Kidney Function and Cognitive Impairment in US Adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study

doi:10.1053/j.ajkd.2008.05.004

American Journal of Kidney Diseases

Volume 52, Issue 2, August 2008, Pages 227-234

https://doi.org/10.1053/j.ajkd.2008.05.004 Get rights and content

Background

The association between kidney function and cognitive impairment has not been assessed in a national sample with a wide spectrum of kidney disease severity.

Study Design

Cross-sectional.

Setting & Participants

23,405 participants (mean age, 64.9 ± 9.6 years) with baseline measurements of creatinine and cognitive function participating in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a study of stroke risk factors in a large national sample.

Predictor

Estimated glomerular filtration rate (eGFR).

Outcome

Cognitive impairment.

Measurements

Chronic kidney disease (CKD) was defined as eGFR less than 60 mL/min/1.73 m². Kidney function was analyzed in 10-mL/min/1.73 m² increments in those with CKD, and in exploratory analyses, across the range of kidney function. Cognitive function was assessed using the 6-Item Screener, and participants with a score of 4 or less were considered to have cognitive impairment.

Results

CKD was associated with an increased prevalence of cognitive impairment independent of confounding factors (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.43). In patients with CKD, each 10-mL/min/1.73 m² decrease in eGFR less than 60 mL/min/1.73 m² was associated with an 11% increased prevalence of impairment (odds ratio, 1.11; 95% confidence interval, 1.04 to 1.19). Exploratory analyses showed a nonlinear association between eGFR and prevalence of cognitive impairment, with a significant increased prevalence of impairment in those with eGFR less than 50 and 100 mL/min/1.73 m² or greater.

Limitations

Longitudinal measures of cognitive function were not available.

Conclusions

In US adults, lower levels of kidney function are associated with an increased prevalence of cognitive impairment. The prevalence of impairment appears to increase early in the course of kidney disease; therefore, screening for impairment should be considered in all adults with CKD.

Section snippets

Study Design

The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study is a nationally representative sample of adults aged 45 years and older in the US population. Recruitment of the REGARDS cohort has been described previously.⁷ Briefly, participants were identified from commercially available lists of residents and recruited through an initial mailing followed by telephone contact. The cooperation rate in REGARDS was 64.6%, and the participation rate was 44.7%. Both are similar to rates

Results

A total of 24,512 participants were recruited into the cohort between January 1, 2004, and November 1, 2007. Of these participants, 23,499 had a nonmissing serum creatinine measurement, and 23,469 of these participants underwent cognitive function testing (Fig 1). We excluded 64 individuals with eGFR less than 10 mL/min/1.73 m², leaving 23,405 participants in the analytic cohort.

Participants included in our analyses had a mean age of 64.9 ± 9.6 (SD) years, 41.0% were African American, and 40.5%

Discussion

In a large national sample of African American and white adults, individuals with lower levels of kidney function were more likely to have cognitive impairment compared with individuals with normal kidney function, independent of prevalent cardiovascular disease and cardiovascular risk factors. These results suggest that CKD, in addition to other modifiable cardiovascular risk factors, may be an important marker of cognitive impairment in US adults.

These results confirm and extend previous

Acknowledgements

The authors acknowledge the participating investigators and institutions: University of Alabama at Birmingham, Birmingham, AL (Study PI, Data Coordinating Center, Survey Research Unit): George Howard, Leslie McClure, Virginia Howard, Libby Wagner, Virginia Wadley, Rodney Go; University of Vermont (Central Laboratory): Mary Cushman; Wake Forest University (ECG Reading Center): Ron Prineas; Alabama Neurological Institute (Stroke Validation Center, Medical Monitoring): Camilo Gomez, David Rhodes,

References (20)

