Renal Artery Stenosis in Cardio- and Cerebrovascular Disease

Transcription

1 Circ J 2007; 71: Renal Artery Stenosis in Cardio- and Cerebrovascular Disease Renal Duplex Ultrasonography as an Initial Screening Examination Osami Kawarada, MD; Yoshiaki Yokoi, MD; Nobuyuki Morioka, MD; Kazushi Takemoto, MT* Background The prevalence and indicative clinical factors of renal artery stenosis (RAS) in the Japanese population are unclear. Methods and Results The aim of this study was to investigate the prevalence of RAS in a selectively referred Japanese population and to determine any clinical factors related to RAS by initially screening with renal duplex ultrasonography. The 750 patients presenting because of possible or known cardio- and cerebrovascular diseases were prospectively studied. Duplex examination was performed in 729 patients (97.2%): 21 patients (2.8%) did not undergo it, because of technical impossibility. Duplex RAS was found in 38 patients (5.2%). Subsequently, a confirmatory renal angiography was obtained in 40 patients, investigating those who had duplex RAS or no duplex examination. Angiographic RAS was found in 35 patients (4.8%). The respective prevalences of duplex and angiographic RAS were 6.3% and 6.7% in coronary artery disease, 8.8% and 9.3% in multivessel coronary artery disease, 7.5% and 8.2% in heart failure, 5.1% and 4.3% in unstable angina pectoris, 20.0% and 22.2% in carotid artery stenosis, 10.3% and 10.2% in stroke, 20.0% and 20.0% in peripheral artery disease, and 12.0% and 11.8% in abdominal aortic aneurysm. Univariate analysis showed that patients with duplex RAS were older and had more atherosclerotic risk factors. Furthermore, they were more likely to be smokers and have hypertension, renal impairment, renal atrophy, left ventricular hypertrophy and cardio- and cerebrovascular diseases. Multivariate stepwise analysis showed that smoking, peripheral artery disease, abdominal aortic aneurysm and renal atrophy were independent predictors of duplex RAS. Conclusions RAS is frequent in Japanese patients with cardio- and cerebrovascular diseases. Initial screening for RAS by duplex ultrasonography is recommended for patients with complications, especially peripheral artery disease, abdominal aortic aneurysm and renal atrophy. (Circ J 2007; 71: ) Key Words: Renal artery stenosis; Renal duplex ultrasonography; Screening Because atherosclerotic renal artery stenosis (RAS) causes cardiorenal problems, it is a matter of concern for both nephrologists and cardiologists. The kidney does not present organ-specific signs or symptoms of ischemia, unlike the heart, brain, or lower limbs. Successful detection of RAS can, therefore, be very difficult in clinical practice. Recent studies have shown a high prevalence of RAS in Western patients undergoing angiography for either suspected coronary artery disease (CAD) or peripheral vascular disease, 1 10 so screening aortography, as a part of an angiographic examination of the coronary or peripheral arteries, focuses on the detection of RAS, although this traditional method remains debatable. Compared with Western countries, atherosclerosis in the renal artery is believed to be less prevalent in the Japanese population, but the actual frequency of RAS in the Japanese population is unclear, although atherosclerotic diseases have been steadily (Received March 19, 2007; revised manuscript received July 27, 2007; accepted August 17, 2007) Departments of Cardiology and *Vascular Laboratory, Kishiwada Tokushukai Hospital, Kishiwada, Japan Mailing address: Osami Kawarada, MD, Department of Cardiology, Kishiwada Tokushukai Hospital, Kamori, Kishiwada, Osaka , Japan. kawarada90@hotmail.com increasing with the changes in lifestyle toward Western habits and the aging of society. The development of renal duplex ultrasonography (RDU) enables noninvasive and accurate evaluation of the renal artery, and has become a new, objective method of determining the natural history and frequency of RAS. 11,12 Therefore, in the present study, we used initial screening with RDU, and subsequent confirmatory angiography, to investigate the prevalence of RAS in a selectively referred Japanese population and to determine any clinical factors related to RAS in a wide cohort of Japanese patients with possible and known cardio- and cerebrovascular diseases. Methods Subjects We prospectively studied 750 patients presenting between January 2002 and December 2002 because of possible or known cardio- and cerebrovascular diseases. All patients were informed about the investigation and gave written informed consent for invasive procedures. CAD, heart failure (HF), unstable angina pectoris (UAP), carotid artery stenosis (CAS), stroke, peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA) were defined as the

