Cerebral small vessel disease and chronic kidney disease (CKD): Results of a cross-sectional study in community-based Japanese elderly

Journal of the Neurological Sciences 272 (2008) 36 – 42 www.elsevier.com/locate/jns

Cerebral small vessel disease and chronic kidney disease (CKD): Results of a cross-sectional study in community-based Japanese elderly Manabu Wada ⁎, Hikaru Nagasawa, Chifumi Iseki, Yoshimi Takahashi, Hiroyasu Sato, Shigeki Arawaka, Toru Kawanami, Keiji Kurita, Makoto Daimon, Takeo Kato Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan Received 1 January 2008; received in revised form 7 March 2008; accepted 28 April 2008 Available online 9 June 2008

Abstract Chronic kidney disease (CKD) is known as a risk factor for cardiovascular disease. In recent years, several experimental and epidemiological studies have suggested that CKD is associated with endothelial dysfunction; thereby, a CKD state may initiate both large and small vessel damage. The association between renal dysfunction and asymptomatic lacunar infarction was reported in a hospital-based study, whereas the relationship between cerebral small vessel disease (SVD)-related lesions and CKD could not be clarified in a community-based study. We performed a cross-sectional study to determine the relationship between silent cerebral SVD-related lesions and CKD in a total of 625 community-based Japanese elderly. In this study, subjects with lower estimated glomerular filtration rate levels tended to have more lacunar infarcts and higher grades of white matter lesions (WMLs). In addition, the mean grades of WMLs or the mean numbers of lacunar infarction in the subjects with albuminuria were greater than those in subjects without albuminuria. In the logistic regression analysis, the association between the presence of CKD and lacunar infarction or moderate WMLs (Fazekas grades 2 and 3) was statistically significant (odds ratio [OR]: 1.86 and 1.50, respectively). Furthermore, as we performed additional analysis, excluding the subjects with stage 2 hypertension (those with casual blood pressure ≧ 160/100 mm Hg) or diabetes, CKD remained to be an independent risk for cerebral SVDrelated lesions. This is the first study showing the relationship between silent SVD-related brain lesions and the presence of CKD, independently of conventional cardiovascular risk factors, in community-based elderly. © 2008 Elsevier B.V. All rights reserved. Keywords: Chronic kidney disease; Small vessel disease; Magnetic resonance imaging; Glomerular filtration rate; Community-based study

1. Introduction Chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of b 60 ml/min per 1.73 m2 or a urinary albumin-creatinine ratio of N 30 mg/g, is widely recognized as an independent risk factor for cardiovascular disease [1,2]. In recent years, epidemiological studies have shown that CKD is a risk factor for cardiovascular events and all-cause mortality [2–4]. To date, CKD is a common progressive disease that is becoming a global public health ⁎ Corresponding author. Fax: +81 23 628 5318. E-mail address: [email protected] (M. Wada). 0022-510X/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.04.029

problem [5]. Considerable evidence for the relationship between renal dysfunction and adverse cardiovascular events was initially obtained from the dialysis population [6,7]. Subsequent epidemiological studies showed that the majority of patients with a moderate degree of renal dysfunction die of cardiovascular causes rather than progress to end-stage renal disease. Overall, the CKD state is recognized as a risk for accelerated atherosclerotic disease, such as coronary heart disease, cerebrovascular disease, and peripheral artery disease [8]. Cerebral white matter lesions (WMLs) and lacunas, often seen in magnetic resonance imaging (MRI) in the elderly, are accepted as an increased risk of stroke or cognitive impairment [9,10]. Whereas most of these findings are

M. Wada et al. / Journal of the Neurological Sciences 272 (2008) 36–42

considered to be caused by cerebral small vessel disease (SVD), the pathogenesis of cerebral SVD has been poorly understood. Although aging and hypertension are recognized as the major risk for SVD, they fail to account for all of the risk for cerebral SVD [11]. For the reasons given above, the evaluation of other risk factors is needed for the understanding of pathogenesis of cerebral SVD. In recent years, using a hospital-based study, Kobayashi and colleagues showed that the decline of renal function is related to asymptomatic lacunar infarction [12]. To the best of our knowledge, however, the relationship between cerebral SVD-related lesions and CKD is not fully understood in community-based subjects. We performed herein a cross-sectional study to determine the relationship between silent cerebral SVD-related lesions and CKD in communitybased subjects that show normal to moderate impairment of renal function. The main objectives of this study were, first, to examine the relationship between CKD and silent SVDrelated brain lesions. Secondly, investigations were conducted to determine if possible associations were independent of conventional cardiovascular risk factors. 2. Subjects and methods

