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Original Paper

Free Access

Reduced Estimated Glomerular Filtration Rate Is Associated with Stroke Outcome after Intravenous rt-PA: The Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) rt-PA Registry

Naganuma M.a · Koga M.a · Shiokawa Y.b · Nakagawara J.d · Furui E.e · Kimura K.f · Yamagami H.g · Okada Y.h · Hasegawa Y.i · Kario K.j · Okuda S.k · Nishiyama K.c · Minematsu K.a · Toyoda K.a

Author affiliations

aDepartment of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Departments of bNeurosurgery and cNeurology, Stroke Center, Kyorin University School of Medicine, Mitaka, dDepartment of Neurosurgery and Stroke Center, Nakamura Memorial Hospital, Sapporo, eDepartment of Stroke Neurology, Kohnan Hospital, Sendai, fDepartment of Stroke Medicine, Kawasaki Medical School, Kurashiki, gStroke Center, Kobe City Medical Center General Hospital, Kobe, hDepartment of Cerebrovascular Diseases, National Hospital Organization, Kyushu Medical Center, Fukuoka, iDepartment of Neurology, St. Marianna University School of Medicine, Kawasaki, jDivision of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, and kDepartment of Neurology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan

Corresponding Author

Kazunori Toyoda, MD

Department of Cerebrovascular Medicine National Cerebral and Cardiovascular Center Fujishirodai 5-7-1, Suita, Osaka 565-8565 (Japan)

Tel. +81 6 6833 5012, Fax +81 6 6872 7486, E-Mail toyoda@hsp.ncvc.go.jp

Related Articles for ""

Cerebrovasc Dis 2011;31:123–129

Abstract

Background: The aim of this study was to determine whether renal dysfunction affects the outcome of stroke patients treated with recombinant tissue plasminogen activator (rt-PA). Methods: A retrospective, multicenter, observational study was conducted to identify the effects of underlying risk factors on intravenous rt-PA therapy using 0.6 mg/kg alteplase in 10 stroke centers in Japan. Consecutive stroke patients with a premorbid modified Rankin Scale (mRS) score ≤3 who received rt-PA were studied. Renal dysfunction was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 on admission. The outcome measures were any intracerebral hemorrhage (ICH) and symptomatic ICH within the initial 36 h; favorable (mRS 0–1) outcome, poor outcome (mRS 4–6) and mortality at 3 months. Results: Of a total of 578 patients (372 men; 64.4%, 71.4 ± 11.7 years old), renal dysfunction was present in 186 patients (32.2%). These patients were older and more commonly had hypertension, atrial fibrillation, prior ischemic heart disease and prior use of antithrombotic agents than patients without renal dysfunction. ICH (27.4 vs. 16.6%) and symptomatic ICH (8.1 vs. 2.6%) was more common in patients with renal dysfunction than in those without. At 3 months, patients with renal dysfunction had higher median mRS scores than those without (3 vs. 2). After multivariate adjustment for established outcome predictors, renal dysfunction was related to any ICH (odds ratio 1.81, 95% confidence interval 1.16–2.84), symptomatic ICH (2.64, 1.10–6.56), poor outcome (1.55, 1.01–2.38), and mortality (2.94, 1.38–6.42). Conclusions: Reduced eGFR was associated with early ICH and 3-month unfavorable outcome in stroke patients receiving intravenous rt-PA.

© 2010 S. Karger AG, Basel


Introduction

Renal dysfunction is increasingly noted as a risk factor for stroke in the general population [1,2], as well as in high-risk patients having diabetes mellitus [3], essential hypertension [4], and preexisting atherothrombotic disease [5,6]. In a large cohort of patients with acute stroke, renal dysfunction was an independent predictor for long-term mortality and poor outcome [7,8,9].

Though intravenous (IV) thrombolysis is a standard therapy for acute stroke patients, the effect of renal dysfunction on vital and functional outcome measures following therapy is inconclusive. As far as we know, only one study (involving 196 stroke patients) reported that a high admission serum creatinine level was independently predictive of a modified Rankin scale (mRS) score ≥3 at 3 months after IV recombinant tissue plasminogen activator (rt-PA) [10]. This study also reported that an impaired estimated glomerular filtration rate (eGFR), defined as <90 ml/min/1.73 m2, tended to be associated with symptomatic intracerebral hemorrhage (ICH). Since renal dysfunction appears to be an important predictor for stroke outcome, its significance for rt-PA-treated patients should be ascertained in a larger cohort using a multicenter design.

