Kristina V. Lou

Frequency of and risk factors for poor cognitive performance in hemodialysis patients

Objective: There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing. Methods: In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥24. Results: Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01). Conclusions: There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥24 also have a high frequency of poor cognitive performance.

Anatomic Brain Disease in Hemodialysis Patients: A Cross-sectional Study

BACKGROUND Although dialysis patients are at high risk of stroke and have a high burden of cognitive impairment, there are few reports of anatomic brain findings in the hemodialysis population. Using magnetic resonance imaging of the brain, we compared the prevalence of brain abnormalities in hemodialysis patients with that in a control population without known kidney disease. STUDY DESIGN Cross-sectional cohort. SETTING & PARTICIPANTS 45 maintenance hemodialysis patients and 67 controls without reported kidney disease, both without history of known stroke. PREDICTOR The primary predictor was dialysis status. Covariates included demographics (age, race, and sex), vascular risk factors (diabetes and hypertension), and cardiovascular disease (coronary artery disease and congestive heart failure). OUTCOMES Magnetic resonance imaging of the brain features, including severity of white matter disease and cerebral atrophy (sulcal prominence and ventricular atrophy), hippocampal size, and small-/large-vessel infarcts. MEASUREMENTS Semiquantitative scale (0-9 for white matter disease and cerebral atrophy, 0-3 for hippocampal size) and infarct prevalence. RESULTS Mean ages of hemodialysis patients and controls were 55 ± 17 (SD) and 53 ± 13 years, respectively. In comparison to controls, hemodialysis patients had more severe white matter disease (1.6 vs 0.7) and cerebral atrophy (sulcal prominence, 2.3 vs 0.6; ventricular enlargement, 2.3 vs 0.9; hippocampal size, 1.3 vs 1.0), with all P < 0.001. In multivariable analyses, hemodialysis status was associated independently with worse white matter disease and atrophy grades. Hemodialysis patients also had a higher prevalence of small- (17.8%) and large- (7.8%) vessel infarcts than controls (combined, 22% vs 0%; P < 0.001). LIMITATIONS The dialysis cohort likely is healthier than the overall US hemodialysis population, partly limiting generalizability. CONCLUSIONS Hemodialysis patients have more white matter disease and cerebral atrophy compared with controls without known kidney disease. Hemodialysis patients also have a high prevalence of unrecognized infarcts.

Cognitive Function and All-Cause Mortality in Maintenance Hemodialysis Patients

BACKGROUND Cognitive impairment is common in hemodialysis patients and is associated with significant morbidity. Limited information exists about whether cognitive impairment is associated with survival and whether the type of cognitive impairment is important. STUDY DESIGN Longitudinal cohort. SETTING & PARTICIPANTS Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients. PREDICTOR Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1. OUTCOMES Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics and dialysis and cardiovascular (CV) risk factors. RESULTS Mean age of participants was 63 years, 53% were men, 23% were African American, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 1.1-3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with a 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55-0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67-0.98), whereas adjustment for CV disease and heart failure resulted in further attenuation (HR, 0.87; 95% CI, 0.72-1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54-0.72), with the relationship remaining significant after adjustment for demographics and dialysis and CV risk factors (HR, 0.79; 95% CI, 0.66-0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82; 95% CI, 0.69-0.96), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83-1.19). LIMITATIONS Patients with dementia were excluded from the full battery, perhaps underestimating the strength of the association. CONCLUSIONS Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, whereas for executive function, this relationship may be explained in part by CV disease burden.

The Kidney Disease Quality of Life Cognitive Function Subscale and Cognitive Performance in Maintenance Hemodialysis Patients

BACKGROUND Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen. STUDY DESIGN Cross-sectional cohort. SETTING & PARTICIPANTS Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session. PREDICTORS KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics. OUTCOMES Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis. MEASUREMENTS Univariate and multivariable linear regression models adjusting for age, sex, race, and end-stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100. RESULTS For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 ± 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P < 0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28-0.36), with modest specificity (range, 0.77-0.81) for identifying worse executive function and memory. LIMITATIONS Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery. CONCLUSIONS The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential.

Depression and all-cause mortality in hemodialysis patients.