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of b 60 ml/min per 1.73 m2. The eGFR of each participant was calculated from the serum creatinine (Cr) value and age using the abbreviated Modification of Diet in Renal Disease (MDRD) equation [14] modified by the Japanese coefficient [15], as follows:
eGFR ml=min per 1:73 m2 ¼ 0:741  175  age0:203  Cr1:154 ðif f emale  0:742Þ eGFR was subsequently stratified into 3 groups: 1) stage 1 (N 90 ml/min/1.73 m2); 2) stage 2 (60 to 89 ml/min/1.73 m2); and 3) stages 3 to 5 (under 60 ml/min/1.73 m2), according to the Kidney Disease Outcome Quality Initiative stages [16]. Spot urine samples were collected early in the morning. The urinary albumin concentration was measured using the immunoturbidimetric assay (N-assay TIA Micro Alb; Nittobo Medical Co., Ltd., Japan) and expressed as urinary albumin-creatinine ratio (UACR) in mg/g creatinine. The intraassay and the interassay coefficient variation for urinary albumin concentration were 0.96 to 1.14% and 0.67 to 1.26%, respectively. All samples were measured at the Biomedical Laboratory (BML), Tokyo, Japan.

2.1. Study population

2.3. Evaluation of cardiovascular risk factors

Details of the present study have been previously reported [13]. All samples were obtained from two different communities in Yamagata Prefecture, Japan, namely, Takahata town and Sagae city. All subjects aged 61 (306 subjects) and 72 years (346 subjects) in Takahata town were invited to participate in the present study. From this group, 223 (72.8%) of the 61-year-old residents and 217 (62.7%) of the 72-yearold residents were enrolled in this study. In Sagae city, we randomly invited 490 residents aged 70 to 72 years (227 men and 263 women). A total of 291 (59.4%) residents in Sagae city participated in this study. Of the 731 subjects, 42 who did not have all the pertinent data (those without information of clinical profiles or blood samples) were excluded. Subjects with possible urinary tract infection were also excluded (n = 45), because this renders the albumin measurement unreliable. Furthermore, subjects with cortical infarcts (n = 1), subjects with a history of lacunar infarction (n = 11), cerebral hemorrhage (n = 2), and subdural hematoma (n = 1) were also excluded in this series. After a comprehensive neurological evaluation was performed on all the participants, we excluded 4 participants as neurologically symptomatic. As a result, samples were collected from the 625 individuals in the local community who had been invited to participate. This study was approved by the Medical Ethics Committee of Yamagata University School of Medicine.

Hypertension was defined as casual blood pressure ≧140/ 90 mm Hg or by current use of anti-hypertensive agents. Serum total cholesterol (TC), triglyceride, high-density lipoprotein (HDL)-cholesterol, fasting plasma glucose, and hemoglobin A1c (HbA1c) were measured from blood samples taken after overnight fasting. Subjects whose serum total cholesterol levels were ≧220 mg/dl or whose triglyceride levels were ≧150 mg/dl or those who were taking medication for hyperlipidemia were defined as having hyperlipidemia. After fasting blood samples were obtained, 75 g oral glucose tolerance test was subsequently examined on those who had not undergone any anti-diabetic therapy. The diagnosis of diabetes was determined according to the World Health Organization criteria [17].

2.2. Definition of chronic kidney disease (CKD) CKD was defined as a urinary albumin-creatinine ratio of N 30 mg/g or an estimated glomerular filtration rate (eGFR)

2.4. Assessments of MRI scans WMLs and lacunas are markers of cerebral small vessel disease visible on MRI [9,18]. These pathological findings suggest that lacunar infarcts and WMLs represent different forms of cerebral SVD: neuropathological findings corresponding to lacunar infarct are thickening and hyaline deposition of the small perforating end arterioles supplying the white matter [19]; on the other hand, those of WMLs are neuronal loss, ischemic demyelination, and gliosis [20,21]. In the present study, we evaluated the relationship between CKD and WMLs/ lacunar infarcts. Axial T1-, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) images were made from each participant. A single trained physician, who was blinded to the participants' clinical details, evaluated SVD-related brain lesions. The