2 RAS in Cardio- and Cerebrovascular Disease cardio- and cerebrovascular diseases. The enrolled patients underwent measurement of ambulatory and seated blood pressures (BP), blood examination, electrocardiography, echocardiography, ankle brachial index (ABI) and the duplex ultrasonography examination of the carotid artery, abdominal aorta, lower limb artery and renal artery, and if deemed necessary, coronary angiography was conducted with written informed consent. Duplex ultrasonography was performed by 5 vascular technicians with extensive experience. Scheduled nonselective and/or selective renal angiography was considered for patients diagnosed with RAS by duplex. When RDU was not performed, patients underwent renal angiography just in case they had resistant hypertension, renal impairment, congestive HF and/or UAP. We analyzed the clinical factor variables, including atherosclerotic risk factors and comorbidities. Patients with known RAS were excluded, as were hemodialysis patients, because noninvasive examinations in them were deemed difficult or unreliable. Criteria of RAS Renal arteries were evaluated by duplex ultrasonography (Aplio SSA-770A; Toshiba: Japan, Aplio SSA 390A; Toshiba: Japan, or ATL HDI 5000; Phillips: USA). Both renal arteries were visualized by combined B-mode and color-doppler ultrasound. Doppler spectral analysis can determine the peak systolic velocity (PSV) in both the renal artery and the abdominal aorta. A PSV >180cm/s in the renal artery and a renal/aorta ratio (RAR) of more than 3.5 was defined as significant RAS, and no detectable signal was graded as complete occlusion, which is 95% sensitive and 90% specific for a greater than 60% diameter reduction by angiography. 13 A diameter reduction >60% by visual estimation was defined as angiographic stenosis. Renal size was determined by B-mode ultrasonographic measurement of the pole-to-pole length. Assessment of Cardiac Disease Coronary angiography was performed in patients with possible CAD and the diameter stenosis was determined by visual estimation: CAD was defined as >75% reduction of lumen diameter. The number of diseased vessels was classified as follows: 1-vessel disease (ie, left anterior descending artery, left circumflex artery, or right coronary artery); 2-vessel disease (ie, in 2 vessels or left main trunk disease without right CAD); 3-vessel disease (ie, in 3 vessels or left main trunk disease with right CAD). Multivessel CAD was defined as 2- or 3-vessel disease. Patients with previous revascularization of a coronary artery were also defined as CAD subjects. A past history or new onset of congestive HF with left ventricular dysfunction or not, or UAP symptoms was defined as congestive HF and UAP, respectively. Assessment of Cerebrovascular Disease Atherosclerosis of the carotid artery was evaluated by duplex ultrasonography. The common, internal and external carotid arteries were visualized by combined B-mode and color-doppler ultrasound. Doppler spectral analysis can determine the PSV by sampling at the area of turbulence and significant CAS was defined as PSV >200cm/s. 14 No detectable signal was graded as complete occlusion. Patients with previous revascularization of carotid artery were also defined as CAS subjects. Stroke was defined as a past history or new onset of a Table 1 Clinical Characteristics stroke event, including transient ischemic attacks No. of patients 750 M/F 467/283 Age (years) 67.8±9.4 (40 88) Hypertension (%) 697 (80.9) Resistant hypertension (%) 111 (14.8) ACE inhibitor and/or ARB use (%) 233 (31.1) Hyperlipidemia (%) 292 (38.9) Diabetes mellitus (%) 195 (26.0) Smoking (%) 292 (38.9) Renal impairment (%) 88 (11.7) Renal atrophy (%) 25 (3.3) Left ventricular hypertrophy (%) 37 (4.9) Coronary artery disease (%) 408 (54.4) Multivessel CAD (%) 210 (28.0) Heart failure (%) 123 (16.4) Unstable angina (%) 245 (32.7) Carotid artery stenosis (%) 36 (4.8) Stroke (%) 89 (11.9) Peripheral artery disease (%) 72 (9.6) Abdominal aortic aneurysm (%) 51 (6.8) Major vascular disease (%) 458 (61.0) The number of major vascular disease (38.9) (44.0) 2 80 (10.7) 3 32 (4.3) 4 15 (2.0) ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease. Major vascular disease=coronary artery disease, carotid artery stenosis, stroke, peripheral artery disease and abdominal aortic aneurysm. Assessment of PAD The presence of PAD was defined as an ABI <0.90. Duplex scanning was also performed to verify the stenotic or occlusive lesion. Patients with previous revascularization of a lower limb artery were also defined as PAD subjects. Assessment of AAA B-mode gray scale images of the abdominal aorta were obtained in both traverse and longitudinal projections. The measurement of aortic diameter was performed at