Correlation of atherosclerotic renal artery stenosis with extracranial carotid and intracranial cerebral artery atherosclerosis in patients with ischemic stroke

Abstract

Objective. This study was to evaluate the relationship of atherosclerotic renal artery stenosis (ARAS) with extracranial carotid arteries atherosclerosis (ECAS) and intracranial cerebral atherosclerosis (ICAS) in ischemic stroke (IS) patients. Methods. This study was a prospective cohort analysis of consecutive patients with IS who had not a history of renal artery stenosis (RAS). Abdominal aortography was performed to screen for RAS after the cerebrovascular diagnostic procedure. Multivariate logistic regression analysis was performed to investigate the association of the clinical variables with significant ARAS (≥ 50%). Results. ARAS was identified in 61 (23.1%) of all patients and 34 patients (12.9%) had significant ARAS (≥ 50%). ECAS (≥ 70%) and ICAS (≥ 50%) was found in 66 (25%) and 48 (18.2%) respectively. Patients with ECAS (≥ 70%) were more likely to have significant ARAS than patients without ECAS (28.8% vs 6.2%, p < 0.001). In multivariate analysis, only advanced age (≥ 60 years) (OR = 2.84, 95% CI 1.01–7.91) and ECAS (≥ 70%) (OR = 5.27, 95% CI 2.396–11.60) were independent risk factors for significant ARAS. Conclusion. Incidental ARAS is a relatively common finding among patients with IS, and there is a close relationship between ARAS and ECAS. Abdominal aortography should be performed to identify ARAS in elderly patients with IS, especially combined with severe ECAS.

Key Words::

• Atherosclerosis
• cerebral and carotid arteries
• ischemic stroke
• renal artery stenosis

Introduction

Cerebrovascular disease (CVD) has become the principal cause of death and disability among middle-aged and elderly people in China (1). Approximately 40–50% of the patients with symptomatic CVD were found to have at least one additional location of atherosclerosis (2). Several previous studies have shown coexisting carotid artery disease to be highly predictive of significant atherosclerotic renal artery stenosis (ARAS) (3–5). Investigating ARAS in ischemic stroke (IS) patients is clinically important because significant ARAS may continue to progress and result in significant morbidity and mortality associated with ischemic nephropathy and end-stage renal disease (ESRD) (6). However, little is known of the prevalence and indicative clinical factors of ARAS among these patients in China. There have been several studies investigating extracranial cerebral arteries with ultrasonography and renal arteries with conventional angiography (7,8). None, however, has performed cerebral angiography and abdominal aortography simultaneously in IS patients. Therefore, in the present study, abdominal aortography was performed to study the relationship of ARAS to atherosclerosis of carotid artery in patients with IS.

Methods

Subjects

For 275 consecutive patients with IS, who underwent cerebral angiography between September 2009 and October 2011, 11 patients with serum creatinine levels of more than 2.5 mg/dl or known/suspected renal artery stenois (RAS) before onset of the stroke were excluded from abdominal aortography. Among the remaining 264 patients (183 males and 81 females; mean age 63.2 ± 9.8 years) were included in this study. All patients were gave written informed consent for invasive procedures. IS was defined as an onset of focal or global neurological deficits lasting over 24 h that were explained by the relevant lesions on computerized X-ray tomography (CT) and/or magnetic resonance imaging scanning (MR), including brain infarction, lacunar infarction and brain infarction plus hemorrhage.

Cerebrovascular angiography was performed following puncture of the femoral artery using the modified Seldinger technique with selective catheterization of the intracranial cerebral and extracranial carotid arteries. After the cerebrovascular diagnostic procedure, abdominal aortography was performed with a 5 F pigtail catheter positioned at the level of the L1–2 vertebrae in the antero-posterior view to assess arterial stenosis of renal artery.

