Diagnosis and management of atherosclerotic renal artery stenosis: improving patient selection and outcomes

Diagnosis and management of atherosclerotic renal artery stenosis: improving patient selection and outcomes Christopher J White* and Jeffrey W Olin SuMMarY Renal artery stenosis (RAS) is common among patients with atherosclerosis, and is found in 20 30% of individuals who undergo diagnostic cardiac catheterization. Renal artery duplex ultrasonography is the diagnostic procedure of choice for screening outpatients for RAS. Percutaneous renal artery stent placement is the preferred method of revascularization for hemodynamically significant RAS, and is favored over balloon angioplasty alone. Stent placement carries a class I recommendation for atherosclerotic RAS according to ACC and AHA guidelines. Discordance exists between the very high (>95%) procedural success rate and the moderate (60 70%) clinical response rate after renal stent placement, which is likely to be a result of poor selection of patients, inadequate angiographic assessment of lesion severity, and the presence of renal parencyhmal disease. Physiologic lesion assessment using translesional pressure gradients, and measurements of biomarkers (e.g. brain natriuretic peptide), or both, could enhance the selection of patients and improve clinical response rates. Longterm patency rates for renal stenting are excellent, with 5-year secondary patency rates greater than 90%. This Review will outline the clinical problem of atherosclerotic RAS and its diagnosis, and will critically assess treatment options and strategies to improve patients outcomes. KeywoRds ischemic nephropathy, renal artery atherosclerosis, renal artery stent, renovascular hypertension REvIEw CRITERIA Papers selected for this Review were identified on PubMed using the search terms renal artery atherosclerosis, renovascular hypertension, renal angioplasty, and renal stent. Only English-language, full-text, peer-reviewed manuscripts published up until August 2008 were used in this Review. The Cochrane database was also searched using the same search terms up until August 2008. Bibliographies of reviewed articles were searched for relevant manuscripts. cme CJ White is Chairman of the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA. JW Olin is Professor of Medicine (Cardiology) and Director of Vascular Medicine in the Zena and Michael A Wiener Cardiovascular Institute and the Marie-Josée and Henry R Kravis Center for Cardiovascular Health at the Mount Sinai Medical Center, New York, NY, USA. Correspondence *Department of Cardiology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA cwhite@ochsner.org Received 15 September 2008 Accepted 4 December 2008 www.nature.com/clinicalpractice doi:10.1038/ncpcardio1448 Continuing Medical Education online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test. Learning objectives Upon completion of this activity, participants should be able to: 1 Review the epidemiology of renal artery stenosis (RAS). 2 Identify optimal diagnostic imaging techniques for RAS. 3 Describe RAS treatment approaches. 4 Evaluate outcomes associated with renal artery stenting. Competing interests The authors and the Journal Editor, Bryony Mearns, declared no competing interests. The CME questions author CP Vega declared that he has served as an advisor or consultant to Novartis, Inc. INTRODUCTION Patients with atherosclerotic coronary artery disease or peripheral arterial disease, associated with uncontrolled hypertension or renal insufficiency, are at increased risk for renal artery stenosis (RAS). 1 When selecting patients for renal artery stenting, both functional and anatomical data should be considered to optimize the benefit of revascularization for each individual. Well-accepted indications for renal artery revascularization are outlined in Box 1. Primary stent placement (the practice of deploying a stent regardless of the result of balloon angioplasty as opposed to provisional stent placement, where stenting is performed only if the balloon angioplasty result is poor), has largely replaced surgical therapy in patients with suitable anatomy who do not respond to medical therapy. 2 In this Review, we examine the management of 176 nature clinical practice cardiovascular medicine march 2009 vol 6 no 3

Box 1 Indications for renal artery revascularization. 2 Hemodynamically significant renal artery stenosis accompanied by one or more of the following features: Uncontrolled hypertension Ischemic nephropathy Cardiac disturbance syndrome (e.g. flash pulmonary edema, uncontrolled heart failure, or uncontrolled angina pectoris) RAS in the context of diagnostic imaging, patient selection to improve the treatment response rate, and procedural safety. PREvALENCE OF RENAL ARTERY STENOSIS The prevalence of RAS depends upon the population examined. Screening renal duplex ultrasonography (DUS) studies demonstrated RAS (>60% stenosis) in 6.8% of individuals in a Medicare population (mean age 77 years). 3 RAS was present in almost twice as many men as women (9.1% versus 5.5%, P = 0.053), but no differences were noted in the prevalence of RAS between white and African American individuals (6.9% versus 6.7%, P = 0.933). An autopsy series found RAS ( 50% stensosis) in 27% of patients older than 50 years, and the proportion rose to 53% in those with a history of diastolic hypertension (>100 mmhg). 4 RAS is the cause of end-stage renal disease in 10 15% of patients commencing kidney dialysis, 5,6 and approximately 25% of elderly patients with renal insufficiency have undiagnosed renal artery stenosis. 7 9 In the general hypertensive population, RAS is the most common (2 5%) secondary cause of hypertension. 10 In the adult population, RAS is predominantly the result of atherosclerosis, although fibromuscular dysplasia commonly found in young women is the next most common cause of RAS. 11 The presence of atherosclerosis in another circulatory bed (i.e. cerebral, coronary, or peripheral vascular) increases the likelihood of RAS being present. 