M. Kurella et al.
Chronic kidney disease and cognitive impairment in menopausal women
Am J Kidney Dis
(2005)
L.P. Fried et al.
The Cardiovascular Health Study: Design and rationale
Ann Epidemiol
(1991)
M.F. Folstein et al.
Mini-Mental StateA practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975)
S.D. Denny et al.
Impact of anemia on mortality, cognition, and function in community-dwelling elderly
Am J Med
(2006)
M. Kivipelto et al.
Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study
Neurology
(2001)
D. Knopman et al.
Cardiovascular risk factors and cognitive decline in middle-aged adults
Neurology
(2001)
R.A. Whitmer et al.
Midlife cardiovascular risk factors and risk of dementia in late life
Neurology
(2005)
M. Kurella et al.
Chronic kidney disease and cognitive impairment in the elderly: The Health, Aging, and Body Composition Study
J Am Soc Nephrol
(2005)
S.L. Seliger et al.
Moderate renal impairment and risk of dementia among older adults: The Cardiovascular Health Cognition Study
J Am Soc Nephrol
(2004)
V.J. Howard et al.
The REasons for Geographic And Racial Differences in Stroke Study: Objectives and design
Neuroepidemiology
(2005)

There are more references available in the full text version of this article.

Cited by (305)

Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review
2024, Pharmacological Research
Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.
Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity
2024, American Journal of Kidney Diseases
Cystatin C–based estimated glomerular filtration rate (eGFR_cys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFR_cr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFR_cys with kidney and cardiovascular outcomes.
Cohort study.
27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study.
eGFR_cys, eGFR_cr, waist circumference, and body mass index (BMI).
All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF).
Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFR_cys with risks of 4 clinical outcomes.
Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFR_cys < 60 mL/min/1.73 m². The baseline prevalence of abdominal obesity (waist circumference ≥ 88 cm for women or ≥ 102 cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15 mL/min/1.73 m² lower eGFR_cys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI < 24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI ≥ 35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFR_cys with mortality, kidney failure, incident ASCVD, or incident HF (all P_interaction > 0.05).
Included only Black and White persons in the United States.
Obesity did not modify the association of eGFR_cys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.
Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C–based eGFR (eGFR_cys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFR_cys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFR_cys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.
Blood Pressure, Incident Cognitive Impairment, and Severity of CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
2023, American Journal of Kidney Diseases
Hypertension is a known risk factor for dementia and cognitive impairment. There are limited data on the relation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with incident cognitive impairment in adults with chronic kidney disease. We sought to identify and characterize the relationship among blood pressure, cognitive impairment, and severity of decreased kidney function in adults with chronic kidney disease.
Longitudinal cohort study.
3,768 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Baseline SBP and DBP were examined as exposure variables, using continuous (linear, per 10-mm Hg higher), categorical (SBP < 120 [reference], 120 to 140, > 140 mm Hg; DBP < 70 (reference), 70 to 80, > 80 mm Hg) and nonlinear terms (splines).
Incident cognitive impairment defined as a decline in Modified Mini-Mental State Examination (3MS) score to greater than 1 standard deviation below the cohort mean.
Cox proportional hazard models adjusted for demographics as well as kidney disease and cardiovascular disease risk factors.
The mean age of participants was 58 ± 11 (SD) years, estimated glomerular filtration rate (eGFR) was 44 mL/min/1.73 m² ± 15 (SD), and the median follow-up time was 11 (IQR, 7-13) years. In 3,048 participants without cognitive impairment at baseline and with at least 1 follow-up 3MS test, a higher baseline SBP was significantly associated with incident cognitive impairment only in the eGFR > 45 mL/min/1.73 m² subgroup (adjusted hazard ratio [AHR], 1.13 [95% CI, 1.05-1.22] per 10 mm Hg higher SBP]. Spline analyses, aimed at exploring nonlinearity, showed that the relationship between baseline SBP and incident cognitive impairment was J-shaped and significant only in the eGFR > 45 mL/min/1.73 m² subgroup (P = 0.02). Baseline DBP was not associated with incident cognitive impairment in any analyses.
3MS test as the primary measure of cognitive function.
Among patients with chronic kidney disease, higher baseline SBP was associated with higher risk of incident cognitive impairment specifically in those individuals with eGFR > 45 mL/min/1.73 m².
