CLINICAL EPIDEMIOLOGY www.jasn.

org

CKD Associates with Cognitive Decline

Minesh Khatri,* Thomas Nickolas,† Yeseon P. Moon,‡ Myunghee C. Paik,‡ Tatjana Rundek,§
Mitchell S. V. Elkind,储 Ralph L. Sacco,§ and Clinton B. Wright§
*Department of Internal Medicine, University of Washington, Seattle, Washington; †Division of Nephrology,
Department of Medicine, and 储Division of Stroke, Department of Neurology, College of Physicians and Surgeons of
Columbia University, New York, New York; ‡Department of Biostatistics, Mailman School of Public Health, Columbia
University, New York, New York; and §Divisions of Stroke and Cognitive Disorders and the Evelyn F. McKnight
Center for Age-Related Memory Loss, Department of Neurology, Miller School of Medicine, University of Miami,
Miami, Florida

ABSTRACT
Cognitive impairment and chronic kidney disease (CKD) will become increasingly prevalent in the aging US
population. Although evidence exists that CKD is a risk factor for cognitive decline, longitudinal studies are
limited and largely have excluded ethnically diverse populations. The Northern Manhattan Study includes a
population-based, prospective, stroke-free cohort. We assessed global cognitive function annually using the
modified Telephone Interview for Cognitive Status (TICS-m) and estimated kidney function using Cockcroft–
Gault creatinine clearance (CCl), Modification of Diet in Renal Disease estimated GFR (eGFR), and serum
creatinine (sCr). We examined the association between CKD and change in TICS-m scores over time,
adjusting for sociodemographic and vascular risk factors. Of 2172 subjects (mean age 71.5 yr, mean follow-up

CLINICAL EPIDEMIOLOGY
2.9 yr), 59% were Hispanic, 20% were black, and 63% were women. Participants with a CCl ⬍60 ml/min and
those with a CCl between 60 and 90 ml/min performed significantly worse on the TICS-m over time than
those with a CCl ⬎90 ml/min, adjusting for potential confounders. Our results were similar when we used
eGFR or sCr to estimate kidney function. In conclusion, decreased kidney function associates with greater
cognitive decline, even in those with mild CKD. Kidney disease may represent a novel mechanism leading to
cognitive impairment and a target for early intervention.

J Am Soc Nephrol 20: 2427–2432, 2009. doi: 10.1681/ASN.2008101090

In recent years, the impact of chronic kidney dis- Cardiovascular Health Study (CHS) and the Rea-
ease (CKD) on cardiovascular disease has be- sons for Geographic and Racial Differences in
come evident,1,2 and this has paved the way for Stroke study included African Americans,11 but
investigations of CKD in relation to diseases to our knowledge no studies included Hispanics.
where cardiovascular risk factors may play a The purpose of this study was to examine mild
causal role. In particular, vascular cognitive dis- and moderate CKD as a predictor of cognitive
orders3– 8 are important because of the staggering decline in a longitudinal multiethnic urban co-
financial and social tolls of cognitive impairment hort that includes black and Hispanic partici-
and dementia, costs that will only rise in our ag-
ing population.9,10 Most studies that have exam- Received October 20, 2008. Accepted July 2, 2009.
ined the relationship between CKD and cogni-
Published online ahead of print. Publication date available at
tion have been cross-sectional and have not www.jasn.org.
considered mildly reduced renal function [i.e.,
Correspondence: Dr. Clinton Wright, Department of Neurology,
estimated GFR (eGFR) between 60 and 90 ml/ Miller School of Medicine, University of Miami, 1120 NW 14th
min3–5,7,8] or have used imprecise estimates of Street, CRB 1349, Miami, FL 33136. Phone: 305-243-1664; Fax:
kidney function.6 In addition, most study popu- 305-243-1680; E-mail: cwright@med.miami.edu

lations have been predominantly white. Both the Copyright 䊚 2009 by the American Society of Nephrology

