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Renal Artery Stenosis/Renovascular Hypertension

Article Last Updated: Jun 6, 2008

Background

Renovascular hypertension (RVHT) denotes nonessential hypertension in which a causal relationship exists between anatomically evident arterial occlusive disease and elevated blood pressure. RVHT is the clinical consequence of renin-angiotensin-aldosterone activation as a result of renal ischemia. Renal artery stenosis (RAS) is a major cause of RVHT and accounts for 1-10% of the 50 million cases of hypertension in the United States.

Apart from the casual relationship of occlusive renal artery disease and hypertension, RAS is also being increasingly recognized as an important cause of chronic renal failure. In older patients, atherosclerosis is the most common cause of RAS. RAS caused by atherosclerosis is generally a progressive disease with increasing luminal narrowing, which may eventually compromise renal blood flow and renal function and structure.

Arterial dysplasias (AD) are an uncommon angiopathy associated with heterogeneous histologic changes that may affect the carotid circulation and the visceral and peripheral arteries. Medial fibroplasia (MFP), as a cause of RAS, usually affects young to middle-aged adults, mostly women, but it can also affect children. It is an important cause of RVHT in children.^{1, 2, 3, 4} The average age range of patients with MFP is 30-40 years. The youngest patient with MFP of the renal artery was reportedly 6 months of age.

Ultimately, MFP results in arterial stenosis, which causes organ ischemia or infarction. The clinical manifestations reflect the arteries involved; it most commonly manifests as hypertension caused by RAS or as strokes caused by carotid artery disease. MFP is one of the most important mimics of vasculitis.

Although MFP is a pathologic diagnosis, characteristic change is seen at vascular imaging. The most common finding is the string-of-beads appearance, caused by areas of relative stenoses or webs alternating with small fusiform or saccular aneurysms of the artery. Approximately 10-30% of patients with RAS have MFP.

Diagnostic imaging plays an essential role in the diagnosis and treatment of RVHT. With an aging population and a possible increase in the prevalence of RAS and ischemic nephropathy, radiologists will play an increasing role in both the diagnosis and treatment of RVHT.^{5, 6, 7, 8}

Pathophysiology

RVHT is the clinical consequence of renin-angiotensin-aldosterone activation. Since Goldblatt's work in 1934, RVHT has become increasingly recognized as a cause of clinically difficult-to-control hypertension and chronic renal insufficiency. Goldblatt demonstrated that occlusion of the renal artery causes ischemia, which then causes an elevation of blood pressure by triggering the release of renin. Increased renin levels help in the conversion of angiotensin I to angiotensin II, causing severe vasoconstriction and aldosterone release. The ultimate cascade of events depends on the presence of a functioning contralateral kidney.⁹

The development of RVHT involves the activation of both limbs of the renin-angiotensin-aldosterone system and is conditioned by the presence or absence of a contralateral kidney. Unilateral renal ischemia initiates an increase in the secretion of renin, which accelerates the conversion of angiotensin I to angiotensin II and which enhances the adrenal release of aldosterone. Aldosterone-mediated sodium and water retention is efficiently handled by the noncompromised kidney; in such cases, the volume is not a contributing factor in angiotensin II–mediated hypertension.

Atherosclerotic disease is usually diffuse and may involve both kidneys. In such cases, the patient may be left with a solitary ischemic kidney that has little reserve capacity for sodium and water excretion; hence, in such cases, volume does play an additive role in the hypertension. An ischemic solitary kidney is unable to perform the pressure diuresis required to handle the aldosterone-induced sodium and water retention. Thus, the resultant volume load further contributes to the hypertension and also suppresses the production of renin by the stenotic kidney.

Angiotensin II causes vasoconstriction of both afferent and efferent arterioles, with a preferential affect on the efferent side. Under physiologic conditions, efferent tone is essential to the maintenance of intraglomerular pressure. Angiotensin blockade increases efferent renal arterial blood flow, which increases intraglomerular pressure and optimizes the glomerular filtration rate (GFR).

In a kidney rendered ischemic by RAS with a reduced afferent blood flow, the intraglomerular pressure and glomerular filtration are maintained by angiotensin II–mediated efferent vasoconstriction. Removal of the efferent vasoconstriction effect by use of angiotensin blockade in the ischemic kidney may reduce the GFR. Angiotensin blockade may be achieved by the use of angiotensin-converting enzyme (ACE) inhibitors.

The use of ACE inhibitors causes a deterioration of renal function in some patients with renovascular disease; this effect is particularly pronounced in patients with bilateral RAS. Because angiotensin predominantly affects the efferent renal arteriole, the decrease in renal blood flow caused by afferent vasoconstriction is less than the decrease in the GFR caused by efferent vasoconstriction. The net result is a decrease in the filtration fraction. By blocking angiotensin, ACE inhibitors eliminate efferent vasoconstriction and cause a decrease in the intraglomerular pressure and the GFR.

