http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(2): 217–221 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2013.846794
CLINICAL STUDY
CKD is associated with recurrent ischemia but not with hemorrhagic transformation in acute ischemic stroke patients Hasan Micozkadioglu1, Ruya Ozelsancak1*, Semih Giray2*, and Zulfikar Arlier2* Department of Nephrology, and 2Department of Neurology, Baskent University Adana Teaching and Training Center, Adana, Turkey
Abstract
Keywords
Background: We investigated the associations of Recurrent Ischemic Stroke (RIS) and Hemorrhagic Transformation (HT) with CKD in acute ischemic stroke patients. Method: The subjects were 160 patients, divided into two groups: with eGFR 560 mL/min/1.73 m2 (CKD), with eGFR 60 mL/min/1.73 m2 (without CKD). Results: Subjects having DM (p ¼ 0.018), CKD (p ¼ 0.025) and treated with ACEI/ARB (p ¼ 0.039) revealed association with RIS. Regression analysis disclosed only CKD (p ¼ 0.04). Carotid artery stenosis (p ¼ 0.030) and serum calcium levels (p ¼ 0.013) showed significant association with HT. Conclusion: Our results disclosed that CKD could be a risk factor for RIS. There is no relation between CKD and HT.
Chronic kidney disease, hemorrhagic transformation, ischemic stroke, vascular disease, proteinuria
Introduction Chronic Kidney Disease (CKD) is a major public health problem increasing all over the world.1 The prevalence of CKD is very high among elderly patients.2 It has been shown that CKD was strongly related to cardiovascular disease.3,4 A number of prospective studies have also disclosed CKD as a risk factor for another vascular disease: Stroke.5–7 In the Rotterdam study, having CKD was a risk factor for only hemorrhagic but not for ischemic stroke.8 A recent study showed sex difference as a risk factor in CKD that was associated with hemorrhagic stroke in men but ischemic stroke in women.9 Meanwhile, ischemic stroke was also significantly associated with CKD in some other studies.10,11 In a previous study, CKD was associated with recurrent cardiovascular disease in unstable coronary syndrome patients.12 Another study found that CKD increased recurrent cardiovascular event risk 1.35-fold in patients with preexisting cardiovascular disease.13 Recurrence of stroke may also be higher in CKD patients compared with those having normal kidney function.14 However, this association is largely not known in acute ischemic stroke patients. In some patients having acute ischemic stroke, Hemorrhagic Transformation (HT) is found in infarction areas. Also, HT can predict worse outcome in those patients. The etiology and the association of HT with CKD are not well known.15,16 *These authors contributed equally to this work. Address correspondence to Hasan Micozkadioglu, Department of Nephrology, Baskent University Adana Teaching and Training Center, Dadaloglu Mah. 39/6, PK: 01250, Yuregir, Adana, Turkey. Tel.: +90 322 327 27 27; Fax: +90 322 327 12 73; E-mail: [email protected]
History Received 21 July 2013 Revised 3 September 2013 Accepted 8 September 2013 Published online 29 October 2013
In this retrospective observational study, it was aimed to evaluate the relation between CKD and the Recurrent Ischemic Stroke (RIS) and also to examine the relation between CKD and HT in acute ischemic stroke patients.
Material and methods The data were analyzed by consecutive patients with acute ischemic stroke onset between January 2010 and July 2011. They were admitted to Baskent University Adana Training and Research Hospital. Subjects were undergone magnetic resonance imaging for cranial, carotid and vertebral artery evaluation. Patients who have died or discharged in 72 h were excluded due to insufficient data. Patients having dialysis treatment or transplantation history were excluded because of confounding factors. Age, gender, history of diabetes mellitus, hypertension, Coronary Artery Disease (CAD), peripheral artery disease, atrial fibrillation, prior stroke history, antihypertensive drugs, anticoagulant drug, blood pressure at admission were recorded. Hypertension was defined as the following criteria: previous hypertension; currently taking antihypertensive medication; or chronically high blood pressure exceeding 140/90 mmHg. Diabetes mellitus was defined as: fasting blood sugar 126 mg/dL; non fasting blood sugar 200 mg/dL; or current use of insulin or oral hypoglycemic agent. Coronary artery disease was defined as: prior myocardial infarction history and/or prior angiographic examination. Recurrent ischemic stroke was defined as having chronic infarction areas in magnetic resonance imaging of the brain. Chronic infarction areas were accepted as evidences of more than one stroke history during their life. Hemorrhagic transformation was defined as having
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hemorrhagic lesions in the center of acute ischemic infarction areas. Identification of kidney damage was established based on the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney foundation guidelines.17 Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease method. Serum creatinine levels at admission were used to calculate GFR. Low GFR was defined when it was 560, which means moderate stage of CKD. Patients with eGFR 560 mL/min/1.73 m2 was defined as having CKD. All patients underwent routine T1 and T2 weighted brain MRI, and 3D-TOF cerebral, carotid and vertebral MR angiography and diffusion MRI. MRI examinations were performed using a 1.5-Tesla MRI unit (Siemens Avanto, Siemens, Erlangen, Germany). All patients underwent routine T1-weighted spin echo (SE), T2-weighted turbo spin echo (TSE) and fluid attenuated inversion recovery (FLAIR), brain MRI, and T1-weighted gradient echo (GRE) 3D time-of-flight (TOF) cerebral, carotid and vertebral MR angiography. Additionally single shot-echo planar (SH-EPI) diffusion weighted brain MRI and apparent diffusion coefficient (ADC) maps were obtained. All patients were reviewed retrospectively based on the written reports. A Vivid 7 color-Doppler ultrasound imager (General Electric, Milwaukee, WI) with a 2.5–5 MHz transducer was used for cardiac ultrasound. Tracings were recorded under 2-dimensional guidance, and measurements were taken at the tip of the mitral valve or just below that point. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography. Serum was assessed using standard laboratory methods (Roche Hitachi analyzer 902, Indianapolis, IN). Statistical analysis was performed using the statistical package SPSS v 17.0 (Chicago, IL). For each continuous variable, normality was checked by Kolmogorov–Smirnov and Shapiro–Wilk tests. Comparisons between groups were applied using one-way Student’s t test for normally distributed data and Mann–Whitney test were used for the data not normally distributed. The categorical variables between the groups were analyzed by using the chi-squared test. Multiple logistic regression analysis was used to show associations between RIS and other risk factors for ischemic stroke. RIS was used as dependent variable. Values of p50.05 were considered as statistically significant. This study is supported by Baskent University School of Medicine. Study was approved by Baskent University Ethics Committee. Ethics Committee Project no: KA12/261. The authors did not receive financial support. There is no experimental investigation on human subjects.