J Am Soc Nephrol 20: 2427–2432, 2009 ISSN : 1046-6673/2011-2427 2427

 CLINICAL EPIDEMIOLOGY www.jasn.org

pants with an elevated risk of dementia and cardiovascular ing (16% versus 19%, P ⫽ 0.03), and alcohol abstention (64%
disease.12,13 versus 74%, P ⬍ 0.0001).
Baseline characteristics of this sample are shown in Table 1,
grouped by both creatinine clearance (CCl) and eGFR levels.
RESULTS Only three participants would be considered to have ESRD
defined by a CCl (n ⫽ 2) or eGFR (n ⫽ 1) of ⬍15 ml/min
The Northern Manhattan Study (NOMAS) includes a pro- (0.1%). Those with worse kidney function tended to be older,
spective cohort with 3298 participants at baseline, and com- female, non-Hispanic, and more educated. A higher propor-
plete data for estimates of kidney and cognitive function were tion of these participants also had cardiac disease and elevated
available for 3029 participants. Of these, 857 participants had tHcy, but a lower proportion had diabetes. A significantly
either died or suffered strokes before their first modified Tele- higher proportion of subjects with low eGFR had hypertension
phone Interview for Cognitive Status (TICS-m), leaving 2172 but not when CCl was used as the metric for kidney disease.
participants for this analysis. Compared with those not in- Table 2 shows coefficients for (1) the annual change in
cluded (n ⫽ 1126), participants in the current sample were TICS-m scores for each measure of kidney function (Table 2,
younger (mean age 66 versus 75 yr, P ⬍ 0.0001) and more likely unadjusted), (2) further adjusted for sociodemographic vari-
to be Hispanic (59% versus 39%, P ⬍ 0.001) and have Medicaid ables (Model 1), and (3) further adjusted for vascular risk fac-
(46% versus 40%, P ⫽ 0.01). The sample was also healthier, tors (Model 2). In our fully adjusted model, participants with a
with a lower baseline creatinine (mean 0.9 versus 1.1 mg/dl, baseline CCl ⬍60 ml/min declined by an average of 0.4 points
P ⬍ 0.0001), lower total homocysteine (tHcy; 2.2 versus 2.4 per year in their TICS-m scores compared with those with a
nmol/L, P ⬍ 0.0001), and lower prevalences of hypertension CCl ⬎90 ml/min (P ⬍ 0.001), whereas those with a CCl be-
(72% versus 77%, P ⫽ 0.01), diabetes (19% versus 27%, P ⬍ tween 60 and 90 ml/min declined by an average of 0.2 points
0.0001), cardiac disease (21% versus 31%, P ⬍ 0.0001), smok- per year (P ⬍ 0.001; Table 2). The results for eGFR were similar

Table 1. Baseline characteristics

Creatinine clearance Estimated GFR
<60 ml/min 60 –90 ml/min >90 ml/min P <60 ml/min 60 –90 ml/min >90 ml/min P
N 503 (23%) 1027 (47%) 642 (30%) 291 (13%) 1241 (57%) 640 (29%)
Demographics
Age at baseline TICS-m 80 (8.1) 71 (7.8) 66 (6.9) ⬍0.001 76 (9.4) 72 (9.1) 68 (8.1) ⬍0.001
(SD)
Women 72% 61% 60% ⬍0.001 69% 64% 59% 0.018
Completed high school 54% 44% 45% ⬍0.001 44% 47% 46% 0.699
Medicaid 36% 48% 48% ⬍0.001 48% 44% 48% 0.098
Race ⬍0.001 ⬍0.001
White 28% 16% 14% 24% 21% 10%
Black 28% 19% 16% 14% 19% 25%
Hispanic 41% 62% 69% 59% 58% 63%
Other 3% 2% 2% 2% 2% 2%
Medical history
Cardiac disease 28% 20% 17% ⬍0.001 29% 21% 16% ⬍0.001
Hypertension 74% 70% 74% 0.246 86% 71% 68% ⬍0.001
Systolic blood pressure, 144.9 (22.9) 142.2 (19.9) 143.1 (20.9) 0.062 147.4 (22.2) 143.1 (20.8) 141.0 (20.3) ⬍0.001
mmHg (SD)
Diastolic blood pressure, 80.9 (11.5) 83.8 (10.8) 85.8 (10.8) ⬍0.001 83.8 (11.3) 83.8 (11.5) 83.6 (10.3) 0.923
mmHg (SD)
Diabetes 15% 18% 24% ⬍0.001 21% 17% 22% 0.045
Total homocysteine ⬍0.001 ⬍0.001
⬍8.4 ␮mol/L 27% 43% 57% 19% 40% 61%
8.4–12 ␮mol/L 45% 43% 34% 46% 45% 31%
⬎12 ␮mol/L 28% 13% 9% 34% 15% 8%
Moderate alcohol 32% 37% 38% 0.133 33% 36% 37% 0.368
consumption
Smoking status
Former smoker 34% 35% 36% 0.261 37% 35% 35% 0.094
Current smoker 14% 17% 17% 14% 15% 20%
Baseline TICS-m score (SD) 29.1 (6.8) 30.6 (6.2) 31.8 (6.7) ⬍0.001 29.6 (6.8) 30.6 (6.4) 31.1 (6.7) 0.040
TICS-m, modified Telephone Interview for Cognitive Status.