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Table 1 Clinical characteristics of the study groups Measures

Age, y Male, % Hypertension, % Systolic BP, mmHg Diastolic BP, mmHg Hyperlipidemia, % TC/HDL-C ratio Diabetes mellitus, % Fasting plasma glucose, mg/dl HbA1c, % Current smoker, % Maximal IMT, mm eGFR, ml/min per 1.73 m2 CKD, %

Non-infarct

Lacunar infarct group

Group (n = 449)

Total (n = 176)

Single (n = 117)

Multiple (n = 59)

67.7 (4.9) 44.8 63.7 140.9 (18.6) 80.8 (10.9) 43.1 3.72 (1.10) 14.0 103.5 (24.5) 5.23 (0.79) 24.6 1.73 (0.73) 77.3 (18.1) 31.8

69.8 (3.8)** 44.9 78.4** 146.0 (19.3)** 82.5 (10.8) 45.5 3.61 (1.10) 14.8 106.2 (21.9) 5.29 (0.71) 26.9 1.75 (0.71) 73.1 (18.1)* 47.7**

69.6 (4.0) 37.6 78.6 145.5 (18.5) 82.2 (10.0) 46.2 3.70 15.4 105.8 (20.0) 5.29 (0.61) 19.7 1.71 (0.65) 73.3 (16.1) 47.9

70.1 (3.2) 59.3 78.0 147.0 (21.0)## 83.0 (12.3) 44.1 3.43 13.6 105.8 (25.5) 5.29 (0.88) 41.4 1.84 (0.82) 72.6 (20.8)# 47.5

Values are percentages, unadjusted means (SD). The difference between the non-infarct group and the total infarct group was tested using the t test. Chi-squared tests were used to compare the proportions. P b 0.05 and P b 0.01 are indicated by * and **, respectively. The differences among the non-infarct, single-infarct, and multiple-infarct groups were tested using the one-way ANOVA. P b 0.05 and P b 0.01 are indicated by # and ##, respectively. Abbreviations: y, years; BP, blood pressure; TC, total cholesterol; HDL, high-density lipoprotein; IMT, intima-media thickness; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease.

definition of cerebral SVD-related lesions in this study was reported previously [13]. In brief, lacunar infarct was defined as a low signal intensity area (3 to 15 mm) on T1-weighted images, and it was also visible as a hyperintense lesion on T2-weighted images on MRI. Furthermore, WML was defined as at least one focal lesion in cerebral white matter with corresponding hyperintensity on FLAIR images. The Fazekas scale was used to score WMLs, as this scale has been shown to reflect the pathological severity of cerebral SVD in post-mortem examinations [20]. One hundred MRI scans were also randomly selected for re-evaluation by the same observer. As described previously, the repeatability (weight kappa) was good for the category of

WMLs (k= 0.86) and moderate for that of lacunar infarcts (k =0.68) [22]. 2.5. Evaluation of carotid atherosclerosis Participants underwent ultrasonography of the carotid arteries to obtain the maximal intima-media thickness (IMT) measurement. The examination included the observation of longitudinal and transverse views of both the common and internal carotid arteries bilaterally. The maximal IMT was measured according to the methods of carotid ultrasonic examination, as reported previously [23].

Table 2 Clinical characteristics of the study groups Measures

Age, y** Male, % Hypertension, %** Systolic BP, mmHg** Diastolic BP, mmHg* Hyperlipidemia, % TC / HDL-C ratio Diabetes mellitus, % Fasting plasma glucose, mg/dl HbA1c, % Current smoker, % Maximal IMT, mm eGFR, ml/min per 1.73 m2* CKD, % *

Grades of white matter lesion (Fazekas scale) Grade 0 (n = 177)

Grade 1 (n = 295)

Grade 2 (n = 98)

Grade 3 (n = 55)

65.2 (5.0) 41.2 53.7 137.1 (18.6) 79.6 (11.3) 46.9 3.79 (1.20) 17.5 104.5 (21.2) 5.23 (0.69) 27.3 1.68 (0.62) 78.8 (15.6) 29.9