Vascular assessments

Significant arterial stenosis was defined as ≥ 50% luminal narrowing of at least one renal artery suggested by Radermacher et al. (9). Intracranial cerebral arteries were defined as the proximal segments of the middle cerebral arteries (MCA), posterior cerebral arteries (PCA), anterior cerebral arteries (ACA) of both sides and the basilar artery (BA). The degree of stenosis in the intracranial cerebral artery was classified as follows: normal, < 50% stenosis, ≥ 50% stenosis or occlusion based on the degree of narrowing of the luminal diameter. The internal carotid arteries (ICA) of the extracranial portion and common carotid arteries of both sides were chosen for the extracranial carotid arteries. For the extracranial carotid artery, the assessment of stenosis was based on the NASCET criteria as follows: normal,< 30% stenosis, 30–70% stenosis, or ≥ 70% stenosis or occlusion (10). All carotid arteries and renal arteries were reviewed by two independent radiologists, and the final decision was made through a consensus meeting after discussion.

Clinical assessments

Diabetes mellitus was defined as a patient's use of oral hypoglycemic agents or insulin. Hypertension was defined as seated systolic blood pressure (BP) ≥ 140 mmHg and/or seated diastolic BP ≥ 90 mmHg or ongoing antihypertensive medication. Smoking was considered as a risk factor if the patient was a current smoker or if there was a history of long- term smoking. Hyperlipidemia was defined as a cholesterol level ≥ 220 mg/dl and/or low-density lipoprotein ≥ 140 mg/dl, or taking cholesterol- lowering agents. Patients with renal insufficiency (serum creatinine level ≥ 2.5mg/dl) were excluded from the study.

Statistical analysis

All analyses were performed using SPSS (version 13.0) and p-values < 0.05 were regarded as statistically significant. The difference between groups was compared by t-test for continuous variables and by the χ² test (or Fisher's exact test when appropriate) for categorical variables. The results are expressed as mean ± SD. Risk factors for the presence of ARAS were evaluated using multivariate logistic regression analysis. Age, sex, smoking, hypertension, diabetes mellitus, hyperlipidemia, extracranial carotid arteries atherosclerosis (ECAS; ≥ 70%) and intracranial cerebral atherosclerosis (ICAS; ≥ 50%) were chosen as independent valuables. Analyzed variables from logistic regression tests are presented as odds ratios (OR) with 95% confidence intervals (CI).

Results

Among 264 IS patients (261 with brain infarction, three with brain infarction plus hemorrhage), the mean age was 63.2 ± 9.8 years (range: 29–83 years), including 183 men (69.3%) and 81 women (30.7%). The clinical and demographic characteristics of these patients were shown in Table I. Hypertension was recognized in 84.1% of patients, smoking in 35.6%, diabetes mellitus in 40.2% and hyperlipidemia in 29.9%. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) were used in 72 (32.4%) hypertensive patients.

Table I. Clinical and demographic characteristics of ischemic stroke patients (n = 264).

Characteristics	Values
Mean age± SD (years)	63.2 ± 9.8
Male gender (%)	183 (69.3)
Smoking (%)	94 (35.6)
Hypertension (%)	222 (84.1)
ACE inhibitors and/or ARB (%)	72 (32.4)
Diabetes mellitus (%)	106 (40.2)
Hyperlipidemia (%)	79 (29.9)
ECAS (≥ 70%)	66 (25.0)
ICAS (≥ 50%)	48 (18.2)

SD, standard deviation; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ECAS, extracranial carotid arteries atherosclerosis; ICAS, intracranial cerebral atherosclerosis.

In this study, 34 (12.9%) patients showed significant ARAS (≥ 50%), which were mostly ostial (88.2%); 28 (10.6%) had unilateral stenosis, while six (2.3%) had bilateral disease (two with occlusion and stenosis and four with bilateral stenosis). Mild ARAS (< 50%) of one or two renal arteries was found in 27 (10.3%) patients. Advanced age (≥ 60 years), ECAS (≥ 70%) showed significant differences between the groups with and without significant ARAS. Significant ARAS was found in 13.8%, 13.5%, 12.3% and 13.9% of patients with smoking, hypertension, diabetes mellitus and hyperlipidemia, respectively (Table II).