Results The subjects were 160 patients with acute ischemic stroke including 70 females, 90 males with a mean age 67.90 12.63 years (range ¼ 35–94 years). Patients were divided into two groups: with eGFR 560 mL/min/1.73 m2 (CKD), with eGFR 60 mL/min/1.73 m2 (without CKD). There were no difference between two groups regarding to age
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(69.84 11.13/67.19 13.11 years), sex [Male: 22 (24.4%)/ Female: 21 (30%)] existence of atrial fibrillation [10 (26.3%)/ 33 (27%)], left ventricular hypertrophy [36 (83.7%)/87 (75.0%)], aortic valve calcification [12 (27.9%)/26 (22.4%)], SBP (145.52 26.68/142.85 23.65 mmHg) and DBP (84.10 12.35/80.22 13.67 mmHg), respectively. As expected, significant differences were found due to the existence of diabetes mellitus [26 (60.5%)/40 (34.2%)] (p ¼ 0.004), hypertension [43 (100%)/102 (87.2%)] (p ¼ 0.012), CAD [25 (58.1%)/46 (39.3%)] (p ¼ 0.048). The characteristics of the subjects regarding to RIS are outlined in Table 1. The number of patients with RIS was 43 (%26.9). Subjects having diabetes mellitus (p ¼ 0.018), CKD (p ¼ 0.025) and treated with ACEI/ARB (p ¼ 0.039) disclosed significant association with RIS in acute ischemic stroke patients. Multiple logistic regression analysis was used to show associations between RIS and other risk factors for acute ischemic stroke. Recurrent ischemic stroke was used as dependent variable and results revealed that only having CKD was the risk factor for RIS (p ¼ 0.04) (Table 2). The characteristics of the subjects regarding to HT are outlined in Table 3. Carotid artery stenosis (p ¼ 0.030) and serum calcium levels (p ¼ 0.013) were significantly associated with HT. Carotid artery stenosis was significantly lower in HT group. Meanwhile, serum calcium levels were significantly higher (9.56 0.52 vs. 9.05 0.56).
Discussion Renal dysfunction is a predictor of all combined vascular events and mortality in stroke patients. Nearly, one-third of acute stroke patients have renal dysfunction.18 In this study, CKD was found 26.9% in acute ischemic stroke patients. Rodriguez et al.19 revealed that left sided cardiac valvular calcifications were associated with covert MRI-defined brain infarcts. Vascular calcification is a well-known complication of CKD but results revealed no significant association between aortic valve calcification and CKD in this study. Firstly, cardiovascular calcifications are usual findings in elderly people as in this research. Secondly, regarding to having CKD, subject number is small in this study. Thirdly, stage 3 CKD is defined as having CKD, probably stage 4 and end-stage patients will show significant results regarding to aortic valve calcification. Weiner et al.13 showed that CKD increased recurrent cardiovascular event risk 1.35-fold in patients with preexisting cardiovascular disease. Subgroup analysis revealed that recurrent stroke risk was 1.30-fold in CKD patients. Another study reported that patients with CKD had a 1.73-fold risk of recurrent non-cardioembolic stroke.20 In this study, it was revealed that RIS was significantly more prevalent in CKD patients. Additionally, having DM and treating with ACEI/ ARB were also more prevalent in patients with RIS. However, regression analysis showed that having CKD was the only factor increasing RIS risk as 2.39-fold. Diabetes mellitus is one of the most important risk factor in cardiovascular disease. Low eGFR and proteinuria showed increased cardiovascular disease risk in type 2 diabetes patients.21 In addition, silent brain infarction is significantly associated with low eGFR and proteinuria in diabetic
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Table 1. The characteristics of the subjects regarding to RIS.
