Cerebral Small Vessel Disease and Kidney Function Predict Long-Term Survival in Patients With Acute Stroke

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1 Cerebral Small Vessel Disease and Kidney Function Predict Long-Term Survival in Patients With Acute Stroke Niku K.J. Oksala, MD, PhD, DSc; Tapani Salonen, MD; Timo Strandberg, MD, PhD; Anni Oksala, MD; Tarja Pohjasvaara, MD, PhD; Markku Kaste, MD, PhD; Pekka J. Karhunen, MD, PhD; Timo Erkinjuntti, MD, PhD Background and Purpose Cerebral small vessel disease reflected by white matter lesions (WMLs) in MRI and kidney function reflected by estimated glomerular filtration rate (egfr) is closely associated in patients without stroke. We studied whether egfr and WMLs predict long-term survival in patients with acute stroke. Methods After exclusion of patients with low egfr (N 5 [1.3%]; 30 ml/min/1.73 m 2 ), consecutive patients with acute stroke (N 378) subjected to MRI and serum creatinine determination were included in the study and prospectively followed-up up to 12 years. Results Of the patients, 71.2% had died during the follow-up, 152 (40.2%) had moderate (egfr 60 ml/min/1.73 m 2 ), and 226 (59.8%) had normal or mildly impaired egfr ( 60 ml/min/1.73 m 2 ). Of the patients, 108 (28.6%) had mild, 68 (18.0%) had moderate, and 202 (53.4%) had severe WMLs. In logistic regression analysis adjusted with age and sex, egfr 60 ml/min/1.73 m 2 was associated with severe WMLs (relative risk 2.77, 95% CI 1.10 to 6.98, P 0.030). In Cox regression survival analysis adjusted with significant covariates, egfr 60 ml/min/1.73 m 2 (1.30, 95% CI 1.00 to 1.68, P 0.047) and severe WMLs (hazard ratio 1.32, 95% CI 1.02 to 1.71, P 0.033) were associated with poor survival, whereas they were not independent from each other. In further analyses, presence of either egfr 60 ml/min/1.73 m 2 or only mild to moderate WMLs, or both, was associated with improved survival compared with all other combinations. Conclusions Cerebral small vessel disease is closely associated with kidney function in patients with acute stroke. Cerebral small vessel disease and kidney function are closely associated predictors of poor poststroke survival. (Stroke. 2010;41: ) Key Words: cerebral glomerular small vessel disease stroke survival Chronic kidney disease and cardiovascular disease are independent risk factors for poor cardiovascular outcome in the general population. 1 Impaired renal function, whether determined by creatinine level, creatinine clearance, urea level, or estimated glomerular filtration rate (egfr), is a predictor of stroke mortality in patients hospitalized for acute stroke. 2 5 The association of cerebral white matter lesions (WMLs) as seen on MRI, microvascular disease, and kidney function has been demonstrated previously in cross-sectional studies in patients without a history of stroke 6 10 and in patients with several stages of renal impairment However, data on patients with acute stroke are lacking. Cognitive decline, a common phenomenon in the elderly, is closely associated with both WMLs 14 and kidney function as determined by egfr. 15 WMLs are a marker of cerebral small vessel disease. 16 Severe WMLs are an important predictor of cardiovascular and noncardiovascular survival in older people without a history of stroke Increased frequency and extent of WMLs also occur in patients with ischemic stroke. 20 In addition, severe WMLs predict long-term survival in patients with acute stroke. 21 Previous studies addressing the effect of renal function on survival of patients with acute stroke did not report data on WMLs. 2 5 The intimate association of glomerular and cerebral small vessel disease has been subject to considerable debate. 