To identify adequate risk factor control in acute stroke patients treated with thrombolysis, a multicenter study group [Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) Study Group] was formed. Here, we determined the association of renal dysfunction based on admission eGFR with stroke outcome after IV rt-PA using the database of this study group.

Patients and Methods

The SAMURAI rt-PA Registry Trial had a multicenter, hospital-based, retrospective, observational, cohort design [11]. Details of this study have been described previously [11,12]. In brief, this study involved 600 consecutive patients with acute ischemic stroke receiving IV rt-PA from October 2005 to July 2008. Of these, 22 patients were ineligible for analysis; 17 patients had dependent activity of daily living before onset, corresponding to an mRS score ≥4, and 5 patients had incomplete 3-month mRS score data. Thus, the remaining 578 patients were included in the present study. Each local ethics committee approved the research protocol. Each patient received a single IV alteplase dose of 0.6 mg/kg, with 10% given as a bolus within 3 h of stroke onset, followed by a continuous IV infusion of the remainder over 1 h [13].

From the database of the SAMURAI rt-PA registers, the data listed in table 1 were extracted for this study. Neurological deficits were assessed using the National Institutes of Health Stroke Scale (NIHSS) score just before and 24 h after rt-PA. Ischemic stroke subtype according to the TOAST categories was elucidated based on information of non-contrast computed tomography (CT), diffusion-weighted magnetic resonance imaging (MRI), magnetic resonance angiography, CT angiography, cervical/transcranial ultrasound, transthoracic or transesophageal echocardiography, and 24-hour Holter monitoring in addition to neurological findings [14].

Table 1

Baseline clinical characteristics

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Kidney function was evaluated based on the eGFR using a revised equation for the Japanese population [15]; eGFR (ml/min/1.73 m2) = 194 × (serum creatinine)–1.094 × (age)–0.287 × 0.739 (for women). To calculate eGFR, admission serum creatinine was used. According to the Kidney Disease Outcomes Quality Initiative guidelines of the National Kidney Foundation [16], renal dysfunction was defined as a reduced eGFR (<60 ml/min/1.73 m2). The stage of renal dysfunction was classified as follows: stage 3 (eGFR 30–59 ml/min/1.73 m2), stage 4 (15–29 ml/min/1.73 m2), and stage 5 (<15 ml/min/1.73 m2 or dialysis).

The major outcome measures were: any ICH defined as CT or MRI evidence of new ICH within the initial 36 h; symptomatic ICH with neurological deterioration corresponding to an increase of ≥1 point from the baseline NIHSS score (Cochrane/National Institute of Neurological Disorders and Stroke definition); favorable and poor outcome at 3 months, and mortality at 3 months. To assess favorable and poor outcome, definitions in the subanalyses of the National Institute of Neurological Disorders and Stroke rt-PA Trial (an mRS of 0–1 and 4–6, respectively) were used [17,18,19,20].

Statistical Analysis

Statistical test results were considered significant if p < 0.05. All analyses were performed using JMP statistical software (version 7.0.1; SAS Institute, Cary, N.C., USA). Baseline clinical characteristics and stroke features were compared using Student’s unpaired t test for parametric continuous variables, Mann-Whitney’s U test for nonparametric variables, and Fisher’s exact test and the χ2 test for categorical variables. To identify independent predictors of ICH within 36 h and stroke outcome at 3 months, multivariate logistic regression analysis was performed. For each outcome, sex, age, and renal dysfunction were initially entered, and the other variables listed in table 1 were chosen by a backward selection procedure using p > 0.10 in the likelihood ratio test for exclusion.

Results

A total of 578 patients (372 men, 71.4 ± 11.7 years old) were studied. Of these, 186 (32.2%) patients had renal dysfunction with eGFR <60 ml/min/1.73 m2; 163 (28.2%) patients belonged to stage 3, 15 (2.6%) to stage 4, and 8 (1.4%) to stage 5. Four patients with stage 5 were on maintenance hemodialysis.

The patients with renal dysfunction were older (p < 0.001) and more commonly had hypertension (p < 0.001), atrial fibrillation (p = 0.001), prior ischemic heart disease (p < 0.001), and prior use of antithrombotic agents (p < 0.001) than patients without renal dysfunction (table 1). Serum total cholesterol (p < 0.001), HDL cholesterol (p = 0.003), and LDL cholesterol (p = 0.043) levels were lower in patients with renal dysfunction than in those without. NIHSS scores were not significantly different between patients with renal dysfunction and those without immediately before [median (interquartile range, IQR); 13 (7–19) vs. 12 (7.25–18), p = 0.423] and 24 h after IV rt-PA [9 (3–18) vs. 7 (3–15), p = 0.070; fig. 1a].

