Refining the Approach to Renal Artery Revascularization

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 2, NO. 3, 2009 2009 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-8798/09/$36.00 PUBLISHED BY ELSEVIER INC. DOI: 10.1016/j.jcin.2008.10.014 STATE-OF-THE-ART PAPERS Refining the Approach to Renal Artery Revascularization Robert D. Safian, MD, FACC, Ryan D. Madder, MD Royal Oak, Michigan Renal artery stenosis (RAS) is caused by a heterogenous group of diseases with different pathophysiology, clinical manifestations, treatment approaches, and outcomes. The 2 most common forms of RAS are fibromuscular dysplasia (FMD) and atherosclerosis (ARAS). Renovascular syndromes are broadly classified into renovascular hypertension and ischemic nephropathy, but these terms are misleading, because they imply a causal relationship between RAS, hypertension, and renal dysfunction, which is difficult to prove in humans. Data supporting renal revascularization are limited by heterogeneous causes of hypertension and renal dysfunction, insufficient understanding of the relationship between RAS and nephropathy, inconsistent techniques for revascularization, ambiguous terminology and end points to assess benefit, and lack of large-scale randomized trials. The purpose of this review is to enhance understanding of the epidemiology, clinical markers, and diagnosis of RAS; the relationship between RAS and important disease states; the distinction between renal ischemia and nephropathy; optimal revascularization techniques; and avoidance of renal injury. (J Am Coll Cardiol Intv 2009;2: 161 74) 2009 by the American College of Cardiology Foundation Renal artery stenosis (RAS) is caused by a heterogenous group of diseases with different pathophysiology, clinical manifestations, treatment approaches, and outcomes. The 2 most common forms of RAS are fibromuscular dysplasia (FMD) and atherosclerosis (ARAS), whereas inflammatory disease of the arterial circulation and congenital abnormalities are far less common (Fig. 1). Traditionally, renovascular syndromes have been broadly classified into 2 categories: renovascular hypertension and ischemic nephropathy. These categories are potentially misleading, because they imply a causal relationship between RAS and hypertension or renal dysfunction, respectively. Although causal relationships are evident in experimental models of RAS, they are more difficult to prove in human diseases. Furthermore, a causal relationship suggests that revascularization of RAS should favorably impact blood pressure and renal From the Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, Michigan. Manuscript received July 18, 2008; revised manuscript received September 29, 2008, accepted October 10, 2008. function, yet available clinical data have failed to demonstrate unequivocal benefits of renal revascularization. The purpose of this review is to place RAS in appropriate perspective, particularly with regard to renal revascularization and the importance of renal ischemia and nephropathy. This See page 183 perspective should incorporate understanding of the epidemiology, clinical markers, and diagnosis of RAS; establish a relationship between RAS and important disease states; distinguish renal ischemia and nephropathy; use optimal revascularization techniques; and avoid renal injury. Epidemiology of RAS FMD. Fibromuscular dysplasia is an uncommon disease of unknown etiology; typically occurs in women 30 years of age; and often affects the renal, carotid, and femoral arteries. Fibromuscular dysplasia should be considered in young patients if severe hypertension is not associated with obesity, oral contraceptives, or

162 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 known renal parenchymal disease. Unilateral or bilateral renal FMD might cause renovascular hypertension, but renal failure is unusual (1). ARAS. Atherosclerotic renal artery stenosis is a common clinical entity, affecting 7% of patients older than age 65 years and 60% of patients with hypertension, coronary or peripheral artery disease, and renal insufficiency (2). Unlike FMD, ARAS rarely causes renovascular hypertension but is commonly associated with renal dysfunction (3). Clinical Manifestations of RAS Abbreviations and Acronyms ACC American College of Cardiology AHA American Heart Association ARAS atherosclerotic renal artery stenosis CTA computerized tomography angiography FMD fibromuscular dysplasia GFR glomerular filtration rate MRA magnetic resonance angiography RAS renal artery stenosis RRI renal resistive index TLG translesional pressure gradient 99M Tc-DTPA technetiumlabeled pentetic acid Hypertension and cardiovascular manifestations. Hypertension manifestations include onset of severe hypertension at age 30 years (FMD) or at age 55 years (ARAS) and resistant, accelerated, or malignant hypertension (3). Cardiovascular manifestations usually occur in the setting of malignant hypertension. The classic manifestation is flash pulmonary edema not explained by coronary artery or valvular disease, especially if left ventricular function is normal (4). Other cardiovascular manifestations include severe hypertension associated with acute coronary syndromes, acute aortic syndromes, stroke, transient cerebral ischemia, intracranial hemorrhage, encephalopathy, and papilledema. Renal manifestations. Renal ischemia might present as acute renal failure, with a rise in serum creatinine within 14 days of initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Although considered a marker for bilateral RAS, this observation is neither sensitive nor specific for RAS (5). Other renal manifestations are subtle or insidious, including unexplained chronic renal failure, small kidney, and asymmetry in renal dimensions (2). Ischemic