N Age (years) Sex (M/F) Hypertension Diabetes mellitus Coronary artery disease Atrial fibrillation Carotid artery stenosis Vertebral artery stenosis Left ventricular hypertrophy Aortic valve calcification SBP (mmHg) DBP (mmHg) Hemoglobin (g/dL) WBC (K/mm3) Platelet (K/mm3) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Trigliycerides (mg/dL) Serum creatinine (mg/dL) Serum calcium (mg/dL) Serum phophorus (mg/dL) Serum albumin (g/dL) eGFR (mL/min/1.73 m2) Chronic kidney disease (CKD) Proteinu¨ri (g/L) CRP (mg/L) ACEI/ARB Ca channel blockers Beta blockers Antiagregant drug
Total
RIS ()
RIS (þ)
p
160 67.90 12.63 90/70 145 (90.6%) 66 (41.3%) 71 (44.3%) 38 (23.8%) 31 (19.6%) 24 (15.2%) 123 (77.4%) 38 (23.9%) 143.56 24.43 81.25 13.40 13.35 1.65 9.72 3.27 280.02 84.47 183.84 52.28 114.07 33.13 36.87 8.99 157.05 97.41 1.07 0.64 9.12 0.58 3.49 0.78 3.69 0.55 75.01 26.65 43 (26.9%) 0.41 1.39 19.26 39.45 63 (39.9%) 96 (60.8%) 51 (32.3%) 11 (6.88%)
105 67.14 13.66 59/46 92 (87.6%) 36 (34.2%) 46 (43.8%) 26 (24.8%) 19 (18.3%) 13 (12.5%) 80 (76.9%) 23 (22.1%) 141.35 23.42 81.24 14.46 13.45 1.65 9.78 3.61 282.70 84.20 187.43 54.14 115.48 31.75 37.09 9.11 156.69 97.57 1.02 0.63 9.11 0.52 3.58 0.76 3.76 0.57 77.51 24.49 22 (21%) 0.59 1.82 20.30 48.38 35 (33.7%) 64 (66.7%) 32 (30.8%) 8 (7.6%)
55 69.35 10.35 31/24 53 (96.3%) 30 (54.5%) 25 (45.4%) 12 (21.8%) 12 (22.2%) 11 (20.4%) 43 (78.2%) 15 (27.3%) 147.83 25.96 81.28 11.22 13.15 1.64 9.60 2.50 274.91 85.53 176.87 48.20 111.40 35.79 36.43 8.82 157.75 98.04 1.17 0.65 9.13 0.72 3.27 0.81 3.52 0.49 70.24 30.03 21 (38.2%) 0.32 1.12 18.75 34.49 28 (51.9%) 32 (33.3%) 19 (35.2%) 3 (5.5%)
NS NS NS 0.018 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.025 NS NS 0.039 NS NS NS
Table 2. Multiple logistic regression analysis between RIS and other risk factors for stroke, with RIS as a dependent variable. 95% CI for Exp (B)
1
CKD Age Sex1 Diabetes mellitus1 Hypertension1 Triglycerides Total cholesterol LDL-cholesterol HDL-cholesterol CAD1 AF LVH AVC ACEI/ARB1 Constant
B
SE
Wald
df
p
Odds ratio
Lower
Upper
0.873 0.017 0.026 0.725 0.593 0.006 0.027 0.020 0.029 0.432 0.295 0.366 0.020 0.527 2.424
0.426 0.018 0.392 0.394 0.879 0.007 0.032 0.032 0.040 0.412 0.474 0.490 0.452 0.399 1.641
4.204 0.901 0.005 3.387 0.455 0.840 0.734 0.388 0.531 1.102 0.388 0.557 0.002 1.745 2.182
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0.040 0.342 0.946 0.066 0.500 0.360 0.392 0.533 0.466 0.294 0.533 0.456 0.965 0.186 0.140
2.395 1.017 1.027 2.065 1.809 1.006 0.973 1.020 1.030 1.541 0.744 0.694 1.020 1.695 0.089
1.039 0.982 0.477 0.954 0.323 0.993 0.915 0.958 0.952 0.687 0.294 0.266 0.421 0.775
5.518 1.053 2.212 4.468 10.130 1.019 1.035 1.086 1.114 3.454 1.884 1.813 2.473 3.706
Note: CAD, coronary artery disease; AF, atrial fibrillation; LVH, left ventricular hypertrophy; AVC, aortic valve calcification.
patients.22 In the same study, regression analysis revealed that proteinuria remained independently associated with silent brain infarction, but eGFR was not.22 In this study, proteinuria was not significantly different between two groups but data in this study included only urine dipstick tests. Vascular protective effects of ACEI/ARB drugs are well known, however the hypotensive effects of these drugs may explain the high prevalence of RIS in patients treated with ACEI/ ARB. Additionally, patients having more severe hypertension
could receive these drugs and severe hypertension could explain the high prevalence of RIS. In some acute ischemic stroke patients, HT was found incidentally.16 There are two mechanisms for HT in acute ischemic stroke patients. One is related to increased vascular permeability and it is suggested to be responsible for HT within 72 h after onset. The second mechanism is spontaneous restoration of blood circulation in the capillary bed during the first 2 weeks.15 The only study on the association between
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Table 3. The characteristics of the subjects regarding to HT.