2428 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 2427–2432, 2009
 www.jasn.org CLINICAL EPIDEMIOLOGY

Table 2. Kidney function and modified Telephone slightly smaller impact on cognitive function over time in His-
Interview for Cognitive Status score panics compared with whites. This association was NS when
Parameter estimate creatinine was used as the metric but showed a trend that did
P
(95% confidence interval)a not reach statistical significance for CCl. Blood pressure can
Trichotomized creatinine clearance impact cognition, so we examined systolic and diastolic BP
Unadjusted continuously using linear and quadratic terms. This did not
CCl ⬍60 ml/min ⫺0.319 (⫺0.460, ⫺0.179) ⬍0.001 alter our findings regarding the association between cognition
CCl 60–90 ml/min ⫺0.164 (⫺0.274, ⫺0.054) 0.004 and kidney function (data not shown). Anemia can also have a
CCl ⬎90 ml/min Reference negative impact on cognition, but adjusting for hematocrit did
Model 1b not affect our results. Finally, we investigated the use of certain
CCl ⬍60 ml/min ⫺0.332 (⫺0.471, ⫺0.192) ⬍0.001
medications that are known to be psychoactive (antidepres-
CCl 60–90 ml/min ⫺0.171 (⫺0.281, ⫺0.062) 0.002
sants, benzodiazepines, ␤-blockers, and antipsychotics) and
CCl ⬎90 ml/min Reference
Model 2c
found that inclusion of these variables in our models did not
CCl ⬍60 ml/min ⫺0.365 (⫺0.511, ⫺0.220) ⬍0.001 change our results and there was no interaction between use of
CCl 60–90 ml/min ⫺0.196 (⫺0.310, ⫺0.083) ⬍0.001 these medications and kidney function.
CCl ⬎90 ml/min Reference
Trichotomized estimated GFR
Unadjusted DISCUSSION
eGFR ⬍60 ml/min ⫺0.268 (⫺0.432, ⫺0.104) 0.001
eGFR 60–90 ml/min ⫺0.126 (⫺0.234, ⫺0.019) 0.022 In this prospective cohort study in a multiethnic stroke-free
eGFR ⬎90 ml/min Reference population, we found that CKD was associated with cognitive
Model 1b
decline and that this relationship extended to those with mildly
eGFR ⬍60 ml/min ⫺0.254 (⫺0.417, ⫺0.091) 0.002
reduced eGFR or CCl.
eGFR 60–90 ml/min ⫺0.130 (⫺0.238, ⫺0.023) 0.017
eGFR ⬎90 ml/min Reference
These results add to the growing body of literature identi-
Model 2c fying an association between kidney disease and cognition.
eGFR ⬍60 ml/min ⫺0.320 (⫺0.492, ⫺0.148) ⬍0.001 Several studies have shown an elevated risk of dementia in
eGFR 60–90 ml/min ⫺0.159 (⫺0.270, ⫺0.048) 0.005 patients with ESRD.14 –16 Longitudinal studies on mild to mod-
eGFR ⬎90 ml/min Reference erate CKD have included an analysis of the CHS, that found
Continuous serum creatinine (per 0.1 mg/dl increase) that an elevated sCr carried a 37% increased risk of incident
Unadjusted ⫺0.027 (⫺0.047, ⫺0.006) 0.010 dementia.6 In the Health, Aging, and Body Composition
Model 1b ⫺0.030 (⫺0.050, ⫺0.010) 0.004 Study, those with an eGFR ⬍60 ml/min had a worse baseline
Model 2c ⫺0.040 (⫺0.061, ⫺0.018) ⬍0.001 modified Mini-Mental Status Examination score and had
a
Parameter estimate represents average point decline per year in modified
Telephone Interview for Cognitive Status score.
higher rates of cognitive impairment over 2 to 4 yr of follow
b
Model 1: adjusted for age, gender, race, education, and insurance status. up.5 Furthermore, the odds of cognitive decline were higher in
c
Model 2: adjusted for covariates in model 1 plus hypertension, diabetes, total those with eGFR ⬍45 ml/min, as compared with those with
homocysteine, alcohol consumption, smoking status, and history of cardiac
disease.
eGFR between 45 and 60 ml/min. Our study demonstrates a
dose–response relationship with cognitive decline that begins
with even milder impairments in kidney function (CCl or
(Table 2). We noted a dose–response relationship between eGFR between 60 and 90 ml/min).
progressively lower kidney function and greater cognitive de- The longitudinal nature of this study and the dose–response
cline. In addition, for each 0.1 mg/dl increase in baseline serum relationship observed strengthen the premise that CKD is an
creatinine (sCr), TICS-m scores declined an average of 0.04 independent risk factor for cognitive decline. A variety of po-
points per year (P ⬍ 0.001; Table 2). Including baseline tential mechanisms support this hypothesis. Most likely, CKD,
TICS-m scores in the models did not alter our findings. through its adverse effects on the cerebral vasculature, poten-
To put these parameter estimates in perspective, we exam- tiates vascular cognitive impairment (VCI). We have shown
ined changes in TICS-m score with age. Scores declined by previously that a CCl between 15 and 60 ml/min is indepen-
0.023 points per year. Thus, in our 60 to 90 ml/min CCl and dently associated with a 43% increase in stroke17 and greater
eGFR categories, declines on the TICS-m were equivalent to white matter disease,18 both of which are risk factors for de-
aging roughly 8 yr and were more pronounced for those with mentia and VCI.15,19 –21 In this study, subjects were stroke-free
worse kidney function. Of note, the effect of aging on TICS-m at baseline, and we censored TICS-m scores if they occurred
scores is not linear, and this approximation is most valid close after an incident stroke. Thus, if kidney disease caused cogni-
to the mean age (71 yr). tive decline, then it must have been through subclinical vascu-
We included interaction terms between variables for race- lar damage or a nonvascular mechanism.
ethnicity and the three estimates of kidney function (sCr, con- Another biologically plausible mechanism involves inflam-
tinuous CCl, and continuous eGFR). Lower eGFR had a mation, which is often greater in a CKD population.22,23 For