12 In patients undergoing cardiac catheterization for suspected coronary artery disease, RAS is found in up to a third of patients (Table 1). 13 17 RAS is present in 30 40% of patients with peripheral artery disease or abdominal aortic aneurysm. 18,19 In a multi variable analysis, Weber-Mzell et al. 14 demonstrated that RAS was more prevalent in patients with extensive coronary artery disease (i.e. multivessel coronary disease) than in patients with single-vessel disease. Table 1 Prevalence of renal artery stenosis at the time of cardiac catheterization. study Number of patients (n) Any RAs (%) NATURAL HISTORY OF RENAL ARTERY STENOSIS Atherosclerotic RAS generally progresses over time and is often associated with loss of renal mass and worsening renal function. 20 24 Progression of RAS lesions is directly related to the underlying severity of stenosis. Progression to occlusion is most likely in patients with severe arterial narrowing ( 60%). 25 Worsening of asymptomatic RAS is associated with a progressive loss of renal function. 20 Atherosclerotic RAS remains a major cause of end-stage renal disease. In a serial angiographic study, decline in renal function was significantly greater among patients with RAS than in normal control participants, and was related to the severity of RAS. 20 In a study of patients starting dialysis secondary to atherosclerotic RAS, the mean survival time was 25 months, and the 2, 5, and 10 year survival rates were 56%, 18%, and 5%, respectively. 26 RAS is an independent predictor of adverse cardiovascular events, such as myocardial infarction, stroke, and cardiovascular death. 20,25 Hemodynamically significant RAS is also associated with renal insufficiency, coronary artery disease, peripheral artery disease, hypertension, and cerebrovascular disease. Survival is reduced among patients with severe RAS compared with those with mild or no RAS. In patients identified as having greater than 75% RAS at the time of cardiac catheterization, 4-year survival was 57%, compared with 89% in patients without RAS (P <0.001). 27 Moreover, survival was independent of prior myocardial revascularization procedures, and patients with bilateral RAS had lower 4-year survival than patients with unilateral RAS (47% versus 59%, P <0.001). 28 RAs > 50% (%) Jean et al. (1994) 13 196 33 18 NR Weber-Mzell et al. (2002) 14 177 25 11 8 Harding et al. (1992) 15 1,302 30 15 36 Rihal et al. (2002) 16 297 34 19 4 Vetrovec et al. (1989) 17 116 29 23 29 Aqel et al. (2003) 113 90 NR 28 10 Bilateral RAs (%) Mean values NA 30.2 19.0 17.4 Abbreviations: NA, not applicable; NR, not reported; RAS, renal artery stenosis. march 2009 vol 6 no 3 WhiTe and olin nature clinical practice cardiovascular medicine 177

Box 2 Risk factors for atherosclerotic renal artery stenosis. 2 Late-onset hypertension (age >55 years) Malignant, refractory, or resistant hypertension Worsening of renal function with an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker Atrophic kidney, or a size discrepancy of greater than 1.5 cm between kidneys Unexplained renal dysfunction Flash pulmonary edema Multivessel coronary artery disease Symptomatic peripheral arterial disease or ankle brachial index of 0.9 or less Box 3 The ideal imaging procedure for identification of renal artery stenosis. 13 Identify both main and accessory arteries Localize the abnormality Characterize the underlying disease (i.e. atherosclerosis, fibromuscular dysplasia) Determine the hemodynamic significance of the lesion Determine the likelihood of a favorable response to revascularization Identify associated pathology (i.e. abdominal aortic aneurysm, renal mass) that could have an effect on the treatment of renal artery disease Detect restenosis after percutaneous or surgical revascularization DIAGNOSIS OF RENAL ARTERY STENOSIS Noninvasive assessment Screening for RAS is appropriate in patients at increased risk for this disease (Box 2). A distinction should be made, however, between identifying patients with RAS who have a very high risk of major cardiovascular events and require aggressive medical management, and the selection of patients for revascularization, which requires a risk-to-benefit analysis and should be made carefully and judiciously following accepted indications for intervention. Whenever possible, noninvasive direct imaging tests (DUS, CT angio graphy [CTA], and magnetic resonance angio graphy [MRA]) are preferable to invasive studies. The optimum RAS imaging strategy is outlined in Box 3. Indirect tests for RAS, such as the captoprilstimulated renal flow scan, the captopril test, and plasma renin assay should be relegated to secondline use because they have poor sensitivity in patients with bilateral renal artery disease or RAS in a single functioning kidney, and in patients with azotemia. 27 Inconclusive results from noninvasive tests should be clarified by performing catheterbased angiography. The hemodynamic severity of RAS should be determined by measuring the translesional pressure gradient. 2 Ultrasonography DUS an excellent method for detecting RAS is the least expensive of the imaging modalities, is highly dependent on the skill level of the technician, and provides useful information about the location and degree of stenosis, kidney size, and other associated disease processes such as obstruction. DUS can be performed without altering the patient s antihypertensive regimen, and does not require administration of potentially toxic contrast agents, all of which makes it the imaging procedure of choice. Figure 1 demonstrates a severe stenosis of the left renal artery before and after renal artery stent implantation. Compared with MRA, DUS has a sensitivity of 84 98% and specificity of 62 99% for the diagnosis of RAS. 29,30 Results of a prospective study that compared DUS with angiography are summarized in Table 2. 31 DUS is also an excellent test for the follow-up of patients with RAS after percutaneous therapy or surgical bypass. 