Normally, the perfusion of the kidney is increased by as much as 5 times, as compared with that of other organs, because it drives glomerular capillary filtration. Both glomerular capillary hydrostatic pressure and renal blood flow are essential components of the GFR.

In patients with RAS, chronic ischemia produces adaptive changes in the kidney that are more pronounced in the tubular tissue. These changes include tubular cell atrophy, atrophy of the glomerular tuft, patchy inflammation and fibrosis of tubular cells, tubular sclerosis, thickening and duplication of the Bowman capsule, and intrarenal arterial medial thickening. In RAS, the GFR is dependent on angiotensin II and other modulators that maintain the balance between the afferent and efferent arteries. However, when perfusion pressure decreases below 70-85 mm Hg, maintaining an adequate GFR may no longer be possible. Significant functional impairment of autoregulation, leading to a decrease in the GFR, is not likely to occur until arterial luminal narrowing exceeds 50%.

In adults, renovascular disease tends to appear at different times, and it affects the sexes differently. Atherosclerotic disease affects mainly the proximal third of the main renal artery, and it is most common among older men. Fibromuscular dysplasia (FMD) involves the distal two thirds and branches of the renal arteries; it is most common among younger women.

Other conditions that may be associated with RVHT include cholesterol embolic disease, acute arterial thrombosis or embolism, aortic dissection, neurofibromatosis, renal arterial trauma, arterial aneurysm, arteriovenous malformation of the renal artery, and polyarteritis nodosa and other vasculitides.

In the first stage, the immediate elevation of blood pressure is a direct result of increased levels of renin. Over days to weeks, the blood pressure remains elevated; the course and presence of elevated renin levels depends on the presence and function of the contralateral kidney. The mechanism by which hypertension is produced in patients with renovascular disease thus changes over time and varies with the sodium balance. With a normally functioning contralateral kidney, volume expansion is avoided, and renin levels remain high. The 2 kidneys function out of sync: The ischemic stenotic kidney produces excessive renin and retains sodium, whereas the comparatively normal kidney continues to excrete sodium and water to maintain normal volume levels. The end result is systemic hypertension that is renin and angiotensin mediated.

In the second phase, in the setting of an ischemic solitary kidney, sodium and water retention, together with the vasopressor effects of angiotensin II, act to maintain renal perfusion pressure. The stimulus to produce renin is impaired, and renin levels thus decrease. In these circumstances, angiotensin II no longer drives the hypertensive state, but the high blood pressure instead results from volume expansion. Thus, perfusion pressure tends to be maintained at the expense of systemic hypertension and volume retention.

Renal perfusion may return to normal if blood flow is normalized during the first 2 phases, and the blood pressure soon returns to a normal level.

In the third phase, hypertension persists, even after patency of the renal artery is restored. Once phase 3 is reached, restoration of renal blood flow may not result in a normalization of the blood pressure, presumably because of secondary irreversible vascular or renal parenchymal disease.

How the initial arterial epithelial injury occurs in patients with atherosclerosis is not clear. Lipid abnormalities, hypertension, cigarette smoking, diabetes mellitus, viral infection, immune injury, and increased homocysteine levels have all been implicated as factors contributing to the endothelial injury. At the site of the endothelial atheromatous lesion, permeability to plasma macromolecules (eg, low-density lipoproteins) is increased, with a subsequent increase in the turnover of endothelial cells, smooth muscle cells, and intimal macrophages. When atherogenic lipoproteins exceed a certain critical mass, the mechanical forces may enhance lipoprotein infiltration in these regions, leading to early atheromatous lesions.

Atherosclerotic RAS may progress in as many as one third of patients, and ongoing ischemic renal parenchymal damage is of concern. Furthermore, despite adequate blood pressure control, this condition is associated with a reduction in renal perfusion pressure, and renal function may deteriorate.

Studies of the natural history of atheromatous RAS obtained by means of sequential abdominal aortography or duplex sonography in patients with documented and medically treated RAS have shown that progressive arterial obstruction occurs in 42-53% of patients within the first 2 years of follow-up. In patients with a high degree of RAS, the rate of progression to complete renal artery occlusion is 9-16%. In a study of 85 patients at the Cleveland Clinic who were followed for 3-172 months, mild to moderate stenosis remained unchanged, but in 39% of patients, lesions of greater than 75% progressed to total occlusion.¹⁰

Leadbetter and Burkland first reported AD of a renal artery in 1938 when they removed an ectopic kidney in a 5-year-old boy who presented with sustained hypertension.^{11, 12} FMD may involve any layer of a visceral artery, and it may be classified as intimal, medial, or adventitial. The medial variety can be subdivided into several more categories.