J Am Soc Nephrol 20: 2427–2432, 2009 Mild CKD and Cognitive Decline 2429
 CLINICAL EPIDEMIOLOGY www.jasn.org

example, total homocysteine is inversely related to kidney been used in other large studies where in-person examination
function,24 and it also may contribute to cognitive impair- is not practical.44,45 Fourth, NOMAS is a population-based
ment.25,26 Although we adjusted for serum tHcy, we did not multiethnic cohort that allows some generalization to blacks
account for other inflammatory markers that could mediate and Hispanics and an urban US population.
cognitive decline, such as IL-6.27 In recent years, basic and In conclusion, we found that CKD is linearly associated
clinical research has supported a causal role for inflammation, with cognitive decline in a multiethnic urban population, ad-
endothelial dysfunction, and oxidative stress in the develop- justing for multiple risk factors. This relationship existed for
ment of vascular disease.28 –31 These derangements are all char- those with mildly reduced kidney function and may be atten-
acteristic of CKD32,33 and further support the kidney’s hypoth- uated in Hispanics compared with whites. Our study adds to
esized role in VCI and Alzheimer’s disease, where the same the growing evidence that kidney disease is a risk factor for
processes may be at work.34 –38 Ours is not a dementia study, cognitive decline and provides a potential novel target for in-
nor do we have data on its subtypes. However, limited data hint tervention to lower the risk of dementia in those also at risk of
at a greater role for CKD in the development of vascular de- CKD. Future studies are needed to address the mechanism by
mentia over Alzheimer’s disease,6 although more research is which CKD might affect cognition, the cognitive domains spe-
needed to clarify these relationships. cifically affected, differential effects of race– ethnicity and age
Another possible mediator is anemia, which is usually found at on this association, and the effects of interventions to slow
more advanced stages of CKD and also is associated with demen- CKD-related cognitive dysfunction.
tia.39 – 41 In fact, the reversal of anemia has been associated with an
improvement in cognitive function.42 However, adjusting for he-
matocrit did not alter our results for any measure of kidney func- CONCISE METHODS
tion, indicating that the underlying mechanisms related to CKD
in this sample are independent of anemia. Cohort
This study has several limitations. First, we relied only on The NOMAS is a population-based, prospective cohort of 3298 sub-
one sCr measurement per subject and did not have repeat mea- jects recruited from northern Manhattan between 1993 and 2001. The
surements to assess change in kidney function. Second, we details of enrollment have been described elsewhere.46 Briefly, com-
lacked urine samples to identify participants with albuminuria munity participants were eligible if they met the following conditions:
as their only manifestation of CKD, and this is relevant because (1) no history of stroke, (2) age greater than or equal to 40 yr, and (3)
albuminuria has been associated with cognitive decline.43 residence in a household with a telephone for at least 3 mo in northern
Third, the Modification of Diet in Renal Disease (MDRD) and Manhattan. The TICS-m, a global test of cognition, was added to our
Cockcroft–Gault formulas are less accurate when the true GFR annual follow-up assessment beginning in 2001 and administered
is ⬎60 ml/min. Although more accurate formulas to estimate yearly.
function are under development and validation and biomark-
ers such as cystatin C show promise, none is currently in clin- Baseline Evaluation and Follow-Up
