Chronic Kidney Disease in Patients with Ischemic Stroke

Chronic Kidney Disease in Patients with Ischemic Stroke Yuuko Tsukamoto, MD,* Wakoh Takahashi, MD,* Shunya Takizawa, MD,* Shiaki Kawada, MD,† and Shigeharu Takagi, MD*

To examine the significance of renal dysfunction in patients who have sustained ischemic stroke, we examined the relationship between the renal function evaluated in terms of estimated glomerular filtration rate (eGFR) and the subtype of brain infarction (BI) in patients with ischemic stroke. A total of 639 patients with BI were enrolled in this study, with 314 subjects without stroke or transient ischemic attack registered as age-matched controls. eGFR was calculated according to the equation 194 3 Cr21.094 3 Age20.287 (20.739 if female), where Cr is serum creatinine concentration, and was classified into four stages: stage I, eGFR $90 mL/min/1.73 m2; stage II, eGFR 6089 mL/min/1.73 m2; stage III, eGFR 3059 mL/min/1.73 m2; and stage IV, eGFR ,29 mL/min/1.73 m2. Stage III-IV was significantly more prevalent in the BI group (38%) than in the control group (22%; P , .001). The odds ratio for stage III-IV was significantly higher in the BI group (1.93; 95% confidence interval [CI], 1.35-2.76). Among the BI subgroups, the odds ratios of stage III-IV for the atherothrombotic type (1.81; 95% CI, 1.23-2.68) and the cardiogenic type (2.25; 95% CI, 1.32-3.83) were significantly higher than that of the control group, but that of stage III-IV for lacunar type was not (1.67; 95% CI, 0.98-2.84). Our results indicate that ischemic stroke is frequently associated with renal dysfunction. Chronic kidney disease might be independent risk factor for infarction, especially for cardiogenic and atherosclerotic types. Key Words: Renal dysfunction—brain infarction—glomerular filtration rate—cerebrovascular risk factor. Ó 2012 by National Stroke Association

Advanced renal dysfunction is often associated with cardiovascular diseases or stroke. Indeed, recent investigations have indicated that even microalbuminuria or mildly decreased glomerular filtration rate (GFR) may be a predictor of cardiovascular disease or stroke.1-6 The estimated prevalence of chronic kidney disease (CKD), defined as GFR ,60 mL/min/1.73 m2, is 5% among adults in the United States7 and as high as 10% in adults in Japan.8 But although CKD may be a risk factor for

From the *Department of Neurology, Tokai University School of Medicine, Kanagawa, Japan; and †HIMEDIC Imaging Center at Lake Yamanaka, Yamanashi, Japan. Received October 8, 2010; accepted December 14, 2010. Address correspondence to Wakoh Takahashi, MD, Department of Neurology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa 259-1193, Japan. E-mail: [email protected]. ac.jp. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2010.12.005

stroke, the prevalence of renal dysfunction among patients with cerebrovascular events has not been well documented. GFR is generally evaluated in terms of estimated GFR (eGFR), calculated from the serum creatinine level,9 making it possible to examine renal function in a large cohort. In this study, we retrospectively estimated renal function in patients admitted to our hospital with ischemic stroke in terms of eGFR, using the reported equation for the Japanese population.10 We then evaluated the relationship between the degree of eGFR reduction and the subtype of brain infarction (BI) or vascular risk factors in the patients with ischemic stroke.

Methods Of the 778 patients admitted to the Department of Neurology, Tokai University Hospital due to stroke or transient ischemic attack between May 2004 and June 2007, 639 with BI (434 males, 205 females; mean age, 69 6 12

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years) who were not undergoing hemodialysis were enrolled in this study. All subjects had been admitted to the hospital within 72 hours after onset of stroke, and 83% had been admitted within 24 hours after onset. The subjects with BI were classified into the following subtypes: atherothrombotic, n 5 318; cardiogenic, n 5 176; lacunar, n 5 104; and other, n 5 41. The diagnosis and classification of BI were based on the criteria of the National Institute of Neurological Disorders and Stroke.11 Magnetic resonance imaging (MRI), computed tomography, or both was performed in all subjects. MRI examinations included T1- and T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted imaging, and the diagnosis of BI was based mainly on MRI images. A few subjects with a contraindication for MRI (eg, a pacemaker) were evaluated based on computed tomography scan only. Control subjects were recruited from patients at HIMEDIC Imaging Center at Lake Yamanaka. Among the 2106 patients who received a brain checkup between April 2003 and March 2005, 314 subjects, ranging in age from 66 to 74 years and with no history of stroke or transient ischemic attack (206 men, 108 women; mean age, 69 6 2 years), were registered as age-matched controls. The profiles of the subjects with BI and the control subjects are summarized in Table 1. Kidney function was evaluated in terms of eGFR, calculated according to the following equation: 194 3 Cr21.094 3 Age20.287 (20.739 if female), where Cr is serum creatinine concentration.10 CKD was then classified into 4 stages based on the modified Kidney Disease Outcomes Quality Initiative clinical practice guidelines on CKD7: stage I, eGFR $90 mL/min/1.73 m2; stage II, 6089 mL/min/1.73 m2; stage III, 3059 mL/min/1.73 m2; stage IV, ,29 mL/min/1.73 m2. The venous blood samples in which serum creatinine concentration was measured had been obtained at admission before any medical treatment, including intravenous drip.