the site of the maximum aortic artery diameter. AAA was defined as an aortic diameter >3.0 cm. Patients with previous repair were also defined as AAA subjects. Evaluation of Atherosclerotic Risk Factors and Comorbidities Hypertension was defined as seated systolic BP 140 mmhg and/or seated diastolic BP 90 mmhg or ongoing therapy for hypertension. Resistant hypertension was defined as systolic BP 140 mmhg or diastolic BP 90 mmhg while on 3 or more antihypertensive medications. Hyperlipidemia was defined as a serum total cholesterol concentration 220 mg/dl and/or a low-density lipoprotein-cholesterol concentration 140 mg/dl or the subject being on lipid-lowering therapy. Diabetes mellitus was defined as a glycohemoglobin concentration 5.9% or the subject following dietary and exercise advice or taking medication. Smoking was defined as being a current smoker. Renal impairment was defined as a serum creatinine 1.3mg/dl. Renal atrophy was defined as 8.0cm poleto-pole on ultrasound examination. The presence of ECG abnormality and the interventricular left ventricular wall

3 1944 KAWARADA O et al. Fig 1. Schematic summary of the study. RAS, renal artery stenosis. Fig 2. Frequency of renal artery stenosis in cardio- and cerebrovascular disease. (Shaded boxes) Duplex renal artery stenosis; (Open boxes) angiographic renal artery stenosis. CAD, coronary artery disease; HF, heart failure; UAP, unstable angina pectoris; CAS, carotid artery stenosis; PAD, peripheral artery disease; AAA, abdominal aortic aneurysm. thickness 11 mm was indicative of left ventricular hypertrophy (LVH). Statistical Analysis Independent variables were age, the number of atherosclerotic risk factors, hypertension, severe hypertension, angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin-receptor blocker (ARB) use, hyperlipidemia, diabetes mellitus, smoking, renal impairment, renal atrophy, LVH, CAD, multivessel CAD, congestive HF, UAP, CAS, stroke, PAD, AAA and the number of major vascular diseases. The major vascular diseases were defined as CAD, CAS, stroke, PAD and AAA. Continuous variables are presented as mean ± standard deviation. Differences between groups were assessed using chi-square analysis (or Fisher s exact test when appropriate) for discrete variables and 2- sided unpaired t-test for continuous variables. Multivariate stepwise logistic regression analysis was performed to detect independent predictors of RAS using factors that had significant relation in univariate analysis. Probability values <0.05 were held to be statistically significant. Analyzed variables were reported with their respective odds ratios (OR) and 95%confidence intervals (CI). Results Clinical Characteristics This study consisted of 750 patients (467 men). Clinical characteristics are summarized in Table 1. Average age was 67.8±9.4 years (range, 40 88). All the traditional atherosclerotic risk factors were present in the study group, with hypertension showing the highest incidence, followed by smoking and hyperlipidemia. Renal impairment and atrophy was detected in 88 patients (11.7%) and 25 patients (3.3%), respectively. In this population, 233 patients (31.1%) were taking ACE inhibitor and/or ARB. Major vascular diseases were present in the study group, with CAD showing the highest incidence, followed by PAD, stroke, CAS and AAA. Major vascular disease was confirmed in 458 patients (61.0%). Prevalence of RAS Of all the enrolled patients, duplex examinations were performed in 729 patients (97.2%), including 1 patient with

4 RAS in Cardio- and Cerebrovascular Disease a solitary kidney (Fig 1). Duplex RAS was found in 38 patients (5.2%), and of them unilateral RAS was found in 34 (89.5%) and bilateral RAS in 4 patients (10.5%). Of the duplex RAS patients, renal atrophy was found in 4 (16.7%) (3 cases: ipsilateral, 1 case: contralateral). Duplex examination was not performed in 21 patients because of technical impossibility, such as obesity, excess bowel gas or previous abdominal surgery. Confirmatory renal angiography was considered for 59 patients with duplex RAS or no duplex examination (Fig1). Nineteen patients who did not give consent were excluded, so as a result, 40 patients underwent selective and/or nonselective renal angiography without complications. Angiographic RAS was found in 35 patients (4.8%). All lesions were located at the ostium or proximal segments of the renal arteries and were atherosclerotic in origin. Unilateral RAS was found in 29 patients (82.9%) and bilateral RAS in 6 patients (17.1%). One case of bilateral RAS had total occlusion of the right renal artery. Angiographic RAS was found in 5 (20%) of the patients with renal atrophy: 4 patients (80%) had ipsilateral renal atrophy and 1 (20%) had contralateral renal atrophy. We further