Approach to and Management of Renovascular Disease
Quinn Capers IV
Joshua Joseph
Debabrata Mukherjee
Renal artery stenosis (RAS) is a common cause of secondary hypertension, and the incidence appears to be rising because of increased atherosclerosis in an aging population. The prevalence of atherosclerotic RAS increases with age, presence of diabetes, peripheral arterial disease, coronary artery disease, hypertension, and dyslipidemia. The most common cause is atherosclerosis, which is the etiology in over 90% of cases, that is, atherosclerotic renal artery stenosis (ARAS). Fibromuscular dysplasia (FMD) accounts for approximately 10% of cases of RAS and is typically seen in young and middle-aged females. RAS may cause renal insufficiency, uncontrolled hypertension, and recurrent congestive heart failure and “flash” pulmonary edema and is associated with increased cardiovascular morbidity and mortality. There have been significant improvements in noninvasive detection of RAS and revascularization techniques have evolved, such that most renal artery (RA) revascularization is now performed percutaneously. Patients with ARAS should also be treated with the same measures that reduce cardiovascular risk in patients with atherosclerosis in any location: statins or other lipid-lowering drugs, drugs that inhibit the reninangiotensin system, antiplatelet drugs, tobacco avoidance, and regular physical activity, among other treatments.
ETIOLOGY
ARAS is by far the most common form of RAS (˜90%). ARAS occurs when atherosclerotic plaque deposition in the renal arteries results in a critical narrowing, restricting blood flow to the renal parenchyma. Most commonly located at the ostia, it is often associated with significant atheromatous disease of the abdominal aorta and is thought to result from “creeping” of atherosclerotic material from the aortic wall into the renal arteries. This predilection for the ostia is an important consideration for the interventionalist when placing stents. A proper technique for stent placement in the case of atherosclerotic RAS at the ostium is to position the stent so that it protrudes very slightly into the aorta. Failure to do so will result in incomplete coverage and scaffolding of the offending plaque.
FMD is a nonatherosclerotic, noninflammatory arterial disease of the musculature of the arterial wall leading to stenosis of small- and medium-sized vessels in the medial to distal segments. FMD most commonly affects the renal and carotid arteries but has been shown to affect arteries throughout the body. It causes 10 to 20% of all RA stenoses and is found in about 1 to 2% of hypertensive patients. FMD is more than four times more common in women and is usually diagnosed from the ages of
15 to 50, although there is a male predominance of intimal FMD. The exact cause of the condition is unknown with a cadre of hormonal, genetic, and environmental factors postulated. Similar to atherosclerosis, there is a proven association with smoking and hypertension. The disease is also more common in first-degree relatives of patients with FMD and patients with angiotensin-converting enzyme allele ACE-I, suggesting a possible genetic link.
15 to 50, although there is a male predominance of intimal FMD. The exact cause of the condition is unknown with a cadre of hormonal, genetic, and environmental factors postulated. Similar to atherosclerosis, there is a proven association with smoking and hypertension. The disease is also more common in first-degree relatives of patients with FMD and patients with angiotensin-converting enzyme allele ACE-I, suggesting a possible genetic link.
Other rarer causes of RAS are arteritis (Takayasu’s disease, polyarteritis nodosa, Kawasaki’s disease, other systemic vasculitides), renal artery aneurysm (RAA), extrinsic compression (neoplasm, Wilms’ tumor, neuroblastoma), syndromic (neurofibromatosis, tuberous sclerosis, Williams’ syndrome, Marfan’s syndrome), radiation induced, and fibrous bands.
Prevalence of ARAS
Although, incidentally discovered RAS is quite common, renovascular hypertension is the etiology in only 1 to 5% of all patients with hypertension. The presence of anatomic RAS does not necessarily establish that the hypertension or renal failure is caused by the RAS. Essential (primary) hypertension may exist for years prior to the development of atherosclerotic RAS later in life. Several series have assessed the prevalence of renovascular disease in patients who have atherosclerotic disease elsewhere. High-grade bilateral RA disease was present in approximately 5 to 15% of patients in series examining patients with other manifestations of disease. A significant proportion (greater than 20%) of patients with lower extremity peripheral arterial disease may have significant RAS. RA disease is detected incidentally at the time of cardiac catheterization in 10 to 30% of patients, and approximately 50% of theses patients may have greater than 50% stenosis.