22 We hypothesized that kidney function as estimated by egfr, potentially reflecting glomerular small vessel disease and cerebral small vessel disease as determined by MRI, might be associated with each other and could be used to predict long-term survival in patients hospitalized for acute stroke. Received April 13, 2010; final revision received May 13, 2010; accepted June 2, From the Division of Vascular Surgery (N.K.J.O.), Department of Surgery, University of Tampere and Tampere University Hospital, Tampere, Finland; the School of Medicine (N.K.J.O., A.O., P.J.K.), Forensic Medicine, University of Tampere and the Laboratory Centre Research Unit, Tampere University Hospital, Tampere, Finland; the Department of Medicine (T. Salonen), Tampere University Hospital, Tampere, Finland; the Institute of Health Sciences/Geriatrics (T. Strandberg), University of Oulu and University Hospital, Unit of General Practice, Oulu, Finland; and the Department of Neurology (T.P., M.K., T.E.), Helsinki University Central Hospital, Helsinki, Finland. Correspondence to Niku K.J. Oksala, Docent, MD, PhD, DSc, Consultant Vascular Surgeon, Department of Surgery and Forensic Medicine, Medical School, University of Tampere and Tampere University Hospital, University of Tampere, Finland. nikuoksala@gmail.com 2010 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Oksala et al Brain, Kidney, and Stroke Survival 1915 Methods Patients The Helsinki Stroke Aging Memory (SAM) cohort comprised a consecutive series of all Finnish (white) patients with suspected stroke admitted to Helsinki University Central Hospital (n 1622) between December 1, 1993, and March 30, 1995, as described in detail previously. 23,24 According to predetermined exclusion criteria, patients without ischemic stroke (n 175), with intracerebral hemorrhage (n 229), or with subarachnoid hemorrhage (n 69) were excluded. Of the 1149 patients with ischemic stroke, we further excluded those aged 55 years (n 258) or 85 years (n 88), those not living in Helsinki (n 158), and those not speaking the Finnish language (n 3). A total of 642 patients fulfilled the inclusion criteria and were invited to a follow-up visit 3 months later. Of these, 71 died (11.1%) before the 3-month follow-up, 82 refused (12.8%), and 3 were lost (0.5%) due to undefined causes. Four hundred eighty-six of the living patients were included in the cohort. 25 Of these, 383 (78.9%) had data on both serum creatinine level and MRI. Of these, patients with low egfr (N 5 [1.3%]; 30 ml/min/1.73 m 2 ) were excluded from the analysis and the final cohort consisted of 378 patients. This final study population did not differ in demographic and medical parameters from the original cohort. A detailed medical and neurological history was taken and stroke subtypes were defined. 24 Atrial fibrillation (AF) was defined by clinical criteria and cardiac arrhythmias other than AF were defined as other arrhythmias. Myocardial infarction (MI), heart failure (HF), and hypertension were based on clinical diagnosis. Diabetes mellitus was defined as previously documented diagnosis, current use of insulin or oral hypoglycemic medication, or fasting blood glucose 7.0 mmol/l. Peripheral artery disease (PAD) was considered if the patient had claudication, 2 peripheral pulses missing, or history of amputation or peripheral arterial surgery due to atherosclerosis. Smoking habits were scored at admission as nonsmokers and smokers (current or former). Laboratory analyses included total cholesterol and creatinine. Stroke severity was assessed using modified Rankin score. 26 Standard Protocol Approvals The study was approved by the ethics committee of the Department of Clinical Neurosciences, Helsinki University Central Hospital, Finland. The study was explained to the patients, and informed consent was obtained. MRI Analysis Patients were subjected to MRI at 3 months and constituted the final study population. MRI was performed with a 1.0-T imaging equipment (Siemens Magnetom) 25 as detailed previously. The protocol included transaxial T2, proton density-, and T1-weighted 5-mm thick slices (conventional spin echo technique) and a 3-dimensional gradient-echo sequence yielding 64 3-mm thick coronal sections. WMLs were rated on proton density-weighted images in accordance with the Leukoaraiosis and Disability in the Elderly rating as no to mild, moderate, and severe degree. The rating atlas has been published. 