analyzed the frequency of RAS in cardioand cerebrovascular complications (Fig 2). RAS was more frequent with extracoronary complications than with CAD. Finally, in the patients with confirmed major vascular diseases, we found duplex RAS in 6.7% (30/445) and angiographic RAS in 6.7% (30/448). Duplex and angiographic RAS were significantly more frequent in patients with confirmed major vascular diseases than those without them (duplex RAS: p=0.020, angiographic RAS: p=0.002). Clinical Factors Related to RAS Univariate analysis showed that the following factors were associated with duplex RAS: age, the number of atherosclerotic risk factors, hypertension, smoking, renal impairment, renal atrophy, LVH, multivessel CAD, CAS, stroke, PAD, AAA and the number of major vascular diseases (Table 2). No significant difference was detected between the proportion of ACE inhibitor and/or ARB use. With these factors, multivariate stepwise logistic regression analysis showed smoking, PAD, AAA and renal atrophy to be the independent predictors of duplex RAS (smoking: OR 2.490, 95%CI , p=0.047; PAD OR 7.594, 95%CI , p=0.010; AAA OR 5.453, 95%CI , p=0.036, renal atrophy: OR6.034, 95%CI , p=0.007) (Table 3). Table 2 Univariate Analysis of Duplex Renal Artery Stenosis 1945 RAS+ RAS (n=38) (n=691) p value Age (years) 71.2± ± Male (%) 28 (73.7) 421 (60.9) Atherosclerotic risk factors 2.3± ± Hypertension (%) 37 (97.4) 554 (80.2) Resistant hypertension (%) 6 (15.7) 101 (14.6) ACE inhibitor and/or ARB use (%) 15 (39.5) 213 (30.8) Hyperlipidemia (%) 15 (39.5) 268 (38.8) Diabetes mellitus (%) 13 (34.2) 172 (24.9) Smoking (%) 24 (63.2) 259 (37.5) Renal impairment (%) 10 (26.3) 76 (11.0) Renal atrophy (%) 4 (10.5) 20 (2.9) Left ventricular hypertrophy (%) 5 (13.2) 32 (4.6) Coronary artery disease (%) 25 (65.8) 372 (53.8) Multivessel CAD (%) 18 (47.4) 186 (26.9) Heart failure (%) 9 (23.7) 111 (16.1) Unstable angina (%) 12 (31.6) 225 (32.6) Carotid artery stenosis (%) 7 (18.4) 28 (4.1) <0.001 Stroke (%) 9 (23.7) 78 (11.3) Peripheral artery disease (%) 14 (36.8) 56 (8.1) <0.001 Abdominal aortic aneurysm (%) 6 (15.8) 44 (6.4) Major vascular diseases 1.6± ±0.9 <0.001 Abbreviations see in Table 1. Table 3 Multivariate Stepwise Logistic Regression Analysis of Duplex Renal Artery Stenosis OR (95%CI) p value Smoking ( ) PAD ( ) AAA ( ) Renal atrophy ( ) OR, odds ratio; CI, confidence interval; PAD, peripheral artery disease; AAA, abdominal aortic aneurysm. Discussion Our main findings are that: (1) initial screening with duplex ultrasonography and subsequent angiography can identify a clinically significant number of patients with RAS without incremental risks, (2) RAS was frequent in this sample of Japanese population, and (3) undiagnosed RAS is potentially and significantly associated with cardiovascular, cerebrovascular and renal complications, especially PAD, AAA and renal atrophy. It is well known that RAS causes poorly controlled hypertension. With the advent of ACE inhibitors, block the renin angiotensin-aldosterone cascade, however, excellent BP control has been demonstrated even in hypertensive patients with RAS. 15 By extrapolation, the same scenario should apply for ARB, but there are few published data. Moreover, ironically, hypertensive patients with cardioand cerebrovascular complications, who are, as our study showed, common even in cases of undiagnosed RAS, are especially good candidates for ACEI and/or ARB use. Consequently, patients with RAS may often be asymptomatic and untreated. According to Rihal et al 16 and Yang et al, 17 46% of Western patients and 75% of Chinese patients with undiagnosed RAS were taking ACE inhibitors. In our study, ACE inhibitor and/or ARB medication was prescribed for 42.9% of Japanese patients with undiagnosed RAS. These findings illustrate the possibility that the renin-angiotensinaldosterone cascade may be blocked in half to two-thirds of RAS patients without a clear diagnosis, despite its progressive nature. 11 RAS has become the leading cause of endstage renal disease (ESRD) in the elderly, 18 and is estimated to be the underlying disease in 14 25% of ESRD cases in Western countries. 19,20 Japanese ESRD patients maintained on chronic dialysis therapy have increased remarkably to over 260,000 in 2006, but the prevalence of RAS in ESRD is unclear in Japan. Based on these data, roughly several tens of thousands of Japanese patients with RAS would appear to be included in this category. Therefore, in Japan, the most practical approach is to search for RAS itself, investigate the prevalence of RAS, and to determine the appropriate clinical factors that indicate the presence of RAS. These are urgent needs from the viewpoint of detecting RAS at the earliest stage possible, before it leads to ESRD. The prevalence of RAS in Western patients has been reported as approximately 10 30% with CAD, particularly