32,33 A common practice is to schedule renal artery DUS within the first few weeks after endo vascular therapy to establish baseline results, and then to repeat the study at 6 months, 12 months, and annually thereafter to look for restenosis. However, this strategy has never been tested in a clinical trial. One drawback of DUS is that its sensitivity is lower for identifying accessory renal arteries (67%) compared with main renal arteries (98%). 29 If the patient has hypertension that cannot be adequately controlled, therefore, and DUS fails to demonstrate RAS, another imaging modality might be needed to identify stenosis in an accessory renal artery. Resistance index The resistance index, which is an adjunctive measure obtained during renal DUS, is the ratio of the peak systolic to end diastolic velocity within the renal parenchyma at the level of the cortical blood vessels. Resistance index is a representation of the amount of small-vessel arterial disease (i.e. nephrosclerosis) within the renal parenchyma. Besides being used to screen patients for possible RAS, the resistance index could be used to stratify patients according to how likely they are to respond to renal inter vention. 34 However, data on 178 nature clinical practice cardiovascular medicine WhiTe and olin march 2009 vol 6 no 3

the ability of resistance index to predict treatment response in patients with RAS are conflicting. Radermacher and associates 34 treated 81 patients with balloon angioplasty alone, 42 patients with angioplasty and stents, and 8 patients with surgical revascularization. These authors demonstrated that an elevated resistance index (>80) was associated with a lower probability of improved blood pressure (BP) or renal function after revascularization, compared with a resistance index of less than 80 regardless of treatment strategy. This study was, however, retrospective and without prespecified end points, and the results have not been duplicated in other reports. 35,36 A prospective study of renal stent placement in 241 patients demonstrated that individuals with an elevated resistance index (>80) achieved a favorable BP response and renal functional improvement at 1 year after renal arterial intervention. 35,36 Zeller and coworkers 36 demonstrated that patients with the most abnormal resistance index values experienced the greatest magnitude of benefit. Until more information becomes available, an elevated resistance index should not be considered a contraindication to performing renal artery revascularization. 2 CT angiography CTA is often used in patients who cannot be adequately imaged with DUS (Figure 2A), such as very obese patients, or patients with excessive abdominal gas. Excellent image quality with enhanced resolution can be obtained with multidetector-row CTA technology. 32,37 The advantages of CTA over MRA include higher spatial resolution, absence of flow-related phenomena that can overestimate the degree of stenosis, and the capability to visualize calcification and metallic implants, such as endovascular stents and stent grafts. The disadvantages of CTA compared with MRA and DUS are exposure to ionizing radiation and the use of potentially nephrotoxic iodinated contrast agents. Depending on the specific technique used, CTA has excellent sensitivity (89 100%) and specificity (82 100%) for detecting RAS. 38 41 Limited data are available on the use of CTA in detecting restenosis after renal artery stent implantation (in-stent restenosis), but this technique also seems to be a promising noninvasive method to evaluate patients after stent implantation. 42 44 CTA is not the ideal screening test for RAS in patients with renal insufficiency because of the potential nephrotoxicity of iodinated contrast agents. Patients must also be able to suspend their respiration for 15 30 s during image acquisition, since respiratory artifacts substantially degrade the image quality. CTA is well-tolerated with an open gantry and, therefore, patients claustrophobia is not usually a limiting factor, as it is for MRA where the gantry is closed. Magnetic resonance angiography MRA, like CTA, provides excellent imaging of the abdominal vasculature and associated anatomical structures (Figure 2B). Patients must be able to hold their breath to minimize motion artifacts during image acquisition so as not to compromise the quality of the study. Compared with CTA, MRA has a sensitivity of 91 100% and a specificity of 71 100%. 45 48 Contrast-enhanced MRA using gadolinium results in improved image quality and reduced imaging time when compared with noncontrast studies, which eliminates some of the artifacts created by the patient s movement. 49,50 A metaanalysis of 39 studies reported a sensitivity and specificity of 94% and 85%, respectively for nonenhanced studies, compared with a sensitivity and specificity of 97% and 93%, respectively for contrast-enhanced studies. MRA does not, however, have the same sensitivity and specificity in patients with fibromuscular dysplasia and is generally not a good screening test if this condition is suspected. 51 A new technology to assess renal ischemia uses blood-oxygen-level-dependent MRI to detect changes in tissue deoxyhemoglobin. Preliminary data indicate that this technique, combined with suppression of tubular oxygen consumption, can be used to assess regional tissue oxygenation in kidneys of patients with vascular occlusive disease. 52 Further studies are warranted in this area. In 2008, Prchal et al. published data that indicated that MRA should not be used in patients with a glomerular filtration rate (GFR) of less than 30 (ml/min)/1.73 m 2 because of an increased risk of nephrogenic systemic sclerosis. 53 In addition, MRA should not be used in patients with metallic (ferromagnetic) implants, such as some mechanical heart valves, cerebral aneurysm clips, and electrically-activated implants (e.g. pacemakers, spinal-cord stimulators). Furthermore, MRA is not useful for follow-up of patients after stent implantation because of artifacts produced by the metallic stent. march 2009 vol 6 no 3 WhiTe and olin nature clinical practice cardiovascular medicine 179

