INTRODUCTION

Mild renal insufficiency is increasingly recognized as an independent risk factor for cardiovascular disease. However, few data exist regarding its relation to risk of ischemic stroke.¹ Certain studies found that there is a relationship between impairment in glomerular filtration rate and carotid intima-media thickness in middle-aged adults that contribute to the occurrence of stoke and transient ischemic attacks (TIA).^2,3 Moreover, several studies concerned about the relation between chronic kidney disease and clinical outcome in patients with acute stroke.^4,5 Hemorrhagic transformation (HT) after cerebral ischemia seems to be related to the endothelial disruption secondary to the ischemic process. Albuminuria has recently been found to be a marker of chronic endothelial damage.⁶ It was found that albuminuria is an independent predictor of hemorrhagic transformation, and particularly of the most severe bleedings, in patients with acute ischemic stroke.⁶ Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited.⁷

The aim of this study is to investigate the relation between the clinical and radiological parameters of stroke and certain biomarkers for early renal impairment (serum creatinine, estimated GFR, micro and macroalbuminuria, and serum potassium).

SUBJECTS AND METHODS

Subjects

This  is a cross sectional study conducted on19  stroke patients, 16(84.2%) males, 3(15.8%) females. Their age ranged from 43 to 85 years with a mean of 56±15.2. They were compared to11 normal control, 8 (72.7%) males and 3 (27.3%) females with a mean age of 55.6±17.5. They were age and sex matched to patients. The patients group had stroke either ischemic or hemorrhagic(either from the start or hemorrhagic transformation after ischemic stroke). Acute and chronic stroke were included. The National Kidney Foundation (NKF), Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board had classified chronic kidney disease (CKD) according to the eGFR into 5 stages.⁸ Stroke patients with mild renal impairment (stage 1 and 2 in which GFR ≥ 60 mL/min/1.73 m²) were included in this study. The rationale for including individuals with GFR ≥ 60 mL/min/1.73 m² is that GFR may be sustained at normal or increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk for the 2 major outcomes of CKD: loss of kidney function and development of cardiovascular disease including stroke.⁸ Excluded from this study patients with moderate or severe renal impairment as measured by eGFR, age less than 40 years, cardioembolic stroke ,neurological diseases other than stroke, metabolic and connective tissue disorders. Uncontrolled hypertension or diabetes mellitus were excluded.

Methods

All subjects were submitted to:-History taking and complete neurovascular and medical examination including modified Rankin Scale (mRS)⁹ for assessment of the stroke disability.

-        Laboratory investigations: Complete blood picture, liver functions tests, fasting and postprandial blood sugar, LDL, HDL cholesterol, triglyceride, ESR, renal functions tests including: urine analysis, serum uric acid, serum creatinine, blood urea, serum albumin, serum sodium (Na+) and potassium (K+) levels, detection of  micro and macroalbumin in urine and estimated GFR.

-        Detection of macroalbumin in urine by immunonephelometric reaction using specific antibodies. This was done on BN ProSpec System using reagents supplied by Siemens (Siemens Healthcare Diagnostics Products GmbH, 35041 Marburg / Germany). Microalbuminuria is defined as microalbumin in urine more than 30 and less than and equal 300 ug/mg creatinine. Macroalbuminuria is albumin in urine more than 300 ug/mg creatinine¹⁰. Glomerular filtration rate (GFR) is  estimated using Modification of Diet in Renal Disease (MDRD) formula¹¹.

-        Duplex–Doppler Studies: All patients are subjected to B-mode and color-coded duplex sonography of the extracranial carotid and vertebral arteries. 

-        Magnetic resonance imaging (MRI) Brain (T1, T2, FLAIR & DWIs) and computerized tomography (CT) brain: MRI was done using 1.5 tesla (General Electric Medical System (Milwaukee). MRI was analyzed for the size¹², the site, the laterality of lesion and if the lesion is ischemic or hemorrhagic.

-        Echocardiography: Transthoracic and transoeso-phygeal (when needed) echocardiography were done as a routine work up for patients with stroke and to exclude cardioembolic lesion.