Background: There are limited data regarding the relationship between depression and mortality in hemodialysis (HD) patients. Methods: Among 323 patients receiving maintenance HD, depression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, with a score of ≥16 consistent with depression. Adjusted Cox proportional-hazards models with additional analyses incorporating antidepressant medication use were used to evaluate the association between depression and mortality. Baseline CES-D scores were used for the primary analyses, while secondary time-dependent analyses incorporated subsequent CES-D results. Results: The mean age was 62.9 ± 16.5 years, 46% of the subjects were women and 22% were African-American. The mean baseline CES-D score was 10.7± 8.3, and 83 (26%) participants had CES-D scores ≥16. During a median (25th, 75th) follow-up of 25 (13, 43) months, 154 participants died. After adjusting for age, sex, race, primary cause of kidney failure, dialysis vintage and access, baseline depression was associated with an increased risk of all-cause mortality (HR 1.51 and 95% CI 1.06-2.17). This attenuated with further adjustment for cardiovascular disease, smoking, Kt/V, serum albumin, log C-reactive protein and use of antidepressants (HR 1.21 and 95% CI 0.82-1.80). When evaluating time-dependent CES-D, depression remained associated with increased mortality risk in the fully adjusted model (HR 1.44 and 95% CI 1.00-2.06). Conclusions: Greater symptoms of depression are associated with an increased risk of mortality in HD patients, particularly when accounting for the most proximate assessment. This relationship was attenuated with adjustment for comorbid conditions, suggesting a complex relationship between clinical characteristics and depression symptoms. Future studies should evaluate whether treatment for depression impacts mortality among HD patients.

Low 25-Hydroxyvitamin D Levels and Cognitive Impairment in Hemodialysis Patients

BACKGROUND AND OBJECTIVES 25-hydroxyvitamin D (25[OH]D) deficiency and cognitive impairment are both prevalent in hemodialysis patients in the United States. This study tested the hypothesis that 25(OH)D deficiency may be associated with cognitive impairment because of its vasculoprotective, neuroprotective, and immune-modulatory properties. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This cross-sectional analysis involved 255 patients enrolled in the Dialysis and Cognition Study between 2004 and 2012. In linear regression models, 25(OH)D was the exposure variable; it was used first as a continuous variable and then stratified as deficient (<12 ng/ml), insufficient (12 to <20 ng/ml), and sufficient (≥20 ng/ml). Principal component analysis was used to obtain the memory and the executive function domains from the individual neurocognitive tests. Scores on individual tests as well as on the memory and executive function domains were the outcome variables. Multivariable models were adjusted for age, sex, race, education, and other potential confounding variables. RESULTS Mean serum 25(OH)D ± SD was 17.2±7.4 ng/ml, with 14%, 55%, and 31% of patients in the deficient, insufficient, and sufficient groups, respectively. Patients in the deficient group were more likely to be women, African American, and diabetic and to have longer dialysis vintage. Higher 25(OH)D levels were independently associated with better performance on several tests of executive function (mean difference on component executive score, 0.16 [95% confidence interval, 0.04-0.28; P=0.01] for each SD higher 25[OH]D). No association was seen with tests assessing memory. CONCLUSIONS 25(OH)D deficiency in hemodialysis patients is associated with worse cognitive function, particularly in domains that assess executive function.

FGF-23 and cognitive performance in hemodialysis patients

Although cognitive impairment is common in hemodialysis patients, the etiology of and risk factors for its development remain unclear. Fibroblast growth factor 23 (FGF‐23) levels are elevated in hemodialysis patients and are associated with increased mortality and left ventricular hypertrophy. Despite FGF‐23 being found within the brain, there are no prior studies assessing whether FGF‐23 levels are associated with cognitive performance. We measured FGF‐23 in 263 prevalent hemodialysis patients in whom comprehensive neurocognitive testing was also performed. The cross‐sectional association between patient characteristics and FGF‐23 levels was assessed. Principal factor analysis was used to derive two factors from cognitive test scores, representing memory and executive function, which carried a mean of 0 and a standard deviation of 1. Multivariable linear regression adjusting for age, sex, education status, and other relevant covariates was used to explore the relationship between FGF‐23 and each factor. Mean age was 63 years, 46% were women and 22% were African American. The median FGF‐23 level was 3098 RU/mL. Younger age, lower prevalence of diabetes, longer dialysis vintage, and higher calcium and phosphorus were independently associated with higher FGF‐23 levels. Higher FGF‐23 was independently associated with a lower memory score (per doubling of FGF‐23, β = −0.08 SD [95% confidence interval, CI: −0.16, −0.01]) and highest quartile vs. lowest quartile (β = −0.42 SD [−0.82, −0.02]). There was no definite association of FGF 23 with executive function when examined as a continuous variable (β = −0.03 SD [−0.10, 0.04]); however, there was a trend in the quartile analysis (β = −0.28 SD [−0.63, 0.07], P = 0.13, for 4th quartile vs. 1st quartile). FGF‐23 was associated with worse performance on a composite memory score, including after adjustment for measures of mineral metabolism. High FGF‐23 levels in hemodialysis patients may contribute to cognitive impairment.