N Age (years) Sex (M/F) Hypertension Diabetes mellitus Coronary artery disease Atrial fibrillation Carotid artery stenosis Vertebral artery stenosis Left ventricular hypertrophy Aortic valve calcification SBP (mmHg) DBP (mmHg) Hemoglobin (g/dL) WBC (K/mm3) Platelet (K/mm3) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Trigliycerides (mg/dL) Serum creatinine (mg/dL) Serum calcium (mg/dL) Serum phophorus (mg/dL) Serum albumin (g/dL) eGFR (mL/min/1.73 m2) Chronic kidney disease Proteinu¨ri (g/L) CRP (mg/L) ACEI/ARB Ca channel blockers Beta blockers Antiagregant drug
Total
HT ()
HT (þ)
p
160 67.90 12.63 90/70 145 (90.6%) 66 (41.3%) 71 (44.3%) 38 (23.8%) 31 (19.6%) 24 (15.2%) 123 (77.4%) 38 (23.9%) 143.56 24.43 81.25 13.40 13.35 1.65 9.72 3.27 280.02 84.47 183.84 52.28 114.07 33.13 36.87 8.99 157.05 97.41 1.07 0.64 9.12 0.58 3.49 0.78 3.69 0.55 75.01 26.65 43 (26.9%) 0.41 1.39 19.26 39.45 63 (39.9%) 96 (60.8%) 51 (32.3%) 11 (6.88%)
133 68.69 12.49 74/59 119 (87.6%) 53 (39.8%) 56 (42.1%) 30 (22.6%) 30 (22.6%) 20 (15%) 104 (78.8%) 30 (22.7%) 142.97 23.21 80.91 13.23 13.27 1.67 9.49 3.02 279.55 84.43 183.13 52.56 114.62 40.09 36.54 9.24 154.72 97.98 1.07 0.67 9.05 0.56 3.49 0.75 3.63 0.55 75.05 25.99 34 (25.6%) 0.38 1.16 20.52 42.11 51 (38.9%) 76 (58%) 39 (29.8%) 9 (6.77%)
27 64.00 12.83 16/11 26 (96.3%) 13 (48.1%) 15 (55.6%) 8 (29.6%) 1 (4%) 4 (16%) 19 (70.4%) 8 (29.6%) 146.44 29.99 82.93 14.36 13.75 1.47 10.82 4.19 282.33 86.26 187.22 51.79 114.07 33.13 36.87 8.99 168.11 95.72 1.07 0.48 9.56 0.52 3.49 1.05 3.88 0.53 74.78 30.20 9 (33.3%) 0.54 2.10 13.25 22.50 12 (44.4%) 20 (74.1%) 12 (44.4%) 2 (7.4%)
NS NS NS NS NS NS 0.030 NS NS NS NS NS NS NS NS NS NS NS NS NS 0.013 NS NS NS NS NS NS NS NS NS NS
GFR and HT after ischemic stroke revealed that low levels of GFR were associated with a high risk of HT.15 In that study, GFR was estimated by a single creatinine measurement performed at admission like in this study. But, in that study, time delay to admission was variable that could affect serum creatinine levels and the GFR of patients. In this study, we selected the patients who were admitted within the 24 h of stroke onset and magnetic resonance imaging was performed at admission. Renal dysfunction has a bleeding tendency because of platelet dysfunction and induces abnormal platelet-vessel wall interaction.23 But, we could not find any association between CKD and HT. Carotid artery stenosis was significantly lower in HT group. That can be explained with the difference of vascular permeability at the stroke area by the existence of carotid artery stenosis. Meanwhile, serum calcium levels were significantly higher in HT group. As an explanation, higher serum calcium levels could negatively affect the control of blood pressure and cause bleeding. Nevertheless, this result is inappropriate with the expectation because ionized calcium is an essential cofactor for coagulation cascade.24 As a limitation of this study, we did not show ionized calcium levels and albumin-corrected calcium levels. However, there was no difference between the groups regarding to serum albumin levels. Other limitations were retrospective design of the study, lack of data about smoking history and antiplatelet drug medication. In conclusion, CKD could be an important risk factor for RIS in acute ischemic stroke patients. Although platelet
dysfunction is a well-known disorder in CKD, no relation is found between CKD and HT in acute ischemic stroke patients.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
References 1. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics. 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–e171. 2. Nissenson AR, Pereira BJ, Collins AJ, Steinberg EP. Prevalence and characteristics of individuals with chronic kidney disease in a large health maintenance organization. Am J Kidney Dis. 2001;37: 1177–1183. 3. Ninomiya T, Kiyohara Y, Tokuda Y, et al. Impact of kidney disease and blood pressure on the development of cardiovascular disease: an overview from the Japan Arteriosclerosis Longitudinal study. Circulation. 2008;118:2694–2701. 4. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events and hospitalization. N Eng J Med. 2004;351:1296–1305. 5. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ. 2010;341:c4249–c4258. 6. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population – the Ohasama Study. Nephrol Dial Transplant. 2007; 22:1910–1915.
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7. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke. 1997;28:557–563. 8. Bos MJ, Koudstaal PJ, Hofman A, Breteler MB. Decreased glomerular filtration rate is a risk factor for hemorrhagic but not for ischemic stroke: the Rotterdam Study. Stroke. 2007;38: 3127–3132. 9. Shimizu Y, Maeda K, Imano H, et al. Chronic kidney disease and drinking status in relation to risks of stroke and its subtypes: the Circulatory Risk in Communities Study (CIRCS). Stroke. 2011;42: 2531–2537. 10. Ninomiya T, Kiyohara Y, Kubo M, et al. Chronic kidney disease and cardiovascular disease in general Japanese population: the Hisayama Study. Kidney Int. 2005;68:228–236. 11. Kokubo Y, Nakamura S, Okamura T, et al. Relationship between blood pressure category and incidence of stroke and myocardial infarction in an urban Japanese population with and without chronic kidney disease. The Suita study. Stroke. 2009;40: 2674–2679. 12. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med. 2002;137:555–562. 13. Weiner DE, Tighiourt H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. Am J Kidney Dis. 2004;44:198–206. 14. Kim SJ, Bang OY. Antiplatelet therapy for preventing stroke in patients with chronic kidney disease. Contrib Nephrol. 2013;179: 119–129. 15. Lee JG, Lee KB, Jang IM, et al. Low glomerular filtration rate increases hemorrhagic transformation in acute ischemic stroke. Cerebrovasc Dis. 2013;35(1):53–59.