CLINICAL FEATURES
More than 90% of cases of RAS are atherosclerotic in nature and involve the ostium and the proximal portion of the main RA with plaque extending into the perirenal aorta. As opposed to atherosclerotic RAS, FMD often affects the distal two thirds of the main RA and the RA branches. Medial fibroplasia is the most common type of FMD and has a characteristic beaded angiographic appearance.
RAS may be associated with any degree of hypertension and is present in a third of patients with malignant or uncontrolled hypertension despite multiple antihypertensive agents. Dustan also noted that as many as 50% of patients with RAS may actually have normal blood pressure (BP). RAS may present with chronic renal insufficiency or end-stage renal failure with or without hypertension with a bland urinary sediment and usually non-nephrotic-range proteinuria. Patients with bilateral RAS or stenosis of an artery to a solitary functioning kidney may present with acute renal failure after administration of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Table 10.1 enumerates clinical clues suggestive of RAS.
TABLE 10.1 CLINICAL CLUES SUGGESTIVE OF RAS | ||||||||||
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Chronically reduced blood flow to the kidney may lead to renal atrophy and diminished glomerular filtration rate (GFR). Severe RAS has been identified in 15 to 25% of patients with end-stage renal failure requiring hemodialysis. While not proof of a cause and effect relationship, RAS is considered an important reversible cause of renal failure. It has been reported that percutaneous RA stenting in selected dialysis patients can salvage renal function and obviate the need for dialysis.
The most common cause of death in patients with ARAS is ischemic heart disease and its complications. This is true of patients with atherosclerosis in any location of the body. However, patients with ARAS carry the additional vascular burdens of severe hypertension; supraphysiologic levels of the proatherogenic, prothrombotic vasoconstrictor angiotensin II; and possibly diminished renal function with its cardiovascular consequences. The presence of RAS is an independent risk factor for cardiovascular and all-cause mortality, and a “dose-dependent” effect has been described, with a graded increase in mortality in patients with severe compared to moderate narrowing of the renal arteries.
Pathophysiology of Hypertension
Preclinical studies for renovascular hypertension have helped us understand the pathophysiology of hypertension in RAS. The renin-angiotensinaldosterone system plays a critical role in this scenario. In animal models, the two kidney-one clip (2Kidney-1Clip) model is considered the representative model for renin-mediated hypertension and is analogous to unilateral RAS clinically. The one kidney-one clip (1Kidney-1Clip) model of renovascular hypertension is a model for volume-mediated hypertension and is similar in pathophysiology to either bilateral RAS or RAS in a solitary functioning kidney clinically. The acute phases of both of these models are quite similar; however, different events occur in the late phase. In the 2Kidney-1Clip model (unilateral RAS), there is decreased renal blood flow to the kidneys that stimulates the production of renin. Renin cleaves the
proenzyme angiotensinogen to form angiotensin I, and in the presence of angiotensin-converting enzyme, it is converted to angiotensin II. Angiotensin II elevates BP directly by causing systemic vasoconstriction, stimulates aldosterone secretion causing sodium reabsorption and potassium and hydrogen ion secretion in the cortical collecting duct, and diminishes glomerular filtration by decreasing glomerular capillary surface area and redistributing intrarenal blood flow. The salt and water retention related to excess aldosterone production is rapidly excreted by the contralateral (normal) kidney by pressure natriuresis in the 2Kidney-1Clip model. This produces a cycle of renin-dependent hypertension. In the 1Kidney-1Clip model of renovascular hypertension, there is a similar decrease in blood flow to the affected kidney(s), causing the production of renin and synthesis of angiotensin II and aldosterone, which causes salt and water retention. In this model without a normal kidney, pressure natriuresis does not occur. The increased aldosterone causes sodium and water retention and volume expansion, which suppresses plasma renin activity, thus changing from renin-mediated hypertension to one of volume-mediated hypertension. During this stage, administration of an ACEI or ARB does not decrease BP or change renal blood flow. Dietary restriction of sodium or administration of diuretics will convert the patient to a renin-mediated form of hypertension and restore sensitivity to ACEIs or ARBs, which then become effective antihypertensive agents. Renal insufficiency may be precipitated in patients when ACEIs/ARBs are administered to patients with bilateral RAS or RAS to a solitary kidney especially in the volume-contracted state.