Table 2 Comparison of duplex ultrasonography and angiography findings of stenosis. 31 stenosis by ultrasonography (%) A Angiographic stenosis (%) 0 59 60 79 80 99 100 Totals 0 59 62 0 1 1 64 60 99 1 31 67 0 99 100 0 1 1 22 24 Totals 63 32 69 23 187 Permission obtained from the American College of Physicians Olin JW et al. (2005) Ann Intern Med 122: 833 838. Figure 2 Abdominal vascular images obtained by noninvasive techniques. (A) CT angiography. (B) Magnetic resonance angiography. B 24 32 38 47 54 60 Biomarkers Renin and brain natriurietic peptide (BNP), are biomarkers of renal ischemia. All manifestations 0 5 10 +15.3 15.3 cm/s Figure 1 Renal duplex ultrasonography. Oblique view of the entire normal right renal artery. The proximal renal artery is to the right and the distal renal artery, as it enters the kidney, is to the left. The renal vein (blue) is above the renal artery (red). of the abnormal physiology related to RAS renovascular hypertension, ischemic nephro pathy, and cardiac destabilization (i.e. pulmonary edema) are caused by hypoperfusion of the kidney, which leads to renin release from the juxtaglomerular cells. Measurement of renin levels is not, however, reliable in clinical practice as many medications (e.g. β-blockers, angiotensinconverting enzyme inhibitors) can stimulate or suppress renin production. In addition, patients with bi lateral renal artery disease, or disease of a single functioning kidney, can have suppressed renin levels because of volume expansion. 27 BNP is a neurohormone that is released from the ventricular myocardium under conditions that cause myo cardial cell stretching, such as congestive heart failure (CHF). BNP promotes diuresis, natriuresis, arterial vasodilation, and antagonizes renin. 54 In vitro data have shown that angiotensin II can directly induce synthesis and release of BNP, 55 and an animal study has indicated that BNP messenger RNA is significantly upregulated 6 h after clipping the renal artery. 55,56 A study by Silva et al., 57 of 27 patients with poorly controlled hypertension and RAS ( 70% stenosis), showed that BNP was elevated (median 187 pg/ml; 25 75% percentiles, 89 306 pg/ml) before stent placement and fell within 24 h of successful stent placement (median 96 pg/ml 25 75% percentiles, 61 182 pg/ml; P = 0.002). Hypertension improved in 17 of 22 patients (77%) with a baseline BNP of more than 80 pg/ml compared with none of the 5 patients with a baseline BNP of 80 pg/ml or less (P = 0.001). The findings of this intriguing study need to be confirmed in a larger cohort of patients. Invasive assessment Catheter angiography The indications for screening angiography for RAS at the time of cardiac or peripheral angiography of other vascular beds were addressed by AHA and ACC recommendations and guidelines published in 2006. 2,58 For patients with risk factors (Box 2) or clinical evidence of RAS, aortography is given a class I recommendation for screening at the time of angiography for other clinical indications. Evidence has been published that nonselective, diagnostic screening renal angio graphy is safe, and is not associated with any incremental risk when performed at the time of cardiac catheterization. 16 A visually estimated stenosis of 70% or greater is considered hemodynamically significant, and is 180 nature clinical practice cardiovascular medicine WhiTe and olin march 2009 vol 6 no 3

a generally accepted indication for percutaneous intervention. 59 Unfortunately, visual estimation of the severity of stenosis has a high degree of interobserver variability and compares poorly with quantitative methods of lesion assessment (Figure 3). Renal frame count, which is analogous to Thrombolysis In Myocardial Infarction frame count in coronary angiography, is another angiographic tool that can be used to assess the adequacy of renal blood flow. Mulumudi and White 60 compared renal frame counts in patients with fibromuscular dysplasia and a group of individuals with normal renal arteries. Renal frame count was defined as the number of cine frames required for contrast to reach the smallest visible distal branch of the renal parenchyma. Compared with normal individuals, mean renal frame count for the arteries of patients with fibromuscular dysplasia was significantly increased (26.9 ± 9.9 versus 20.4 ± 3.0, 95% CI 21.4 32.4, P = 0.0001). 60 Renal frame count takes into account macrovascular blood flow in the main renal artery and its segmental branches, as well as micro vascular resistance in the cortex and medulla, and is a potentially valuable angiographic tool for assessing renal blood flow. Translesional pressure gradient The relief of hemodynamic obstruction (translesional pressure gradient) without injury to the renal parenchyma, rather than the cosmetic improvement of angiographic stenosis, is the ultimate goal of RAS reperfusion (Figure 4). An expert consensus panel of the AHA recommended that a peak systolic gradient of at least 20 mmhg, or a mean pressure gradient of 10 mmhg, be used to identify candidate lesions for revascularization in symptomatic patients with RAS. 59 The value of absolute threshold pressure gradients has been questioned. A 10 mmhg translesional pressure gradient might not be as physiologically important when systolic BP is 200 mmhg, as when systolic BP is 140 mmhg. Translesional pressure gradients can be unreliable indicators of borderline lesions because the gradient is dependent upon the diameter of the catheter placed across the lesions, the aortic pressure, the degree of stenosis, the distal vascular bed, and the renal venous pressure. The catheter itself can introduce an artificial gradient. 