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16. Moriya Y, Takahashi W, K|j|ma C, et al. Predictors for hemorragic transformation with intravenous tissue plasminogen activator in acute ischemic stroke. Tokai J Exp Clin Med. 2013;38:24–27. 17. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39:S261–S266. 18. Tsagalis G, Akrivos T, Alevizaki M, et al. Renal dysfunction in acute stroke: an independent predictor of long-term all combined vascular events and overall mortality. Nephrol Dial Transplant. 2009;24:194–200. 19. Rodriguez CJ, Bartz TM, Longstreth Jr WT, et al. Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study. J Am Coll Cardiol. 2011;57: 2172–2180. 20. Kuwashiro T, Sugimori H, Ago T, Kamouchi M, Kitazono T. Risk factors predisposing to stroke recurrence within one year of noncardioembolic stroke onset: Fukuoka Stroke registry. Cerebrovasc Dis. 2012;33:141–149. 21. Yokoyama H, Araki S, Haneda M, et al. Chronic kidney disease categories and renal-cardiovascular outcomes in type 2 diabetes without prevalent cardiovascular disease: a prospective cohort study (JDDM25). Diabetologia. 2012;55:1911–1918. 22. Bouchi R, Babazono T, Yoshida N, et al. Relationship between chronic kidney disease and silent cerebral infarction in patients with type 2 diabetes. Diabet Med. 2010;27:538–543. 23. Sohal AS, Gangji AS, Crowther MA, Treleaven D. Uremic bleeding: pathophysiology and clinical risk factors. Thromb Res. 2006;118:417–422. 24. Inoue Y, Miyashita F, Toyoda K, Minematsu K. Low serum calcium levels contribute to larger hematome volume in acute intracerebral hemorrhage. Stroke. 2013;44:2004–2006.
CLINICAL STUDY
CKD is associated with recurrent ischemia but not with hemorrhagic transformation in acute ischemic stroke patients Hasan Micozkadioglu1, Ruya Ozelsancak1*, Semih Giray2*, and Zulfikar Arlier2* Department of Nephrology, and 2Department of Neurology, Baskent University Adana Teaching and Training Center, Adana, Turkey
Abstract
Keywords
Background: We investigated the associations of Recurrent Ischemic Stroke (RIS) and Hemorrhagic Transformation (HT) with CKD in acute ischemic stroke patients. Method: The subjects were 160 patients, divided into two groups: with eGFR 560 mL/min/1.73 m2 (CKD), with eGFR 60 mL/min/1.73 m2 (without CKD). Results: Subjects having DM (p ¼ 0.018), CKD (p ¼ 0.025) and treated with ACEI/ARB (p ¼ 0.039) revealed association with RIS. Regression analysis disclosed only CKD (p ¼ 0.04). Carotid artery stenosis (p ¼ 0.030) and serum calcium levels (p ¼ 0.013) showed significant association with HT. Conclusion: Our results disclosed that CKD could be a risk factor for RIS. There is no relation between CKD and HT.
Chronic kidney disease, hemorrhagic transformation, ischemic stroke, vascular disease, proteinuria
Introduction Chronic Kidney Disease (CKD) is a major public health problem increasing all over the world.1 The prevalence of CKD is very high among elderly patients.2 It has been shown that CKD was strongly related to cardiovascular disease.3,4 A number of prospective studies have also disclosed CKD as a risk factor for another vascular disease: Stroke.5–7 In the Rotterdam study, having CKD was a risk factor for only hemorrhagic but not for ischemic stroke.8 A recent study showed sex difference as a risk factor in CKD that was associated with hemorrhagic stroke in men but ischemic stroke in women.9 Meanwhile, ischemic stroke was also significantly associated with CKD in some other studies.10,11 In a previous study, CKD was associated with recurrent cardiovascular disease in unstable coronary syndrome patients.12 Another study found that CKD increased recurrent cardiovascular event risk 1.35-fold in patients with preexisting cardiovascular disease.13 Recurrence of stroke may also be higher in CKD patients compared with those having normal kidney function.14 However, this association is largely not known in acute ischemic stroke patients. In some patients having acute ischemic stroke, Hemorrhagic Transformation (HT) is found in infarction areas. Also, HT can predict worse outcome in those patients. The etiology and the association of HT with CKD are not well known.15,16 *These authors contributed equally to this work. Address correspondence to Hasan Micozkadioglu, Department of Nephrology, Baskent University Adana Teaching and Training Center, Dadaloglu Mah. 39/6, PK: 01250, Yuregir, Adana, Turkey. Tel.: +90 322 327 27 27; Fax: +90 322 327 12 73; E-mail: [email protected]
History Received 21 July 2013 Revised 3 September 2013 Accepted 8 September 2013 Published online 29 October 2013
In this retrospective observational study, it was aimed to evaluate the relation between CKD and the Recurrent Ischemic Stroke (RIS) and also to examine the relation between CKD and HT in acute ischemic stroke patients.