proenzyme angiotensinogen to form angiotensin I, and in the presence of angiotensin-converting enzyme, it is converted to angiotensin II. Angiotensin II elevates BP directly by causing systemic vasoconstriction, stimulates aldosterone secretion causing sodium reabsorption and potassium and hydrogen ion secretion in the cortical collecting duct, and diminishes glomerular filtration by decreasing glomerular capillary surface area and redistributing intrarenal blood flow. The salt and water retention related to excess aldosterone production is rapidly excreted by the contralateral (normal) kidney by pressure natriuresis in the 2Kidney-1Clip model. This produces a cycle of renin-dependent hypertension. In the 1Kidney-1Clip model of renovascular hypertension, there is a similar decrease in blood flow to the affected kidney(s), causing the production of renin and synthesis of angiotensin II and aldosterone, which causes salt and water retention. In this model without a normal kidney, pressure natriuresis does not occur. The increased aldosterone causes sodium and water retention and volume expansion, which suppresses plasma renin activity, thus changing from renin-mediated hypertension to one of volume-mediated hypertension. During this stage, administration of an ACEI or ARB does not decrease BP or change renal blood flow. Dietary restriction of sodium or administration of diuretics will convert the patient to a renin-mediated form of hypertension and restore sensitivity to ACEIs or ARBs, which then become effective antihypertensive agents. Renal insufficiency may be precipitated in patients when ACEIs/ARBs are administered to patients with bilateral RAS or RAS to a solitary kidney especially in the volume-contracted state.
Mechanism of ACEI/ARB-mediated Azotemia in RAS
Two potential mechanisms exist by which renal function may worsen with the use of ACEs/ARBs. One mechanism may occur with any antihypertensive agent when it lowers the critical perfusion pressure and affects renal perfusion. This mechanism has been validated by infusing sodium nitroprusside in patients with high-grade bilateral RAS, which led to worsening renal function. Below the critical perfusion pressure, which may vary with the degree of stenosis and among individuals, the urine output, renal blood flow, and GFR decline. They return to normal when the BP increases above the critical perfusion pressure. The second mechanism is related to the direct effects of blocking angiotensin II on intraglomerular perfusion pressures. Patients with high-grade bilateral RAS or RAS to a solitary kidney may be highly dependent on angiotensin II for glomerular filtration. Under these circumstances, the vasoconstrictive effect of angiotensin II on the efferent arteriole maintains normal transglomerular gradient, thus allowing glomerular filtration to remain normal despite markedly diminished blood flow. When an ACEI/ARB is given, the efferent arteriolar tone is decreased, leading to reduction in glomerular filtration. A similar clinical scenario may be seen in patients with decompensated heart failure who are sodium depleted.
Progression of ARAS. Knowledge of the natural history of ARAS is extremely important in the management of these patients. Most natural history studies reported in the literature are retrospective studies. The rates of progression ranged from 36 to 71%.
Angiographic Progression. In Schreiber’s series, only 16% of patients went on to total occlusion over a mean follow-up of 52 months. However, the rate of progression to total occlusion occurred more frequently (39%) when there was greater than 75% stenosis on the initial renal arteriogram. Zierler et al. utilized renal duplex ultrasound to prospectively study anatomic progression of atherosclerotic renovascular disease. If the renal arteries were normal, only 8% progressed over 36 months. However, at 3 years, 48% of patients progressed from less than 60% stenosis to ≥60% stenosis. The renal arteries that progressed to occlusion all had ≥60% stenosis at the initial visit. Progression of RAS occurred at an average rate of 7% per year for all categories of baseline disease combined.
Renal Atrophy. The effect of RAS on kidney size has been well studied. Using duplex ultrasound, Caps and colleagues prospectively followed up 204 kidneys in 122 patients with known RAS for a mean of 33 months. The 2-year cumulative incidence of renal atrophy was 5.5, 11.7, and 20.8% in kidneys with a baseline RA disease classification of normal, less than 60% stenosis, and ≥60% stenosis (P = 0.009, log rank test), respectively.
Prognosis with RAS. The mere presence of atherosclerotic RAS, even prior to developing end-stage renal disease, portends a poor prognosis. Patient survival decreases as the severity of RAS increases with 2-year survival rates of 96% in patients with unilateral RAS, 74% in patients with bilateral RAS, and 47% in patients with stenosis or occlusion to a solitary functioning kidney. As the serum creatinine increases, the survival decreases in patients with atherosclerotic RAS. The 3-year probability of survival in one study was 92 ± 4% for patients with a serum creatinine less than 1.4 mg/dL, 74 ± 8% for patients with a serum creatinine of 1.5 to 1.9 mg/dL, and 51 ± 8% for patients with a serum creatinine ≥2.0 mg/dL.