27 In no to mild degree of WMLs, periventricular lesions included no more than a small cap or thin lining and in other white matter areas no more than large focal lesions. In moderate degree of WMLs, the periventricular lesions included no more than a large cap and a smooth halo and the other white matter areas no more than focal confluent lesions. The severe degree of WMLs included cases with extending caps or irregular halo in the periventricular area and diffusely confluent lesions or extensive white matter change in other white matter areas. The intra- and interobserver reliabilities for rating basic WMLs in periventricular and other white matter areas were tested previously and were found to be good. 25,28,29 However, we did not retest intra- and interobserver reliabilities using atlas-based assessment of the present follow-up study. 27 Of the patients, 108 (28.6%) had mild, 68 (18.0%) had moderate, and 202 (53.7%) had severe WMLs. Because there were no differences in survival analyses between moderate and mild WML categories, these categories were combined. Determination of egfr Renal function on admission was calculated using the abbreviated equation of the Modification Diet for Renal Disease, 30 which estimates egfr: egfr (ml/min/1.73 m 2 ) serum creatinine (exp[ 1.154]) age (exp[0.203]) (0.742 if female). All the patients in our cohort were of white origin and therefore no correction had to be made for black race. egfr was classified on the basis of internationally accepted classification. 31 Patients with low (Stages 4 and 5) egfr (N 5 [1.3%]; 30 ml/min/1.73 m 2 ) and very low survival rate were excluded from the analysis. Patients were divided into those with normal or mildly impaired (N 226 [59.8%]; Stages 1 to 2; egfr 60 ml/min/1.73 m 2 ) egfr and those with low to moderate (N 152 [40.0%]; Stage 3; egfr 60 ml/min/1.73 m 2 ) egfr. Survival Long-term survival data and causes of death at September 21, 2006, were obtained from Statistics Finland. The mean ( SD) follow-up time was years with a range between 0.3 and 12.8 years. Of the 378 patients with MRI data, 269 (71.2%) had died during the follow-up and data on survival were obtained in all the cases. Of all the dead subjects, the cause of death could not be verified for 8 cases (2.1%) with a death certificate. The outcome events were death from any cause and specific causes of death. Statistical Analysis SPSS/WIN (Version 12.0; SPSS Inc) software was used. The 2 test was used to test dichotomous variables and Student t test for independent samples to test continuous variables. Binary logistic regression analysis was used to study the association of different degrees of egfr and WMLs. Kaplan Meier log-rank test was used to analyze the effect of different factors on survival (sex, hypertension, diabetes mellitus, AF, HF, MI, PAD, smoking, modified Rankin score, WML degree, and egfr). The cumulative hazard function was also used and according to these analyses, the proportional hazards assumption was met for each parameter included in further models. Three models were constructed, the first using covariates known to associate both with egfr and WMLs (Model 1: age, sex, and stroke severity as assessed by modified Rankin score), another with classic factors associated with stroke (Model 2: age, sex, stroke severity, hypertension, diabetes mellitus, AF, HF, MI, PAD, smoking, and serum cholesterol), and the third using covariates proven to predict survival in univariate analyses with Kaplan Meier log-rank test (Model 3: age, sex, modified Rankin score, AF, HF, PAD). All 4 different combinations of egfr and WML were also tested in the models: (1) egfr 60 ml/min/1.73 m 2 mild to moderate WMLs; (2) egfr 60 ml/min/1.73 m 2 severe WMLs; (3) egfr 60 ml/min/1.73 m 2 mild to moderate WMLs; and (4) egfr 60 ml/min/1.73 m 2 severe WMLs. All the analyses were also performed including patients with first-ever stroke only (78.8%). Because the results were similar in both analyses, all the stroke cases were included in the study. Statistical significance was set at P 0.05 and borderline significance was considered at P Results Patient Characteristics Patients with egfr 60 ml/min/1.73 m 2 (N 152 [40.2%]) were older (P ), were more often females (P ), had more seldom history of MI (P 0.013), had higher serum creatinine level on admission (P ), and had more often severe WMLs (P 0.003) compared with those with