High blood pressure is a strong risk factor for dementia and cognitive impairment in studies of adults without kidney disease. High blood pressure and cognitive impairment are common in adults with chronic kidney disease (CKD). The impact of blood pressure on the development of future cognitive impairment in patients with CKD remains unclear. We identified the relationship between blood pressure and cognitive impairment in 3,076 adults with CKD. Baseline blood pressure was measured, after which serial cognitive testing was performed over 11 years. Fourteen percent of participants developed cognitive impairment. We found that a higher baseline systolic blood pressure was associated with an increased risk of cognitive impairment. We found that this association was stronger in adults with mild-to-moderate CKD compared with those with advanced CKD.
Risk Factors for Incident CKD in Black and White Americans: The REGARDS Study
2023, American Journal of Kidney Diseases
Little information exists on the incidence of and risk factors for chronic kidney disease (CKD) in contemporary US cohorts and whether risk factors differ by race, sex, or region in the United States.
Observational cohort study.
4,198 Black and 7,799 White participants aged at least 45 years, recruited from 2003 through 2007 across the continental United States, with baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m² and eGFR assessed again approximately 9 years later.
Age, sex, race (Black or White), region (“stroke belt” or other), education, income, systolic blood pressure, body mass index, diabetes, coronary heart disease, hyperlipidemia, smoking, and albuminuria.
(1) eGFR change and (2) incident CKD defined as eGFR <60 mL/min/1.73 m² and ≥40% decrease from baseline or kidney failure.
Linear regression and modified Poisson regression were used to determine the association of risk factors with eGFR change and incident CKD overall and stratified by race, sex, and region.
Mean age of participants was 63 ± 8 (SD) years, 54% were female, and 35% were Black. After 9.4 ± 1.0 years of follow-up, CKD developed in 9%. In an age-, sex-, and race-adjusted model, Black race (β = −0.13; P < 0.001) was associated with higher risk of eGFR change, but this was attenuated in the fully adjusted model (β = 0.02; P = 0.5). Stroke belt residence was independently associated with eGFR change (β = −0.10; P < 0.001) and incident CKD (relative risk, 1.14 [95% CI, 1.01-1.30]). Albuminuria was more strongly associated with eGFR change (β of −0.26 vs −0.17; P = 0.01 for interaction) in Black compared with White participants. Results were similar for incident CKD.
Persons of Hispanic ethnicity were excluded; unknown duration and/or severity of risk factors.
Established CKD risk factors accounted for higher risk of incident CKD in Black versus White individuals. Albuminuria was a stronger risk factor for eGFR decrease and incident CKD in Black compared with White individuals. Living in the US stroke belt is a novel risk factor for CKD.
Kidney Disease and Brain Health: Current Knowledge and Next Steps
2023, American Journal of Kidney Diseases
Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk
2022, Journal of Diabetes and its Complications
We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes.
Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up.
CKD at baseline was more common in CARMELINA than CAROLINA (eGFR<60 in 72.6 % and 19.6 %, macroalbuminuria in 35.0 % and 4.1 %, respectively). Baseline eGFR was related to A&E in CARMELINA (b = 0.02 per 10 ml/min/1.73m², 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = −0.01 per doubling of UACR mg/g, 95%CI [−0.02,−0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = −0.01, 95%CI [−0.03,−0.0001] per doubling of UACR mg/g).
eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting.
NCT01897532
NCT01243424

View all citing articles on Scopus

: Originally published online as doi:10.1053/j.ajkd.2008.05.004 on June 27, 2008.

View full text

Original InvestigationPathogenesis and Treatment of Kidney DiseaseKidney Function and Cognitive Impairment in US Adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study

Background

Study Design

Setting & Participants

Predictor

Outcome

Measurements

Results

Limitations

Conclusions

Section snippets

Study Design

Results

Discussion

Acknowledgements

Am J Kidney Dis

Ann Epidemiol

J Psychiatr Res

Am J Med

Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study

Neurology

Cardiovascular risk factors and cognitive decline in middle-aged adults

Neurology

Midlife cardiovascular risk factors and risk of dementia in late life

Neurology

Chronic kidney disease and cognitive impairment in the elderly: The Health, Aging, and Body Composition Study

J Am Soc Nephrol

Moderate renal impairment and risk of dementia among older adults: The Cardiovascular Health Cognition Study

J Am Soc Nephrol

The REasons for Geographic And Racial Differences in Stroke Study: Objectives and design

Neuroepidemiology

Original Investigation
Pathogenesis and Treatment of Kidney Disease
Kidney Function and Cognitive Impairment in US Adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study