Statistical Analysis

All patients’ data were analyzed using SPSS 10 for Windows XP. Qualitative data were expressed as frequency (%). Quantitative results were expressed as the mean±SD for parametric data while for nonparametric data were expressed as median (25^th-75^th percentile). Comparisons of the mean differences between 2-groups were performed using student's t-test (parametric) or Mann Whitney test (Non-parametric). Spearman correlation was used. P value was considered significant if less than or equal to 0.05.

RESULTS

Clinical Data: The duration of illness in the cases showed a median of 45 days. The modified Rankin Scale (mRS) of the cases ranged from 1 to 5. Four cases showed score 1 (21.1%), while score 2 was present in 6 cases (31.6%). Score 3, 4, 5 were present in 4 (21.1%), 2 (10.5%), 3 (15.8%) cases, respectively. Only 4(21.1%) patients had no risk factors and the rest had one or more risk factors. The most common one was hypertension in 13 patients (68.4%) followed by ischemic heart disease in 7 patients (36.8%). Four patients (21.1%) were diabetics and4 were smokers. Only one patient had high serum cholesterol and high uric acid level (5.3%).

Imaging and Duplex Studies: Imaging studies were normal in only one patient (5.3%), but shows small, moderate, large,  sized lesion in 5, 7, 6 cases  respectively (26.3%, 36.8%, 31.6%). Seven patients (36.8%) had left side lesion and 8 patients (42.1%) had right side lesion and 3 (15.8%) had bilateral lesion. Twelve patients (63.2%) had ischemic stroke, while 7 patients (36.8%) had hemorrhagic stroke (4 patients had hemorrhagic transformation after ischemic stroke and 3 from the start). Eleven patients (57.9%) had stroke in the domain of anterior circulation, 3 patients (15.8%) had stroke in the domain of posterior circulation and 5 patients (26.3%) had both. Abnormal duplex was found in 17 (89.5%) of the cases while 2 patients (10.5%) showed normal duplex.

Biochemical Results: The serum level of creatinine, albumin, Na+, K+, blood urea, estimated GFR,  microalbumin in urine for both cases and control were shown in table 1. Although the median of microalbuminuria in patients was increased more than controls (61 versus 15 ug/mgcreatinine), yet no statistically significant difference was found between them as regards biochemical results.  Patients were subdivided according to the presence and absence of microalbuminuria. Ten patients (52.6%) had albumin in urine and 9 patients (47.4%) had no microalbumin in urine. There was decrease in the eGFR in patients with albuminuria (79.2±28.7) than those without microalbuminuria (102.1±23.8). The difference was near statistical significance (P=0.077). Significant increase in creatinine level in patients with albuminuria (1.1±0.3) than those without microalbuminuria (0.8±0.1) (P=0.05). There was no statistically significant difference between patients with albuminuria and those without as regard the other biochemical data (P˃0.05). As regard risk factors, statistically significant decrease in serum albumin was found in hypertensive and diabetic patients (P=0.04, 0.006 respectively). These patients also showed increased level of albuminuria but not reaching the significant level (P˃0.05) (Table 2). There was no statistically significant relation between patients with risk factors and those without as regard the other biochemical data (P˃0.05). On comparing the laboratory data in the cases with the imaging results, There was no statistically significant relation between the presence or absence of ischemic or hemorrhagic lesion, site, size, side of lesion& duplex studies and biochemical data. However patients with hemorrhagic lesion, posterior circulation and right side lesion showed increased median level of albuminuria but still not reaching the significant level (P˃0.05). Also lower eGFR was found in hemorrhagic and right sided lesion but this was statistically insignificant (P˃0.05) (Table 2). There was significant positive correlation between duration of illness and albuminuria (r=0.653, P=0.002). No significant correlation was found between the biochemical data and mRS. (P˃0.05).

Table 1. Biochemical data in control  and patients.

Table 2. Relation of the laboratory data of  patients to some risk factors and imaging studies.