61 The physio logical limitation of translesional pressure gradients needs to be recognized that is, the principle that organ perfusion is related to the perfusion pressure distal to the stenosis, but A 11 Medis 10 9 8 7 6 5 4 3 B 11 10 Medis 2 1 R = 0.51, P<0.0001 1 2 3 4 5 6 7 8 9 10 11 Visual 9 8 7 6 5 4 3 2 1 C 11 10 Visual 9 8 7 6 5 4 3 R = 0.827, P<0.0001 2 1 R = 0.56, P<0.0001 1 2 3 4 5 6 7 8 9 10 11 Toshiba Figure 3 (A) Quantitative angiographic stenosis (Medis, Leiden, Netherlands) compared with visual estimation of peripheral arterial stenosis. (B) Quantitative angiographic stenosis (Medis, Leiden, Netherlands) compared with quantitative angiographic stenosis (Toshiba). (C) Visual estimation of peripheral arterial angiographic stenosis compared with quantitative angiographic stenosis (Toshiba). Permission obtained from Wolters Kluwer Health White CJ (2006) Catheterbased therapy for atherosclerotic renal artery stenosis. Circulation 113: 1464 1473. 116 not to the pressure gradient itself. 62 Translesional pressure gradients can be altered by factors that affect blood flow, such as cardiac output, march 2009 vol 6 no 3 WhiTe and olin nature clinical practice cardiovascular medicine 181

A B C Aorta Renal artery GR: 57 mmhg GR: 28 mmhg GR: 0 mmhg Figure 4 Treatment of renal artery stenosis with balloon angioplasty and stenting. (A) Angiogram showing substantial narrowing of the renal artery and a systolic pressure gradient of 57 mmhg. (B) After balloon angioplasty, the angiographic stenosis is improved with a residual translesional gradient of 28 mmhg. (C) Following stent placement, minor angiographic improvement is evident, but the hemodynamic gradient has completely resolved. systemic BP, and the vasodilatory state of the renal microvasculature. Renin secretion from a hypoperfused kidney is a key element in the development of reno vascular hypertension. De Bruyne and colleagues 63 investigated the concept of a threshold translesional pressure gradient, and their study quantified the degree of functional stenosis required to trigger renin production. A good correlation existed between the ratio of systolic BP in the aorta (P a ) to the systolic pressure in the renal artery distal to the stenosis (P d ), and absolute pressure gradients. The authors also demonstrated no significant increase in renal vein renin levels for a P d /P a gradient greater than 0.9, which identified a group of patients who are unlikely to benefit clinically from renal revascularization. Fractional flow reserve Another method to determine the severity of angiographic RAS is to quantify the fractional flow reserve (FFR). The FFR is a measure of pressure in the coronary circulation, which is based on the principle that flow across a conduit artery is proportional to pressure across the vascular bed and is inversely proportional to the resistance of the vascular bed. Under conditions of maximum hyperemia (i.e. maximum vaso dilation), the flow through the conduit artery is maximal, while the resistance of the vascular bed is at a minimum and constant. Any reduction in flow under these conditions is caused by the stenosis and is proportional to the ratio of pressure distal to the stenosis and the pressure proximal to the stenosis. FFR is measured after induction of maximum hyperemia (e.g. after intrarenal administration of intrarenal papa verine) using a non obstructive wire with a pressure transducer located at its distal segment. In a study by Mitchell et al., 64 renal FFR was measured after renal stent placement in 17 patients with refractory hypertension and moderate to severe (50 90% stenosis), uni lateral RAS. Ten patients had normal baseline renal FFR ( 0.80), whereas an abnormal baseline renal FFR (<0.80) was recorded in seven patients. Preprocedure BP, severity of RAS, the number of antihypertensive medications being taken, and estimated GFR did not differ between the two groups. At 3 months after intervention, 86% of patients with an abnormal renal FFR experi enced improvement in their BP, compared with only 30% of those with normal renal FFR (P = 0.04). No differences were seen in the baseline systolic, mean, or hyperemic translesional pressure gradients among patients whose BP improved and those in whom it did not. Neither systolic, mean, or hyperemic translesional pressure gradients, nor the severity of angiographic stenosis, were predictive of BP improvement. 64 TREATMENT OF RENAL ARTERY STENOSIS Revascularization Control of BP with medical therapy does not prevent progression of RAS; 65,66 however, the effect of lipid-lowering medications (i.e. statins) is not known. A randomized trial of optimum medical therapy compared with balloon angioplasty for the treatment of renovascular hypertension found that 16% of medically treated patients experienced renal artery occlusion within 1 year, compared to none of the patients treated with angioplasty. 67 Percutaneous, catheter-based therapy has replaced surgical renal revascularization for atherosclerotic RAS because of the increased morbidity and mortality associated with surgery. 68 71 Three randomized trials have compared renal artery balloon angioplasty with medical therapy for the treatment of renovascular hyper tension. The findings of these studies support the superiority of catheter-based therapy. Plouin and colleagues 72 found that BP reduction was greater among 23 patients who underwent angioplasty than among 26 patients who received medical therapy (systolic BP 14 ± 20 mmhg 182 nature clinical practice cardiovascular medicine WhiTe and olin march 2009 vol 6 no 3

