The Cognition–Kidney Disease Connection: Lessons From Population-Based Studies in the United States

Abstract

Related Articles, p. 216 & p. 227 Related Articles, p. 216 & p. 227 As the proportion of elderly individuals in the US population rises, chronic diseases that affect the elderly are assuming increasing importance; these conditions include both chronic kidney disease (CKD) and cognitive impairment.1Castro A, Coresh J: CKD surveillance using laboratory data and population-based surveys (NHANES). Am J Kidney Dis (in press)Google Scholar, 2Plassman B.L. Langa K.M. Fisher G.G. et al.Prevalence of cognitive impairment without dementia in the United States.Ann Intern Med. 2008; 148: 427-434Crossref PubMed Scopus (639) Google Scholar In this issue of the American Journal of Kidney Diseases, researchers explore the relationship between these 2 conditions in large, population-based, elderly US cohorts.3Barzilay J.I. Fitzpatrick A.L. Luchsinger J. et al.Albuminuria and dementia in the elderly: A community study.Am J Kidney Dis. 2008; 52: 216-226Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 4Kurella Tamura M. Wadley V. Yaffe K. et al.Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.Am J Kidney Dis. 2008; 52: 227-234Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar Both studies reveal an independent and graded association between CKD and cognitive functioning; but what is the basis and the significance of the cognition–kidney disease connection? Cognitive impairment describes a spectrum of disease ranging from minimal cognitive deficits that may occur with relatively normal aging to mild cognitive impairment to severe dementia; the most common causes of cognitive impairment and dementia are Alzheimer disease pathology, cerebrovascular disease, or a combination of these. The estimated prevalence of mild cognitive impairment, defined as cognitive decline greater than expected for an individual's age and education level that does not interfere notably with activities of daily life, ranges from 3% to 20% in individuals aged 65 years and older.5Gauthier S. Reisberg B. Zaudig M. et al.Mild cognitive impairment.Lancet. 2006; 367: 1262-1270Abstract Full Text Full Text PDF PubMed Scopus (1814) Google Scholar Dementia is characterized by acquired impairment in multiple behavioral and neuropsychological domains including memory, language and speech, visuospatial ability, cognition, and mood or personality, with the requirement that this impairment interfere with daily activities; dementia prevalence in the United States is as high as 6% to 10% among individuals aged 65 years and older.6Chapman D.P. Williams S.M. Strine T.W. Anda R.F. Moore M.J. Dementia and its implications for public health.Prev Chronic Dis. 2006; 3: A34PubMed Google Scholar While over half of dementia cases are classified as Alzheimer disease, where memory is more prominently affected, the majority of non-Alzheimer dementia is related to vascular causes. Differentiating between Alzheimer disease and vascular dementia is often difficult, as there is likely significant overlap between these entities, with vascular lesions modifying Alzheimer disease expression and vice versa.7O'Brien J.T. Erkinjuntti T. Reisberg B. et al.Vascular cognitive impairment.Lancet Neurol. 2003; 2: 89-98Abstract Full Text Full Text PDF PubMed Scopus (1010) Google Scholar Cognitive impairment may be due to vascular disease alone, and, in the setting of repeated vascular insults, may progress to vascular dementia. Accordingly, cognitive impairment due to vascular disease may exhibit a step-wise onset, frequently develops in the absence of clinically recognized stroke, occurs in the setting of small-vessel cerebrovascular disease often without focal neurologic deficits, and typically manifests with executive function deficits (eg, managing and adjusting a medication regimen).8Emery V.O. Gillie E.X. Smith J.A. Interface between vascular dementia and Alzheimer syndrome Nosologic redefinition.Ann N Y Acad Sci. 2000; 903: 229-238Crossref PubMed Scopus (10) Google Scholar Brain imaging in individuals with cognitive impairment can reveal large volume infarcts, lacunes, leukoaraiosis (synonymous with white matter disease), and any combination of the above, all of which could suggest a cerebrovascular etiology.5Gauthier S. Reisberg B. Zaudig M. et al.Mild cognitive impairment.Lancet. 2006; 367: 1262-1270Abstract Full Text Full Text PDF PubMed Scopus (1814) Google Scholar, 9de Leeuw F.E. De Groot J.C. Oudkerk M. et al.Aortic atherosclerosis at middle age predicts cerebral white matter lesions in the elderly.Stroke. 