69.1 (4.2) 46.4 67.8 142.1 (18.8) 81.3 (10.8) 40.7 3.67 (1.04) 12.2 103.2 (22.4) 5.26 (0.84) 23.7 1.76 (0.75) 76.2 (18.5) 35.3

70.1 (3.8) 42.9 83.7 149.1 (17.9) 82.8 (10.5) 46.9 3.62 (1.07) 17.3 107.7 (27.0) 5.33 (0.81) 21.9 1.69 (0.70) 74.7 (19.3) 41.8

70.5 (2.8) 50.9 85.5 148.0 (17.9) 83.8 (10.5) 44.5 3.62 (1.09) 9.1 103.3 (32.1) 5.09 (0.52) 32.7 1.93 (0.89) 70.2 (19.8) 52.7

Values are percentages, unadjusted means (SD). The differences among 4 groups were tested using the one-way ANOVA. Chi-squared tests were used to compare the proportions. P b 0.05 and P b 0.01 are indicated by * and **, respectively. Abbreviations: y, years; BP, blood pressure; TC, total cholesterol; HDL, high-density lipoprotein; IMT, intima-media thickness; CKD, chronic kidney disease.

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Table 3 Numbers of lacunar infarction or grades of white matter lesions based on eGFR and albuminuria eGFR (ml/min/1.73 m2) N90 Albuminuria No (N = 81) Numbers of LI Grades of WML

0.21 (0.56) 0.84 (0.77)

b60

60–89 Albuminuria Yes (N = 36) 0.58 (1.11) 1.11 (0.98)

No (N = 317) §

0.41 (0.95) 0.99 (0.86)§

Albuminuria Yes (N = 101) ║

0.55 (0.95) 1.19 (0.94)║

No (N = 59)

Yes (N = 31)

0.66 (1.23)* 1.24 (0.94)*

0.87 (1.89)║ 1.29 (0.97)║

Values are unadjusted means (SD). Abbreviations: eGFR, estimated glomerular filtration rate; LI, lacunar infarction; WML, white matter lesion. *P b 0.05 compared with eGFR greater than 90 ml/min per 1.73 m2 without albuminuria. § P N 0.05 compared with eGFR greater than 90 ml/min per 1.73 m2 without albuminuria. ║ P N 0.05 compared with eGFR greater than 90 ml/min per 1.73 m2 with albuminuria.

2.6. Data analysis The Statistical Package for the Social Sciences (SPSS Inc. ver.15.0) was used for all analyses. Because the distribution of eGFR levels appeared to be left-skewed, they were normalized by logarithmic transformation. Chi-squared tests were used to compare the proportions, and the t test or ANOVA was used to compare normally distributed data between two or more groups. Pearson correlation coefficients were used to measure the correlations between eGFR and other variables. The mean numbers of lacunar infarcts and the mean grades of WMLs were compared using ANOVA based on a CKD state (group 1, normal; group 2, stage 1 (N90 ml/min/1.73 m2 of eGFR) with albuminuria; group 3, stage 2 (60–89 ml/min/1.73 m2 of eGFR) without albuminuria; group 4, stage 2 with albuminuria; group 5, stages 3 to 5 (b 60 ml/min/1.73 m2of eGFR) without albuminuria; group 6, stages 3 to 5 with albuminuria). To examine whether CKD is an independent risk factor for silent SVD-related lesions, the odds ratio (OR) was calculated for the likelihood of lacunar infarction and moderate WMLs (Fazekas grades 2 and 3) by multivariate logistic regression analysis. In addition, the OR was also calculated for the likelihood of lacunar infarction or moderate WMLs (Fazekas grades 2 and 3) by multivariate logistic regression analysis, excluding the subjects with stages 1 and 2 hypertension or stage 2 hypertension (classification provided in the JNC 7 report [1]), respectively. Furthermore, as we excluded subjects with diabetes, logistic regression analysis was also performed to examine the relationship between CKD and SVD-related lesions. Probability values were 2-tailed, and values of b0.05 were considered significant. 3. Results 3.1. Clinical variables and small vessel disease-related brain abnormalities of study subjects The detailed clinical characteristics of the participants are summarized in Tables 1 and 2. In the present study, 176 subjects (28.2%) were found to have one or more lacunar infarcts on their MRIs. In addition, at least one WML(s) was seen in 448 subjects, and 153 subjects showed moderate