versus 7 ± 23 mmhg, P = 0.24; diastolic BP 8 ± 11 mmhg versus 1 ± 12, P = 0.04). A study by Webster et al. 73 of 55 patients with bilateral RAS also demonstrated a significant improvement in BP among those treated with angioplasty versus patients who received medical therapy. In a third study, 106 patients were randomly assigned to balloon angioplasty or medical therapy. 67 At 3 months, 22 of the 50 medically treated patients (44%) had failed to respond adequately to therapy and required angioplasty, which demonstrated the superiority of percutaneous intervention. In addition, the results of a controlled trial demonstrated a statistically significant benefit for angioplasty with stenting compared with medical therapy for reduction in systolic BP (21.9 ± 10.5 versus 10.9 ± 8.5, P <0.05) and diastolic BP (10.4 ± 6.3 versus 7.7 ± 4.1, P <0.05). 74 Finally, two metaanalyses concluded that renal angioplasty was superior to medical therapy for BP control and for improving renal function. 75,76 Stenting versus balloon angioplasty Balloon angioplasty is much less effective than stent placement for treating atherosclerotic aorto-ostial plaque (Figure 5). Renal stents have been shown to lower the translesional pressure gradient significantly when compared with balloon dilation alone. 77 The superiority of renal stents over balloon angioplasty alone has also been confirmed in a randomized trial and in two meta-analyses (Figure 6). 78 80 This evidence led to a class I guideline recommendation by the ACC and AHA for primary stent placement in athero sclerotic RAS. 2 Analogous to findings from coronary artery stent trials, renal stent patency correlates with acute gain and larger stent minimum lumen diameters. 81,82 Reported restenosis rates for renal stents range from 11% to 14%. 78,83 86 Two studies reported 5-year renal stent primary patency rates approaching 80%, and secondary patency rates greater than 90%. 83,84 Selection of patients Optimum selection of patients for renal revasculari zation is more complex than a visual estimation of stenosis, or a measurement of a translesional pressure gradient. Patients with RAS have multifactoral reasons for hypertension and renal insufficiency that might or might not improve as renal blood flow improves. Perhaps the most common reason that patients fail to improve after renal revasculari zation is over estimation of Percentage (%) 100 80 60 40 20 0 57% P <0.05 88% Procedure success 48% P <0.05 Balloon Stent 14% Restenosis Figure 5 Superiority of renal stenting compared with balloon angioplasty in a randomized trial. Data from van de Ven PJ et al. (1999) Lancet 353: 282 286. 78 the severity of RAS by angio graphy. The ostial segment of the renal artery has a complex threedimensional geometry that can be very difficult to appreciate with two-dimensional angiographic imaging. Angioplasty or stent placement in mildly narrowed renal arteries would not be expected to be of much clinical benefit, and could be the reason why no more than 60 70% of patients with hypertension improve after renal revascularization (Figure 7). 80 Many patients have had essential (primary) hypertension for years and then develop atherosclerotic RAS late in life. The presence of anatomic RAS does not establish that RAS is the cause of a patient s hypertension or renal failure. Renovascular hypertension Despite a technical success rate exceeding 95% for renal artery stent placement, wide variation remains in the reported rates of hyper tension improvement with this technique. At least some of this outcome variability is attributable to the lack of standard reporting criteria, 59 but poor selection of patients could be an even more important factor. 63,64 Although the majority of patients with atherosclerotic RAS and hyper tension will experience improved BP control, or require fewer medications (or both), very few patients will be cured of hypertension (Figure 7). 79,83,84,87 Patients with the highest systolic BPs experience the greatest decreases in systolic BP after renal artery stenting, but BP improvement does not march 2009 vol 6 no 3 WhiTe and olin nature clinical practice cardiovascular medicine 183

Balloon studies Stent studies P <0.001 Mean ± 95% CI 0 50 Success rate (%) 77% (68 86%) 98% (95 100%) Figure 6 Results of a meta-analysis showing procedural success rates for balloon angioplasty compared with renal artery stent placement. Data from Leertouwer TC et al. (2000) Radiology 216: 78 85. 80 Published trials 0 20 40 60 80 Percentage of patients treated (%) 100 Cured Improved Figure 7 Cure and response rates for renal stent treatment of hypertension. Data from Leertouwer TC et al. (2000) Radiology 216: 78 85. 80 100 correlate with patient age, sex, ethnicity, severity of stenosis, number of vessels treated, baseline diastolic BP, or baseline serum creatinine level. 88 Bilateral RAS (odds ratio 4.6, P = 0.009) and mean arterial pressure greater than 110 mmhg (odds ratio 2.9, P = 0.003) are, however, associated with improvement in BP after renal artery stent placement. 86 Studies that compared the results of renal artery stenting in elderly ( 75 years) versus younger patients, or in women versus men, have failed to show any difference in response to renal stent placement. 89,90 Ischemic nephropathy Two small trials have indicated that renal artery stent placement improves or stabilizes renal function in patients with atherosclerotic ischemic nephropathy. In the first study, 32 patients with unexplained renal insufficiency and hemodynamically significant RAS had a fourfold reduction in the rate of progression of renal insufficiency after renal artery stent placement. 91 The majority of these patients had bilateral stenosis or disease of a single functioning kidney, although unilateral disease was present in seven patients. Another study confirmed improvement or stabilization of renal function in patients who underwent successful renal artery stent placement for bilateral stenosis or disease of a single functioning kidney ( 70% stenosis). 92 One of the best predictors of improved renal function after renal revascularization is the rate of decline in renal function. The more rapid the onset and severity of the renal insufficiency, the more likely revascularization is to be of benefit (Figure 8). 93 A meta-analysis of 10 studies showed that serum creatinine levels improve in about 25% of patients who undergo renal artery stent placement, remain the same in about half of patients, and worsen in the remainder. 