III. RENAL ARTERIAL DISEASE

A. Prevalence and Natural History

Renal artery stenosis (RAS) is both a common and progressive disease in patients with atherosclerosis and a relatively uncommon cause of hypertension (166,167). From a limited epidemiological database, it is estimated that atherosclerotic RAS may affect as many as 6.8% of people aged 65 years and older(168). However, atherosclerotic RAS is common in cohorts that have clinically evident atherosclerosis in other arterial circulations. For example, 22% to 59% of patients with PAD have hemodynamically significant RAS (as defined by a stenosis greater than 50%) (169–179). In individuals with historie of proven MI, 12% of postmortem examinations demonstrate the presence of an RAS of 75% or greater. Despite the high prevalence of RAS in these atherosclerotic subgroups, it remains controversial as to which lesions are associated with important clinical sequelae.

B. Clinical Clues to the Diagnosis of RAS

RECOMMENDATIONS

Class I

1. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with the onset of hypertension before the age of 30 years.(Level of Evidence: B)

2. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with the onset of severe hypertension [as defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report (187)] after the age of 55 years. (Level of Evidence: B)

3. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with the following characteristics: (a) accelerated hypertension (sudden and persistent worsening of previously controlled hypertension); (b) resistant hypertension (defined as the failure to achieve goal blood pressure in patients who are adhering to full doses of an appropriate 3-drug regimen that includes a diuretic); or (c) malignant hypertension (hypertension with coexistent evidence of acute end-organ damage; i.e., acute renal failure,acutely decompensated congestive heart failure,new visual or neurological disturbance, and/or advanced [grade III to IV] retinopathy). (Level ofEvidence: C)

4. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with new azotemia or worsening renal function after the administration of an ACE inhibitor or an angiotensin receptor blocking agent. (Level of Evidence:B)

5. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with an unexplained atrophic kidney or a discrepancy in size between the 2 kidneys of greater than 1.5 cm.(Level of Evidence: B)

6. The performance of diagnostic studies to identify clinically significant RAS is indicated in patients with sudden, unexplained pulmonary edema (especially in azotemic patients). (Level of Evidence: B)

Class IIa

1. The performance of diagnostic studies to identify clinically significant RAS is reasonable in patients with unexplained renal failure, including individuals starting renal replacement therapy (dialysis or renal transplantation). (Level of Evidence: B)

Class IIb

1. The performance of arteriography to identify significant RAS may be reasonable in patients with multivessel coronary artery disease and none of the clinical clues (Fig. 10) or PAD at the time of arteriography. (Level of Evidence: B)

2. The performance of diagnostic studies to identify clinically significant RAS may be reasonable in patients with unexplained congestive heart failure or refractory angina (see Section 3.5.2.4 of the full-text guidelines). (Level of Evidence: C)

Several clinical features raise the suspicion of RAS and provide relative indications for application of more specific diagnostic testing strategies. Such diagnostic testing strategies should be performed when establishment of the RAS diagnosis is likely to offer information that can beneficially be linked to an effective patient-specific treatment strategy.

C. Diagnostic Methods

RECOMMENDATIONS

Class I

1. Duplex ultrasonography is recommended as a screening test to establish the diagnosis of RAS. (Level of Evidence: B)

2. Computed tomographic angiography (in individuals with normal renal function) is recommended as a screening test to establish the diagnosis of RAS.(Level of Evidence: B)

3. Magnetic resonance angiography is recommended as a screening test to establish the diagnosis of RAS.(Level of Evidence: B)

4. When the clinical index of suspicion is high and the results of noninvasive tests are inconclusive, catheter angiography is recommended as a diagnostic test to establish the diagnosis of RAS. (Level of Evidence: B)

Class III

1. Captopril renal scintigraphy is not recommended as a screening test to establish the diagnosis of RAS.(Level of Evidence: C)

2. Selective renal vein renin measurements are not recommended as a useful screening test to establish the diagnosis of RAS. (Level of Evidence: B)