2000; 31: 425-429Crossref PubMed Scopus (98) Google Scholar, 10de Leeuw F.E. Richard F. de Groot J.C. et al.Interaction between hypertension, apoE, and cerebral white matter lesions.Stroke. 2004; 35: 1057-1060Crossref PubMed Scopus (156) Google Scholar CKD is a risk state for cardiovascular disease and cerebrovascular disease in large part because of the high prevalence of traditional cardiovascular disease risk factors in patients with reduced kidney function, including older age, diabetes, hypertension, and dyslipidemia.11Weiner D.E. Tabatabai S. Tighiouart H. et al.Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease.Am J Kidney Dis. 2006; 48: 392-401Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 12Weiner D.E. Tighiouart H. Elsayed E.F. et al.The Framingham predictive instrument in chronic kidney disease.J Am Coll Cardiol. 2007; 50: 217-224Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Like CKD, cognitive impairment is also associated with cardiovascular disease risk factors. Hypertension, diabetes, and dyslipidemia are all associated with cognitive decline,13Knopman D. Boland L.L. Mosley T. et al.Cardiovascular risk factors and cognitive decline in middle-aged adults.Neurology. 2001; 56: 42-48Crossref PubMed Scopus (727) Google Scholar, 14Kalmijn S. Foley D. White L. et al.Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men The Honolulu-Asia aging study.Arterioscler Thromb Vasc Biol. 2000; 20: 2255-2260Crossref PubMed Scopus (328) Google Scholar, 15Curb J.D. Rodriguez B.L. Abbott R.D. et al.Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance.Neurology. 1999; 52: 971-975Crossref PubMed Google Scholar, 16Petrovitch H. White L. Masaki K.H. et al.Influence of myocardial infarction, coronary artery bypass surgery, and stroke on cognitive impairment in late life.Am J Cardiol. 1998; 81: 1017-1021Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar most notably in the setting of small-vessel cerebrovascular disease.17Ross G.W. Petrovitch H. White L.R. et al.Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study.Neurology. 1999; 53: 337-343Crossref PubMed Google Scholar The relationship between nonvascular dementia, specifically Alzheimer disease, and both cerebrovascular disease and vascular disease risk factors is less clear, with some studies showing no association between cognition and hypertension18Morris M.C. Scherr P.A. Hebert L.E. Glynn R.J. Bennett D.A. Evans D.A. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study.Arch Neurol. 2001; 58: 1640-1646Crossref PubMed Scopus (177) Google Scholar, 19Posner H.B. Tang M.X. Luchsinger J. Lantigua R. Stern Y. Mayeux R. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function.Neurology. 2002; 58: 1175-1181Crossref PubMed Scopus (271) Google Scholar, 20in't Veld B.A. Ruitenberg A. Hofman A. Stricker B.H. Breteler M.M. Antihypertensive drugs and incidence of dementia: the Rotterdam Study.Neurobiol Aging. 2001; 22: 407-412Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar while others have found associations between cognitive impairment and traditional cardiovascular disease risk factors including hypertension and hyperlipidemia.21Kivipelto M. Helkala E.L. Laakso M.P. et al.Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study.BMJ. 2001; 322: 1447-1451Crossref PubMed Scopus (1267) Google Scholar, 22Skoog I. Lernfelt B. Landahl S. et al.15-year longitudinal study of blood pressure and dementia.Lancet. 1996; 347: 1141-1145Abstract PubMed Google Scholar Other risk factors may contribute—several studies have shown associations between nontraditional cardiovascular disease risk factors, including hyperhomocysteinemia and inflammation, with subsequent cognitive decline. Notably, these findings are less consistent than seen for traditional risk factors and studies did not typically account for kidney disease.23Schmidt R. Schmidt H. Curb J.D. Masaki K. White L.R. Launer L.J. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study.Ann Neurol. 2002; 52: 168-174Crossref PubMed Scopus (588) Google Scholar, 24Seshadri S. Beiser A. Selhub J. et al.Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.N Engl J Med. 2002; 346: 476-483Crossref PubMed Scopus (2783) Google Scholar Given the known associations of CKD with cardiovascular and cerebrovascular disease, it follows that CKD, defined by reduced glomerular filtration rate (GFR) and/or albuminuria, could be associated with further manifestations of cerebrovascular disease beyond overt stroke, namely cognitive impairment. As presented in Fig 1, this association may be mediated through factors intrinsic to or exacerbated by CKD, or may represent parallel manifestations of systemic vascular disease concurrently affecting 2 different vascular organs—the brain and the kidney—with albuminuria and reduced GFR both readily ascertained markers of systemic vascular disease. In this issue of AJKD, 2 large population-based studies further explore this connection. Barzilay et al examined the cross-sectional association between urine albumin-creatinine ratio and cognitive impairment in individuals from the Cardiovascular Health Study (CHS) who participated in the Cardiovascular Health Cognition Study.3Barzilay J.I. Fitzpatrick A.L. Luchsinger J. et al.Albuminuria and dementia in the elderly: A community study.Am J Kidney Dis. 2008; 52: 216-226Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar They first screened individuals using the Modified Mini-Mental State Examination (3MS) between 1991 and 1994 and later selectively administered a more extensive cognitive battery in 1998 and 1999 to all African American participants and the higher-risk white participants; 2,389 (74%) participants undergoing extensive cognitive testing had provided urine samples approximately 2 years prior to this testing, although 73 of these individuals were excluded as dementia diagnosis predated initial cognitive screening. The results of this study are impressive: with each doubling of urine albumin-creatinine ratio, the risk of mild cognitive impairment increased by 10% and dementia increased by 22% in univariate analysis. The association of albuminuria with dementia remained significant in multivariable analysis. This result is likely driven by vascular changes, as the authors further demonstrate that the presence of albumin-creatinine ratio greater than 30 mg/g is associated with higher white-matter hyperintensity grade and the strength of the association between albuminuria and dementia is higher for the vascular dementia subtype. There are weaknesses to this study, most notably the lack of concurrent assessment of cognitive function, albuminuria, and brain imaging. While this introduces potential ascertainment biases, these factors most likely bias toward not finding a relationship as dementia, albuminuria, and cerebrovascular disease are all risk factors for death. Kurella-Tamura et al examined the cross-sectional association between estimated GFR and cognitive impairment in individuals from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.4Kurella Tamura M. Wadley V. Yaffe K. et al.Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.Am J Kidney Dis. 2008; 52: 227-234Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar They assessed cognitive impairment in 23,405 people aged 65 and older using a relatively crude but easily administered tool—the 6-item screener—which includes 3 questions assessing orientation and 3 questions assessing memory; cognitive impairment was defined by 4 or fewer correct answers. Despite the limitations of this cognitive tool, the investigators found a sharp and graded rise in the prevalence of cognitive impairment at lower estimated GFR levels. In adjusted analyses, each 10-mL/min/1.73 m2 decrease in estimated GFR below 60 mL/min/1.73 m2 was associated with an 11% increase in prevalence of impairment (OR, 1.11; 95% confidence interval, 1.04 to 1.19). There are several weaknesses to this study, most notably the limitations of the cognitive assessment procedure which utilized a screening instrument rather than detailed neuropsychologic testing, limiting the ability to better define the severity and nature of cognitive impairment in the REGARDS participants. Prior to the studies by Barzilay et al and Kurella Tamura et al in this issue of AJKD, there were limited evaluations of cognition in individuals with kidney disease. In a prior study evaluating the CHS cohort, Seliger et al reported that kidney disease, defined by baseline serum creatinine greater than 1.3 mg/dL in women and greater than 1.5 mg/dL in men, was associated with an increased risk of developing vascular dementia but not Alzheimer dementia in elders who reported baseline good or excellent health.25Seliger S.L. Siscovick D.S. Stehman-Breen C.O. et al.Moderate renal impairment and risk of dementia among older adults: The Cardiovascular Health Cognition Study.J Am Soc Nephrol. 