nephropathy is an important cause of chronic kidney disease and end-stage renal disease, representing the primary etiology of end-stage renal disease in 5% to 15% of patients initiating dialysis each year (6). Assessment of RAS and Its Clinical Significance Screening for RAS. There are no guidelines for routine screening for RAS. In some patients, the diagnosis of RAS is made incidentally during angiographic evaluation of lower extremity arterial diseases, whereas in others a high index of suspicion is required, on the basis of existing guidelines (Table 1). The mere presence of angina, congestive heart failure, coronary artery disease, and peripheral artery disease are not strong indications for evaluation of RAS in the absence of other considerations mentioned in the preceding text. Impromptu drive-by renal arteriography during unrelated angiographic procedures is not recommended. Establish the diagnosis of RAS. If clinical manifestations suggest RAS, the contemporary approach is to use renal duplex ultrasound, magnetic resonance angiography (MRA), or computerized tomography angiography (CTA) to identify RAS. Assessment of the renin-angiotensin system is not recommended (2). Invasive angiography is sometimes recommended to confirm the diagnosis of RAS; determine the etiology; identify dual, accessory, or aberrant renal arteries; identify diseases of the abdominal aorta; and evaluate the nephrogram. The angiographic technique is important to minimize renal injury, prevent atheroembolization, and obtain high-quality images. In most cases, abdominal aortography with digital subtraction provides superb images of the abdominal aorta and renal circulation, with a power injector and 10 to 15 cc of contrast (Fig. 2). Because 30% of patients have dual, accessory, or aberrant renal arteries (Fig. 3), selective angiography alone might preclude complete assessment of the renal arteries. Once anatomic RAS is recognized, it is important to establish a relationship between RAS and vital organ injury. The complete evaluation of patients with ARAS and vital organ injury must include a baseline assessment of nephropathy and renal ischemia. Relationship Between RAS and Renal Dysfunction The renal artery, the kidney, and renal function. In simplistic terms, the kidney is a filter with inflow (renal arteries), outflow (renal veins), and a reservoir (renal pelvis, ureters, and bladder) (Fig. 4). Apart from diseases of outflow (renal vein obstruction) and collection (obstructive uropathy), filter dysfunction might be due to inflow impairment (RAS and renal ischemia) or filter impairment (nephropathy) or both. When RAS and nonvascular etiologies of renal dysfunction co-exist, it might be difficult to establish RAS as the culprit. Patients with nephropathy might not improve after renal artery revascularization, depending on the extent of baseline nephropathy before revascularization and the degree of renal injury after revascularization (2,7). The relationship between renal ischemia and nephropathy is central to understanding published studies and ongoing trials of RAS, and failure to do so is the most important source of ambiguity about the benefits of renal revascularization. Clinical evaluation of nephropathy. The clinical evaluation for nephropathy includes serum creatinine, urinalysis, renal duplex ultrasound to assess renal dimensions and renal resistive

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 163 Figure 1. The Most Common Types of Renal Artery Stenosis (Left) Fibromuscular dysplasia, characterized by a beaded appearance of the mid or distal renal artery in which the beads are larger than the vessel (medial fibroplasia). (Right) Atherosclerotic renal artery stenosis, characterized by stenosis of the ostium and proximal renal artery. index, and selective renal arteriography in some patients to assess cortical blood flow and intrarenal arteriolar patterns (Table 2, Fig. 5). Individually, none of these parameters is an absolute predictor of outcome, and over-reliance on any single test might exclude patients who might benefit from revascularization (8). In any given patient, certain measures might indicate greater degrees of nephropathy than others, but advanced nephropathy is characterized by proteinuria 1 g/day, renal length 10 cm, and resistive index 0.8 (2). Serum creatinine is the most common measure of renal function but is limited for assessing the extent of dysfunction or for distinguishing nephropathy from renal ischemia. Serum creatinine is insensitive to glomerular filtration rate (GFR) until 50% to 75% of renal mass has been lost (Fig. 6). Stated in another way, a patient who loses 50% of renal mass (as might occur after nephrectomy or with unilateral renal artery occlusion) should have a normal creatinine; serum creatinine 2 mg/dl in a patient with unilateral ARAS is generally indicative of significant nephropathy (9). Clinical evaluation of renal ischemia. Patients with RAS and abnormal perfusion by objective measurements should be considered to have renal ischemia. Several noninvasive methods have utility for estimating renal blood flow, assessing the hemodynamic significance of RAS, and identifying renal ischemia (Table 3). Nuclear scintigraphy with technetium-labeled pentetic acid ( 99M Tc-DTPA) is reliable for measuring fractional renal blood flow and, when used in conjunction with 125 I-Iothalamate, allows accurate mea- Figure 2. Conventional Abdominal Aortogram With Digital Subtraction Angiography (Anteroposterior Projection) The early (left), mid (middle), and late (right) phases of contrast injection are shown. Aortography is used to identify the configuration of the renal arterial origin (see Fig. 3) as well as associated disease of the abdominal aorta and visceral circulation.