Table II. Comparison of clinical characteristics and cerebral stenosis between patients with and without ARAS.

Characteristics	ARAS (≥ 50%) (n = 34)	No ARAS (n = 230)	p
Mean age ± SD (years)	66.4 ± 8.3	62.8 ± 10.0	0.179
Old age (≥ 60 years)	29 (85.3%)	149 (64.8%)	0.017
Male gender (%)	23 (67.6%)	160 (69.6%)	0.821
Smoking (%)	13 (38.2%)	81 (35.2%)	0.745
Hypertension (%)	30 (88.2%)	192 (83.5%)	0.479
ACE inhibitors and/or ARB (%)	9 (30.0%)	63 (32.8%)	0.910
Diabetes mellitus (%)	13 (38.2%)	93 (40.4%)	0.792
Hyperlipidemia (%)	11 (32.4%)	68 (29.6%)	0.740
ECAS (≥ 70%)	19 (55.9%)	47 (20.4%)	0.000
ICAS (≥ 50%)	9 (26.5%)	39 (17.0%)	0.222

ARAS, atherosclerotic renal artery stenosis; SD, standard deviation; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ECAS, extracranial carotid arteries atherosclerosis; ICAS, intracranial cerebral atherosclerosis.

The severity and distribution of ECAS and ICAS in the 264 patients are summarized in Table III. The prevalence of significant ARAS was nine (6.2%) among the 145 patients without ECAS, two (8.7%) among the 23 patients with ECAS < 30%, four (13.3%) among the 30 patients with ECAS 30–70% and 19 (28.8%) among the 66 patients with ECAS ≥ 70%. Patients with severe ECAS (≥ 70% or occlusion) were more likely to have significant ARAS than patients without it (28.8% vs 6.2%, p < 0.0001). The difference in prevalence of significant ARAS between the groups with and without ICAS was not statistically significant.

Table III. The severity and distribution of stenosis in the renal artery and cerebral arteries.

(a) ECAS
	Severity of stenosis
	Normal	< 30%	30–70%	≥ 70% or occlusion
NO ARAS	136	21	26	47
ARAS (≥ 50%)	9	2	4	19
(b) ICAS
	Severity of stenosis
	Normal	< 50%		≥ 50% or occlusion
NO ARAS	168	23		39
ARAS (≥ 50%)	23	2		9

ARAS, atherosclerotic renal artery stenosis; ECAS, extracranial carotid arteries atherosclerosis; ICAS, intracranial cerebral atherosclerosis.

From the logistic regression model, advanced age (≥ 60 years) (OR = 2.84, 95% CI 1.01–7.91) and ECAS (≥ 70%) (OR = 5.27, 95% CI 2.396–11.60) were proved to be the factors that were independently associated with significant ARAS (Table IV).

Table IV. Logistic regression analysis of significant ARAS.

Variable	OR	95% CI	p
Old age (≥ 60 years)	2.836	1.016–7.913	0.047
ECAS (≥ 70%)	5.272	2.396–11.60	0.000
ICAS (≥ 50%)	2.478	0.997–6.157	0.051

ARAS, atherosclerotic renal artery stenosis; OR, odds ratios; CI, confidence intervals; ECAS, extracranial carotid arteries atherosclerosis; ICAS, intracranial cerebral atherosclerosis.

Discussion

Diagnosis of ARAS at an early stage is very important because the natural history and outcomes can be modified by timely intervention. Making an early diagnosis of ARAS is difficult because ARAS has few characteristic clinical or laboratory manifestations. Up to the present time, renal arteriography is still the only gold standard to diagnose ARAS for its accuracy in finding the position and the severity of the stenosis. Some investigators suggest that CT angiography (CTA) or ultrasonography may replace angiography for detecting ARAS (11–13). These techniques are non-invasive and therefore carry a lower adverse event rate than catheter angiography, but diagnostic accuracy is sometimes a problem. Identification of ARAS by these techniques sometimes requires catheter angiography for confirmation and measurement of the degree of stenosis. Thus, catheter angiography remains a clinically important technique for patients with suspected ARAS. So screening aortography in this study, as a part of an angiographic examination of the cerebrovascular arteries, focuses on the detection of ARAS, although this method remains debatable.

