INTRODUCTION
Cerebrovascular diseases are common in chronic renal failure (CRF) patients undergoing hemodialysis (HD) and represent a major cause of death in such patients1-5.
Silent cerebral infarction (SCI) has not been thoroughly investigated in HD patients although it may be a significant risk factor for cerebrovascular diseases.
The aim of this work is to identify silent brain infarction in chronic renal failure patients maintained on hemodialysis, and try to answer the question " Is chronic renal failure and hemodialysis per se a risk factor of cerebrovascular infarction or not ? ". Also to look for other risk factors to detect patients who are at high risk to develop such silent infarction.
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PATIENTS AND METHODS
This study was performed in the department of neurology, Kasr El-Aini hospitals, Cairo University, Egypt. It included 40 patients (25 males and 15 females) with chronic renal failure on regular hemodialysis with a (mean age: 55±7.597) and 20 age and sex matched healthy control individuals. All patients with history of previous cerebrovascular accidents or transient ischemic attacks, patients with diabetes mellitus, atrial fibrillation, ischemic heart disease, dyslipidemia, were excluded.
Patients were further subdivided to the following subgroups according to the presence of SCI into Group 1 (Patients with SCI) and Group 2 (Patients without SCI); and according to the duration of HD into Group A (HD of three years or less) and Group B (HD of more than three years).
Methods:
All patients were subjected to the following:
i- Clinical evaluation: history taking, general and neurological examination. We stratified patients depending on their means arterial blood pressures (MABP)9 into four groups in an incremental manner stratification: Str.1 (MABP ranged from 95 to 104) Str.2 (MABPs ranged from 105 to 114) Str.3 (MABPs ranged from 115 to 124), Str.4 (included those with MABPs of 125 or more).
ii- Laboratory tests: Complete blood count (CBC); renal function tests (blood urea [using urease-colorimetric method and three reagents (Rs) R1 buffer, R2 urease enzyme and R3 alkaline with aqueous primary urea standard]6 and creatinine [using colorimetric Jaffe kinetic method and two reagents R1 sodium hydroxide, R2 picric acid with creatinine standard]7); Liver functions tests (Serum albumin, Prothrombin time, Prothrombin concentration and liver enzymes); Serum electrolytes (Sodium, Potassium, Calcium); Blood sugar and Lipid profile.
iii- Duplex and Doppler studies: Doppler and duplex of both carotids and vertebrobasilar system were performed in all patients. Examination was performed with 7.5 MHz linear phased array transducer on a Hewlett-Packard Sonnos 1000 and 2000 machines and an Acuson XP 128 machine. The patient was examined in the supine position with the neck exposed, extended and slightly rotated to the side opposite the examined vessel while resting on a pillow that was positioned at a 45° angle. The ultrasound transducer was placed over carotid arteries from the beginning of their origin till tip of flow divider (branches of carotid arteries).8
iv- Magnetic resonance imaging (MRI): Magnetic resonance imaging [MRI] of the brain was performed to all patients and controls [General Electric Sigma Advantage 1.0-Tesla /T system] using standard acquisition settings and times to produce T1 and T2 weighted, spin-echo sequences and FLAIR in axial, coronal and sagittal planes. T1 and T2 weighted images in axial planes were performed at 10mm. thick slices. The existence of cerebrovascular strokes was evaluated on brain magnetic imaging, infarction was defined as a focal area of 3mm. or more in diameter [slice cut section diameter] in both T1 and T2 weighted images which was visible as low signal intensity area on T1 weighted image and high signal intensity in T2 weighted image, often it was surrounded by a hyperintense gliotic rim on the FLAIR sequence. As mentioned above, only infarcts 3 mm or greater were identified and classified according to size (maximum of the anterior-posterior, right to left and rostral-caudal dimensions), number, and location (cortical, subcortical). An infarct that involved the cortex, even if it extended to subcortical regions as well, was termed cortical. If the infarct had no cortical locations, it was considered subcortical. The category of cortical + subcortical refers to combined infarcts, at least one of which was cortical and one subcortical. Reproducibility studies have documented good agreement both within and between readers for lesions 3 mm or greater, but less so for lesions less than 3 mm.9 Dilated perivascular spaces were distinguished from infarcts on the basis of their location (along perforating or medullary arteries, often symmetrical bilaterally) and the absence of gliosis. An MRI infarct was considered a silent infarct if there was no self-report i.e. symptoms of TIA or stroke at baseline before the MRI that was performed as part of study10. MRI data were evaluated by a single neuroradiologist who was blinded to patients’ clinical data.
v- Hemodialysis: Patients received dialysis using single pass machines with cellulose acetate-hollow fiber dialyzers and standard tubing. There was no dialyzer reuse, patients underwent dialysis three times per week in sessions lasting 3-4.5 h. with dialyzer flow rate of 500 ml/min using bicarbonate or acetate –based dialysate solution of standard composition. Patients were considered maintained on hemodialysis when they required supportive dialysis therapy for at least 30 days and continuation of dialysis in the outpatient nephrology clinics.
Statistical Methods:
SPSS (Statistical Package for the Social Science) software version 13.0 was used in the analysis of all obtained data. Statistical analysis was performed with the use of parametrical and non-parametrical studies Chi-square, t-test and r-test on the base of SPSS. We used multiple regression analysis to evaluate the independent determinants of silent brain infarctions. P-value was considered significant if <0.05.
RESULTS
Characteristics of the study group are shown in Table (1). There were no statistically significant differences between patients and controls as regard age (p>0.05).
The percentage of SCI was higher in patients’ group (n=16, 40%) compared to control group (n=1, 5%) (p=0.0032).