Fig. 1

Neurological deficits and outcome of patients with and without renal dysfunction. NIHSS score just before and 24 h after IV rt-PA therapy (a) and mRS score at 3 months (b) in patients with and without renal dysfunction. a Horizontal lines in boxes = Median NIHSS score; boxes = IQR; whiskers = upper and lower 90% ranges.

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Any ICH [51 (27.4%) vs. 65 patients (16.6%), p = 0.004] as well as symptomatic ICH within 36 h from IV rt-PA therapy [15 (8.1%) vs. 10 patients (2.6%), p = 0.004], was more common in the patients with renal dysfunction than in those without. After multivariate logistic regression analysis, renal dysfunction was significantly related to both any ICH (odds ratio, OR, 1.81, 95% confidence interval, CI, 1.16–2.84, p = 0.009) and symptomatic ICH (2.64, 1.10–6.56, p = 0.031; table 2). When the value of eGFR (a continuous variable) was used instead of eGFR <60 ml/min/1.73 m2 (a categorical variable) as an indicator of renal dysfunction, it was related to any ICH (OR 0.89, 95% CI 0.80–0.99 per 10-ml/min/1.73 m2 increase, p = 0.029) but not symptomatic ICH (0.89, 0.73–1.08, p = 0.231).

Table 2

Characteristics associated with ICH within 36 h

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At 3 months, the patients with renal dysfunction had higher mRS scores than those without [median (IQR); 3 (1–5) vs. 2 (1–4), p < 0.001; fig. 1b]. Twenty-five patients (13.4%) with renal dysfunction had died; of these, 5 died of stroke, 6 of heart disease (4 heart failure, 1 myocardial infarction, and 1 infectious endocarditis), 6 of severe infection (3 sepsis and 3 pneumonia), and 8 of unknown causes. In contrast, 15 patients (3.8%, p < 0.001) without renal dysfunction had died; of these, 9 died of stroke, 2 of pneumonia, and 4 of unknown causes. Similarly, favorable outcome was less common [48 (25.8%) vs. 149 patients (38.0%), p = 0.004], and poor outcome was more common [89 (47.9%) vs. 136 patients (34.7%), p = 0.003] in patients with renal dysfunction than in those without. After multivariate logistic regression analysis, renal dysfunction was significantly related to poor outcome (OR 1.55, 95% CI 1.01–2.38, p = 0.046) and mortality (OR 2.94, 95% CI 1.38–6.42, p = 0.006), although it was not related to favorable outcome (OR 0.70, 95% CI 0.44–1.09, p = 0.114; table 3). When the value of eGFR was used instead, it was significantly related to mortality (OR 0.81, 95% CI 0.67–0.96 per 10-ml/min/1.73 m2 increase, p = 0.020), but not to favorable outcome (OR 1.09, 95% CI 0.99–1.20, p = 0.081) or poor outcome (OR 0.95, 95% CI 0.86–1.04, p = 0.268).

Table 3

Characteristics associated with outcome at 3 months

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Discussion

In this observational study, we determined the influence of renal dysfunction on early ICH and the long-term outcome of ischemic stroke patients receiving IV rt-PA therapy. The major finding was that renal dysfunction, defined as reduced eGFR (<60 ml/min/1.73 m2), which was calculated using the admission creatinine level, was related to any ICH and symptomatic ICH within 36 h, as well as poor outcome (mRS 4–6) and death at 3 months, although it was not related to favorable outcome (mRS 0–1).

According to the result of the largest postmarketing surveillance on rt-PA, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study [21], advanced age, body weight, atrial fibrillation, high systolic blood pressure, hyperglycemia, admission NIHSS score, and current infarction on baseline imaging scans were associated with symptomatic ICH. In addition, advanced age, male sex, use of antiplatelet agents other than aspirin, congestive heart failure, higher diastolic blood pressure, hyperglycemia, higher NIHSS score, current infarction, and premorbid dependency were related to death at 3 months. Similar results have been reported in several other studies [22,23,24,25,26]. However, these studies did not assess renal dysfunction as a potential factor affecting stroke outcome. The present study is unique in that renal dysfunction was included as a potential factor and was proven to be associated with patient outcome after rt-PA.

Alteplase is metabolized by the liver, and liver function affects the half-life of alteplase [27]. In this study, liver disease was not associated with stroke outcome. In contrast, renal dysfunction might not prolong the half-life of alteplase. For example, the plasma concentration-time profile of alteplase was not altered after bilateral nephrectomy in rat models [28].

