Impact of Albuminuria on Early Neurological Deterioration and Lesion Volume Expansion in Lenticulostriate Small Infarcts
Background and Purpose—Albuminuria, a marker of chronic kidney disease, is associated with an increased risk of incident stroke and unfavorable long-term outcomes. However, the association of albuminuria with short-term outcomes and change in infarct volume in patients with acute small subcortical infarction remains unknown.
Methods—We retrospectively reviewed 85 consecutive patients with acute small subcortical infarcts in the lenticulostriate artery territory who were admitted to our stroke center within 24 hours of symptom onset and underwent serial diffusion-weighted imaging (DWI). Albuminuria was determined based on the urinary albumin-to-creatinine ratio obtained from a first morning spot urine after admission. Infarct volume was measured on axial sections of the initial and follow-up DWI. Early neurological deterioration (END) was defined as an increase of ≥2 points in the National Institutes of Health Stroke Scale score during the first 5 days after admission.
Results—Albuminuria (UACR ≥30 mg/g creatinine) was observed in 14 of 18 patients with END (77.8%) and in 25 of 67 patients without END (37.3%), P=0.002. Multivariate logistic regression analysis revealed that albuminuria was associated with END after adjustment for age, low estimated glomerular filtration rate (<60 mL/min per 1.73 m2), and infarct volume on initial DWI (odds ratio, 6.64; 95% confidence interval, 1.62–27.21; P=0.009). In addition, albuminuria was an independent predictor of increase in infarct volume using multivariate linear regression analysis (β coefficient=0.217; P=0.038).
Conclusions—Our findings suggest that albuminuria is associated with END and infarct volume expansion in patients with small subcortical infarcts in the lenticulostriate artery territory.
Among patients with infarcts involving the lesion supplied by the lenticulostriate arteries (LSAs), ≈20% to 40% of them present with progressive motor deficit within the first few days after symptom onset and have a worse clinical outcome.1,2 The causes of small subcortical infarcts in the LSA territory are highly varied and include atheroma of the parent artery, occlusion attributable to cardiogenic embolism, microatheroma arising at the orifice or proximal portion of the penetrating branch, and lipohyalinosis of the arterioles.3,4 The infarct size often expands in the majority of cases of penetrating artery infarcts with neurological deterioration.1,5 However, the mechanism underlying neurological deterioration and infarct volume expansion in acute small subcortical infarcts is still unknown.
Recently, it has been noted that the hemodynamics of the vascular beds of the brain and the kidney are similar, and attention has been focused on the brain–kidney interaction.6–8 Additionally, a similar vascular structure has been observed in the penetrating arteries of the brain and the juxtamedullary afferent arterioles of the kidney.7 Albuminuria, a marker of chronic kidney disease, is associated with an increased risk of incident stroke and unfavorable long-term outcomes.9 Moreover, albuminuria may indicate vascular endothelial dysfunction, which leads to neuronal damage via blood–brain barrier impairment. In this study, we sought to explore whether albuminuria can be used to identify neurological deterioration and infarct volume expansion in patients with acute small subcortical infarcts in the LSA territory.
Materials and Methods
This retrospective study included consecutive patients with a diagnosis of single small subcortical infarcts localized in the LSA territory who were admitted to our stroke center within 24 hours of symptom onset between January 2009 and October 2012, in whom brain diffusion-weighted imaging (DWI) on admission was available. Small subcortical infarct was defined as an infarct lesion <20 mm in diameter on initial DWI. We identified 85 patients with single small subcortical infarcts in the LSA territory (basal ganglia, corona radiata, and internal capsule) who were evaluated by serial DWI within 5 days. Study sample selection is provided in Figure I in the online-only Data Supplement. In this study, patients who had middle cerebral artery stenosis, previous myocardial infarction, angina, or peripheral artery disease were not excluded. The study was approved by the Ethics Committee of Chubu Rosai Hospital.
Albuminuria was determined based on the urinary albumin-to-creatinine ratio (UACR) obtained from spot urine analysis on the first morning after admission. The UACR was calculated from the urinary albumin, which was estimated using the latex agglutination method and urinary creatinine concentration. Albuminuria was classified into one of the following 3 categories: normoalbuminuria, <30 mg/g creatinine; microalbuminuria, 30–299 mg/g creatinine; and macroalbuminuria, ≥300 mg/g creatinine. Each patient’s estimated glomerular filtration rate (eGFR) was calculated using the following 3-variable Japanese equation: GFR (mL/min per 1.73 m2)=194×serum creatinine−1.094×age−0.287×0.739 (if female).10 A low eGFR was defined as <60 mL/min per 1.73 m2. All of the magnetic resonance imaging examinations were performed on a Signa Horizon 1.5T instrument (GE Healthcare, Milwaukee, WI). The DWI sequence parameters are presented in the online-only Data Supplement. To identify the change in infarct volume, a follow-up DWI study was performed within 5 days after admission. Examples of single small subcortical infarcts on serial DWI are shown in the Figure. The change in infarct volume (Δ infarct volume) was defined as the difference between the initial and follow-up DWI volumes. DWI infarct volume measurements were performed by a trained radiologist who was blinded to the clinical information. All DWI scans were saved in Digital Imaging and Communications in Medicine (DICOM) format for importation into ImageJ software using Sync Measure 3D plugin software (National Institutes of Health, Bethesda, MD)11 to calculate infarct areas extracted for evaluation. For further details, see Figure II in the online-only Data Supplement. Stroke severity at admission and on days 2, 3, and 5 of hospitalization was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score. Early neurological deterioration (END) was defined as an increase of ≥2 points in the NIHSS score during the first 5 days after admission. We divided the patients into 2 groups according to the presence or absence of END.