In this study, hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation (AF), and ischemic heart disease (IHD) were evaluated as vascular risk factors in all subjects. These risk factors were diagnosed according to the following criteria: diabetes mellitus, hemoglobin A1c $5.9% or receiving an antidiabetic agent; hyperlipidemia, total cholesterol $220 mg/dL or triglyceride $150 mg/ dL, or receiving an antihyperlipidemic agents; hypertension, blood pressure $ 140/90 mm Hg continuously during admission or receiving an antihypertensive agent. Subjects exhibiting a blood pressure drop to within the normal range without any medical treatment were not considered to have hypertension. IHD was defined as the detection of an ischemic alteration on electrocardiography (ECG) or a history of any medical treatment for IHD. AF was diagnosed based on 24-hour ambulatory ECG performed on admission. In control subjects, all risk factors were defined based on blood samples or ECG obtained at the time of brain checkup, or on a history of any medical treatment for each risk factor.

Statistical Analysis Statistical analyses were done using the c2 test or logistic regression analysis. The c2 test was used to compare the prevalence of stage I-II and stage III-IV CKD between the BI and control groups. Logistic regression analysis was used to estimate the odds ratio (OR) of stage III-IV CKD and established risk factors for each group. All data were analyzed using StatView version 5.0 (SAS Institute, Cary, NC).

Results The distribution of CKD stages the BI and control groups is shown in Figure 1. Stage II was the most common stage in both groups. The prevalence of stage III-IV CKD was significantly greater in the BI group (38% vs 22%; P , .001). Among the BI subgroups, stage III-IV

Table 1. Profiles of BI and control subjects BI group

Number of subjects Age, years, mean 6 SD Males, % Hypertension, % Diabetes mellitus, % Hyperlipidemia, % IHD, % AF, %

Controls

Atherothrombotic

Cardiogenic

Lacunar

Others

Total

314 69 6 2 65 36 8 19 9 2

318 70 6 11 68 68 33 34 12 12

176 72 6 10 67 55 17 24 13 71

104 67 6 11 71 73 21 31 7 4

41 56 6 18 53 34 7 19 7 9

639 69 6 12 67 63 25 30 11 27

Hypertension was defined as blood pressure of $140/90 mm Hg continuously during admission or receiving an antihypertensive agent. Diabetes mellitus was defined as hemoglobin A1c $5.9% or receiving an antidiabetic agent. Hyperlipidemia was defined as total cholesterol $220 mg/dL and/or triglyceride $150 mg/dL or receiving an antihyperlipidemic agent. AF and IHD were diagnosed by ECG at admission or based on a history of any medical treatment for AF or IHD.

CHRONIC KIDNEY DISEASE IN ISCHEMIC STROKE Prevalence (%)

Control

60 BI

40

20

549

III-IV CKD (OR, 1.81; 95% CI, 1.23-2.68) were all significantly higher for the atherothrombotic subgroup compared with controls (Table 3). The adjusted ORs for AF (OR, 93.17; 95% CI, 42.06-206.36) and stage III-IV CKD (OR, 2.25; 95% CI, 1.32-3.83) were also significantly higher for the cardiogenic subgroup compared with controls. In the lacunar subgroup, the adjusted ORs for hypertension (OR, 4.42; 95% CI, 2.65-7.36) and diabetes mellitus (OR, 2.42; 95% CI, 1.28-4.59) were significantly higher compared with controls, but the adjusted OR of stage III-IV CKD (OR, 1.67; 95% CI, 0.98-2.84) was not (Table 3).

0 Stage

Stage

Stage

Stage

Stage of CKD

Discussion

Figure 1. Distribution of CKD stages in the BI and control groups. In both groups, stage II was the most common stage. Stage III-IV CKD had a tendency toward greater prevalence in the BI group.