ical use. To minimize misclassification in those with GFR ⬎60 Trained bilingual research assistants and study physicians collected
ml/min, we used both formulas in addition to the sCr to esti- demographic, medical, and laboratory data at enrollment using stan-
mate kidney function. We employed this approach to demon- dardized data collection techniques and risk factor questions based on
strate the consistency of our results across methods of estimat- the Centers for Disease Control and Prevention Behavioral Risk Fac-
ing kidney function and for internal validation. Also, this tor Surveillance System. Subjects were contacted annually via tele-
sample may have been biased due to an inherent survivor effect phone starting in 1998 to gather information regarding illnesses, hos-
as participants were healthier than those not included at base- pitalizations, vital status, and cardiovascular events.
line, and the TICS-m was not administered to subjects until
several years into the study. However, this most likely would Estimation of Kidney Function
have reduced the apparent effect of kidney function on cogni- Baseline kidney function was estimated using sCr, CCl using the
tion. Finally, unmeasured confounding, stemming from insuf- Cockcroft–Gault formula, and eGFR using the MDRD formula:
ficient data on the length of exposure to vascular risk factors
such as hypertension or diabetes mellitus or on the severity of CCl ⫽ 共 140 ⫺ age)
underlying vascular disease, are limitations. ⫻ (weight in kg)/(serum creatinine ⫻ 72)
Despite these limitations, there are several strengths to this
study. First, this was a longitudinal study with repeated assess- ⫻ (0.85 for women)
ments of cognition supporting a causal role of CKD in cogni-
tive decline. Second, because there is no consensus on the pre- eGFR ⫽ 186.3 ⫻ 共 serum creatinine⫺1.154)
ferred method of estimating kidney function in Hispanics, we ⫻ (age⫺0.203) ⫻ (0.742 for women) ⫻ (1.21 for blacks)
used three different estimations of kidney function, which
were all in agreement. Third, we assessed cognition using the Serum creatinine was treated as a continuous variable. Further-
TICS-m, a tool that is not constrained by ceiling effects and has more, CCl and eGFR were trichotomized as follows: ⬍60 ml/min, 60

2430 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 2427–2432, 2009
 www.jasn.org CLINICAL EPIDEMIOLOGY

to 90 ml/min, and ⬎90 ml/min (reference). Serum creatinine was ACKNOWLEDGMENTS

measured by the kinetic Jaffe reaction. We did not include partici-
pants in this analysis if they were missing data to estimate any of the We thank the staff of the Northern Manhattan Study, in particular
three measures of kidney function (n ⫽ 82, 2.5%). Janet DeRosa, Project Manager. This work is supported by grants
from the National Institute of Neurological Disorders and Stroke
(R01 NS 29993 and K02 NS059729), the American Heart Association
Cognitive Assessment (0735387N), and the Irving General Clinical Research Center (M01
As a global measure, the TICS-m was designed to assess a variety of
RR00645). M.K. was supported by a grant from the Sarnoff Cardio-
cognitive domains, including attention, language, calculation, and
vascular Research Foundation. C.B.W. is supported by the Evelyn F.
immediate recall of ten words.47 The TICS-m includes a delayed recall
McKnight Center for Age-Related Memory Loss.
of the ten words and has been validated in clinical and research set-
tings.44,47,48 Only 187 participants did not have TICS-m evaluations
(5.6%). Incomplete TICS-m tests were not analyzed, because the total
DISCLOSURES
score is not valid.
None.

Other Covariate Measures

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2432 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 2427–2432, 2009