3. Plasma renin activity is not recommended as a useful screening test to establish the diagnosis of RAS.(Level of Evidence: B)

4. The captopril test (measurement of plasma rennin activity after captopril administration) is not recommended as a useful screening test to establish the diagnosis of RAS. (Level of Evidence: B)

Renal artery stenosis is best diagnosed with an imaging modality. The ideal tool should evaluate both the main and accessory renal arteries, assess the hemodynamic significance of the demonstrated lesions, identify the site and severity of the stenosis, and identify associated perirenal pathology, including the presence of an abdominal aortic aneurysm or renal or adrenal masses. Direct imaging modalities such as duplex ultrasound, CTA, and MRA are best suited to serve as effective diagnostic screening methods. The choice of imaging procedure will depend on the availability of the diagnostic tool, the experience and local accuracy of the chosen modality, and patient characteristics (e.g., body size, renal function,contrast allergy, and presence of prior stents or metallic objects that may serve as contraindications to MRA or CTA techniques).

SUMMARY OF NONINVASIVE RENAL ARTERY DIAGNOSTIC IMAGING

STRATEGIES. There are relative advantages and disadvantages to each of the aforementioned imaging modalities.Captopril renography has been validated in a large number of patients but is limited in value to a subset of all potential renovascular patients and is of limited value in patients with significant azotemia, bilateral RAS, or RAS to a single functioning kidney. Duplex renal sonography,because of the critical role of the sonographer, is accurate in experienced laboratories and is thus ideally performed in high-volume accredited laboratories. The diagnostic accuracy of these ultrasound-based examinations is further limited in patients with large body habitus or intestinal gas obscuring visualization of the entirety of the renal artery. Computed tomographic angiography currently provides higher spatial resolution than MRA and may be more readily available; however, the requirement to use iodinated contrast makes it an unattractive modality in patients with impaired renal function.Gadolinium-enhanced MRA provides excellent and lessnephrotoxic characterization of the renal arteries, surrounding vessels, renal mass, and perhaps renal function,but it remains the most costly renal artery examination. It is far less useful in patients who have had a metallic renal

artery stent placed because of the inability to image insideof the stent to detect restenosis. Comparisons of contrast-enhanced 3-dimensional MRA and multidetector CTA with digital subtraction catheter angiography in a large number of arterial segments have demonstrated equally high sensitivities for detection of hemodynamically significant stenoses for MRA and CTA (greater than 90%), with excellent interobserver and intermodality agreement (kappa equals 0.88 to 0.90) (180).

1. Catheter Angiography.

The indications for catheterbased contrast renal angiography include (a) individuals in whom there are prespecified indications to suspect clinically important RAS (“clinical clues”) in whom definitive diagnostic noninvasive images cannot be obtained and (b) individuals in whom these prespecified clinical indications and patient consent have been documented and in whom concomitant angiographic access has been obtained for peripheral angiography or coronary angiography. Catheterbased contrast angiography is associated with a low rate of serious adverse outcomes.

2. Renin.

A. SELECTIVE RENAL VEIN RENIN STUDIES.

The utility of renal vein renin measurements depends on the ability to differentiate the unilateral elevation of renin concentration from the renal vein that drains the kidney with renal artery disease from the systemic plasma renin levels and/or renal vein renin levels collected from the contralateral (normal) kidney.The test may have more utility in establishing an indication for nephrectomy in patients with renal artery occlusion than in identifying patients with RAS who may derive benefit from revascularization (181); for pediatric patients with questionably severe RAS before revascularization; or for patients with very marked aortoiliac-renal atherosclerosis, in whom revascularization could carry unusually high risk.

B. PLASMA RENIN ACTIVITY: CAPTOPRIL TEST.

The overall sensitivity of this test is 61%, with a specificity of 86% for the detection of RAS; however, this test is less accurate in patients who are volume expanded or who have chronic renal failure, bilateral renal artery disease, or disease to a solitary functioning kidney. Plasma renin activity is not recommended as a useful screening test to establish the diagnosis of RAS.