Material and methods The data were analyzed by consecutive patients with acute ischemic stroke onset between January 2010 and July 2011. They were admitted to Baskent University Adana Training and Research Hospital. Subjects were undergone magnetic resonance imaging for cranial, carotid and vertebral artery evaluation. Patients who have died or discharged in 72 h were excluded due to insufficient data. Patients having dialysis treatment or transplantation history were excluded because of confounding factors. Age, gender, history of diabetes mellitus, hypertension, Coronary Artery Disease (CAD), peripheral artery disease, atrial fibrillation, prior stroke history, antihypertensive drugs, anticoagulant drug, blood pressure at admission were recorded. Hypertension was defined as the following criteria: previous hypertension; currently taking antihypertensive medication; or chronically high blood pressure exceeding 140/90 mmHg. Diabetes mellitus was defined as: fasting blood sugar 126 mg/dL; non fasting blood sugar 200 mg/dL; or current use of insulin or oral hypoglycemic agent. Coronary artery disease was defined as: prior myocardial infarction history and/or prior angiographic examination. Recurrent ischemic stroke was defined as having chronic infarction areas in magnetic resonance imaging of the brain. Chronic infarction areas were accepted as evidences of more than one stroke history during their life. Hemorrhagic transformation was defined as having
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hemorrhagic lesions in the center of acute ischemic infarction areas. Identification of kidney damage was established based on the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney foundation guidelines.17 Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease method. Serum creatinine levels at admission were used to calculate GFR. Low GFR was defined when it was 560, which means moderate stage of CKD. Patients with eGFR 560 mL/min/1.73 m2 was defined as having CKD. All patients underwent routine T1 and T2 weighted brain MRI, and 3D-TOF cerebral, carotid and vertebral MR angiography and diffusion MRI. MRI examinations were performed using a 1.5-Tesla MRI unit (Siemens Avanto, Siemens, Erlangen, Germany). All patients underwent routine T1-weighted spin echo (SE), T2-weighted turbo spin echo (TSE) and fluid attenuated inversion recovery (FLAIR), brain MRI, and T1-weighted gradient echo (GRE) 3D time-of-flight (TOF) cerebral, carotid and vertebral MR angiography. Additionally single shot-echo planar (SH-EPI) diffusion weighted brain MRI and apparent diffusion coefficient (ADC) maps were obtained. All patients were reviewed retrospectively based on the written reports. A Vivid 7 color-Doppler ultrasound imager (General Electric, Milwaukee, WI) with a 2.5–5 MHz transducer was used for cardiac ultrasound. Tracings were recorded under 2-dimensional guidance, and measurements were taken at the tip of the mitral valve or just below that point. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography. Serum was assessed using standard laboratory methods (Roche Hitachi analyzer 902, Indianapolis, IN). Statistical analysis was performed using the statistical package SPSS v 17.0 (Chicago, IL). For each continuous variable, normality was checked by Kolmogorov–Smirnov and Shapiro–Wilk tests. Comparisons between groups were applied using one-way Student’s t test for normally distributed data and Mann–Whitney test were used for the data not normally distributed. The categorical variables between the groups were analyzed by using the chi-squared test. Multiple logistic regression analysis was used to show associations between RIS and other risk factors for ischemic stroke. RIS was used as dependent variable. Values of p50.05 were considered as statistically significant. This study is supported by Baskent University School of Medicine. Study was approved by Baskent University Ethics Committee. Ethics Committee Project no: KA12/261. The authors did not receive financial support. There is no experimental investigation on human subjects.
Results The subjects were 160 patients with acute ischemic stroke including 70 females, 90 males with a mean age 67.90 12.63 years (range ¼ 35–94 years). Patients were divided into two groups: with eGFR 560 mL/min/1.73 m2 (CKD), with eGFR 60 mL/min/1.73 m2 (without CKD). There were no difference between two groups regarding to age
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(69.84 11.13/67.19 13.11 years), sex [Male: 22 (24.4%)/ Female: 21 (30%)] existence of atrial fibrillation [10 (26.3%)/ 33 (27%)], left ventricular hypertrophy [36 (83.7%)/87 (75.0%)], aortic valve calcification [12 (27.9%)/26 (22.4%)], SBP (145.52 26.68/142.85 23.65 mmHg) and DBP (84.10 12.35/80.22 13.67 mmHg), respectively. As expected, significant differences were found due to the existence of diabetes mellitus [26 (60.5%)/40 (34.2%)] (p ¼ 0.004), hypertension [43 (100%)/102 (87.2%)] (p ¼ 0.012), CAD [25 (58.1%)/46 (39.3%)] (p ¼ 0.048). The characteristics of the subjects regarding to RIS are outlined in Table 1. The number of patients with RIS was 43 (%26.9). Subjects having diabetes mellitus (p ¼ 0.018), CKD (p ¼ 0.025) and treated with ACEI/ARB (p ¼ 0.039) disclosed significant association with RIS in acute ischemic stroke patients. Multiple logistic regression analysis was used to show associations between RIS and other risk factors for acute ischemic stroke. Recurrent ischemic stroke was used as dependent variable and results revealed that only having CKD was the risk factor for RIS (p ¼ 0.04) (Table 2). The characteristics of the subjects regarding to HT are outlined in Table 3. Carotid artery stenosis (p ¼ 0.030) and serum calcium levels (p ¼ 0.013) were significantly associated with HT. Carotid artery stenosis was significantly lower in HT group. Meanwhile, serum calcium levels were significantly higher (9.56 0.52 vs. 9.05 0.56).