The most predominant type of infarction was the lacunar (p=0.013) and sites where subcortical and basal ganglionic (p=0.038). There was no statistically significant difference as regard lateralization of site of infarction (right, left or bilateral). There were no statistically
Group 1 (SCI) had longer mean duration of HD compared to Group 2 (Non-SCI) (p=0.001). All patients of Group 1 (SCI) (n=16, 100%) had a duration of HD of more than 3 year, while only 29.166% (n=7) of group 2 (Non-SCI) had a duration of HD of more than 3y (p=0.002). Smoking was more in Group 1 (68.75%) compared to Group 2 (29.16%) (p=0.04) and there were no significant differences in the duration, amount or the type of smoking among the two groups (p>0.05); yet there were no significant difference among smokers and non-smokers in terms of SCI (p>0.05). There was no significant difference in hematocrit values between Group 1 and 2 (p>0.05). Comparison of different variables among Group 1 and 2 is shown in Table (2).
IMT was significantly increased in Group 1 (SCI) compared to Group 2 (Non-SCI) (p=0.02) and to controls (p=0.013). About 56.25% of patients of group1 (patients with SCI) had increased intima media thickness (IMT), while in group2 (patients without SCI) only 12.5% of patients were having increased IMT (p=0.02).
Group B (HD > 3y) was associated with SCI (p<0.0001) higher age (p=0.05), MABP (p=0.002), urea (p=0.0001), creatinine values (p=0.003), hematocrit (p=0.048) compared to Group A (HD≤3 years). There was no significant among both groups in terms of smoking. Comparison of different variables among group A and B is shown in Table (3).
There was a statistically significant positive correlation between duration of HD and MABP (i.e. MABP was higher with longer duration of HD) (r=0.783, p=0.001). There was a significant positive correlation between MABP and creatinine (r=0.659, p=0.0001). There was no statistically significant correlation between the duration of hemodialysis and the hematocrit values of patients (p>0.05).
Estimation of the percent of patients with SCI in each stratification of MABP showed that the percentage significantly increased with each 10 increment in MABP. There were no patients with SCI in Str.1, while the percent was 25% in Str.2, then increased to 63% in Str.3, to reach 100% in Str.4. (Figure 1).
The identified independent risk factors for SCI in CRF patients where a duration of HD>3 years (p=0.041), hypertension (0.022) and age (0.019). Elevated urea, creatinine, change in hematocrit, smoking and increased IMT were not identified as independent risk factors for SCI in CRF patients (p>0.05).
DISCUSSION
In the present study we found a higher percentage of silent brain infarctions in patients with chronic renal failure on hemodialysis compared to controls.
Silent brain infarction (SCI) may be sometimes asymptomatic, but is an important predictor of stroke5,11,12.
Chronic kidney diseases are associated with increased risk of incident ischemic strokes or transient ischemic attacks. Although, some of the risk of chronic kidney diseases is due to its association with traditional vascular risk factors, the value of renal insufficiency remained after adjustment of traditional cerebrovascular risk factors and persisted as an important independent marker for ischemic stroke risk11,13-15 which may be associated with high mortality in patients with chronic renal failure on hemodialysis16.
In the present study, silent brain infarctions were mainly lacunar and were distributed mainly in the subcortical white matter and basal ganglionic regions in MRI brain of chronic renal failure patients on HD. Martinez-Vea et al.17 described same finding in patients with CKD but in the predialysis phase. Kobayashi et al.18 showed that the predominant type of SCI was lacunar.
In the present study, Patients with SCI had significantly longer durations of HD and the percentage of patients with SCI was significantly higher in the group of patients undergoing dialysis for more than 3 years. Also MABP, urea and creatinine were significantly higher in such patients. Hata et al.19 showed that HD significantly decreased blood flow velocities measured by transcranial Doppler sonography and such changes is significantly related to loss of body weight, amount of fluid removal and changes in hematocrit. Postiglione et al.20 found a significant decrease in flow velocities in middle cerebral artery following dialysis. On the contrary Nakatani et al.12 have shown that SCI is not related to the duration of HD and supported his findings with the results of kawagishi et al.21, who concluded that HD did not accelerate atherosclerosis. Yet the difference in the definition of variables and the methods analysis of results may have lead to this controversy.
In the present study, the IMT was increased in the patients with SCI compared to those without SCI. Ogawa et al.22 have shown that IMT was significantly increased in CRF patients undergoing HD. Other studies identified serum homocysteine23; lipoprotein (a)24; C-reactive protein and Hepatocyte growth factor16 as independent risk factors for SCI; all of which are linked to vascular endothelial functions. Yet increased IMT was not identified as an independent risk factor for SCI in CRF.
We identified duration of HD>3 years, Hypertension and age as independent risk factors for SCI in HD patients. Smoking, elevated urea, creatinine, hematocrit were not identified as independent risk factors for SCI in CRF. Nakatani et al.12 results disagreed with ours as they defined CRF, age and smoking as independent risk factor but not duration of HD nor hypertension.
Conclusion
Duration of HD>3 years, age and hypertension are independent risk factors for SCI in CRF. Other factors as smoking and elevated urea, creatinine and hematocrit are not independent risk factors but would rather interact with other risk factors to further increase risk for SCI in CRF patients. Control of risk factors especially hypertension and smoking would relatively reduce the risk of SCI in HD patients and hence prevent cerebrovascular accidents that would lead to high morbidity and mortality.
Aknowledgement:
Special thanks to all the staff members of the renal dialysis unit, Cairo University Hospitals for their kind help and support although the study.
[Disclosure: Authors report no conflict of interest]
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