3 1916 Stroke September 2010 Table 1. Demographics and Clinical and Laboratory Characteristics of 378 Patients With Acute Stroke Variable All (N 378) egfr 60 ml/min/1.73 m 2 (N 152) egfr 60 ml/min/1.73 m 2 (N 226) P Mean age (SD) 70.7 (7.6) 73.8 (6.4) 68.8 (7.6) Female sex, no. (%) 197 (52.1) 97 (63.8) 100 (44.2) Hypertension, no. (%) 184 (48.7) 79 (52.0) 105 (46.5) DM, no. (%) 91 (24.1) 30 (19.7) 61 (27.0) AF, no. (%) 75 (19.8) 36 (23.7) 39 (17.3) HF, no. (%) 80 (21.2) 38 (25.0) 42 (18.7) MI, no. (%) 70 (18.5) 19 (12.5) 51 (22.6) PAD, no. (%) 43 (11.4) 16 (10.5) 27 (11.9) Smoking, no. (%) 185 (48.9) 66 (43.4) 119 (52.7) Total cholesterol, mmol/l (SD) 5.6 (1.2) 5.6 (1.3) 5.6 (1.1) Creatinine on admission, mol/l (SD) 90.5 (24.2) (22.6) 79.7 (18.7) Poor modified Rankin score, no. (%) 137 (36.2) 61 (40.1) 76 (33.6) Severe WML 203 (53.7) 96 (63.2) 107 (47.3) *Stroke Aging Memory (SAM) cohort according to egfr. Poor modified Rankin score (ie, Rankin score 3 5), cerebral WMLs. Dichotomous variables: 2 test; continuous variables: Student t test for independent samples. DM indicates diabetes mellitus. egfr 60 ml/min/1.73 m 2 (N 226 [59.8%]; Table 1). egfr values were normally distributed. To test whether WMLs are indeed associated with egfr, further analyses were adjusted with age and sex. According to logistic regression analysis adjusted with age and sex, egfr 60 ml/min/1.73 m 2 was associated with severe degree of WMLs (relative risk 2.77, 95% CI 1.10 to 6.98, P 0.030). Factors Affecting Long-Term Survival In Kaplan Meier univariate analysis, history of AF (P ), HF (P ), PAD (P 0.004), and poor modified Rankin score (P ) were associated with poor survival, whereas sex (P 0.840), hypertension (P 0.824), diabetes (P 0.230), MI (P 0.182), and smoking (P 0.099) were not associated with survival. Poor survival was predicted by egfr 60 ml/min/1.73 m 2 (6.3, 95% CI 4.9 to 7.7 versus 9.0, 95% CI 7.9 to 10.0 years, P ; Figure A) and by severe WMLs (6.0, 95% CI 4.8 to 7.4 versus 9.3, 95% CI 8.0 to 10.6 years, P ; Figure B). Strikingly, these survival curves were almost superimposable. In further analyses testing all the 4 possible combinations of egfr and WML stages, presence of both egfr 60 ml/min/1.73 m 2 and mild to moderate WMLs was associated with favorable outcome (11.3, 95% CI 9.6 to 13.1 years) compared with all other combinations of egfr and WMLs (P to 0.004; Figure C). To account for multiple factors, Cox regression survival analysis was performed. In analysis adjusted with age, sex, and stroke severity (Model 1), egfr 60 ml/min/1.73 m 2 (hazard ratio [HR]1.30, 95% CI 1.00 to 1.67, P 0.047) and severe WMLs with a borderline significance (HR 1.27, 95%CI 0.99 to 1.63, P 0.067) were associated with impaired survival (Table 2). Inclusion of both of these predictors in the model resulted in lack of significant association with survival indicating a possible interaction of egfr with WML stage (Table 2). To account for a possible residual confounding effect of associated comorbidities, in further analysis adjusted with classical risk factors (age, sex, stroke severity, hypertension, diabetes, AF, HF, MI, PAD, smoking, and serum cholesterol; Model 2), egfr 60 ml/min/1.73 m 2 (HR 1.37, 95% CI 1.04 to 1.79, P 0.025) and severe WMLs (HR 1.34, 95% CI 1.03 to 1.74, P 0.028) remained associated with impaired survival (Table 2). Inclusion of both of these predictors in the model resulted in lack of significant association with survival as shown previously. In a third model (Model 3), the analyses were repeated adjusting with significant predictors from previous Kaplan Meier univariate analyses (age, sex, stroke severity, AF, HF, PAD). In these analyses, egfr 60 ml/min/1.73 m 2 (HR 1.30, 95% CI 1.00 to 1.68, P 0.047) and severe WMLs (HR 1.32, 95% CI 1.02 to 1.71, P 0.033) were associated with impaired survival, whereas