WMLs (Grades 2 and 3 on the Fazekas scale) on their MRIs according to the Fazekas scale. The relationship between the decline of eGFR and adverse SVD-related brain lesions was indicated. The age, prevalence of hypertension, systolic and diastolic BP, and prevalence of CKD were higher in subjects with lacunar infarct(s) than in those without it. A comparison among four grades of WMLs indicated that subjects with high grades of WMLs had a tendency towards higher age, prevalence of hypertension, systolic and diastolic BP, and prevalence of CKD (Table 2). 3.2. Association between MRI findings and levels of eGFR As shown in Table 3, subjects with lower eGFR levels tended to have more lacunar infarcts and higher grades of WMLs. In addition, the mean grades of WMLs or the mean numbers of lacunar infarction in the subjects with albuminuria were greater than the subjects without albuminuria. In subjects without albuminuria, the mean number of lacunar infarctions and the mean grade of WMLs among three groups were statistically significant (lacunar infarction, P = 0.019; WMLs, P = 0.026); however, these associations were not statistically significant in the subjects with albuminuria.

Table 4 Correlation coefficients of variables with eGFR Variables

r

P-value

Age, years Systolic BP, mmHg Diastolic BP, mmHg TC/HDL cholesterol ratio Fasting plasma glucose, mg/dl HbA1c, % Number of lacunas Grades of white matter lesion Maximal IMT, mm

− 0.062 − 0.032 − 0.122 − 0.154 − 0.025 − 0.014 − 0.119 − 0.126 0.005

0.122 0.423 0.002 b0.001 0.527 0.724 0.003 0.002 0.906

Pearson correlation coefficients were used to measure the correlations between eGFR and other variables. Abbreviations: eGFR, estimated glomerular filtration rate; BP, blood pressure; TC, total cholesterol; HDL, high-density lipoprotein; IMT, intima-media thickness.

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Table 5 OR (95% CI) for the presence of lacunar infarct (s) or white matter lesions in elderly subjects

Table 7 OR (95% CI) for the presence of lacunar infarct (s) or white matter lesions in elderly subjects without stage 2 hypertension

Multivariate logistic regression analysis

Multivariate logistic regression analysis

Unadjusted

Model 1

Model 2

Unadjusted

OR (95% CI)

OR (95% CI)

OR (95% CI)

OR (95% CI) OR (95% CI) OR (95% CI)

Presence of chronic kidney disease Lacunar infarction 1.98 1.85 (1.38–2.83)** (1.27–2.70)** Moderate white matter 1.73 1.50 lesions (1.19–2.51)** (1.00–2.24)* eGFR, 10 mLml/min per 1.73 m2 increment Lacunar infarction 0.86 0.88 (0.78–0.96)** (0.79–0.97)* Moderate white matter 0.88 0.89 lesions (0.78–0.98)* (0.79–0.99)*

1.86 (1.28–2.72)** 1.50 (1.01–2.25)* 0.87 (0.78–0.97)* 0.89 (0.79–0.99)*

The odds ratios for lacunar infarcts (0 = subjects with no infarct; 1 = subjects with one or more infarcts) were calculated using a multiple logistic regression analysis. The odds ratios for moderate white matter lesions (0 = Grades 0 and 1 on Fazekas scale; 1 = Grades 2 and 3 on Fazekas scale) were also examined. P b 0.01 and P b 0.05 are indicated by ** and *, respectively. Model 1: adjusted for age, sex, hypertension, TC/HDL cholesterol ratio, diabetes mellitus, and current smoker. Model 2: adjusted for age, sex, hypertension, TC/HDL cholesterol ratio, diabetes mellitus, current smoker, and maximal IMT. Abbreviations: WML, white matter lesion; TC, total cholesterol; HDL, highdensity lipoprotein; IMT, intima-media thickness.