D. Treatment of Renovascular Disease: Renal Artery Stenosis

Treatment of renal arterial disease should serve to aid in the normalization of blood pressure and to preserve renal function. Both medical (pharmacological) and revascularization strategies should be considered for patients with documented renal arterial disease.

1. Medical Treatment.

RECOMMENDATIONS

Class I

1. Angiotensin-converting enzyme inhibitors are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: A)

2. Angiotensin receptor blockers are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: B)

3. Calcium-channel blockers are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: A)

4. Beta-blockers are effective medications for treatment of hypertension associated with RAS. (Level of Evidence:A)

Multiple studies have now shown that ACE inhibitors and calcium-channel blockers are effective in the treatment of hypertension in the presence of RAS (182–186). These results address primarily the treatment of hypertension, but diminution in the progression of renal disease has also been demonstrated.There is also evidence that alternative therapies, basedlargely on chlorothiazide, hydralazine, and beta-blockers, also appear effective to achieve target blood pressures in individuals with RAS. Although the angiotensin II receptor blockers also have an evidence base of efficacy for normalization of blood pressure in individuals with RAS, their effects need to be tested further in large randomized trials. There are currently few objective clinical clues that permit selection of specific patient cohorts that would best be treated by medical therapy versus renal arterial revascularization, which remains an area of active clinical investigation. Individuals with atherosclerotic disease and hypertension should be treated according to the goals of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (187).

2. Indications for Revascularization.

A. ASYMPTOMATIC STENOSIS.

RECOMMENDATIONS

Class IIb

1. Percutaneous revascularization may be considered for treatment of an asymptomatic bilateral or solitary viable kidney with a hemodynamically significant RAS. (Level of Evidence: C)

2. The usefulness of percutaneous revascularization of an asymptomatic unilateral hemodynamically significant RAS in a viable kidney is not well established and is presently clinically unproven. (Level of Evidence:C)

There are no well-controlled prospective randomized investigations to measure the relative risk and benefit of endovascular interventions (or associated medical therapies) in individuals with asymptomatic renal artery disease, and thus, the role of such interventions remains controversial. Recommendations regarding the role of percutaneous revascularization of asymptomatic renal disease are made largely on the basis of expert opinion and are not based on evidence that treatment of asymptomatic RAS improves any renal or systemic outcome, including renal preservation, blood pressure, or cardiovascular morbidity or mortality. Therefore, these recommendations must be individualized for the patient by each treating physician.

B. HYPERTENSION.

RECOMMENDATIONS

Class IIa

1. Percutaneous revascularization is reasonable for patients with hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication. (Level of Evidence: B)

The current evidence base suggests that patients with severe atherosclerotic RAS and accelerated, resistant, and malignant hypertension may expect to receive some clinical benefit, including improved blood pressure control, the need for fewer medications, or both. However, “cure” of hypertension is rare, improvement in blood pressure control is common, and a moderate fraction of individuals do not achieve measurable benefit .

C. PRESERVATION OF RENAL FUNCTION.

RECOMMENDATIONS

Class IIa

1. Percutaneous revascularization is reasonable for patients with RAS and progressive chronic kidney disease with bilateral RAS or a RAS to a solitary functioning kidney. (Level of Evidence: B)

Class IIb

1. Percutaneous revascularization may be considered for patients with RAS and chronic renal insufficiency with unilateral RAS. (Level of Evidence: C)

Revascularization is effective in stabilizing or improving renal function in patients with symptomatic atherosclerotic RAS (188 –193). Several factors may argue against renal revascularization or predict poorer outcomes, including the presence of proteinuria greater than 1 g every 24 hours, renal atrophy, severe renal parenchymal disease, and severe diffuse intrarenal arteriolar disease. Moreover, the adverse consequences of renal atheroembolization at the time of surgical revascularization have been documented(194). Similarly, potentially severe atheroembolization may be provoked by renal percutaneous revascularization methods (195).

D. IMPACT OF RAS ON CONGESTIVE HEART FAILURE AND UNSTABLE ANGINA.

RECOMMENDATIONS

Class I

1. Percutaneous revascularization is indicated for patients with hemodynamically significant RAS and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema (see text).(Level of Evidence: B)

Class IIa

2. Percutaneous revascularization is reasonable for patients with hemodynamically significant RAS and unstable angina (see text). (Level of Evidence: B)

The potential physiological benefits of renal stent placement include reperfusion of the ischemic kidney(s), resulting in a reduction in the stimulus to renin production, which decreases angiotensin and aldosterone production, thereby decreasing peripheral arterial vasoconstriction and the tendency to develop an expanded extracellular fluid volume. Improvement in renal perfusion enhances glomerular filtration and therefore promotes natriuresis. Finally, in patients with a solitary kidney or bilateral RAS, the ability of the patient to tolerate long-term administration of angiotensin antagonist medications may be facilitated by relief of a hemodynamic renal artery obstruction. The recommendations in these guidelines are intended to apply to individuals with refractory heart failure or unstable angina in whom nonrenal exacerbating factors have been evaluated and in whom there are reasonable clinical indications to suggest the presence of RAS (e.g., systemic atherosclerosis), as is more fully described in the full-text version of the guidelines.

3. Catheter-Based Interventions.

RECOMMENDATIONS

Class I

1. Renal stent placement is indicated for ostial atherosclerotic RAS lesions that meet the clinical criteria for intervention. (Level of Evidence: B)

2. Balloon angioplasty with bailout stent placement if necessary is recommended for fibromuscular dysplasia lesions. (Level of Evidence: B)

Percutaneous transluminal renal balloon angioplasty is the treatment of choice for symptomatic RAS caused by fibromuscular dysplasia (188,196–198). However, in atherosclerotic RAS, balloon angioplasty alone is associated with a lower procedural success rate and a higher restenosis rate (189,199–205). Aorto-ostial stenoses represent the most common atherosclerotic lesions and are prone to vascular recoil due to confluent plaque that extends from the wall of the aorta into the ostium of the renal artery. These atherosclerotic aorto-ostial lesions are generally considered unsuitable for treatment by balloon angioplasty alone(197,198,206).Stent placement has consistently proven superior to balloon angioplasty in the treatment of renal artery atherosclerotic lesions (207,208). For renal artery atherosclerotic lesions, the larger the poststent minimal lumen diameter, as measured by quantitative vascular angiography, the better the late stent patency (209). Similar to coronary stents,larger-diameter renal arteries have lower restenosis rates than smaller-diameter vessels (210,211).

4. Surgery for RAS.

RECOMMENDATIONS

Class I

1. Vascular surgical reconstruction is indicated for patients with fibromuscular dysplastic RAS with clinical indications for interventions (same as for PTA), especially those exhibiting complex disease that extends into the segmental arteries and those having macroaneurysms. (Level of Evidence: B)

2. Vascular surgical reconstruction is indicated for patients with atherosclerotic RAS and clinical indications for intervention, especially those with multiple small renal arteries or early primary branching of the main renal artery. (Level of Evidence: B)

3. Vascular surgical reconstruction is indicated for patients with atherosclerotic RAS in combination with pararenal aortic reconstructions (in treatment of aortic aneurysms or severe aortoiliac occlusive disease).(Level of Evidence: C)

A. RESULTS OF OPERATIVE THERAPY.

Surgical treatment of renovascular hypertension affords good clinical outcomes(212–216). The risk of surgery increases in patients who require concomitant aortic reconstruction, in patients with renal insufficiency, and when aortic grafts are used as a source of the bypass graft. The need for reoperation has been reported in 5% to 15% and survival in 65% to 81% ofpatients (212–216).