To determine the associations between albuminuria and END, we used multivariate logistic regression models after adjustment for potential confounders. In addition, multivariate linear regression was used to assess for independent association of albuminuria with Δ infarct volume. For detailed statistical analysis procedures, see Methods in the online-only Data Supplement.
Of the 85 patients (60 men, mean age 69.8 years), 18 (21.2%) patients had END during the first 5 days after admission. The characteristics of patients are summarized in Table I in the online-only Data Supplement. We performed an initial DWI at 15 [8–21] hours after symptom onset and a follow-up DWI at 73 [48–84] hours after the initial DWI. There were no significant differences in the time interval between initial and follow-up DWI between patients with and without END. Albuminuria (UACR ≥ 30 mg/g creatinine)mg/g crecreatinine) was observed in 14 of 18 patients with END (77.8%) and in 25 of 67 patients without END (37.3%), P=0.002. In the univariate analysis, older age, albuminuria, and low eGFR were associated with END. Multivariate logistic regression analysis revealed that albuminuria was an independent predictor of END after adjustment for age, low eGFR, and infarct volume on initial DWI (odds ratio [OR], 6.64; 95% confidence interval [CI], 1.62–27.21; P=0.009; Table 1). Furthermore, microalbuminuria (n=31) was also significantly associated with END (OR, 6.86; 95% CI, 1.58–29.69; P=0.010). Macroalbuminuria (n=8) was significantly associated with END using univariate analysis (OR, 6.30; 95% CI, 1.08–36.66; P=0.041). In contrast, low eGFR was not independently associated with END (OR, 2.95; 95% CI, 0.82–10.64; P=0.098). Using the Spearman rank correlation test, log-transformed UACR correlated with Δ infarct volume (r=0.300; P=0.006) as shown in Figure III in the online-only Data Supplement. In contrast, eGFR was not correlated with Δ infarct volume (r=−0.086; P=0.430). In addition, albuminuria was an independent predictor for increase in infarct volume after adjustment for age, sex, baseline NIHSS score, the time interval between serial DWI, and infarct volume on initial DWI using multivariate linear regression analysis (β coefficient=0.217; P=0.038; Table 2).
The preliminary results of the present study demonstrated that albuminuria is associated with END and infarct volume expansion of small subcortical infarcts in the LSA territory. These findings have potential clinical implications in elucidating the mechanism for the progression of penetrating artery infarcts.
With recent advances in magnetic resonance imaging technology, an association between serial DWI findings and neurological deterioration has been demonstrated. Several studies1,5 have indicated that an increase in lesion volume during the acute phase of deep subcortical infarcts is associated with neurological deterioration and poor outcome. The majority of progressing penetrating artery infarcts is considered to be because of atheroma in the parent artery or microatheroma arising at the orifice or proximal portion of the penetrating branch itself, and they have been implicated in the concept of so-called intracranial branch atheromatous disease proposed by Caplan.3 The mechanism underlying the progression of small subcortical infarcts is not fully understood. A recent study reported an association between brachial-ankle pulse wave velocity, which is a marker of arterial stiffness, and neurological deterioration during the acute phase of deep small subcortical infarcts as well as the possibility that higher brachial-ankle pulse wave velocity levels may serve as a marker for vascular endothelial impairment in cerebral small-vessel disease.12 Because albuminuria is also a marker of vascular endothelial dysfunction, patients with albuminuria may have microcirculation disorders attributable to impaired vasodilatation in the cerebral penetrating arteries, which leads to the lesion growth. The mechanism underlying the progression of small subcortical infarcts may involve not only propagating thrombus, but also endothelial dysfunction in the penetrating arteries themselves. A similarity in the hemodynamics of the vascular beds of the brain and kidney has been previously noted,6,7 and this similarity is an important factor in considering an association between cerebral penetrating artery infarction and kidney impairment. A previous study has suggested that juxtamedullary afferent arterioles are small and that short vessels exposed to high pressures must maintain a strong vascular tone to provide a large pressure gradient in a short distance.13 A similar vascular structure is also observed in the penetrating arteries of the brain, and thus the appearance of albuminuria could be a marker of vascular damage in these arteries. In the present study, eGFR was not associated with infarct expansion and END. Furthermore, previous research also found that proteinuria, but not low eGFR, was associated with neurological deterioration or a poor functional prognosis after ischemic stroke.14,15 Thus, there may be a discrepancy between the effects of proteinuria and low eGFR on the short-term prognosis for ischemic stroke.8
Several limitations of our study should be addressed. First, because the present study had a retrospective design and a small sample size, a causal relationship was not clearly indicated by the results. Second, we evaluated small subcortical infarcts in the LSA territory within 24 hours of symptom onset and the possibility that there were a few patients in whom progression had already stopped at the time of admission cannot be ruled out. Third, albuminuria was determined from a single measurement of the UACR, and therefore neither the possible influence of acute phase reactions nor changes over time were evaluated. Fourth, although there was no uniformity in the timing of follow-up DWI, the interval between initial and follow-up DWI was not significantly different between patients with and without END. Therefore, we assumed that this limitation would not have a major influence on the interpretation of our results. Finally, there could have been some bias because acute medical therapy was left to the discretion of the attending physician, and ≈70% to 80% of patients received aspirin or argatroban (anticoagulant) in addition to edaravone (radical scavenger).
In conclusion, albuminuria could be a useful biomarker for predicting the progression of small subcortical infarcts in the LSA territory. Further prospective studies are needed to confirm our findings.
We thank Takahito Kaji for his statistical advice.
Sources of Funding
This study was supported by research funds provided to promote the hospital functions of the Japan Labor Health and Welfare Organization.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.003164/-/DC1.
- Received September 29, 2013.
- Accepted October 16, 2013.
- © 2013 American Heart Association, Inc.
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