3.3. Association between eGFR and other variables The results of the correlation coefficients between eGFR and other variables are summarized in Table 4. These data showed that eGFR was negatively correlated with diastolic BP (r = − 0.122, P = 0.002), TC/HDL cholesterol ratio (r = Table 6 OR (95% CI) for the presence of lacunar infarct (s) or white matter lesions in elderly subjects without diabetes Multivariate logistic regression analysis Unadjusted

Model 1

Model 2

OR (95% CI)

OR (95% CI)

OR (95% CI)

Presence of chronic kidney disease Lacunar infarction 1.90 (1.28–2.80)** Moderate white matter 1.65 lesions (1.10–2.48)*

1.77 (1.17–2.66)** 1.47 (0.97–2.28)

1.78 (1.18–2.70)** 1.48 (0.96–2.29)

The odds ratios for lacunar infarcts (0 = subjects with no infarct; 1 = subjects with one or more infarcts) were calculated using a multiple logistic regression analysis. The odds ratios for moderate WMLs (0 = Grades 0 and 1 on Fazekas scale; 1 = Grades 2 and 3 on Fazekas scale) were also examined. P b 0.01 and P b 0.05 are indicated by ** and *, respectively. Model 1: adjusted for age, sex, hypertension, TC/HDL cholesterol ratio, and current smoker. Model 2: adjusted for age, sex, hypertension, TC/HDL cholesterol ratio, current smoker, and maximal IMT. Abbreviations: WML, white matter lesion; TC, total cholesterol; HDL, highdensity lipoprotein; IMT, intima-media thickness.

Presence of chronic kidney disease Lacunar infarction 2.61 (1.44–4.74)** Moderate white matter 2.35 lesions (1.22–4.56)*

Model 1

2.90 (1.55–5.44)** 2.19 (1.08–4.44)*

Model 2

2.89 (1.54–5.44)** 2.07 (1.01–4.23)*

The odds ratios for lacunar infarcts (0 = subjects with no infarct; 1 = subjects with one or more infarcts) were calculated using a multiple logistic regression analysis. The odds ratios for moderate WMLs (0 = Grades 0 and 1 on Fazekas scale; 1 = Grades 2 to 3 on Fazekas scale) were also examined. P b 0.05 and P b 0.01 are indicated by * and **, respectively. Model 1: adjusted for age, sex, TC/HDL cholesterol ratio, diabetes, and current smoker. Model 2: adjusted for age, sex, TC/HDL cholesterol ratio, diabetes, current smoker, and maximal IMT. Abbreviations: WML, white matter lesion; TC, total cholesterol; HDL, highdensity lipoprotein; IMT, intima-media thickness.

− 0.154, P b 0.001), numbers of lacunas (r = − 0.119, P = 0.003), and grades of WMLs (r = −0.126, P = 0.002). 3.4. Adjusted relationship between cerebral small vessel disease-related lesions and CKD In logistic regression analysis, the association between the presence of CKD and lacunar infarction or moderate WMLs (Fazekas grades 2 and 3) was statistically significant after adjustment for age, sex, and cardiovascular risk factors (Table 5). In addition, these associations were not changed after further adjustment with maximal IMT. All analyses described above were also tested after exclusion of the participants with diabetes; however, the association between the presence of CKD and silent lacunar infarction did not change (Table 6). As the multivariate logistic regression analysis was performed after exclusion of subjects with stages 1 and 2 hypertension (subjects with casual blood pressure ≧ 140/90 mm Hg or with current use of antihypertensive agents), the relationship between the presence of CKD and cerebral SVD-related lesions was not statistically significant (data not shown); however, as we excluded only subjects with stage 2 hypertension (subjects with casual blood pressure ≧ 160/100 mm Hg or with current use of anti-hypertensive agents), the association between the presence of CKD and silent SVD-related lesions was statistically significant (Table 7). 4. Discussion To our best knowledge, this is the first community-based study on the association between CKD and silent SVDrelated lesions. We herein showed CKD to be an independent risk factor for silent lacunar infarction in a