DIAGNOSIS
The decision to evaluate patients for RAS should be based on the clinical likelihood of the individual patient having RAS. The clinical clues listed in Table 10.1 will help identify individuals with high pretest likelihood of RAS. Although a systolic abdominal bruit is common and nonspecific, the presence of a systolic/diastolic bruit especially over the epigastrium may point to underlying RA disease, especially in individuals with FMD. The presence of a diastolic component to the bruit indicates that the degree of narrowing of the artery is severe since there is continued flow during diastole. Once having made the decision to screen an individual for RAS, there are multiple options available as listed below. The screening test of choice depends on the equipment and expertise that are available at a given institution. In experienced hands, duplex ultrasonography, computed tomographic angiography (CTA), and MRA are all excellent diagnostic tests.
Anatomic Considerations
The renal arteries arise just below the SMA. The right RA arises anterolaterally, while the left RA arises posterolaterally. The right RA lies behind
the IVC. Accessory renal arteries supplying the poles of the kidneys and duplicated main renal arteries are seen in 10 to 30% of individuals. The left renal vein is a large structure that lies between the SMA and the aorta, usually crosses the aorta anteriorly and demonstrates phasic flow (varies with respiration). The RA is a low-resistance vascular bed and demonstrates flow in both systole and diastole under normal circumstances.
the IVC. Accessory renal arteries supplying the poles of the kidneys and duplicated main renal arteries are seen in 10 to 30% of individuals. The left renal vein is a large structure that lies between the SMA and the aorta, usually crosses the aorta anteriorly and demonstrates phasic flow (varies with respiration). The RA is a low-resistance vascular bed and demonstrates flow in both systole and diastole under normal circumstances.
Duplex Ultrasound
Ultrasonography is an ideal imaging modality in patients with RAS. In experienced centers, it can predict the presence or absence of RAS with a high degree of accuracy, identify patients likely to achieve a beneficial response after revascularization (PTA, stent, surgery), follow the course of disease and kidney size in patients followed medically, and follow patients for the presence of restenosis after PTA and stent implantation. Duplex ultrasound is associated with a steep learning curve. It becomes difficult in obese patients and those with excess bowel gas. It is important to visualize the entire RA from the origin to the kidney parenchyma. This is accomplished by scanning from both an anterior approach and an oblique approach. By performing the duplex in this fashion, one is assured of detecting RAS from both atherosclerosis and FMD. The sensitivity of identifying accessory renal arteries is only approximately 60 to 70%.
Diagnostic Criteria for RAS
Blood flow in the renal arteries normally demonstrates a low resistance pattern (broad systolic waveforms and forward flow during diastole). Peak systolic velocity (PSV) ranges from 75 to 125 cm/s in adults and children. The principal criterion for the diagnosis of RAS is Doppler flow based. The most universally accepted velocity criteria for significant RAS (70% stenosis) are (a) PSV > 200 cm/s measured in the area of stenosis and/or (b) Renal-aortic ratio ≥3.5. If the end-diastolic velocity is ≥150 cm/s, the stenosis is usually greater than 80%. Table 10.2 lists a well-accepted algorithm using these criteria.
Renal Resistive Index
A renal resistive index (RRI) greater than 80 may help identify patients with intrinsic renal disease who may not benefit from percutaneous revascularization.
The RRI is determined by measuring the PSV (Vmax) and end-diastolic velocities (Vmin) in cm/s from an intrarenal artery (usually the cortical vessels). RRI = [1 -(Vmin ÷Vmax)] × 100. The measurements are obtained from the upper, middle, and the lower third of each kidney and the measurements averaged.
The RRI is determined by measuring the PSV (Vmax) and end-diastolic velocities (Vmin) in cm/s from an intrarenal artery (usually the cortical vessels). RRI = [1 -(Vmin ÷Vmax)] × 100. The measurements are obtained from the upper, middle, and the lower third of each kidney and the measurements averaged.
TABLE 10.2 DUPLEX VELOCITY AND RATIO CRITERIA TO ASSESS HEMODYNAMIC SIGNIFICANCE | ||||||||||||||||
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