depression was measured only at baseline without subsequent longitudinal periodic assessment.
Depressive mood can be labile and it may be unreasonable to expect depressive mood at a single
measurement to be strongly predictive of outcomes several years later. Chronic persistent depressive mood
with multiple assessments during the course of the study, rather than a single baseline measurement, may
be more likely to be associated with mortality. 73,74 Although the findings of this study are novel, several
limitations must be acknowledged. In comparison to other studies, sample size and resulting number of
deaths were small. This did not allow us to perform separate analyses for different dialysis modalities or
various other subgroups. Thus, although the magnitude of the HR is large, issues related to study power
limitations highlight the importance of revisiting the question with larger samples. Second, the study
sample comprised prevalent dialysis patients. Given the excess early mortality in incident patients with
ESRD,75 our cohort likely represents a healthier patient population who survived the initial dialysis period.
In addition, because participants were selected on the basis of strict eligibility criteria, results may not be
generalizable to the dialysis population as a whole. The prevalence of cognitive impairment and mortality
may have been underestimated because patients with a history of stroke were excluded. Another potential
limitation is that the screening to exclude patients with dementia was based on medical history and
abbreviated test scores with no formal cognitive/neurologic diagnostic evaluation. Cases of (early)
dementia may have gone undetected and thereby biased the prevalence estimate of cognitive impairment.
However, the absence of severe cognitive impairment in neuropsychological tests (ie, performance _3 SDs
less than normative values) coupled with findings of preserved daily functioning and low mean age suggest
that our sample most likely was dementia free at the time of assessment. Third, this report does not
include timedependent analyses. Cognitive functioning was measured only once at baseline; thus, we do
not know whether cognitive function improved or declined during follow-up. In all probability, cognitive
functioning may have deteriorated further, possibly progressing to dementia in some cases, 76 and more
patients may have developed cognitive dysfunction during the 7-year followup, but these effects were not
assessed. Finally, even in longitudinal data such as these, issues of causality cannot be answered
definitively. Although the analyses presented here showed that compromised cognitive functioning
preceding death by as much as 7 years was strongly associated with higher risk of mortality, we cannot
conclude that high levels of cognitive abilities cause dialysis patients to live longer. By controlling for
illness severity markers, comorbid conditions, and other well-being indices (QoL and depression) at the
time of data collection, we were able to show that higher levels of cognition are protective well in advance
of death and not simply an indicator of better health status. This suggests that the association between
cognitive function and mortality may reflect processes different from those underlying a simple relation
between comorbid conditions and mortality. Despite its limitations, this study has important clinical
implications. Previously, mild cognitive impairment has been overlooked as a potentially important factor
in the clinical management of dialysis patients. Data presented here indicate that cognitive functioning can
serve as a sensitive indicator of subsequent mortality. These data suggest that it may be valuable to include
a cognitive assessment in the routine evaluation of patients on dialysis therapy. Various cognitive
interventions successful in other populations77,78 assuming causality could potentially improve or halt
decrements in cognitive functioning associated with ESRD, thus decreasing the risk of mortality, possibly
through improved adherence. In conclusion, this is the first demonstration of a strong association between
poor cognitive functioning and mortality in a dialysis sample after extensive adjustment for case-mix and
other known (clinical and psychosocial) risk factors. Replication of this finding in other renal patient
samples is necessary. Future work should address the questions regarding predictors of cognitive
functioning in patients with ESRD and explore the potential mechanisms through which cognition impacts
on mortality.