Microalbuminuria in Patients with Recent Ischaemic Cerebrovascular Stroke: A Cross Sectional Study

Objectives: Microalbuminuria is an integrated marker of both kidney disease and endothelial with global vascular risk. study assess the association of microalbuminuria with risk of nondiabetic nonhypertensive ischaemic Materials and Methods: cases studied. Diabetes mellitus, family history of DM, hypertension, nephropathy, atrial fibrillation, chronic liver disease, systemic infection, neoplasm, recent myocardial infection, females during menstruation and pregnancy were excluded from the study.


INTRODUCTION
The incidence of cerebrovascular stroke is gradually increasing in all parts of world. It is the second commonest cause of death and fourth leading cause of disability worldwide. But throughout world rise in stroke risk profile, lack of awareness and lack of prevention programmes serves to widen stroke prevention gap [1]. According to WHO 2009 report in India prevalence is 90-222 per lakh population and 6,398,000 DALYs (Disability Adjusted Life Years) [2].
The realisation that atherosclerosis is an inflammatory state has lead to search for new stroke risk factors. Microalbuminuria has been associated with many diseases like diabetes, hypertension and coronary arterial disease [3,4]. With availability of relatively simple methods for detection of microalbuminuria many studies have been conducted in different parts of world as a marker of stroke risk in nondiabetic nonhypertensive population.
Microalbuminuria reflects systemic transvascular leakiness for albumin [5], which allows higher degree of lipid insudation [6] into large vessel wall linking to atherogenesis. There is a close relation between atherosclerosis, endothelial dysfunction (ED) and leakage of protein through glomerulus. In endothelial dysfunction most potent endogeneous vasodilator Nitric oxide production is hampered which leads to arterial vasoconstriction [7]. This causes increase arterial as well as glomerular pressure and permeability. In endothelial dysfunction glomerular basement membrane loses normal negative charges and loss of heparin like proteoglycan promoting thrombus formation and enhance atherosclerosis. Hence microalbuminuria is gaining recognition as a marker of atherogenic milieu and ischaemic stroke. Microalbuminuria and atherosclerosis found in endothelial dysfunction is manifested as increased intima media thickness of common carotid arteries [8,9].
Slowik et al. [10] were the first to report significant correlation between microalbuminuria and severity of stroke. Nancy B. Beamer et al. [11] described microalbuminuria as an independent predictor of vascular end point. Meng Lee et al. [12] studied 12 prospective cohort studies with a total of 48596 participants and 1263 stroke events and found that microalbuminuria was associated with greater risk after adjustment for cardiovascular risk factors.
They found that baseline microalbuminuria have a risk of future stroke approximately 90% greater than those without microalbuminuria. P. C. Mathur et al. [13] investigated the incidence, risk factor and severity of stroke with microalbuminuria in nondiabetic ischaemic stroke in Indians (68%).

MATERIALS AND METHODS
The study was undertaken at SCB Medical College, Cuttack, India during the period from October 2013 to September 2014. Sixty (60) patients with clinical diagnosis of recent ischaemic stroke confirmed by non contrast CT scan of brain were taken for study. Severity of neurological deficit was measured by Scandinavian Stroke Scale. Thirty (30) cases of age and sex matched healthy person were taken as controls. Diabetes mellitus, family history of diabetes, patients with impaired glucose tolerance, previous history of hypertension, case of nephropathy and abnormal urine analysis (glycosuria, haematuria, pyuria, proteinuria), atrial fibrillation, infection, intracranial haemorrhage, neoplasm, females during menstrual period and pregnancy were excluded from study [14].
Microalbuminuria (MA) can be defined as urinary albumin excretion rate of 20-300 mg/L in spot sample or 30-300 mg/24 hrs urine collection or urine albumin creatinine ratio in first voided morning sample is 30-300 micro g/mg [15]. In this study, microalbuminuria was defined as 20-300 mg/L. Urine samples were taken from morning urination sample within 24 hours of admission. Nephelometric micral assay (immunoprecipitation) was used based on colour shift of polyclonal antihuman antibody (sheep)to human albumin labelled with gold [16], manufactured by Dade Behring, Germany. Analytical sensitivity >95 percent; Analytical specificity >80 percent.
Scandinavian Stroke Scale was used for clinicometric assessment in acute stroke patients. It is a stroke impairment scale evaluates level of consciousness, eye movement, power in arm, hand and leg, orientation, speech, facial paresis and gait and in total score ranging from 0 to 58. Scandinavian stroke scale is easier than NIHSS for clinical practice in acute stroke patients. Stroke scores below 22 has poor prognosis. It is not used for follow up patients [17,18].
Non contrast CT Scan of Brain was done within 24 hours of occurrence of stroke. Detailed clinical examination, Complete CBC count, urine Routine & microscopic examination, FBS, HbA1C, S creatinine and S. Urea, S. lipid profile, Liver Function Test were also done.
Statistical analysis was performed by using software SPSS version 18.0. The data were expressed as the mean ± SD, unpaired student 't' test , Chi square test, 95% confidence limit p <0.05 was taken as level of significance. Spearman rho correlation was done between MA and score of Scandinavian stroke scale to see the significance of the test.

