Chronic Kidney Disease is Associated with Cognitive Decline: the Northern Manhattan Study (NOMAS) Seattle VA Chief of Medicine Rounds June 9, 2009

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1 Chronic Kidney Disease is Associated with Cognitive Decline: the Northern Manhattan Study (NOMAS) Seattle VA Chief of Medicine Rounds June 9, 2009 Minesh Khatri Internal Medicine R2

2 Background Patients with end stage renal disease (ESRD) have an increased burden of vascular disease In fact, they have up to 30 times increased risk of adverse vascular events as compared to the general population. In recent years, moderate chronic kidney disease (CKD) has emerged as an independent risk factor for vascular disease as well.

3 Complications of CKD Source: Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:

4 CKD: the Growing Epidemic Prevalence of CKD is 13% 26 million US adults in 2000 CKD Prevalence: NHANES From 1991 to 2004, the number of people on renal replacement therapy has more than doubled Coresh, et al. Prevalence of Chronic Kidney Disease in the United States. JAMA. 2007;298(17):

CKD and Cerebrovascular Disease Prior analyses of the Northern

of stroke, and an increased burden of white matter disease White

cognitive decline, and dementia Source: Khatri M, et al. Stroke.

5 CKD and Cerebrovascular Disease Prior analyses of the Northern Manhattan Study have shown that CKD carries a 43% increased risk of stroke, and an increased burden of white matter disease White matter disease: associated with increased risk of stroke, cognitive decline, and dementia Source: Khatri M, et al. Stroke Dec;38(12): Nickolas T, et al. Stroke Oct;39(10):2876-9

6 CKD and Cognition Cognitive impairment and dementia have huge emotional and economic costs to society Prevalence of cognitive impairment is high in an ESRD population, but less is known about mild-moderate CKD Current studies limited by: cross-sectional design lack of race-ethnic diversity less precise estimates of kidney function

7 Hypothesis Is there a longitudinal association between chronic kidney disease and cognitive decline in a multi-ethnic population?

9 Methods Cognitive testing was instituted in 2001 Assessed using the modified telephone interview for cognitive status (TICS-m) Re-administered annually Baseline kidney function was estimated using: Cockcroft-Gault creatinine clearance (CCl) MDRD estimated glomerular filtration rate (egfr) Serum creatinine

10 Methods Analyses performed using mixed effects modeling, adjusting for a variety of confounders Subjects excluded from study if: missing kidney function or cognition data prevalent stroke TICS-m scores censored after incident strokes Outcome variable: change in TICS-m score over time

11 Results Data available on 2,172 subjects Mean follow-up time: 2.9 years Demographics: mean age at baseline TICS-m was 72 yrs 63% women 59% Hispanics, 20% blacks, and 18% whites Distribution of kidney function (CCl): ml/min : 23% ml/min : 47% > 90 ml/min : 30%

education, hypertension, diabetes, total homocysteine,

12 Multivariate Analyses ** Adjusted for age, gender, race, time between TICS-m testing, insurance status, education, hypertension, diabetes, total homocysteine, alcohol consumption, smoking status, and history of cardiac disease

13 Results Sensitivity analyses performed No significant changes with certain medications, anemia, or ApoE alleles A smaller effect of CKD on cognition for Hispanics compared to whites with egfr, while there was a trend with CCl

14 Biological Plausibility Patients with CKD have Clustering of traditional cardiovascular risk factors Endothelial dysfunction Oxidative stress Uremic toxins (ADMA) (Valkonen et al, Lancet 2001) Inhibits NO synthesis (powerful regulator of cerebral blood flow) Inflammation Hyperparathyroidism Anemia

15 Limitations One measure of creatinine only No urinary protein Lack of in-depth neuropsychiatric testing Relatively short follow-up time Survivor bias Lack of power to specifically explore race interactions No dementia subtyping

16 Strengths Longitudinal study with multiple annual follow-ups Several estimates of kidney function Racially diverse, population-based cohort Use of the modified TICS

17 Conclusions Kidney disease is a growing epidemic with farreaching consequences CKD may be an independent risk factor for cognitive decline, which may start even with mild impairments of kidney function An assessment of cognitive function should be considered in the evaluation of patients with CKD Further research is needed to better characterize this association and possible mechanisms, which may potentially provide a target for therapeutic intervention

18 Acknowledgments Ralph Sacco Thomas Nickolas Bernadette Boden-Albala Clinton Wright Yeseon Moon Mitchell Elkind Myunghee Paik Pascal Goldschmidt Deb Schwinn Ann-Marie Schmidt Sarnoff Endowment

Harborview Lunch Conference June 17, Minesh Khatri Internal Medicine R1

The Effects of Kidney Disease on the Brain: an Epidemiological Perspective Harborview Lunch Conference June 17, 2008 Minesh Khatri Internal Medicine R1 What does this have to do with this? Background Patients