inclusion of both of these predictors in the model resulted in lack of significant association with survival (Table 2). When analyzing all the 4 possible combinations of egfr and WMLs with adjusted Cox regression survival analysis, presence of both egfr 60 ml/min/1.73 m 2 and mild to moderate WMLs was associated with favorable outcome in long-term follow-up compared with all other groups (Table 3). Different adjusted models (Models 1, 2, and 3; see Statistical Analyses ) resulted in similar results. Discussion In the present study, for the first time to our knowledge, we demonstrated that cerebral small vessel disease is connected to kidney function as estimated by egfr in patients hospitalized for acute stroke. Whether this association is due to coexisting glomerular small vessel disease remains to be elucidated in future studies. In addition, we demonstrated that

4 Oksala et al Brain, Kidney, and Stroke Survival 1917 Figure. Univariate analysis of the effect of egfr (ml/min/1.73 m 2 ) and cerebral WMLs as determined by MRI on stroke survival in Stroke Aging Memory Cohort in patients hospitalized for acute stroke. The effect of egfr (A); WMLs (B); and different combinations of both (C; end point: all-cause death). Kaplan Meier log-rank test. small vessel disease and kidney function are closely associated predictors of poor poststroke survival. We speculate that cerebral small vessel disease and glomerular small vessel disease might have a common soil of pathogenesis and therefore be closely connected with each other 22 not only due to anatomic and vasoregulatory similarities. First, cerebral small vessel disease is reflected by WMLs 16,32 and WMLs are directly related with risk of recurrent strokes 17,18,33 35 and poor survival mostly due to cardiovascular causes ,21 Second, the association of WMLs and glomerular small vessel disease has been demonstrated in several different stages of kidney disease involving predialysis patients and patients with end-stage kidney disease. 6,7,11 13 Third, metabolic alterations and disturbances in cerebral blood flow have been demonstrated to be associated with degree of renal function. 8,9 Our results are in accordance with these findings because in the present study, severe white matter lesions were more frequent (63.2% versus 47.3%) in patients with low to moderate egfr compared with those with egfr 60 ml/min/1.73 m 2. The association of low egfr and severe WMLs was also demonstrated after adjusting for age and sex, the factors previously known to associate with renal function and WMLs, also labeled as age-related white matter changes. 27 According to survival analysis, the survival curves for egfr and WMLs were almost superimposable in line with the HRs for low egfr and WMLs suggesting a possible associated cause of the small vessel disease in the brain and kidney, not unlikely. Previous findings on the association of calculated creatinine clearance, creatinine level, high urea or ratio of urea to creatinine, and egfr with long-term survival in patients hospitalized for acute stroke 2 5 are in line with our findings. Using the same cohort, we have previously demonstrated the effect of WMLs 21 and cognitive status 36 on long-term survival after acute stroke. Interestingly, cognitive function, kidney function, and WMLs have been shown to be closely associated with each other, 6,14,15 most probably due to coexisting cerebral and glomerular small vessel disease. The intimate association of cerebral and glomerular small vessel disease is supported by the coexistence of lipohyalinosis and