DISCUSSION
Microalbuminuria has been a marker for monitoring diabetes mellitus for years. In the present study the frequency of microalbuminuria and its correlation with neurological deficit in ischaemic stroke has been demonstrated by cross sectional study in 60 diagnosed ischaemic stroke patients.
It was noted that among cases mean age was 61.1±13.27. Among controls mean age was 59±14.2. Among microalbuminuria positive group mean age was 60.7±16.3 years as opposed by microalbuminuria negative group 56±13.2 years. Among cases below 50 years prevalence was 10.3%, between 50-60 years 27.5%, above 60 years it was 65%. This shows microalbuminuria incidences increases with ages. In study done by J Chowdhary, N Sultana [19] incidence of microalbuminuria was 80% among age more than 60 years, which is similar to our study. According to Beamer et al age is an independent factor for presence of MA in stroke patients [11]. But in our study it may be due to older patients having severity of neurological dysfunction.
Among cases with microalbuminuria positives there was 55.2% were males and 44.8% were females and in microalbuminuria negatives males are 61.3% and 38.7% females. In both groups microalbuminuria is more common in males but not statistically significant. This was consistent with study by Turaj et al. [20] where male were more with no statistical significance.
Urine microalbumin was tested among age and sex matched cases and controls showed recent stroke have 4.75 times more incidence of microalbuminuria in cases compared to control groups. Incidence of microalbuminuria among ischaemic stroke cases were 48.3% and among controls 10% with 95% CI was 0.360-0.161. Interestingly a similar high prevalence of microalbuminuria in stroke patients was observed by Beamer et al. [11] where microalbuminuria was present in 30% of stroke patients and 10% of controls matched for stroke risk factors. Turaj et al. [10] found 46.1% incidence of microalbuminuria in acute non diabetic ischaemic stroke as opposed to only 13.5% controls. In another study by Slowik et al. [10] microalbuminuria was found in 46.7% of acute ischaemic stroke patients, 16.5% of subjects with history of stroke and 16.7% of healthy control 3 . With reference to study done by Muhammed Ahsan et al. [21] in Pakisthan, microalbuminuria incidence was 48.2% with mean value 63.54±6.6.
Prevalence of microalbuminuria in different subtypes of infarction were 50% in MCA infarct, 16.7% in ACA infarct, 3.3% in PCA infarct, lacunar infarcts in 16.6% and combination of territories in 13.3%. Here microalbuminuria did not differ among major sub types of stroke. According to Beamer prevalence of microalbuminuria did not differ among major sub types of strokes [11] and after adjusting diabetes, hypertension microalbuminuria was weakly prognostic, however in patients with history of transient ischaemic attack, recent and remote stroke it was an independent marker for future attack [11].
Analysing association of presenting symptoms with microalbuminuria, loss of consciousness was present in 68% of patients with microalbuminuria compared to 32% MA negative cases. According to Turaj et al. [10] patients with microalbuminuria, loss of consciousness was associated in 35.5% cases. This may be the fact that the severity of cases was more in our group of patients.
It has been studied that MA in general population correlates with factors that increase atherosclerosis i.e high blood pressure, high triglyceride, low HDL, increased carotid intima thickness [22]. S. urea, S. creatinine, S. lipid profile were found similar in cases and controls and not statistically significant. According to Arboix et al. [14] atrial fibrillation is an independent risk factor of microalbuminuria, associated with higher in-patients mortality in ischaemic stroke patients, but in our study atrial fibrillation has been excluded. Mykkanen  Meta-analysis by Meng Lee et al. [12] have highlighted that stroke risk might get reduced when microalbuminuria incidence is reduced, which can be achieved through angiotensin receptor blocker or ACE inhibitors. As the prevalence of MA ranged from 12-40% in population it is cost effective to screen and reduce cerebrovascular events.

LIMITATIONS
Our study has some limitations. Our study did not have consecutive recruitment of patients and numbers of patients included were relatively small. Moreover, as the study was cross sectional in design, it is not easy to predict exactly whether MA preceded stroke or vice versa. Future cohort studies with large samples will be helpful in providing an answer.

CONCLUSION
Microalbuminuria increases the ischaemic stroke risk because of association between microalbuminuria with carotid intima media thickness and reflecting increased vascular endothelial permeability leading to endothelial dysfunction.
The present study found microalbuminuria in 48.33% non diabetic nonhypertensive ischaemic stroke and degree of MA increases with severity of stroke. Hence it is important to screen high risk patients for microalbuminuria on regular basis. Limiting urinary albumin excretion with angiotensin receptor inhibitor may reduce vascular events including stroke beyond blood pressure lowering effect. Moreover interventional trials are needed to establish whether the correction of increased urine albumin excretion rate in its own right modifies the risk of adverse vascular events.

CONSENT
All authors declare that written informed consent was obtained from the patients for study.

ETHICAL APPROVAL
All authors hereby declare that all experiments have been examined and approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.