164 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 Table 1. ACC/AHA Guidelines for Renal Arterial Disease (2) Level of Evidence Class 1. Clinical indications for evaluation for RAS Hypertension manifestations Hypertension onset age 30 yrs (FMD) B I Hypertension onset age 55 yrs (ARAS) B I Resistant hypertension C I Accelerated hypertension C I Malignant hypertension C I Renal manifestations Acute renal failure after ACEI/ARB B I Unexplained small kidney B I Asymmetry in renal dimensions 1.5 cm B I Unexplained chronic renal failure B II A New dialysis B II A Cardiovascular manifestations Unexplained pulmonary edema B I Multivessel CAD alone B II B PAD alone B II B Unexplained CHF C II B Refractory angina C II B 2. Screening tests for RAS RDU, MRA, CTA B I Contrast angiography for ambiguous noninvasive tests B I Captopril renal scintigraphy C III Selective renal vein sampling B III Plasma renin activity B III Captopril-stimulated renin secretion B III 3. Indications for revascularization* Asymptomatic bilateral ARAS C II B Asymptomatic solitary ARAS C II B Asymptomatic unilateral ARAS C II B RAS and Class I indications for RAS evaluation B II A RAS and intolerance to medication B II A Bilateral ARAS and progressive renal dysfunction B II A Solitary ARAS and progressive renal dysfunction B II A Unilateral ARAS and chronic renal dysfunction C II B ARAS and unexplained pulmonary edema B I ARAS and unexplained recurrent CHF B I ARAS and unstable angina B II A 4. Recommendations for pharmacological treatment ACEI or ARB for RAS and hypertension A I Calcium channel blockers for RAS and hypertension A I Beta-blockers for RAS and hypertension A I 5. Type of renal artery revascularization Renal stent for ARAS patients who meet criteria B I Angioplasty for FMD, with bailout stenting B I Class I: conditions for which there is evidence for and/or general agreement that a given procedure or treatment is beneficial, useful, and effective. Class II: conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: usefulness/efficacy is less-wellestablished by evidence/opinion. Class III: conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases might be harmful. Level of Evidence A: data derived from multiple randomized clinical trials or meta-analyses. Level of Evidence B: data derived from a single randomized trial or nonrandomized studies. Level of Evidence C: only consensus opinion of experts, case studies, or standard-of-care. *Assumes hemodynamically significant ARAS. ACC/AHA American College of Cardiology/American Heart Association; ACEI angiotensin converting enzyme inhibitor; ARAS atherosclerotic renal artery stenosis; ARB angiotensin receptor blocker; CAD coronary artery disease; CHF congestive heart failure; CTA computerized tomography angiography; FMD fibromuscular dysplasia; MRA magnetic resonance angiography; PAD peripheral arterial disease; RAS renal artery stenosis; RDU renal duplex ultrasound.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 165 Figure 3. Schematic Representation of Common Configurations of Renal Arterial Origins From the Abdominal Aorta (A) Single renal artery occurs in 55% of population. (B) Single renal artery with early bifurcation occurs in 14% of population. (C) Dual arterial circulation in which 2 major renal arteries supply a single kidney occurs in 8% of population. (D) Single major renal artery and 1 or more smaller accessory renal arteries occur in 7% of population. Other configurations (not shown) occur in 16%, including aberrant origins of the renal arteries from other visceral vessels, iliac arteries, and aortic bifurcation (modified from Uflacker R. Atlas of Vascular Anatomy, 2nd edition. Philadelphia, Pennsylvania: Lippincott, Williams, and Wilkins, 2007:609). surement of total- and single kidney-gfr (10 12). In patients with unilateral RAS, hypoperfusion of the stenotic kidney is reasonable evidence for renal ischemia; patients with normal renal blood flow might have RAS but not ischemia. The invasive evaluation of renal ischemia is based on hemodynamic assessment of RAS rather than renal artery perfusion per se. Stenosis severity determined by visual estimates or quantitative angiography has a poor correlation with hemodynamic significance (13). Translesional pressure gradients (TLG) 20 mm Hg, with small catheters or special pressure wires, are considered hemodynamically significant (14). Fractional flow reserve can determine the hemodynamic significance of RAS, and fractional flow reserve 0.80 might predict a favorable blood pressure response to revascularization (13,15). Intravascular ultrasound is extremely useful for assessing vessel dimensions and stenosis severity in FMD patients and, when used with TLG, provides useful assessment of ischemia and improvement after angioplasty. Intravascular ultrasound might be used to guide stenting for ambiguous ARAS (16). Renal frame counts and renal blush scores are used to assess the hemodynamic significance of RAS (17), but high frame counts and low blush scores might be observed with nephropathy without RAS (18 20). Table 2. Clinical Evaluation of Renal Parenchymal Disease (Nephropathy) Factor Comment Figure 4. Schematic Representation of the Kidney as a Filter Overall filter function is influenced by inflow to the filter (renal artery stenosis and renal ischemia), integrity of the filter (nephropathy), outflow from the filter (renal vein obstruction), and disorders of collection (obstructive uropathy). Serum creatinine Proteinuria Renal dimensions RRI Renal arteriogram Renal biopsy RRI renal resistive index. Easy to measure and inexpensive. Relatively insensitive to degree of renal dysfunction (see Fig. 6) and not reliable for differentiating nephropathy from renal ischemia. Easy to measure and inexpensive. Proteinuria 1 g/24his a good indication of nephropathy, but lesser degrees of proteinuria are less reliable. Renal length 10 12 cm is generally favorable. Renal length 6 cm indicates irreversible renal injury (atrophic kidney). RRI 0.7 is a good measure of reversibility. Although RRI 0.8 indicates parenchymal disease, it should not be used as the sole indicator of irreversible renal dysfunction. Preservation of cortical blood flow and absence of intrarenal arteriolar disease are indicators of reversible renal dysfunction. Poor cortical blood flow and severe diffuse intrarenal arteriolar disease are markers of advanced nephropathy (see Fig. 5). Reliable for histologic confirmation of nephropathy but not practical for most patients

166 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 Figure 5. Arteriographic Patterns of Progressive Nephropathy (A) Normal kidney (renal resistive index [RRI] 0.6) with normal cortical blood flow and intrarenal arteriolar circulation. (B) Mild hypertensive nephropathy (RRI 0.7) with mild diffuse intrarenal arteriolar narrowing and preserved cortical flood flow. (C) Advanced hypertensive nephropathy (RRI 0.8), with diminished cortical blood flow, vascular pruning (arrows), and diffuse intrarenal arteriolar narrowing. (D) End-stage kidney due to hypertensive nephropathy (RRI 0.9). with no cortical blood flow and extensive intrarenal arteriolar disease. New classification for RAS, renal ischemia, and nephropathy. We propose the following classification to allow identification of patients with and without nephropathy and with and without renal ischemia (Table 4, Fig. 7): Type 1: normal kidneys (no nephropathy); Type 2: nephropathy (parenchymal disease); Type A: no renal ischemia (hemodynamically insignificant RAS); and Type B: renal ischemia (hemodynamically significant RAS). This classification offers a reasonable framework for evaluation of patients with RAS and allows identification of patients with normal (Type 1) and abnormal (Type 2) kidneys and with normal (Type A) and abnormal (Type B) renal perfusion. The goals of the classification are to provide more consistent terminology, offer a framework for evaluating renal ischemia and nephropathy, and guide management decisions. The best candidates for revascularization are those with vital organ injury, renal ischemia, and no nephropathy. : Technical Considerations Technique of renal artery revascularization. For FMD patients, balloon angioplasty is the intervention of choice, and stenting is used for bail-out indications. Procedural success approaches 100%, and restenosis occurs in 10% within 10 years (21,22). Renal angioplasty is better in discrete lesions in major renal arteries and worse in diffuse FMD in small segmental, arcuate, and interlobar vessels. Because renal arteriography is not reliable for assessment of FMD stenosis severity or vessel dimensions, we recommend the pressure wire and intravascular ultrasound to assess TLG, vessel

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 167 Figure 6. Relationship Between GFR and Serum Creatinine Concentration Loss of 50% of glomerular filtration rate (GFR) is not associated with measurable elevation of serum creatinine. When 75% of GFR is lost, there is a strong relationship between GFR and serum creatinine (modified from reference [9]). dimensions, and stenosis severity. Patients with nonobstructive FMD should be treated conservatively. In patients with ARAS, stenting is recommended to eliminate elastic recoil, minimize dissection, and maximize lumen enlargement (Fig. 8). Most studies report procedural success rates of 95% to 100%, residual diameter stenosis 10 %, restenosis rates of 10% to 15% within 1 year, and major complications in 2% (14). There are a number of important technical and procedural considerations to avoid renal artery injury, kidney injury, and atheroembolization. Selective renal arteriography should be guided by abdominal aortography; the catheter-in-catheter or no-touch techniques should be used to minimize contact with the aortic wall and injury to the renal ostium during guiding catheter engagement (23) (Fig. 9). The nephrotoxic effects of radiographic contrast are minimized by maintaining adequate hydration, limiting contrast volume, and using digital subtraction angiography. Renal embolization during revascularization seems to be fairly common (24), and 1 small randomized study suggested potential benefit of a combination of distal embolic protection and intravenous abciximab (25). Because 14% of patients have early renal bifurcations, complete renal protection might not be possible. All patients should be evaluated for post-procedural nephropathy and have regular follow-up. Outcomes After Failure of renal revascularization to cure hypertension. After ARAS revascularization, hypertension cure (normal blood pressure, no medication) is observed in 10% of patients, regardless of the revascularization technique (26,27). The explanations for why renal revascularization does not cure hypertension are somewhat speculative, and available data are limited by heterogeneous causes of hypertension and renal dysfunction, insufficient understanding of the relationship between renal ischemia and nephropathy, inconsistent techniques for revascularization, ambiguous terminology and end points to assess clinical benefit, and the lack of large-scale randomized trials. There is a persistent misperception that ARAS patients have renovascular hypertension, and contemporary reviews continue to use this terminology (14,26). Whereas the experimental Goldblatt models are compelling demonstrations of renin-angiotensin activation due to RAS (28), the mechanisms of hypertension in humans with and without RAS are far more complex and include sympathetic and cerebral nervous system activation, vasoactive oxygen species, abnormalities in endothelial dependent relaxation, and ischemic and hypertensive intrarenal injury (29 31). Patients with ARAS do not have renovascular hypertension, as evidenced by similarities in the extent of renin activation compared with hypertensive patients without RAS and the low cure rate of hypertension after successful revascularization (32,33). The most likely explanations are that patients with ARAS have essential hypertension, many do not have renal ischemia, and unrecognized hypertensive nephropathy leads to self-perpetuating hypertension. Failure of renal revascularization to improve renal function. Several studies documented improvement in creatinine and in the slope of reciprocal creatinine after stenting, compatible with beneficial effects of revascularization on renal function (34 36). Nevertheless, 25% to 30% have deterioration in renal function despite revascularization. The explanations for failure to improve or stabilize renal function after revascularization are multifactorial, including revascularization of patients without renal ischemia, insensitivity of the creatinine to changes in GFR when 50% of renal mass is revascularized (e.g., unilateral ARAS) (Fig. 6), failure to identify baseline nephropathy, and procedure-induced nephropathy. The key observation in prior studies of ischemic nephropathy is the crucial importance of baseline renal Table 3. Clinical Evaluation of Renal Artery Perfusion and Renal Ischemia Noninvasive assessment of renal blood flow 125 I-Iothalamate GFR (Total GFR) 99M Tc-DTPA (split renal function and single-kidney GFR) Invasive assessment of significance of RAS Percent diameter stenosis by visual estimates or quantitative angiography Translesional pressure gradient Fractional flow reserve Intravascular ultrasound Renal frame counts Renal blush score GFR glomerular filtration rate; RAS renal artery stenosis; 99M Tc-DTPA technetium-labeled pentetic acid.

168 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 Table 4. Classification of RAS, Renal Perfusion, and Renal Parenchymal Disease Type I A I B II A II B Perfusion NL* Renal ischemia NL* Renal ischemia Parenchymal disease No No Yes Yes Scr NL URAS NL NL or 1 NL or 1 BRAS NL or 1 Proteinuria No No Might be present Might be present RRI 0.7 0.7 0.8 0.8 Arteriolar narrowing None None or mild Yes Yes Arteriolar pruning None None Yes Yes Cortical blood flow NL NL 2 2 Biopsy NL NL Abnormal Abnormal Nuclear GFR NL URAS: NL 2 URAS: 2 DTPA split function BRAS: NL or 2 BRAS: 2 URAS: SYM URAS: ASYM URAS: SYM URAS: ASYM BRAS: SYM BRAS: SYM or ASYM BRAS: SYM BRAS: SYM or ASYM TLG None 20 mm Hg None 20 mm Hg FFR NL 0.8 NL 0.8 *These patients have anatomic renal artery stenosis (RAS) but no renal ischemia (normal perfusion). 1 increased; 2 decreased; ASYM asymmetric; BRAS bilateral renal artery stenosis; DTPA 99M -Tc-labeled pentetic acid; FFR fractional flow reserve; GFR glomerular filtration rate; NL normal; RRI renal resistive index; Scr serum creatinine; SYM symmetric; TLG translesional pressure gradient; URAS unilateral renal artery stenosis. function (36 38): Baseline creatinine 1.5 mg/dl is the single strongest predictor of late death (39), and the risk of renal failure rises 3-fold for each increment of 1.0 mg/dl in baseline creatinine (3). ARAS and cardiovascular outcomes. Four-year survival rates are 57% and 89% for patients with and without ARAS, respectively, and mortality rates are higher with more severe ARAS and with bilateral ARAS (2,40). Although ARAS adds incremental risk to cardiovascular morbidity and mortality, there are no data that renal revascularization improves cardiovascular outcomes. The CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial is randomizing 1,080 patients with ARAS to optimal medical therapy or to optimal medical therapy plus renal artery stenting (41). Patients must have unilateral or bilateral ARAS, resistant hypertension, and/or chronic kidney disease stage 3. The primary end point is a composite of cardiovascular or renal death, stroke, myocardial infarction, hospital stay for heart failure, progressive renal insufficiency, or the need for renal replacement therapy. The results of CORAL are expected in 2010; a potentially important limitation is the lack of baseline assessment of nephropathy and renal ischemia. Approach to Specific Clinical Situations Hypertensive RAS patients without vital organ injury. In older patients with new or refractory hypertension, imaging studies are reasonable to detect ARAS, but revascularization is controversial in the absence of renal ischemia or cardiovascular injury (Fig. 10). For patients with no nephropathy and normal renal blood flow (Type 1A), we would intensify the antihypertensive regimen and follow patients clinically for the development of vital organ injury. For patients with unilateral or bilateral ARAS, no nephropathy, and abnormal perfusion, we would reclassify such patients as having renal ischemia (Type 1B). Hypertensive patients with vital organ injury. Hypertensive patients with manifestations of vital organ injury should undergo an imaging study to detect RAS. The best candidates for revascularization are those with minimal or no nephropathy and renal ischemia (Type 1B). The worst candidates are those with advanced nephropathy (Type 2), especially if renal ischemia is absent (Type 2A). Renal FMD. For asymptomatic patients 30 years old with controlled or resistant hypertension, CTA is reasonable to diagnose FMD. Recommendations for revascularization are influenced by patient age, FMD location and distribution, hemodynamic significance of stenosis, and tolerance of antihypertensive medication. In the majority, angioplasty is appropriate to control hypertension. Because 25% of patients with renal FMD have carotid FMD, carotid duplex ultrasound is recommended if renal FMD is identified. In addition, patients with carotid FMD might have berry aneurysms of the circle of Willis, so intracranial MRA or CTA is advisable, too. Decisions about revascularization of renal FMD are simpler than ARAS, because of the high ( 80%) cure rate and durability (90% patency at 10 years) after angioplasty. Because hypertensive FMD patients generally have renovascular hypertension, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are usually effective. Patients who do not respond or develop vital organ injury should be considered for revascularization.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 169 Figure 7. Schematic Illustration of Disorders of Nephropathy (Type 1 or 2) and Renal Ischemia (Type A or B) Type 1A normal kidneys, no renal ischemia: in the presence of unilateral or bilateral atherosclerotic renal artery stenosis (ARAS), serum creatinine (Scr), total glomerular filtration rate (GFR), and single-kidney GFR (SK-GFR) are normal, and renal perfusion is symmetric. Type 1B normal kidneys, renal ischemia: in the presence of renal ischemia and unilateral ARAS, Scr and total GFR are normal, stenotic kidney GFR is abnormal, and renal blood flow is asymmetric. With bilateral RAS, Scr and total GFR are normal, and SK-GFR is abnormal. Renal blood flow might be symmetric (shown here) or asymmetric. Type 2A nephropathy, no renal ischemia: in the presence of unilateral or bilateral ARAS, Scr, total GFR, and SK-GFR are abnormal and, renal perfusion is symmetric. Type 2 B nephropathy, renal ischemia: in the presence of unilateral ARAS, Scr, total GFR, and SK-GFR are abnormal, and renal perfusion is asymmetric. With bilateral ARAS, Scr, total GFR, and SK-GFR are abnormal, and renal blood flow might be symmetric (shown here) or asymmetric. Invasive assessment of renal ischemia might be useful and complements the nuclear blood flow evaluation, particularly when nephropathy is present. Clinical follow-up is recommended; uncontrolled hypertension or new vital organ injury should prompt repeat invasive evaluation. Unilateral ARAS. If studies demonstrate normal kidneys and renal ischemia (Type 1B), we consider this a manifestation of unilateral vital organ injury. This form of renal ischemia is not mentioned in American College of Cardiology/ American Heart Association (ACC/AHA) guidelines, but such patients could be considered for renal stenting. The physician might be confronted by a more challenging decision in patients with serum creatinine 2 mg/dl and unilateral ARAS. In these patients, nephropathy is highly likely (Type 2), and preservation of renal function is less likely after revascularization. If such patients develop cardiovascular injury, renal revascularization might be reasonable if renal ischemia is present (Type 2B), although renal function might not improve; recommendations in these patients should be individualized. Bilateral ARAS or ARAS of a solitary kidney. Patients with bilateral ARAS or ARAS of a solitary kidney might have global severe renal ischemia and are more prone to pulmonary edema than those with unilateral RAS. Patients with severe bilateral ARAS, minimal or no nephropathy, renal ischemia (Type 1B), and cardiovascular injury are ideal

170 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 Figure 8. Endovascular Revascularization of Atherosclerotic Renal Artery Stenosis (Left) Baseline image before intervention (same as Fig. 1, right panel). (Middle) Suboptimal angiographic result after balloon angioplasty, characterized by significant residual stenosis, elastic recoil, and dissection (arrow). (Right) Final result after stent placement demonstrates optimal lumen enlargement. Figure 9. Schematic Illustrations of Invasive Techniques to Avoid Renal Artery Injury and Atheroembolization During Renal Artery Stenting (Left) Catheter-in-catheter technique employs a tapered 4- or 5-F soft-tip diagnostic catheter loaded inside a 6- or 7-F guiding catheter. After the renal artery is engaged with the diagnostic catheter, the 0.014-inch angioplasty wire is advanced across the stenosis and positioned distally. The guiding catheter is advanced over the diagnostic catheter, and once positioned the diagnostic catheter is removed. (Right) The no-touch technique uses a 0.035-inch J wire inside the guiding catheter, to lift the tip off the aortic wall. With the 0.035-inch wire in place, the guiding catheter is aligned with the renal artery, and a 0.014-inch guidewire is used to cross the stenosis. The 0.035-inch guidewire is removed, and the guiding catheter is advanced over the 0.014-inch wire to engage the renal artery.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 171 Figure 10. Algorithm for the Evaluation, Treatment, and Follow-Up of Patients With RAS RAS renal artery stenosis. candidates for renal revascularization. Evidence for nephropathy might be missed if serum creatinine is the only measure of renal function. Such patients should be considered for revascularization if nuclear GFR is 60 cc/min/ 1.73 m 2, even in the absence of cardiac or cerebral dysfunction, before the development of more advanced renal dysfunction. Nuclear blood flow studies and/or invasive assessment of ischemia are useful in patients with bilateral ARAS to identify the more hemodynamically impaired renal artery and to serve as a baseline for follow-up. Patients with end-stage renal disease. In the absence of diabetes or other confirmed nephropathy, it is reasonable to perform an imaging study to diagnose ARAS in patients who have been on dialysis for 1 year (2). Patients with unilateral stenosis or occlusion are unlikely to benefit, but patients with bilateral ARAS or occlusion might separate from dialysis after renal revascularization (Fig. 11) (42). Follow-up of patients with RAS. There are no ACC/AHA guidelines for following patients with RAS. Our approach to all RAS patients includes semiannual assessment of blood pressure, serum creatinine, and vital organ injury. We obtain annual or biannual evaluation of nuclear GFR and split renal blood flow for ARAS patients. After stenting for ARAS, we repeat nuclear blood flow studies at 3 months and annually thereafter. Initial improvement in stentedkidney GFR followed by deterioration is suggestive of restenosis. Conclusions Despite publication of the 2005 ACC/AHA guidelines, there is persistent controversy about renal artery revascularization. This controversy stems from imprecise understanding of renal vascular syndromes and their relationship to hypertension and renal dysfunction and is compounded by failures to differentiate renal ischemia from nephropathy, resulting in confusing and conflicting data about outcomes. Accordingly, we propose new rules for patients with renal vascular diseases (Table 5): Rule #1: The term renovascular hypertension should be reserved specifically for patients with renin-dependent hypertension, in whom revascularization is expected to cure hypertension. For practical purposes, this is true for many patients with FMD but not with ARAS. Rule #2: Hypertension in patients with ARAS might be classified as controlled, refractory, accelerated, or malignant, depending on the clinical circumstances. Patients with ARAS and hypertension should not be classified as having renovascular hypertension, because there is no compelling evidence that ARAS causes hypertension, and cure of hypertension after revascularization is rare. Rule #3: The term renal ischemia should be reserved for patients with RAS and abnormal renal perfusion (unilateral or bilateral).

172 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 Figure 11. Renal Arteriographic Findings in a 72-Year-Old Man With End-Stage Renal Failure on Dialysis for 7 Months Left and right panels demonstrate chronic total occlusion of the right and left renal arteries, respectively (top), high-grade residual stenosis and dissection after balloon angioplasty (middle, arrows), and widely patent renal arteries after stenting (bottom). He remained off dialysis for 7 years after revascularization with a stable serum creatinine of 1.5 to 1.7 mg/dl but died after a large stroke due to cardiac embolization from atrial fibrillation. Rule #4: The term renal artery stenosis should be used for patients with anatomic stenosis but has no implications regarding renal ischemia. Rule #5: The term nephropathy should be reserved for patients with renal parenchymal disease. Ischemic nephropathy should be reserved for patients with renal Table 5. New Terminology for Renal Vascular Diseases Hypertension Renovascular hypertension: renin-dependent hypertension, typical of young patients with FMD; characterized by high likelihood of cure of hypertension after revascularization. Essential hypertension: typical form of hypertension in elderly persons, associated with manifestations of atherosclerosis; causal relationship between ARAS and hypertension is absent. Controlled hypertension: blood pressure controlled with 2 medications according to current guidelines. Refractory hypertension: blood pressure exceeds current guidelines despite 3 medications. Accelerated hypertension: previously controlled hypertension becomes progressively uncontrolled, exceeds current guidelines, and remains poorly controlled despite multiple additional medications. Malignant hypertension: uncontrolled hypertension associated with acute renal or cardiovascular injury. Renal artery stenosis (no ischemia) Unilateral RAS: anatomic unilateral RAS without objective renal ischemia Bilateral RAS: anatomic bilateral RAS without objective renal ischemia Renal ischemia Unilateral RAS: objective renal ischemia in the distribution of the stenotic renal artery Bilateral RAS: objective renal ischemia in one or both renal arteries. Nephropathy (parenchymal disease) Ischemic nephropathy: renal parenchymal disease due to long-standing intrarenal arteriolar disease associated with generalized atherosclerosis. Diabetic nephropathy: renal parenchymal disease due to long-standing diabetes. Hypertensive nephropathy: renal parenchymal disease due to long-standing hypertension, intrarenal arteriolar disease, and self-perpetuating hypertension Other nephropathies: renal parenchymal diseases associated with other known glomerular or interstitial renal diseases. Procedure related nephropathy: acquired parenchymal injury (transient or permanent) that might be related to acute tubular necrosis, radiographic contrast, renal embolization, or other causes. Abbreviations as in Table 1.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 3, 2009 173 parenchymal disease associated with longstanding atherosclerosis and intrarenal arteriolar disease. Other forms of nephropathy might be based on the presence of known diseases, such as diabetes (diabetic nephropathy), hypertension (hypertensive nephropathy), or interstitial diseases (interstitial nephropathy) or might be acquired as a complication of revascularization (acute tubular necrosis, contrast nephropathy, and renal embolization). Rule #6: Medical therapies, particularly antihypertensive drug therapy and therapies to limit ARAS, are the primary therapies for all patients with RAS. Rule #7: The optimal use of renal artery revascularization is poorly defined. Contemporary decisions about renal revascularization must include an assessment of the severity and functional significance of RAS (renal ischemia), the condition of the kidneys (nephropathy), and the association between RAS and vital organ injury. 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