79 The worsening in serum creatinine level is likely to be caused by either contrast nephropathy or atheroembolization. Atheroembolic debris retrieval has been described in several series, and atheroembolization is apparently quite common with renal stent placement. 94 96 Although the surrogate end point of successful emboli retrieval has been documented, clinical end points, such as the safety and efficacy of embolic protection devices, remain to be demonstrated. Cardiac disturbance syndromes Cardiac disturbance syndromes attributable to RAS include exacerbations of coronary ischemia and CHF, which is caused by peripheral arterial vasoconstriction, volume overload, or both. Renovascular disease can also complicate the management of patients with heart failure by preventing the use of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. The importance of renal artery stent placement in the treatment of cardiac disturbance has been described in a series of patients who presented with either CHF or an acute coronary syndrome. 97 Successful renal stent placement resulted in a significant decrease in BP and control of symptoms in 42 of 48 patients (88%). Some patients underwent both coronary and renal intervention, while others had only renal artery stent placement because coronary lesions were unsuitable for revascularization. Immediate treatment effects and those at 8 months, as assessed by Canadian 184 nature clinical practice cardiovascular medicine WhiTe and olin march 2009 vol 6 no 3

Cardiovascular Society angina class and NYHA functional status, did not differ between the combined coronary and renal revascularization group and the renal-stent-only group, which indicated that renal revascularization was the most beneficial intervention. 97 In another study, 39 patients underwent renal artery stent implantation for control of CHF, 98 18 of whom (46%) had bilateral RAS, and the other 21 (54%) had stenosis of a solitary functioning kidney. Renal artery stent implantation was technically successful in all patients. Improvements in BP and renal function were recorded in 72% and 51% of patients, respectively, and renal function was stable in 26% of patients. The mean number of hospitalizations for CHF fell from 2.4 ± 1.4 before intervention to 0.3 ± 0.7 after renal stenting (P <0.001). During follow-up (mean 21.3 months) 77% of patients had no further hospitalizations. Improvements in BP and renal function after revascularization occur because of a reduction in stimulation of the renin angiotensin system. In addition, successful angioplasty allows patients who could not otherwise be treated with angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers without exacerbating renal failure, to take these beneficial medications. SAFETY ISSUES Diagnosis Catheter-based angiography can lead to complications associated with vascular access or catheter trauma. In addition, systemic and renal toxicity can be caused by iodinated contrast agents. The incidence of major complications associated with peripheral vascular angiography ranges from 1.9% to 2.9% (Table 3). 99 Atheroembolism, vessel dissection, and arterial perforation caused by catheterization of the renal artery are rare (<1%), but often devastating, events. Anaphylactic reactions to contrast media occur in less than 3% of patients, and less than 1% require hospitalization. 100 The risk of contrast-induced nephropathy is increased in patients with baseline chronic renal insufficiency, diabetes mellitus, multiple myeloma, and those who are receiving other nephrotoxic drugs such as aminoglycosides. Patients who develop contrast-induced nephropathy have a poor prognosis. 101 Optimum prevention requires vigorous hydration and the use of as little contrast as possible. Other adjunctive strategies, including pretreatment with N-acetylcysteine, intravenous Postangioplasty slope variation (mg/dl)/days 0.002 0.001 0.000 0.001 0.002 0.0020 0.0015 0.0010 0.0005 Slope preangioplasty (mg/dl)/days bicarbonate, or both, can be considered, although their effectiveness remains unclear. 102 Treatment Embolic protection devices Embolic protection devices were developed for clinical use in saphenous-vein coronary bypass grafts and for cerebral protection during carotid stenting. Percutaneous embolic protection devices can be divided into three categories: filters, distal occlusion balloons with aspiration of debris, and proximal occlusion balloons with reversal of flow. The aorto-ostial nature of most RAS makes proximal occlusion devices unsuitable. Distal occlusion balloons and filters are, therefore, the most common devices that have been used off-label for renal protection during stent placement. Renal atheroembolization has been documented by renal biopsies and by DUS in patients undergoing surgical revascularization of RAS. 103,104 Cholesterol crystals and plaque debris lodge in small capillaries and distal arterioles where they cause a local inflammatory response that results Responders Nonresponders 0.0000 0.0005 0.0010 Figure 8 Relationship between changes in slope values of reciprocal serum creatinine plot versus time before and after percutaneous transluminal renal angioplasty. The horizontal line differentiates patients as responders (top) and nonresponders (bottom). Reprinted with permission from Elsevier Muray S et al. (2002) Rapid decline in renal function reflects reversibility and predicts the outcome after angioplasty in renal artery stenosis. Am J Kidney Dis 39: 60 66. 93 march 2009 vol 6 no 3 WhiTe and olin nature clinical practice cardiovascular medicine 185