Renal dysfunction is a bystander of stroke, since it is associated with traditional vascular risk factors, including aging, hypertension, diabetes mellitus, dyslipidemia, and smoking [29]. In addition, renal dysfunction is now known to be an independent predictor for stroke [1,2,5,30,31], partly via nontraditional vascular risk factors, e.g. inflammatory factors, and homocysteinemia. However, the effect of these nontraditional risk factors on stroke outcome has not been clarified, in particular after rt-PA. In patients with acute stroke not receiving IV rt-PA, albuminuria was independently associated with hemorrhagic transformation [32]. Since ICH is a major cause of poor outcome for thrombolysed patients, renal dysfunction may affect chronic outcome after rt-PA via increasing ICH risk. Moreover, renal dysfunction might impair endothelial release of t-PA [33], and increase plasminogen activator inhibitor-1 activity [34] and plasma levels of lipoprotein(a) [35]; these abnormalities might obstruct the reperfusion phenomenon and worsen stroke outcome after IV rt-PA.

An interesting finding regarding the patients who died was that indirect death other than stroke was common as the cause of death for patients with renal dysfunction, though direct stroke death accounted for most of the causes of death for patients without renal dysfunction. This finding suggests that patients with renal dysfunction often had heart problems and susceptibility to infection, developed dependency and died due to non-stroke complications.

Certain limitations need to be considered prior to interpretation of the present results. First, patients who did not receive IV rt-PA were not included in this study. Thus, the influence of renal dysfunction on stroke outcome could not be compared between patients who were treated with rt-PA and those who were not. Second, renal dysfunction was correlated with older age, hypertension, atrial fibrillation, prior ischemic heart disease, and prior use of antithrombotic agents, and this multicolineality may inflate the variances of the parameter estimates. Thus, the present association of renal dysfunction with outcome measures after multivariate analyses may be overestimated to some extent. Third, eGFR was not measured prior to stroke onset, and therefore eGFR may have been affected by stroke. Fourth, eGFR was calculated using admission creatinine levels, which may have been impaired by acute stroke effects. Repeated assessment in the chronic stroke stage is needed to ascertain that the present patients with reduced eGFR have chronic kidney disease. Fifth, urinary albumin was not measured. Generally, urinary albumin increases during acute ischemic stroke [36]. Finally, the present results based on low-dose rt-PA therapy (0.6 mg/kg) may not be applicable to the regular dose therapy (0.9 mg/kg).

In conclusion, reduced eGFR based on the admission creatinine level was predictive of an unfavorable outcome after IV rt-PA in acute stroke patients. In patients with renal dysfunction, additional therapeutic strategies to improve the efficacy of rt-PA are needed.

Disclosure Statement

M.K. received a grant from the Japan Cardiovascular Research Foundation (The Bayer Scholarship for Cardiovascular Research). J.N. received honoraria from Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, and Lundbeck. Y.O. received a honorarium from Mitsubishi Tanabe Pharma and a consulting fee from Lundbeck. K.M. received research support from the Ministry of Health, Labour and Welfare, Japan, research grants for cardiovascular diseases, grant-in-aid, the Foundation for Biomedical Research and Innovation, Mitsubishi Tanabe Pharma Corporation, and Kyowa Hakko Kirin Pharma, Inc., Hitachi Medical Corporation. K.T. received research support from grants-in-aid (H20-Junknaki-Ippan-019) from the Ministry of Health, Labour and Welfare, Japan.


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Author Contacts

Kazunori Toyoda, MD

Department of Cerebrovascular Medicine National Cerebral and Cardiovascular Center Fujishirodai 5-7-1, Suita, Osaka 565-8565 (Japan)

Tel. +81 6 6833 5012, Fax +81 6 6872 7486, E-Mail toyoda@hsp.ncvc.go.jp


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: March 02, 2010
Accepted: September 15, 2010
Published online: November 17, 2010
Issue release date: January 2011

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

For additional information: https://www.karger.com/CED


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References

  1. Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, Wareham NJ: Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study. J Intern Med 2004;255:247–256.
  2. Ninomiya T, Kiyohara Y, Kubo M, Tanizaki Y, Doi Y, Okubo K, Wakugawa Y, Hata J, Oishi Y, Shikata K, Yonemoto K, Hirakata H, Iida M: Chronic kidney disease and cardiovascular disease in a general Japanese population: the Hisayama study. Kidney Int 2005;68:228–236.
  3. Guerrero-Romero F, Rodriguez-Moran M: Proteinuria is an independent risk factor for ischemic stroke in non-insulin-dependent diabetes mellitus. Stroke 1999;30:1787–1791.
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