Discussion Renal dysfunction is a predictor of all combined vascular events and mortality in stroke patients. Nearly, one-third of acute stroke patients have renal dysfunction.18 In this study, CKD was found 26.9% in acute ischemic stroke patients. Rodriguez et al.19 revealed that left sided cardiac valvular calcifications were associated with covert MRI-defined brain infarcts. Vascular calcification is a well-known complication of CKD but results revealed no significant association between aortic valve calcification and CKD in this study. Firstly, cardiovascular calcifications are usual findings in elderly people as in this research. Secondly, regarding to having CKD, subject number is small in this study. Thirdly, stage 3 CKD is defined as having CKD, probably stage 4 and end-stage patients will show significant results regarding to aortic valve calcification. Weiner et al.13 showed that CKD increased recurrent cardiovascular event risk 1.35-fold in patients with preexisting cardiovascular disease. Subgroup analysis revealed that recurrent stroke risk was 1.30-fold in CKD patients. Another study reported that patients with CKD had a 1.73-fold risk of recurrent non-cardioembolic stroke.20 In this study, it was revealed that RIS was significantly more prevalent in CKD patients. Additionally, having DM and treating with ACEI/ ARB were also more prevalent in patients with RIS. However, regression analysis showed that having CKD was the only factor increasing RIS risk as 2.39-fold. Diabetes mellitus is one of the most important risk factor in cardiovascular disease. Low eGFR and proteinuria showed increased cardiovascular disease risk in type 2 diabetes patients.21 In addition, silent brain infarction is significantly associated with low eGFR and proteinuria in diabetic
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Table 1. The characteristics of the subjects regarding to RIS.
N Age (years) Sex (M/F) Hypertension Diabetes mellitus Coronary artery disease Atrial fibrillation Carotid artery stenosis Vertebral artery stenosis Left ventricular hypertrophy Aortic valve calcification SBP (mmHg) DBP (mmHg) Hemoglobin (g/dL) WBC (K/mm3) Platelet (K/mm3) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Trigliycerides (mg/dL) Serum creatinine (mg/dL) Serum calcium (mg/dL) Serum phophorus (mg/dL) Serum albumin (g/dL) eGFR (mL/min/1.73 m2) Chronic kidney disease (CKD) Proteinu¨ri (g/L) CRP (mg/L) ACEI/ARB Ca channel blockers Beta blockers Antiagregant drug
Total
RIS ()
RIS (þ)
p
160 67.90 12.63 90/70 145 (90.6%) 66 (41.3%) 71 (44.3%) 38 (23.8%) 31 (19.6%) 24 (15.2%) 123 (77.4%) 38 (23.9%) 143.56 24.43 81.25 13.40 13.35 1.65 9.72 3.27 280.02 84.47 183.84 52.28 114.07 33.13 36.87 8.99 157.05 97.41 1.07 0.64 9.12 0.58 3.49 0.78 3.69 0.55 75.01 26.65 43 (26.9%) 0.41 1.39 19.26 39.45 63 (39.9%) 96 (60.8%) 51 (32.3%) 11 (6.88%)
105 67.14 13.66 59/46 92 (87.6%) 36 (34.2%) 46 (43.8%) 26 (24.8%) 19 (18.3%) 13 (12.5%) 80 (76.9%) 23 (22.1%) 141.35 23.42 81.24 14.46 13.45 1.65 9.78 3.61 282.70 84.20 187.43 54.14 115.48 31.75 37.09 9.11 156.69 97.57 1.02 0.63 9.11 0.52 3.58 0.76 3.76 0.57 77.51 24.49 22 (21%) 0.59 1.82 20.30 48.38 35 (33.7%) 64 (66.7%) 32 (30.8%) 8 (7.6%)
55 69.35 10.35 31/24 53 (96.3%) 30 (54.5%) 25 (45.4%) 12 (21.8%) 12 (22.2%) 11 (20.4%) 43 (78.2%) 15 (27.3%) 147.83 25.96 81.28 11.22 13.15 1.64 9.60 2.50 274.91 85.53 176.87 48.20 111.40 35.79 36.43 8.82 157.75 98.04 1.17 0.65 9.13 0.72 3.27 0.81 3.52 0.49 70.24 30.03 21 (38.2%) 0.32 1.12 18.75 34.49 28 (51.9%) 32 (33.3%) 19 (35.2%) 3 (5.5%)
NS NS NS 0.018 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.025 NS NS 0.039 NS NS NS
Table 2. Multiple logistic regression analysis between RIS and other risk factors for stroke, with RIS as a dependent variable. 95% CI for Exp (B)
1
CKD Age Sex1 Diabetes mellitus1 Hypertension1 Triglycerides Total cholesterol LDL-cholesterol HDL-cholesterol CAD1 AF LVH AVC ACEI/ARB1 Constant
B
SE
Wald
df
p
Odds ratio
Lower
Upper
0.873 0.017 0.026 0.725 0.593 0.006 0.027 0.020 0.029 0.432 0.295 0.366 0.020 0.527 2.424
0.426 0.018 0.392 0.394 0.879 0.007 0.032 0.032 0.040 0.412 0.474 0.490 0.452 0.399 1.641
4.204 0.901 0.005 3.387 0.455 0.840 0.734 0.388 0.531 1.102 0.388 0.557 0.002 1.745 2.182
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
0.040 0.342 0.946 0.066 0.500 0.360 0.392 0.533 0.466 0.294 0.533 0.456 0.965 0.186 0.140
2.395 1.017 1.027 2.065 1.809 1.006 0.973 1.020 1.030 1.541 0.744 0.694 1.020 1.695 0.089
1.039 0.982 0.477 0.954 0.323 0.993 0.915 0.958 0.952 0.687 0.294 0.266 0.421 0.775
5.518 1.053 2.212 4.468 10.130 1.019 1.035 1.086 1.114 3.454 1.884 1.813 2.473 3.706
Note: CAD, coronary artery disease; AF, atrial fibrillation; LVH, left ventricular hypertrophy; AVC, aortic valve calcification.