5 1918 Stroke September 2010 Table 2. Cox Regression Analysis on the Association of egfr and Severe Cerebral WMLs as Determined by MRI With Poor Long-Term Survival in 378 Patients With Acute Stroke in the SAM Cohort 12-Year Overall Mortality egfr Model WML Model egfr WML Model Variable HR 95% CI P HR 95% CI P HR 95% CI P Model 1 (adjusted with age, sex, poor modified Rankin score) egfr 60 ml/min/1.73 m Not included Severe WML Not included Model 2 (adjusted with age, sex, poor modified Rankin score, hypertension, diabetes, AF, HF, MI, PAD, smoking, serum cholesterol) egfr 60 ml/min/1.73 m Not included Severe WML Not included Model 3 (adjusted with age, sex, poor modified Rankin score, AF, HF, PAD) egfr 60 ml/min/1.73 m Not included Severe WML Not included Poor modified Rankin score (ie, Rankin score 3 5). Reference egfr 60 ml/min/1.73 m 2 or mild moderate WMLs. Cox proportional hazards regression model. endothelial dysfunction in both glomerular small vessel 37,38 and cerebral small vessel disease. 39 As a limitation, however, it must be emphasized that decreased egfr is a measure of decreased renal function, but it does not necessarily show that the decreased renal function is due to small vessel disease. In our cohort, the proportion of patients with egfr 60 ml/min/1.73 m 2 was rather high, up to 40.2%, whereas in a previous study of patients with acute stroke, this proportion was 28.1%. 5 However, similar prevalence was found in another study (36.0%). 4 In line with a previous study, our patients with low egfr were older and included more women. 5 In another study, assessed by serum creatinine level, the proportion of patients with high values ( 124 mol/l) was 26.0%. 3 Acute renal failure has been reported to occur among 14.3% of patients with acute stroke, 5 but we were not able to reliably exclude patients with acute renal failure in our cohort because we had a single determination of creatinine at admission. It must be emphasized that there are several causes of decreased egfr; it could represent acute dehydration on admission, a concurrent infection, or renal artery stenosis as well as small vessel renovascular disease. Because acute renal failure itself is an independent prognostic factor for mortality after stroke, 40 our results may underestimate the prognostic value of chronically lowered egfr. To avoid bias from low egfr ( 30 ml/min/1.73 m 2 ), 5 patients were excluded from the analysis. It must emphasized that Modification Diet for Renal Disease was the only feasible option to determine egfr. Modification Diet for Renal Disease has not been validated in the very elderly or malnourished patients, which is a potential source of bias in the present study. Despite the obvious shortcomings, our prospective study has several strengths. The cohort is a consecutive one and patients were reviewed by senior neurologists in the working group; also, the severity of stroke was quantitated according to the modified Rankin score. We consider it beneficial that our unit is responsible for primary stroke management of all inhabitants living in the Helsinki area. Also, the survival data are comprehensive with a small amount of unresolved deaths. We consider there is a possibility of selection bias due to formation of the cohort 3 months after the index stroke. This may limit generalization of the results. According to additional retrospectively obtained data in the Helsinki University Hospital district during the collection of the cohort from an independent organization (Statistics Finland), up to 64% of stroke-related deaths occurred in women. The proportion of women (52.1%) in the present study suggests that some women may have died before hospital assessment at 3 months. Due to exclusion of patients, the true survival rate may be underestimated. Another weakness is that we have no data on proteinuria, which has previously been associated Table 3. Cox Regression Analysis on the Association of Different Combinations of egfr and cerebral WMLs as Determined by MRI With Poor Long-Term Survival in 378 Patients With Acute Stroke in the SAM Cohort 12-Year Overall Mortality Relative to Reference Group egfr 60 ml/min/ egfr 60 ml/min/ egfr 60 ml/min/ egfr 60 ml/min/ 1.73 m 2 WML MM 1.73 m 2 WML S 1.73 m 2 WML MM 1.73 m 2 WML S Reference Group HR 95% CI P HR 95% CI P HR 95% CI P HR 95% CI P egfr 60 ml/min/1.73 m 2 WML MM egfr 60 ml/min/1.73 m 2 WML S egfr 60 ml/min/1.73 m 2 WML MM egfr 60 ml/min/1.73 m 2 WML S WML MM indicates mild moderate cerebral WMLs; WML S, severe WMLs. Cox proportional hazards regression model with age, sex, and poor modified Rankin score as covariates.