Cognitive Performance before and during Hemodialysis: A Randomized Cross-Over Trial

Background and Aims: Hemodialysis (HD) patients are educated and counseled during the HD procedure. There are few studies assessing whether cognitive performance varies with dialysis. Methods: Using a randomized cross-over design, 40 patients were assigned to one of two sequences: testing 1 h before dialysis followed 1 month later by testing during the first hour of dialysis (n = 21) versus testing during the first hour of dialysis followed 1 month later by 1 h before dialysis (n = 19). Cognitive tests were administered at each testing period. Mixed regression models evaluated for a dialysis effect (difference between test performance before vs. during dialysis) while adjusting for potential learning (difference between first and second tests). Results: In models accounting for period of testing, there was no difference in test performance between 1 h before versus during the first hour of HD for all administered cognitive tests (p > 0.05). A learning effect was detected between first and second test administration in two tests, specifically, the Word List Learning and the Digit Symbol Substitution Test. Conclusions: We found no difference in cognitive performance depending on the time of testing, suggesting that cognitive tests performed during the first hour of dialysis are a valid assessment of cognitive performance.

Association of sleep disturbances with cognitive impairment and depression in maintenance hemodialysis patients

BACKGROUND There are few data on the relationship of sleep with measures of cognitive function and symptoms of depression in dialysis patients. METHODS We evaluated the relationship of sleep with cognitive function and symptoms of depression in 168 hemodialysis patients, using multivariable linear and logistic regression. Sleep disturbances were assessed using the sleep subscale battery of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Health Experience Questionnaire. The cognitive battery assessed a broad range of functioning including global ability, verbal intelligence, supraspan learning, auditory retention, visual retention, attention/mental processing speed, visual construction/fluid reasoning and motor speed. Depressive symptoms were assessed using the Center for Epidemiological Studies of Depression (CESD) Scale, with depression indicated by a CESD score >16. RESULTS Mean (SD) age of participants was 62 (17) years, 49% were women, 30% were African American and 33% had diabetes. There was no significant relationship between sleep score and performance on any neurocognitive test (p>0.13, for all multivariable analyses). The prevalence of depression increased from 16% in the highest quartile (best) of sleep score, to 31% in the lowest quartile (worst) of sleep score. In multivariable analyses, each 1 SD increase in sleep score was associated with a 2.18 (95% confidence interval, 1.07-3.29, p<0.001) lower CESD score. Results were consistent when considering individual components of both the CESD and sleep score. CONCLUSIONS Disturbances in sleep are associated with symptoms of depression but not measures of cognitive function. Dialysis patients with disturbances in sleep should be screened for depression.

Measures of blood pressure and cognition in dialysis patients

There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients. The Cognition and Dialysis Study is an ongoing investigation of cognitive function and its risk factors in six Boston area hemodialysis units. In this analysis, we evaluated the relationship between different domains of cognitive function with systolic and diastolic blood pressure, pulse pressure, and intradialytic changes in systolic blood pressure, using univariate and multivariable linear regression models adjusted for age, sex, race, education, and primary cause of end‐stage renal disease. Among 314 participants, mean age was 63 years; 47% were female, 22% were African American, and 48% had diabetes. The mean (SD) of systolic blood pressure, diastolic blood pressure, pulse pressure, and intradialytic change in systolic blood pressure were 141 (21), 73 (12), 68 (15), and −10 (24) mmHg, respectively. In univariate analyses, the performance on cognitive tests primarily assessing executive function and processing speeds was worse among participants with lower diastolic blood pressure and higher pulse pressure. These relationships were not statistically significant, however, in multivariable analyses. There was no association between cognitive function and systolic blood pressure or intradialytic change in systolic blood pressure in either univariate or multivariable analyses. We found no association between different measures of blood pressure and cognitive function in cross‐sectional analysis. Longitudinal studies are needed to confirm these results.