CKD was most prevalent in the cardiogenic subgroup (46%), followed by the atherothrombotic (36%), lacunar (31%), and other (26%) subgroups (Fig 2). The prevalence of stage III-IV CKD was statistically significantly different in the cardiogenic subgroup compared with the lacunar (P 5 .016) and other (P 5 .034) subgroups (Fig 2). We next evaluated the relative risks of established risk factors and stage III-IV CKD for BI using logistic regression analysis (Table 2). The adjusted ORs (adjusted for age and sex) for hypertension (OR, 2.53; 95% confidence interval [CI], 1.86-3.46), diabetes mellitus (OR, 3.21; 95% CI, 2.015.12), hyperlipidemia (OR, 1.51; 95% CI, 1.05-2.18), and AF (OR, 15.69; 95% CI, 7.46-32.97) were significantly higher in the BI group compared with the controls. The adjusted OR for stage III-IV CKD was also significantly increased versus the controls (OR, 1.93; 95% CI, 1.35-2.76). When the relative risks of these risk factors were evaluated for subtypes of BI, the adjusted ORs for hypertension (OR, 2.78; 95% CI, 1.96-3.94), diabetes mellitus (OR, 4.47; 95% CI, 2.75-7.25), hyperlipidemia (OR, 1.80; 95% CI, 1.21-2.69), AF (OR, 4.20; 95% CI, 1.87-9.46), and stage P=0.034

CKD stage III+IV(%)

P=0.016

50 40 30

In this study, the prevalence of stage III-IV CKD was 38% in the BI group, compared with 22% in the agematched control group (P ,.001). One possible reason for this apparent association is the similarity of risk factors for stroke and CKD; hypertension, diabetes mellitus, and several other established risk factors for stroke also accelerate the development of renal dysfunction.12 On the other hand, CKD itself might be a risk factor for stroke or cardiovascular disease.1-6 An analysis of our findings by logistic regression analysis supports the idea that CKD might be an independent risk factor for stroke. Among the subtypes of BI, the cardiogenic type was significantly more closely associated with stage III-IV CKD compared with the lacunar and other types. The adjusted OR for stage III-IV CKD was significantly increased in both the cardiogenic and atherosclerotic subgroups compared with controls. The relationship between renal dysfunction and the BI subtype is not well understood; however, the degree of renal dysfunction has been shown to be associated with degree of carotid atherosclerosis on ultrasonography,13 and our finding of a significant correlation between stage III-IV CKD and atherosclerotic BI seems to be consistent with that association. As for the correlation between CKD and cardiogenic type, an association between renal dysfunction and elevated coagulant biomarkers has been suggested,14,15 and increased coagulability in patients with renal dysfunction might favor thrombus formation as an embolic source.16 We also found that stage III-IV CKD was significantly less prevalent in the lacunar BI subgroup than in the Table 2. Relative risks of established risk factors and stage III-IV CKD for BI

20 10 0 Athero thrombotic

Cardiogenic

Lacunar

Other

Subtypes of BI

Figure 2. Prevalence of stage III-IV CKD according to BI subtype. Stage III-IV CKD was significantly more prevalent in the cardiogenic subgroup than in the lacunar subgroup (P 5 .016) or the others group (P 5 .034).

Hypertension Diabetes mellitus Hyperlipidemia IHD AF Stage III-IV CKD

OR (95% CI)

P value

2.53 (1.86-3.46) 3.21 (2.01-5.12) 1.51 (1.05-2.18) 1.03 (0.62-1.71) 15.69 (7.46-32.97) 1.93 (1.35-2.76)

,.001 ,.001 .025 .889 ,.001 .003

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Table 3. Relative risks of established risk factors and stage III-IV CKD according to BI subtype Atherothrombotic

Hypertension Diabetes mellitus Hyperlipidemia IHD AF Stage III-IV CKD

Cardiogenic

Lacunar

OR (95% CI)

P value

OR (95% CI)

P value

OR (95% CI)

P value

2.78 (1.96-3.94) 4.47 (2.75-7.25) 1.80 (1.21-2.69) 1.06 (0.61-1.83) 4.20 (1.87-9.46) 1.81 (1.23-2.68)

,.001 ,.001 .003 .825 .005 .026

1.33 (0.80-2.21) 1.50 (0.75-2.99) 1.48 (0.83-2.63) 1.25 (0.59-2.64) 93.17 (42.06-206.36) 2.25 (1.32-3.83)

.256 .246 .483 .547 ,.001 .026

4.42 (2.65-7.36) 2.42 (1.28-4.59) 1.32 (0.77-2.25) 0.67 (0.28-1.56) 1.75 (0.54-5.63) 1.67 (0.98-2.84)

,.001 .006 .308 .356 .343 .567

cardiogenic subgroup, and that the adjusted OR for stage III-IV CKD did not differ significantly between the lacunar subgroup and controls. Previous investigations have suggested that CKD might be a strong predictor of cerebral white matter hyperintensities.17-19 Lacunar infarction often coexists with cerebral white matter hyperintensities detected on MRI, and both types of lesion have been categorized as cerebral small-vessel disease in histopathological examination.20,21 Further studies with a larger group of patients are needed to examine the possible relationship between lacunar-type BI and CKD. In conclusion, our results indicate that ischemic stroke is frequently associated with renal dysfunction, as demonstrated by decreased eGFR. Although we fid not investigate other markers of renal dysfunction, such as proteinuria, our findings suggest that CKD might be an independent risk factor for BI, especially of the cardiogenic and atherosclerotic subtypes.

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