The prevalence and risk factors of ARAS in patients with IS varies considerably in the literature. The prevalence of ARAS ranges from this study indicated that ARAS is a relatively common finding among patients with carotid artery disease. Nakamura et al. (4) reported that the prevalence of RAS was 27% in patients with severe carotid artery stenosis, which is consistent with our findings. Most researchers reported that older age was one of the strongest independent predictors of ARAS (14–16). In this study, the presence of severe ECAS and older age were determined to be independently associated with the risk of significant ARAS in patients with IS.

The correlation between ARAS and ECAS is stronger than that between ARAS and ICAS. The reasons behind this difference are uncertain. The difference may be attributed to the diameter of the vessels. Early autopsy study has found that the severity of cerebral atherosclerosis was well correlated with the size of the vessels (17). The diameter of the renal artery is approximately 5–7 mm at the trunk. The ICA is more than 8 mm at the bifurcation and about 5 mm beyond the bifurcation in diameter. The diameter of the MCA is approximately 3 mm; it is usually the largest intracranial cerebral artery, next only to the ICA (18). The size of the renal arteries is closer to that of the carotid arteries than that of the intracranial arteries; it may explain the difference.

Besides size, several hypotheses have been suggested, including the different roles of the conventional vascular risk factors (19), different antioxidant enzyme activities (20), different histological characters (18), different roles of the inflammatory markers (21) and different roles of metabolic syndrome (22) in the intracranial artery and carotid artery. These hypotheses may contribute in part to the difference in atherosclerosis.

There are different opinions on whether hypertension is a risk factor of ARAS. The incidence of RAS in the general hypertensive population ranged from 10.4% to 20.3% (23). In our study, 30 (13.5%) patients with significant ARAS have history of hypertension, while hypertension is not the independent predictor of ARAS. According to Yang et al. (24), 75% of Chinese patients with undiagnosed RAS were taking ACE inhibitors. In present study, ACE inhibitor and/or ARB medication was prescribed for 30.0% of Chinese patients with undiagnosed significant RAS. Several Western angiographic studies report that the proportion of bilateral RAS is 20–40% of significant RAS cases (25); our study and previous Japanese studies (3,26) found that bilateral RAS was less than 20% in significant RAS cases. Careful administration of ACE inhibitor and/or ARB medication is safe in the majority patients with RAS. However, in the case of bilateral RAS or unilateral RAS in a solitary functioning kidney, use of an ACE inhibitor and/or ARB medication may lead to a mild increase in serum creatinine up, even to serious progressive renal failure and hyperkalemia (27). So close monitoring of renal function after prescription of an ACE inhibitor and/or ARB in these patients should be necessary.

In patients with severe carotid artery stenosis, effectively restoring cerebral blood flow by either surgical or endovascular methods is important. However, RAS is considered to carry at least some responsibility for postoperative renal dysfunction. To avoid hyperperfusion of cerebral blood flow after carotid artery angioplasty and/or stenting, the reduction of systemic BP using antihypertensive drugs is considered necessary, while also inducing a reduction in renal perfusion pressure. In this condition, renal dysfunction or acute renal failure may occur in cases of significant RAS. Therefore, it is considered useful to obtain preoperative information about renal artery disease in patients with severe ECAS undergoing carotid artery angioplasty and/or stenting.

Our results indicate that there is a close relationship between ARAS and ECAS in patients with IS. Careful concern about renal artery disease is needed when treating elderly IS patients who have severe ECAS; therefore, abdominal aortography should be performed to screen for ARAS after the cerebral angiography among these patients.

Acknowledgments

The authors gratefully acknowledge the staff of the department neurology of Changzhou Second Hospital Affiliated to Nanjing Medical University for their excellent support.

Disclosure

The authors have no conflicts of interest to disclose.