6 Oksala et al Brain, Kidney, and Stroke Survival 1919 with vascular disease independent of glomerular filtration rate. Due to the homogenous population, the present results may not be applicable to other populations. We demonstrated that kidney function is closely associated with cerebral small vessel disease in patients hospitalized for acute stroke. Furthermore, we demonstrated that kidney function and cerebral small vessel disease are closely associated predictors of poor poststroke survival. Acknowledgments We thank Statistics Finland for their expert assistance in the data collection. Sources of Funding This study was supported by grants from the Maire Taponen Foundation; the Paavo Nurmi Foundation; The Finnish Angiologic Association; the Medical Council of the Academy of Finland (Helsinki); the Clinical Research Institute, Helsinki University Central Hospital; the Yrjö Jahnsson Foundation (Helsinki); the Finnish Cultural Foundation and the Elli and Elvi Oksanen Fund of the Pirkanmaa Fund under the auspices of the Finnish Cultural Foundation (Tampere); the Medical Research Fund of Tampere University Hospital; the Finnish Medical Foundation; and the Finnish Foundation for Cardiovascular Research (Helsinki). None. Disclosures References 1. Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Griffith J, Salem DN, Levey AS, Sarnak MJ. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis. 2006;48: Friedman PJ. Serum creatinine: an independent predictor of survival after stroke. J Intern Med. 1991;229: MacWalter RS, Wong SY, Wong KY, Stewart G, Fraser CG, Fraser HW, Ersoy Y, Ogston SA, Chen R. Does renal dysfunction predict mortality after acute stroke? A 7-year follow-up study. Stroke. 2002;33: Yahalom G, Schwartz R, Schwammenthal Y, Merzeliak O, Toashi M, Orion D, Sela BA, Tanne D. Chronic kidney disease and clinical outcome in patients with acute stroke. Stroke. 2009;40: Tsagalis G, Akrivos T, Alevizaki M, Manios E, Stamatellopoulos K, Laggouranis A, Vemmos KN. Renal dysfunction in acute stroke: an independent predictor of long-term all combined vascular events and overall mortality. Nephrol Dial Transplant. 2009;24: Weiner DE, Bartolomei K, Scott T, Price LL, Griffith JL, Rosenberg I, Levey AS, Folstein MF, Sarnak MJ. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis. 2009;53: Khatri M, Wright CB, Nickolas TL, Yoshita M, Paik MC, Kranwinkel G, Sacco RL, DeCarli C. Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (NOMAS). Stroke. 2007;38: Kanai H, Hirakata H, Nakane H, Fujii K, Hirakata E, Ibayashi S, Kuwabara Y. Depressed cerebral oxygen metabolism in patients with chronic renal failure: a positron emission tomography study. Am J Kidney Dis. 2001;38(suppl 1):S129 S Michaelis T, Videen JS, Linsey MS, Ross BD. Dialysis and transplantation affect cerebral abnormalities of end-stage renal disease. J Magn Reson Imaging. 1996;6: Ikram MA, Vernooij MW, Hofman A, Niessen WJ, van der Lugt A, Breteler MM. Kidney function is related to cerebral small vessel disease. Stroke. 2008;39: Martinez-Vea A, Salvado E, Bardaji A, Gutierrez C, Ramos A, Garcia C, Compte T, Peralta C, Broch M, Pastor R, Angelet P, Marcas L, Sauri A, Oliver JA. Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CKD. Am J Kidney Dis. 2006;47: Fazekas G, Fazekas F, Schmidt R, Kapeller P, Offenbacher H, Krejs GJ. Brain MRI findings and cognitive impairment in patients undergoing chronic hemodialysis treatment. J Neurol Sci. 1995;134: Kim CD, Lee HJ, Kim DJ, Kim BS, Shin SK, Do JY, Jang MH, Park SH, Kim YS, Kim YL. High prevalence of leukoaraiosis in cerebral magnetic resonance images of patients on peritoneal dialysis. Am J Kidney Dis. 2007;50: Breteler MM, van Swieten JC, Bots ML, Grobbee DE, Claus JJ, van den Hout JH, van Harskamp F, Tanghe HL, de Jong PT, van Gijn J. Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study. Neurology. 1994;44: Buchman AS, Tanne D, Boyle PA, Shah RC, Leurgans SE, Bennett DA. Kidney function is associated with the rate of cognitive decline in the elderly. Neurology. 2009;73: Inzitari D. Leukoaraiosis: an independent risk factor for stroke? Stroke. 2003;34: Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS. Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke. J Neurol Neurosurg Psychiatry. 