Table 3 Complications of renal stent placement. study Number of patients death (%) dialysis (%) White et al. (1997) 81 100 0 0 0.75 Tuttle et al. (1998) 85 129 0 0 4.1 Burket et al. (2000) 88 127 0 0.7 0.7 Rocha-Singh et al. (2005) 114 208 0.6 0 2.6 Dorros et al. (1998) 115 163 0.6 0 1.8 Mean values NA 0.25 0.14 1.99 Abbreviations: NA, not applicable; NR, not reported. Percentage change in GFR (%) 15 10 5 0 5 10 15 n = 100 P <0.05 10 ± 20 Control 12 ± 21 EPD 10 ± 20 IIb/IIIa inhibitor Major complications (%) 9 ± 31 Both Figure 9 Improvement in renal function with interaction between use of an EPD and a glycoprotein IIb/IIIa inhibitor during renal stent placement. Permission obtained from Wolters Kluwer Health Cooper CJ et al. (2008) Embolic protection and platelet inhibition during renal artery stenting. Circulation 117: 2752 2760. 111 Abbreviations: EPD, embolic protection device; GFR, glomerular filtration rate. in intimal hyper proliferation and subsequent vessel occlusion. Renal dysfunction is a common result. Kawarda and associates 103 demonstrated microembolic signals (athero matous embolization) detected by DUS at the time of renal artery stenting in all 13 patients who were examined. In another study, approximately a third of a group of 44 patients who underwent surgical therapy for atherosclerotic RAS had biopsyproven atheroembolization. 105 Atheroembolism was associated with an increase in surgical morbidity and a dramatic reduction in 5-year survival compared with patients who had no evidence on biopsy of renal athero embolization (54% versus 85%, P = 0.011). A distal occlusion balloon (Guardwire, Percusurge, Inc., Sunnyvale, CA) embolic protection device used off-label for renal protection during stent deployment has been described in several studies. 96,106,107 Total angiographic success with successful stent placement was accomplished, and visible debris was aspirated from every renal artery. At 6 months after the procedure, renal function had not deteriorated in any of the patients, and had actually improved in five individuals with baseline renal insufficiency. Filter embolic protection devices have been used in several small series. 108,109 In one study, visible emboli were captured in 65% of the filters. 106 No patients suffered acute deterioration in renal function and 95% of patients experienced stabilization or improvement in renal function. 106 The use of intravenous glycoprotein IIb/IIIa platelet receptor inhibitors could have a role in improving outcomes after renal stent placement, by the same mechanism that they improve outcomes after coronary intervention. 110 Embolic protection devices and glycoprotein IIb/IIIa inhibitors used together could protect the renal microcirculation from atheroembolization and platelet aggregation, which seems to be ubiquitous. In a study of 100 patients, the use of an embolic protection device alone, a glycoprotein IIb/IIIa inhibitor (abciximab) alone, an embolic protection device plus a glycoprotein IIb/IIIa inhibitor, and a control (placebo) were compared. 111 Patients in the placebo, embolicprotection-device-alone, and glycoprotein IIb/ IIIa inhibitor groups demonstrated a decline in GFR (P <0.05), but GFR improved among patients who received both an embolic protection device and a IIb/IIIa glycoprotein inhibitor (Figure 9). An interaction was observed between abciximab and embolic protection (P <0.05) that favored combination treatment. CONCLUSIONS Catheter-based therapy for symptomatic (hypertension, ischemic nephropathy, or cardiac destabilization syndromes), hemodynamically significant, atherosclerotic RAS is the preferred method of revascularization. Stent placement is favored over balloon angioplasty and carries a class I recommendation for treatment of atherosclerotic RAS. 2 Discordance between the high (>95%) procedural success and the moderate (60 70%) clinical response after stenting is likely to be a result of three factors: poor selection of patients, poor discrimination of lesion severity by angiography, and the concomitant presence of parencyhmal renal disease. Preliminary data indicate that the use of physiologic lesion 186 nature clinical practice cardiovascular medicine WhiTe and olin march 2009 vol 6 no 3

assessment with pressure gradients, renal FFR, and biomarkers (e.g. BNP), could enhance lesion selection and result in improved clinical response rates. 57,64 Further studies in large series of patients are needed to establish the clinical role of these strategies. The development of new technologies to improve the safety and efficacy of renal intervention further are on the horizon. Several investigators have demonstrated the feasibility and safety of embolic protection, although prospective trials to determine the efficacy of these devices in preservation of renal function have not yet been performed. The current longterm patency rates for renal stenting are excellent, with restenosis rates approaching 10% and 5-year secondary patency rates exceeding 90%. Given the importance of improving vessel patency acutely, and of preventing late lumen loss, a potential role for drug-eluting stents exists in patients at high risk for restenosis, those with small (<4.5 mm diameter) reference vessels, and those with in-stent restenosis. 81,82,112 KEY POINTS Renal artery stenosis is the most common (2 5%) secondary cause of hypertension Among patients entering dialysis treatment, 10 15% have renal artery stenosis, which is a potentially preventable cause of end-stage renal disease Renal artery stenosis is an independent predictor of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular death Duplex ultrasonography an excellent test to detect renal artery stenosis is the least expensive of the imaging modalities, is dependent on technician skill, and provides useful information about the degree of stenosis, kidney size, and other associated disease processes such as obstruction Percutaneous catheter-based therapy is the preferred method of revascularization for symptomatic, hemodynamically significant renal artery stenosis The discordance between the high (>95%) procedural success and the moderate (60 70%) clinical response rates is likely to be a result of poor selection of patients, poor discrimination of lesion severity by angiography, and the concomitant presence of parencyhmal renal disease References 1 Jacobson HR (1988) Ischemic renal disease: an overlooked clinical entity? 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