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community-based study of Japanese elderly. The results of the present study also demonstrated that CKD was an independent risk factor for silent white matter lesions. To date, the reduction in kidney function has been considered to be an independent risk factor for cardiovascular events and all-cause mortality [2–4,7]. Most studies of cardiovascular outcomes have shown that a breakpoint for increased risk for recurrent myocardial infarction, congestive heart failure, and cardiovascular death occurs under an eGFR of 60 ml/min/ 1.73 m2. Furthermore, reduced kidney function was also found to be an independent risk factor even in prospective studies of general populations [3,7,24]. This is the first investigation showing the relationship between silent SVDrelated brain lesions and CKD in community-based subjects. Several possible explanations for the association between CKD and cerebral SVD-related lesions are proposed. A reduction of GFR is associated with conventional cardiovascular risk factors, such as aging, hypertension, diabetes, and decreased HDL cholesterol levels [25]. These risk factors, especially aging and hypertension, could accelerate the cerebral SVD in subjects with CKD. Decreased kidney function may reflect systemic vascular damage. It is acceptable that hypertensive subjects already have a certain degree of systemic vascular damage because hypertension is a major risk factor for the progression of systemic arteriosclerosis. As a result of a previous investigation that confirmed the pathological features in post-mortem examinations, the development of renal arteriosclerosis and glomerular sclerosis was closely associated with reduced GFR [26]. The results of the present investigation suggest that the CKD state may, to some extent, be a marker of cerebral small vessel injuries in community-based Japanese elderly who had been considered neurologically asymptomatic. However, the association between CKD and cerebral SVDrelated lesions remains statistically significant even after adjustment with conventional cardiovascular risk factors. Furthermore, as we performed additional analysis, excluding the subjects with hypertension or diabetes, CKD remained to be an independent risk for the presence of SVD-related lesions in community-based elderly subjects. It is remarkable that CKD is a risk factor for silent SVD-related lesions in subjects without stage 2 hypertension (subjects whose systolic/diastolic blood pressure was below 160/100 mmHg). For the reasons given above, CKD-related metabolic disorders may affect cerebral small vessels to a lesser extent in subjects with normotension or mild hypertension. It has also been speculated that endothelial dysfunction could be the pathophysiological mechanisms involved in the association between CKD and SVD-related brain lesions [25,27]. Our previous study showed that increased levels of thrombomodulin, which reflect systemic vascular dysfunction, were associated with cerebral SVD-related lesions [22]. Endothelial dysfunction is recognized as one of the initial mechanisms that lead to atherosclerosis [25]. Impairment of endothelial function, which occurs in both large and small vessels, is present in renal disease [27]. In

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recent years, nitric oxide (NO) has been recognized as an important vasodilating substance [27]; thereby, much attention has been focused on the relationship between NO and arteriosclerosis. Recent studies have indicated that asymmetric dimethylarginine (ADMA), a competitive inhibitor of NO synthase, is one of the main factors involved in CKD-related endothelial dysfunction [28,29]. The plasma concentration of ADMA is increased in relation to endothelial dysfunction and a decreased production of NO. Furthermore, the CKD state is likely to be associated with increased levels of other cardiovascular risk factors, such as inflammation, oxidative stress, insulin resistance, and thrombogenic factors [30,31]. These factors could result in SVD in subjects with CKD. Some limitations of the present study require consideration. First, the estimated GFR, which was made using the prediction equation derived from the MDRD study, was based on a single blood sample. This is common practice in epidemiological studies, but, in a clinical setting, it is recommended that multiple samples be obtained. A study using multiple samples should be performed to obtain more consistent results of the eGFR. Second, a potential misclassification of SVD-related lesions is noted as a methodological limitation. Although good or moderate agreement was obtained, we may have systematically under- or overestimated lacunar infarcts or WMLs determined on the basis of a visual assessment scale. Moreover, the pathological confirmation of SVD visible on MRI is relatively limited because it is partly linked to the low mortality rate soon after radiological evaluation. Third, we did not have sufficient information regarding the duration or the severity of conventional risk factors. Fourth, in this study, we could not evaluate whether the association between CKD and the incidence of cerebral SVD might be affected in part by the use of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). There is some convincing evidence indicating that blocking the renin-angiotensin system with ACE inhibitors or ARB is an effective therapy for the regression of CKD [16]. Because many of the participants of the current study are treated by general practitioners, we are unable to provide reliable information on medication with ACE inhibitors, or ARB. For the reasons given above, we could not exclude the possibility that treatment might have affected the study results. Fifth, it must be noted that the values of eGFR may reflect systemic arteriosclerosis. The values of eGFR could not specifically evaluate the severity of cerebral SVD. We speculate that the reduction of eGFR may be associated with systemic vascular damage, which is not specific for cerebral small vessel disease. Sixth, because this was a cross-sectional study, we could not infer a causal relationship between the presence of CKD and the risk of future stroke or cognitive decline for elderly people with SVD-related brain lesions. Extensive prospective studies are needed to establish the link between CKD and future stroke or dementia in populations with lower cardiovascular risk, such as community-based elderly.

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