*p<0.05 = significant

DISCUSSION

Mild degrees of renal dysfunction are associated with increased risk of incident ischemic stroke or TIA in patients with pre-existing atherothrombotic disease.¹  The aim of this study was to investigate the relation between the clinical and radiological parameters of stroke and certain biomarkers for renal impairment(serum creatinine, estimated GFR, microalbuminuria, and serum potassium).Our results showed that the median of microalbuminuria in patients was increased more than controls (61 versus 15 ug/mgcreatinine). Our results did not reach the significant level that can be attributed to small sample size. About 52.6% of patients had albuminuria. Also, there was significantly positive correlation between duration of illness and albuminuria (r=0.653, P=0.002). Among 6,685 patients, a quarter of patients had chronic kidney disease (CKD). Patients with CKD exhibited 1.54-fold hazard ratios of incident ischemic stroke or TIA.¹ Albuminuria was found to be a significant and independent predictor of parenchymal hemorrhage.⁶ These findings coincide with our results, as we found patients with hemorrhagic lesion showed increased level of albuminuria. Association between stroke risk and certain renal biomarkers as estimated GFR, albuminuria and cystatin C have previously been established in many studies. However, the authors did not know which of the three biomarkers was most strongly related to stroke.¹³ In a recent study, albuminuria was found to be more strongly related to ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C.¹⁴ Our results showed that albuminuria and lower eGFR were found in hemorrhagic right sided lesion but this was statistically insignificant. The non significant results could be attributed to small sample size. As regard risk factors in our study, statistically significant decrease in serum albumin was found in hypertensive and diabetic patients (P=0.04, 0.006 respectively). Hypertensive and diabetic patients showed increased level of microalbuminuria but not reaching the significant level. Yoon et al.¹⁵ postulated that serum albumin at admission would be a useful predictor of the functional outcome after ischemic stroke and trials for the correction of hypoalbuminemia would be helpful to decrease the risk of poor outcome. However in our study, no difference was found between patients and control as regard serum albumin, only the significance was found within the patients group in hypertensive and diabetic patients. Therefore, active therapeutic trials for the correction of hypoalbuminemia especially for these patients may be beneficial for the prevention of recurrent stroke and poor outcome. In a meta-analysis study, it was found that microalbuminuria was associated with increased risk of subsequent stroke in all subgroups of the studies (general population, diabetics, those with known stroke).¹⁶ The relationships of microalbuminuria with a variety of risk factors, such as hypertension, diabetes and metabolic syndrome, may contribute, at least in part, to explain the enhanced cardiovascular risk conferred by microalbuminuria.¹⁷ HbA1c ≥ 6.2% and micro/macro albuminuria interact to markedly increase the ischemic stroke risk which explain a large proportion of risk in patients with type 2 diabetes mellitus harboring both risk factors. ¹⁸ In a meta-analysis prospective cohort studies ,They suggested  that persons with elevated UAE levels may especially benefit from more intensive vascular risk reduction.¹⁹ Some studies found that there is an association between impairment in GFR and carotid intima-media thickness (IMT) in middle-aged adults that implicated to the occurrence of stoke and TIA.^2,3 Another study found that subjects with microalbuminuria had greater common carotid artery (CCA) IMT than those without microalbuminuria. This relationship was only partly mediated by hypertension.²⁰ On the contrary, our results found no significant relation between duplex findings and eGFR or microalbuminuria. However it partially agreed with the later study in increased level of microalbuminuria in hypertensive patients. The difference between these studies and ours may be attributed to small sample size and different laboratory techniques used. On comparing the laboratory data in the cases of the present study with the imaging results, no significant relation was found .However in another study, albuminuria was associated with a white matter hyperintensity.²¹ The difference could be attributed to small sample size and different statistical methods used in our study. Regarding the role of potassium in stroke, it was found that among diuretic users, there was an increased risk for stroke associated with lower serum potassium. Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake.⁷ However in our study, no significant relation between potassium and clinical or imaging data of the patients.  In conclusion, There is a strong evidence that albuminuria is linked to stroke especially hemorrhagic, with long duration of illness and in hypertensive and diabetic patients. It was suggested that persons with elevated albuminuria levels may especially benefit from more intensive vascular risk reduction. The use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptors blockers (ARBS) already known to lower albuminuria in patients with diabetes or hypertension; and this subsequently, should reduce the risk of secondary stroke.  

[Disclosure: Authors report no conflict of interest]

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