2004; 15: 1904-1911Crossref PubMed Scopus (268) Google Scholar This was an important finding as it offered information both on the prevalence of cognitive impairment and allowed hypothesis generation as to the mechanism of cognitive impairment in CKD; however, it also lacked concurrent ascertainment of imaging and cognition. Other notable work originates from the Health, Aging, and Body Composition Study (Health ABC), where Kurella Tamura et al noted poorer baseline performance on the 3MS examination as well as a steeper decline in performance on this test over 4 years among those elderly individuals with lower estimated GFR levels as compared to those with estimated GFR of at least 60 mL/min/1.73 m2.26Kurella M. Chertow G.M. Fried L.F. et al.Chronic kidney disease and cognitive impairment in the elderly: the health, aging, and body composition study.J Am Soc Nephrol. 2005; 16: 2127-2133Crossref PubMed Scopus (338) Google Scholar Lastly, cross-sectional investigations using National Health and Nutrition Examination Survey (NHANES) 1999-2002 data have evaluated the association between cognitive performance and kidney disease. In one report of NHANES 1999-2002 participants, microalbuminuria, defined by urine albumin-creatinine ratio of 30 to 300 mg/g was independently associated with poorer performance on the 2-minute Digit Symbol Substitution Test (DSST), but only in the setting of peripheral arterial disease.27Kuo H.K. Lin L.Y. Yu Y.H. Microalbuminuria is a negative correlate for cognitive function in older adults with peripheral arterial disease: results from the U.S. National Health and Nutrition Examination Survey 1999-2002.J Intern Med. 2007; 262: 562-570Crossref PubMed Scopus (25) Google Scholar In a second study, worse cognitive performance was noted among 39 NHANES III participants between the ages of 20 and 59 years with estimated GFR below 60 mL/min/1.73 m2 than among participants with intact kidney function of similar age.28Hailpern S.M. Melamed M.L. Cohen H.W. Hostetter T.H. Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III).J Am Soc Nephrol. 2007; 18: 2205-2213Crossref PubMed Scopus (146) Google Scholar This NHANES III study is limited by a very small sample size with CKD. The findings in both of these population-based studies are important and likely broadly generalizable, considerably expanding upon the prior work in this field. Essentially, these studies mark individuals with CKD as being at high risk for prevalent cognitive impairment. The implications, both for screening for cognition impairment as well as for care of individuals with CKD, are notable. For internists, neuropsychiatric specialists, and geriatricians, future prediction models could utilize albuminuria and reduced estimated GFR to help identify patients who could benefit from more detailed cognitive screening—a process that can take several hours per patient. For internists, nephrologists, and others caring for CKD patients, these studies raise awareness of an entirely new dimension of challenges. As management of chronic diseases becomes increasingly complex (for example, blood pressure and heart failure regimens routinely require 4 to 6 prescriptions), it is incumbent upon those caring for CKD patients to recognize that these individuals may have difficulty with medication regimens and care plans—and that nonadherence may not be by choice but rather reflect the more intrinsic barrier of understanding their own medical care. Although future projects should assess the association of albuminuria and GFR with incident cognitive impairment and dementia, this research is an important first step in identifying how our patients manage, or rather fail to manage, the complexities of modern, pharmaceutical-intensive chronic medical care. Support: None. Financial Disclosure: None. Albuminuria and Dementia in the Elderly: A Community StudyAmerican Journal of Kidney DiseasesVol. 52Issue 2PreviewDementia is associated with microvascular disease of the retina. In this study, we examine whether cognitive status (normal cognition, mild cognitive impairment, and dementia) is associated with albuminuria, a microvascular disorder of the kidney. Full-Text PDF Kidney Function and Cognitive Impairment in US Adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) StudyAmerican Journal of Kidney DiseasesVol. 52Issue 2PreviewThe association between kidney function and cognitive impairment has not been assessed in a national sample with a wide spectrum of kidney disease severity. Full-Text PDF