2005;76: Kuller LH, Arnold AM, Longstreth WT Jr, Manolio TO, O Leary DH, Burke GL, Fried LP, Newman AB. White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study. Neurobiol Aging. 2007;28: Kerber KA, Whitman GT, Brown DL, Baloh RW. Increased risk of death in community-dwelling older people with white matter hyperintensities on MRI. J Neurol Sci. 2006;250: Wen W, Sachdev PS. Extent and distribution of white matter hyperintensities in stroke patients: the Sydney Stroke Study. Stroke. 2004;35: Oksala N, Oksala A, Pohjasvaara T, Vataja R, Kaste M, Karhunen P, Erkinjuntti T. Age-related white matter changes predict stroke death in long-term follow up. J Neurol Neurosurg Psychiatry. 2009;80: Seliger SL, Longstreth WT Jr. Lessons about brain vascular disease from another pulsating organ, the kidney. Stroke. 2008;39: Oksala NK, Heikkinen M, Mikkelsson J, Pohjasvaara T, Kaste M, Erkinjuntti T, Karhunen PJ. Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PlA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival. Stroke. 2007;38: Pohjasvaara T, Erkinjuntti T, Vataja R, Kaste M. Comparison of stroke features and disability in daily life in patients with ischemic stroke aged 55 to 70 and 71 to 85 years. Stroke. 1997;28: Mantyla R, Aronen HJ, Salonen O, Pohjasvaara T, Korpelainen M, Peltonen T, Standertskjold-Nordenstam CG, Kaste M, Erkinjuntti T. Magnetic resonance imaging white matter hyperintensities and mechanism of ischemic stroke. Stroke. 1999;30: van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19: Pantoni L, Basile AM, Pracucci G, Asplund G, Bogousslavsky J, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D. Impact of age-related cerebral white matter changes on the transition to disability the LADIS study: rationale, design and methodology. Neuroepidemiology. 2005; 24: Mantyla R, Erkinjuntti T, Salonen O, Aronen HJ, Peltonen T, Pohjasvaara T, Standertskjold-Nordenstam C. Variable agreement between visual rating scales for white matter hyperintensities on MRI. Comparison of 13 rating scales in a poststroke cohort. Stroke 1997;28: Mantyla R, Aronen HJ, Salonen O, Korpelainen M, Peltonen T, Standertskjold-Nordenstam C, Erkinjuntti T. The prevalence and distribution of white-matter changes on different MRI pulse sequences in a post-stroke cohort. Neuroradiology. 1999;41: Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130: Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, De Zeeuw D, Hostetter TH, Lameire N, Eknoyan G. Definition and classification of chronic kidney disease: a position statement from Kidney

7 1920 Stroke September 2010 Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67: Inzitari D, Simoni M, Pracucci G, Poggesi A, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O Brien J, Barkhof F, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L. Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med. 2007;167: Pantoni L, Garcia J. The significance of cerebral white matter abnormalities 100 years after Binswanger s report. A review. Stroke. 1995;26: Briley DP, Haroon S, Sergent SM, Thomas S. Does leukoaraiosis predict morbidity and mortality? Neurology. 2000;54: Inzitari D, Cadelo M, Marranci ML, Pracucci G, Pantoni L. Vascular deaths in elderly neurological patients with leukoaraiosis. J Neurol Neurosurg Psychiatry. 1997;62: Oksala N, Jokinen H, Melkas S, Oksala A, Pohjasvaara T, Hietanen M, Vataja R, Kaste M, Karhunen P, Erkinjuntti T. Cognitive impairment predicts poststroke death in long-term follow up. J Neurol Neurosurg Psychiatry. 2009;80: Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol. 2002;13: Wong TY, Coresh J, Klein R, Muntner P, Couper DJ, Sharrett AR, Klein BE, Heiss G, Hubbard LD, Duncan BB. Retinal microvascular abnormalities and renal dysfunction: the Atherosclerosis Risk In Communities study. J Am Soc Nephrol. 2004;15: Fernando MS, Simpson JE, Matthews F, Brayne C, Levis CE, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O Brien JT, Ince PG. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006;37: Covic A, Schiller A, Mardare NG, Petrica L, Petrica M, Mihaescu A, Posta N. The impact of acute kidney injury on short-term survival in an Eastern European population with stroke. Nephrol Dial Transplant. 2008; 23: