Renovascular Disease
John F. Setaro, MD, FACC, FSCAI
Key Points
Atherosclerotic disease underlies renal artery stenosis in 90% of cases.
Guidelines recommend revascularization as a Class I indication for hemodynamically significant renovascular disease with recurrent unexplained heart failure or flash pulmonary edema.
Invasive evaluation may include angiography with measurement of percentage stenosis as well as more physiologic measures such as resting ratio of distal artery to aortic pressure (Pd/Pa) <0.90, hyperemic fractional flow reserve value (Pd/Pa) <0.80, hyperemic mean gradient >20 mm Hg, hyperemic systolic gradient >20 mm Hg, or intravascular ultrasound (IVUS)-derived MLA <8.6 mm sq.
Self-expanding stent placement by femoral access is the most common technique in treatment of renal artery stenosis.
I. Introduction
This chapter aims to survey disorders of the renal vessels, with an emphasis on diagnosis and treatment of arterial disease (medical, transcatheter, surgical), as well as to review novel catheter-based techniques (such as renal sympathetic denervation) designed to treat multidrug-resistant hypertension and other circulatory conditions.
Renovascular disease, often termed renal artery stenosis, is typically of atherosclerotic origin and is a relatively frequent finding, particularly in the older population who may have concomitant atherosclerotic disease in other vascular distributions. Yet most structural renovascular disease that may be visible angiographically does not cause hypertension (renovascular hypertension) or renal ischemia as large angiographic series have demonstrated, with recent major trial evidence showing that optimized medical therapy rather than mechanical intervention may be appropriate in most cases. However, a subset of individuals who have resistant hypertension,1 advancing renal dysfunction (especially with bilateral disease),2 or flash pulmonary edema should be identified and treated by revascularization.3
II. Anatomic Considerations
In most cases, there is a single renal artery bilaterally (typically 5-7 mm diameter), with origins at the L1-L2 level of the aorta, each dividing into segmental, lobar, interlobar, arcuate, and interlobular branches.4 In a minority of cases, anatomic variations may include dual renal arteries, accessory renal arteries, or early segmental branching renal arteries.5 When the main renal artery is occluded, potential collateral sources (intercostal, lumbar, internal iliac, and adrenal arteries) may provide immediate viability but not long-term preservation of functioning renal mass.4,6
III. Pathophysiologic Factors and Natural History
A. Systemic Hypertension Caused by Renovascular Disease The mechanism of systemic hypertension caused by renovascular disease was first elucidated in 1934 through Goldblatt’s experimental renal artery clamping models7 and is founded upon reduced renal perfusion pressure leading to activation of the renin-angiotensin system with consequent release of serum renin and angiotensin II. Renin is released in response to diminished perfusion pressure at the juxtaglomerular apparatus of the afferent renal arterioles and in response to reduced sodium and chloride delivery to the macula densa segment of the ascending loop of Henle.8 In turn, systemic vasoconstriction, sympathetic activation, and aldosterone-mediated depression of sodium excretion with consequent volume expansion will follow.
B. Pulmonary Congestion
1. These pathologic adaptations can promote sudden pulmonary congestion (flash pulmonary edema) and may exacerbate myocardial ischemia in vulnerable individuals. Locally, efferent arteriolar constriction governed by release of angiotensin II acts as a compensatory response favoring continued renal perfusion and explains why in the
setting of significant bilateral disease (or unilateral disease in a uninephric individual), there will be a rise in serum creatinine when antihypertensive pharmacologic inhibitors of the renin-angiotensin system are used. On the other hand, when unilateral disease is present, inhibitors of the renin-angiotensin system may be very useful in controlling hypertension (caused by activation of the renin-angiotensin system in renovascular hypertension), without a rise in serum creatinine, provided that the contralateral kidney is healthy and that functional renal mass is preserved.9
2. The abnormal vasoconstricted as well as volume-expanded pathophysiologic state of true renovascular hypertension highlights the importance of combined vasodilator and diuretic therapy for pharmacologic management.8
C. Late Renal Ischemia and Dysfunction It is interesting to consider that late renal ischemia and dysfunction may be founded upon several factors beyond simple reduced arterial blood flow, given that the kidney has relatively minimal oxygen requirements.10,11 These extraischemic factors may encompass direct hypertensive injury to both ischemic and unaffected kidney, distal atheroembolic phenomena, and the generation of angiotensin II-based profibrotic mediators (transforming growth factor-beta [TGF-β], nuclear factor-kB, and platelet-derived growth factor [PDGF]).4,12,13 Restoring renal artery blood flow alone through relief of stenosis may not be enough to reverse many of these late changes.14
D. Atherosclerotic Renovascular Disease
1. The progressive nature of atherosclerotic renovascular disease is underscored by several series that showed significant rates of progression of stenosis as well as occlusion by angiography or duplex ultrasound: progression in 44% of individuals and occlusion in 16% at 4 years,15 progression in 11% of individuals at 2.6 years,16 and progression in 35% of individuals at 3 years and 52% at 5 years (49% at 3 y if the baseline stenosis was >60%).17
2. Untreated severe disease with reduced renal blood flow may lead to the ischemic loss of functioning renal mass and has been linked to greater degree of stenosis and higher blood pressure.18 In a second series, at 1 year there was at least a 1.0 cm reduction in kidney size in 13% of subjects with unilateral disease and in 43% of subjects who had bilateral disease.19
IV. Clinical Presentations
A. Literature The medical literature supports a significant association between renovascular disease (typically defined as structural anatomic lesions greater than 50% stenosis diameter) and classical Framingham atherosclerotic risk factors (smoking, diabetes, hyperlipidemia, age), as well as aortic and peripheral vascular disease (38%)
and coronary artery disease (6.3%-23%), with a 7% prevalence of renovascular disease in the general older population.3,4,22,23 A correlation has been noted between renovascular disease and two- to three-vessel coronary artery disease.24 Longitudinal studies support the progressive nature of renovascular disease as noted above, especially when lesions are initially found to be severe, but it has been pointed out correctly that most of these retrospective as well as prospective series predate the inception of ideal medical therapies (aspirin, clopidogrel and other novel antiplatelet compounds, statins, modern antihyperglycemic agents, renin-angiotensin-aldosterone inhibitors) and lifestyle interventions (diet and weight control, exercise, sodium restriction, and smoking cessation).4 This observation also sheds light on why optimized medical therapy has proved equally effective as revascularization in the most recent randomized prospective trials.25 Presence and severity of renovascular disease is also associated with all-cause long-term mortality, likely reflecting the adverse implications of generalized systemic atherosclerotic vascular disease.26
B. Population The true prevalence of renovascular hypertension is less than 1% in the general population but may be much higher in states of resistant hypertension27,28,29 or in the presence of other suggestive clinical features listed below (7.3% of 837 of such patients had at least a 70% stenosis of one or both renal arteries).30,31 Clinical indicators of physiologically significant renovascular disease include (1) multidrug-resistant hypertension1,32 or malignant hypertension (Grade III or IV Keith-Wagener retinal changes [hemorrhages and exudates, papilledema, respectively] have been associated) or the rapid acceleration of previously well-regulated hypertension,33 (2) disparity in renal size or the presence of an atrophic (ischemic) kidney, (3) rise in serum creatinine following administration of inhibitors of the renin-angiotensin system (suggesting bilateral disease or unilateral disease in single kidney), or (4) sudden unexplained pulmonary edema or medically refractory angina pectoris. Onset of hypertension at a very young or a very old age may also provide a clue to significant renovascular disease (Table 8.1). The finding of a systolic and diastolic abdominal bruit radiating to the flank may be of contributory interest, yet as a physical sign lacks high sensitivity or specificity for the diagnosis of physiologically significant renovascular disease.
TABLE 8.1. Clinical Indicators Favoring a Search for Renovascular Hypertension | |
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V. Atherosclerotic Renovascular Disease
A. It is estimated that atherosclerotic disease underlies renal artery stenosis in 90% of cases.27 Nonatherosclerotic causes, the most frequent being fibromuscular dysplasia, are reviewed below. In most cases, the presence of structural atherosclerotic renovascular disease is not the cause of hypertension (renovascular hypertension) or ischemia of the kidney, and historically most catheter-based revascularizations that were performed without good evidence favoring true renovascular hypertension did not afford benefit.34 In parallel with this observation, recent trial evidence, presented below, indicates that patients who have well controlled hypertension and normal renal function should be treated conservatively. Yet resistant hypertension, flash pulmonary edema, or progressive renal impairment with renal ischemia (especially in the context of bilateral disease), may require revascularization, thus improving clinical management and preventing the need for renal replacement therapy.35,36
B. Because there is considerable clinical overlap among states of (1) essential hypertension, (2) renovascular hypertension, (3) anatomic renal artery stenosis, (4) diabetic nephropathy, and (5) chronic renal impairment, methods of assessing the functional significance of anatomic renal artery disease will assume importance, as noted below.37,38 Alternatively, although proteinuria is a feature in many forms of renal disease including ischemia, renal disease unrelated to stenosis may be reflected in an active urinary sediment (typically acellular in the setting of renal ischemia).4,39 Additionally, elevated creatinine in the setting of unilateral stenotic disease suggests nonstenotic etiologies because a single remaining healthy contralateral kidney that is well perfused will maintain a normal creatinine value.27 However, a rapid rise in serum creatinine may portend a better result postrevascularization, suggesting reversibility.4,33 Of note, a group of investigators has reported a 24% prevalence of severe atherosclerotic renovascular disease in end-stage renal disease patients being considered for dialysis.40
VI. Nonatherosclerotic Renovascular Disease
A. Fibromuscular Dysplasia
1. The most common cause of nonatherosclerotic renovascular disease is fibromuscular dysplasia, often seen in younger women who are hypertensive yet otherwise free of classic atherosclerotic risk factors. One-third of cases of renal artery fibromuscular dysplasia are bilateral, and there is a familial component as well as a genetic association with polymorphisms of the renin-angiotensin system, specifically higher frequency of the angiotensin-converting enzyme (ACE) I allele.41 It has been proposed that, because this allele is linked to lower circulating levels of angiotensin-converting enzyme and possibly lower tissue levels of angiotensin II (which regulates vascular smooth muscle growth and synthetic activity), the presence of the I allele may foster abnormal remodeling of the arterial media thus promoting fibromuscular dysplasia.41
2. Unlike the atherosclerotic lesion which classically involves the aorta and ostium and proximal renal artery, a fibromuscular dysplastic stenosis tends to show a beaded
appearance (reflecting the tissue webs or baffles that restrict blood flow), and resides in the distal two-thirds of the main renal artery or its principal branches42 (Fig. 8.1).
3. As distinct from atherosclerotic renovascular disease, fibromuscular dysplasia rarely progresses to total occlusion or ischemic nephropathy. In addition to predilection for young females, fibromuscular dysplastic renovascular disease has been linked to tobacco consumption, alpha-1 antitrypsin deficiency, use of ergotamine or methysergide, pheochromocytoma, type IV Ehlers-Danlos syndrome, cystic medial necrosis, Alport syndrome, neurofibromatosis, and coarctation of the aorta.43 This species of renovascular disease responds well to simple balloon angioplasty and exhibits durable results, without the need for intra-arterial stent placement44 (Figs. 8.1, 8.2, 8.3).
B. Other Rare Nonatherosclerotic Forms of Renovascular Disease Other rare nonatherosclerotic forms of renovascular disease include vasculitis, neurocutaneous syndromes such as neurofibromatosis, Takayasu arteritis, aneurysms, congenital or posttraumatic arteriovenous fistulae, congenital bands, postradiation changes, spontaneous dissection, thromboembolization (typically cardiac in origin, from atrial fibrillation), atheroembolization, steal syndrome in the setting of celiac axis occlusion, or the vascular compressive effects of large renal cysts, pheochromocytoma, retroperitoneal fibrosis, or posttraumatic external scarring (Page kidney).37,45 Regarding renal artery thromboembolization, there is scant experience reported in the literature describing catheter-based techniques for renal reperfusion, for instance local thrombolysis. Posttransplant renal vasculopathy, often appearing within 1 year of transplant, presents with renal impairment, hypertension, and circulatory congestion and is best managed with angioplasty and stenting.46
 FIGURE 8.1: Renovascular disease: Fibromuscular dysplasia. Diagnostic angiography using a 5F internal mammary artery catheter to inject the right renal artery in a 67-year-old female patient who demonstrated three-drug-resistant hypertension. Procedure was conducted via the right common femoral artery. There is a slight inferior angulation to the origin of the right renal artery. Note the beaded appearance of the mid-vessel consistent with fibromuscular dysplasia. Courtesy of Jeptha P. Curtis MD. |
 FIGURE 8.2: Renovascular disease: Fibromuscular dysplasia. Following administration of 7000-u unfractionated heparin, using a telescoping technique, a 7F renal double curve sheath guide was advanced over the 5F internal mammary artery catheter. Following the finding of a 15 mm Hg mean gradient across the stenotic region, angioplasty was performed using a 4.0 mm then a 5.0 mm balloon to a maximum pressure of 6 atm. |
 FIGURE 8.3: Renovascular disease: Fibromuscular dysplasia. Completion angiogram shows favorable result, revealing <20% residual stenosis. Subsequent clinical course is noteworthy for minimization of antihypertensive regimen and good preservation of renal function. |
VII. Diagnostic Examinations
When clinical presentation is strongly suggestive of functionally significant renovascular disease, noninvasive assessment is indicated, with several methods each harboring advantages and disadvantages.
A. Renal Duplex Ultrasound Renal duplex ultrasound is useful when good acoustic windows are available in leaner individuals. When performed well technically and interpreted in a competent manner, this method can define kidney sizes, chart the progression of loss of renal mass, estimate the degree of echogenicity of the renal cortex, and illustrate the condition of the distal microvasculature. A physiologically significant stenosis may be reflected by a peak systolic velocity of >200 cm/s and a renal artery/aortic peak systolic velocity ratio of 3.5.47 Renal resistive index (peak systolic velocity−end diastolic velocity/peak systolic velocity) can demonstrate the degree of microvascular resistance and may predict benefit of revascularization. However, threshold values have not yet been fully
defined in the literature,42 although 0.80 conventionally has been the upper limit of normal. Higher values suggest distal microvascular disease and have been linked with failure to improve clinically following main artery revascularization.48
B. Captopril Renal Artery Scintigraphy Captopril renal artery scintigraphy uses nuclear perfusion assessments before and after ACE inhibitor stimulation to determine whether arterial flow is dependent on efferent arteriolar vasoconstriction under the influence of angiotensin II, therefore confirming that functionally significant renovascular hypertension is present.49 When comparing two kidneys, abnormal unilateral function may identify significant renovascular disease and predict improvement following revascularization.50 However, while specificity is high, sensitivity may not be adequate, particularly in cases of bilateral disease (or unilateral disease in a single kidney) or low glomerular filtration rate. There is little role for previous methods such as intravenous pyelography or measurement of plasma renin activity. Early studies indicate a promising role for assays of brain natriuretic peptide (BNP, or B-type natriuretic peptide) in predicting blood pressure response postrevascularization.51
C. Angiography
1. CT angiography may provide useful images, but radiation burden and nephrotoxic radiocontrast exposure represent concerns. Moreover, this technique may fail to distinguish intraluminal stenosis from extravascular calcification.42 Stenosis of >75% (or 50% with poststenotic dilatation) may be considered significant.
2. MR angiography is probably the most useful contemporary technique, requiring no radiation, although there is a false positive rate. A stenosis of >80% may be viewed as significant. However, its gadolinium contrast agent must be used with great caution when renal disease is present given the risk of development of nephrogenic systemic sclerosis. Questions also surround the significance of long-term deposition of gadolinium in bone and brain tissue.
3. Invasive renal vein sampling for renin measurement has suboptimal sensitivity and specificity, although lateralizing values predict treatment response.
4. Percutaneous renal angiography carries the risks of any invasive catheter-based procedure (bleeding, infection, embolization, vessel or kidney damage, radiation exposure, radiocontrast requirement), yet provides excellent images, is highly sensitive and specific for the depiction of vascular stenosis, permits immediate physiologic assessments, and allows balloon or stent revascularization in the same setting. Angiography is, however, relatively low risk and serves as the gold standard for visualization of the renal arteries.
Femoral artery access is most commonly used, but upper extremity (radial or brachial artery) can be employed if the origin of the renal artery is angulated inferiorly42 or if there is major infrarenal aortoiliac disease (Fig. 8.1). Nonselective abdominal aortography performed at the T12-L1 level uses a pigtail catheter with power injection using dilute radiocontrast and digital subtraction angiography.47 The nonselective view elucidates the presence and number of renal arteries, as well as important
aortic conditions such as protruding atherosclerotic plaque that could interfere with subsequent selective renal angiography.42,47 With advanced renal impairment, carbon dioxide may act safely as a contrast medium.
5. In terms of angiographic views, selective renal artery angiography may require a slight degree of left anterior oblique angulation given the anterior origin of the right renal artery that is slightly superior to the orifice of the left renal artery, arising more posteriorly.4 From the femoral approach, catheter selection may include internal mammary (Fig. 8.1), JR4, cobra, renal double curve, hockey stick, multipurpose, or SOS Omni.42,47 Via upper extremity approaches, a 90-cm long 6F or 7F vascular sheath may prove useful, through which a 5F or 6F internal mammary artery, multipurpose, or JR4 catheter can be advanced to the orifice of the renal artery.
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