5 1946 KAWARADA O et al. more frequent in cases of severe CAD, and 20 40% with extracoronary atherosclerosis In the Japanese population, according to previous study of simultaneous angiographic examination and cardiac catheterization, 6.4% of patients with CAD had significant RAS. 21 Autopsy studies report that approximately 12% of Japanese patients with myocardial infarction or stroke had RAS. 22,23 The present study revealed a prevalence of duplex and angiographic RAS in 6 7% of CAD cases, 8 10% of multivessel CAD in particular, and 10 23% of extracoronary atherosclerosis. Furthermore, several Western angiographic studies report that the proportion of bilateral RAS is 20 40% of significant RAS cases, 1,2 our study and a previous Japanese study 21 found that bilateral RAS was less than 20% in significant RAS cases. Considering these findings, renal artery atherosclerosis rates in the Japanese population may be getting close to those in Western populations. Our univariate analysis showed that patients with duplex RAS were older and had more atherosclerotic risk factors. Furthermore, they were more likely to have hypertension, smoking, renal impairment, renal atrophy, LVH and major cardio- and cerebrovascular diseases, such as CAD, especially multivessel CAD, CAS, PAD, AAA and stroke. On multivariate stepwise analysis, PAD, AAA and renal atrophy, as well as smoking, were independent predictors of duplex RAS. PAD and AAA are atherosclerotic disorders extending from the abdominal aorta to the infrapopliteal artery, and RAS has a larger plaque burden in the ostial or proximal renal artery, which is shown as an extension of a markedly irregular and shaggy aorta. Considering these similar atherosclerotic morphologies, we can assume a strong association between PAD, AAA and RAS. As already reported, RAS patients have a significant risk of ipsilateral renal atrophy, 24 which is accompanied by contralateral, as well as ipsilateral, parenchymal injury. 25 In this clinical study, we further observed that renal atrophy had a high predictive rate for the presence of RAS on the ipsilateral or contralateral side. That is, in clinical practice careful attention should be paid to the size of both kidneys. In patients with small kidneys in particular, intensive examination of RAS is warranted, and any atrophic kidney should be identified before the irreversible parenchymal disease stage. Unexpectedly, resistant hypertension, congestive HF and UAP, which can be precipitated by RAS, and in some cases clearly improved by renal revascularization, 26 were not identified as risk factors of RAS. As for the reasons for this finding, first, as mentioned earlier, we consider that the advent of new antihypertensive drugs makes BP control easier. Multifactorial disorders, such as congestive HF and UAP, may be overlooked during busy clinical practice. Second, the presence of silent RAS may be associated with this scenario. Third, ultrasonographically significant RAS may not be physiologically significant to the kidney. Even so, establishment of an early diagnosis for morphologically significant RAS and then a wait-and-see approach is entirely appropriate for the management of RAS, 27 with subsequent treatment for clinically significant RAS accompanied by acceleration of hypertension, progressive renal disorder, and the onset of congestive HF or UAP. 28 Therefore, the detection of RAS by initial duplex ultrasonography is justified. Study Limitations This study did not use population-based data. Also, there may be limitations in the application of RDU. Angiographic evaluation for patients without duplex RAS was not performed. Technically, the RDU examination may require a steep learning curve, and be operator- or machine-dependent. Patient conditions, such as obesity, excess bowel gas or previous abdominal surgery, can prevent detection of the renal arteries. Also, RDU has anatomical limitations, such an inability to detect stenotic lesions in branch, multiple or accessory renal arteries. Conclusion In Japan, clinical suspicion regarding RAS seems to be insufficient and the results of this study suggest that the first step toward identification of RAS is closer consideration of patients with cardiovascular, cerebrovascular and renal complications, especially PAD, AAA and renal atrophy. We emphasize the importance of screening Japanese patients with these indicative clinical factors for RAS by initially performing duplex ultrasonography. Acknowledgments The authors thank the staff of the cardiac catheterization and vascular laboratory of Kishiwada Tokushukai Hospital for their excellent support. 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