patients.22 In the same study, regression analysis revealed that proteinuria remained independently associated with silent brain infarction, but eGFR was not.22 In this study, proteinuria was not significantly different between two groups but data in this study included only urine dipstick tests. Vascular protective effects of ACEI/ARB drugs are well known, however the hypotensive effects of these drugs may explain the high prevalence of RIS in patients treated with ACEI/ ARB. Additionally, patients having more severe hypertension
could receive these drugs and severe hypertension could explain the high prevalence of RIS. In some acute ischemic stroke patients, HT was found incidentally.16 There are two mechanisms for HT in acute ischemic stroke patients. One is related to increased vascular permeability and it is suggested to be responsible for HT within 72 h after onset. The second mechanism is spontaneous restoration of blood circulation in the capillary bed during the first 2 weeks.15 The only study on the association between
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Table 3. The characteristics of the subjects regarding to HT.
N Age (years) Sex (M/F) Hypertension Diabetes mellitus Coronary artery disease Atrial fibrillation Carotid artery stenosis Vertebral artery stenosis Left ventricular hypertrophy Aortic valve calcification SBP (mmHg) DBP (mmHg) Hemoglobin (g/dL) WBC (K/mm3) Platelet (K/mm3) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Trigliycerides (mg/dL) Serum creatinine (mg/dL) Serum calcium (mg/dL) Serum phophorus (mg/dL) Serum albumin (g/dL) eGFR (mL/min/1.73 m2) Chronic kidney disease Proteinu¨ri (g/L) CRP (mg/L) ACEI/ARB Ca channel blockers Beta blockers Antiagregant drug
Total
HT ()
HT (þ)
p
160 67.90 12.63 90/70 145 (90.6%) 66 (41.3%) 71 (44.3%) 38 (23.8%) 31 (19.6%) 24 (15.2%) 123 (77.4%) 38 (23.9%) 143.56 24.43 81.25 13.40 13.35 1.65 9.72 3.27 280.02 84.47 183.84 52.28 114.07 33.13 36.87 8.99 157.05 97.41 1.07 0.64 9.12 0.58 3.49 0.78 3.69 0.55 75.01 26.65 43 (26.9%) 0.41 1.39 19.26 39.45 63 (39.9%) 96 (60.8%) 51 (32.3%) 11 (6.88%)
133 68.69 12.49 74/59 119 (87.6%) 53 (39.8%) 56 (42.1%) 30 (22.6%) 30 (22.6%) 20 (15%) 104 (78.8%) 30 (22.7%) 142.97 23.21 80.91 13.23 13.27 1.67 9.49 3.02 279.55 84.43 183.13 52.56 114.62 40.09 36.54 9.24 154.72 97.98 1.07 0.67 9.05 0.56 3.49 0.75 3.63 0.55 75.05 25.99 34 (25.6%) 0.38 1.16 20.52 42.11 51 (38.9%) 76 (58%) 39 (29.8%) 9 (6.77%)
27 64.00 12.83 16/11 26 (96.3%) 13 (48.1%) 15 (55.6%) 8 (29.6%) 1 (4%) 4 (16%) 19 (70.4%) 8 (29.6%) 146.44 29.99 82.93 14.36 13.75 1.47 10.82 4.19 282.33 86.26 187.22 51.79 114.07 33.13 36.87 8.99 168.11 95.72 1.07 0.48 9.56 0.52 3.49 1.05 3.88 0.53 74.78 30.20 9 (33.3%) 0.54 2.10 13.25 22.50 12 (44.4%) 20 (74.1%) 12 (44.4%) 2 (7.4%)
NS NS NS NS NS NS 0.030 NS NS NS NS NS NS NS NS NS NS NS NS NS 0.013 NS NS NS NS NS NS NS NS NS NS
GFR and HT after ischemic stroke revealed that low levels of GFR were associated with a high risk of HT.15 In that study, GFR was estimated by a single creatinine measurement performed at admission like in this study. But, in that study, time delay to admission was variable that could affect serum creatinine levels and the GFR of patients. In this study, we selected the patients who were admitted within the 24 h of stroke onset and magnetic resonance imaging was performed at admission. Renal dysfunction has a bleeding tendency because of platelet dysfunction and induces abnormal platelet-vessel wall interaction.23 But, we could not find any association between CKD and HT. Carotid artery stenosis was significantly lower in HT group. That can be explained with the difference of vascular permeability at the stroke area by the existence of carotid artery stenosis. Meanwhile, serum calcium levels were significantly higher in HT group. As an explanation, higher serum calcium levels could negatively affect the control of blood pressure and cause bleeding. Nevertheless, this result is inappropriate with the expectation because ionized calcium is an essential cofactor for coagulation cascade.24 As a limitation of this study, we did not show ionized calcium levels and albumin-corrected calcium levels. However, there was no difference between the groups regarding to serum albumin levels. Other limitations were retrospective design of the study, lack of data about smoking history and antiplatelet drug medication. In conclusion, CKD could be an important risk factor for RIS in acute ischemic stroke patients. Although platelet
dysfunction is a well-known disorder in CKD, no relation is found between CKD and HT in acute ischemic stroke patients.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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