In 1967, McCormack et al classified AD on the basis of the primary site of involvement of arterial wall, as determined histologically.¹³ Their classification of fibrosing lesions of renal arteries included the categories of intimal fibroplasia, medial fibrosis with microaneurysms, subadventitial fibroplasia, and fibromuscular hyperplasia. They first coined the term chain of beads to describe radiographic changes in MFP of the renal artery. The term has subsequently been modified to string of beads. MFP is the most common variety of AD and represents 85% of the cases. The string-of-beads sign is classically seen in MFP.

A similar radiographic appearance can be caused by subadventitial fibroplasia, but in this variant, the size of the aneurysms does not exceed the diameter of the renal artery. MFP may appear as a single stenosis of a visceral artery, but it is more often seen as multiple stenoses with intervening outpouchings forming a chain. Radiographically, this is depicted as a string-of-beads sign.

Histologically, MFP can be subdivided into 2 types: a peripheral form and a diffuse form. The peripheral form generally affects the outer media, replacing the smooth muscle with fibrous-appearing tissue. The diffuse form affects the media more extensively, with replacement of the media with fibrous tissue interspaced by medial thinning. The media may be completely absent in some areas, giving rise to aneurysmal dilatation. Although FMD was initially described in the renal arteries, many other visceral arteries are now known to be involved, and multiple visceral-artery aneurysms have been reported.

Although the pathogenesis is not completely understood, humoral, mechanical, and genetic factors may play a role, as may mural ischemia.¹⁴ Hormonal factors have been implicated because MFP and subadventitial fibroplasias are found predominantly in women. The common association with ptotic kidneys has supported the mechanical theory in which stretching of the renal artery may be responsible for the development of FMD.

Ischemia caused by inadequate nutrition of the renal artery by the vasa vasora has been implicated. A deficiency of alpha-1-antitrypsin has also been implicated in the development of various disorders affecting medium-sized arteries, including those affected by intracranial aneurysms, cervicocephalic arterial dissections, and FMD. Some have suggested that a heterozygous alpha-1-antitrypsin deficiency may be a genetic risk factor for FMD.

The natural history of MFP is relatively benign, with progression occurring in only a minority of patients. Anatomic progression of MFP in the renal artery has been reported in 12-66% in patients with main renal artery disease. However, renal function deterioration, as assessed by measuring the serum creatinine level or a reduction in renal size, seldom occurs despite progression of RAS, as demonstrated angiographically.

Complete obstruction of the renal artery, leading to total renal infarction, has been reported. Studying potential artery donors with angiographic evidence of AD, Goncharenko et al found that 26% developed hypertension, as compared with 6% of age- and sex-matched control subjects.¹⁵ Medical treatment of MFP-associated hypertension poses the risk of a further reduction of renal blood flow, which may result in ischemic atrophy or even total infarction of the involved kidney. Isolated renal artery dissection is a rare condition that has also been reported in association with MFP.

Hepatic and superior mesenteric involvement in FMD occurs less frequently, and sporadic cases of severe intestinal ischemia and hepatic artery aneurysm rupture have been reported. FMD is a rare cause of abdominal aortic aneurysm. The consequences of RAS are hypertension, which may be particularly difficult to control or which may require the use of multiple antihypertensive agents (with increased adverse effects), and possibly a progressive loss of renal function. The discovery of atherosclerotic renal vascular disease frequently occurs in the setting of generalized vascular disease (eg, cerebral, cardiac, peripheral disease), with the consequences associated with disease in those vascular beds.

Neurofibromatosis is a rare cause of RAS and usually occurs secondary to fibrous proliferation of the intima or media. Less commonly, neurofibromatous tissue affects the adventitia; the resulting periarterial fibrosis causes RAS that is indistinguishable from RAS of other causes. These lesions usually occur at the origin of the artery, and they may be bilateral.

Congenital stenosis (coarctation of renal artery) is extremely rare and is assumed to be congenital because of its occurrence early in life. This type of stenosis is generally confined to the main renal artery, and it may be associated with aortic coarctation. Some cases may eventually involve changes related to arteritis, FMD, or neurofibromatosis.

Transplant RAS is seen in about 10% of patients after renal transplantation, and it is the most important form of treatable hypertension. In renal transplantation patients, RAS may occur as a complication of surgery, as a result of transplant rejection, or as intrinsic vascular disease; transplant RAS usually occurs in the first year after surgery and, rarely, after the third year. Patients usually present with hypertension and, occasionally, an elevated serum creatinine level.

The extent to which the RAS stenosis contributes to the hypertension is difficult to determine because rejection is a frequent cause of vascular disease, and systemic hypertension often accompanies rejection. Of the 20% of patients with renal failure whose blood pressure is normal, 50% become hypertensive after renal transplantation. With this complex background and the ever-present complication of graft rejection and acute tubular necrosis, one may lose sight of RAS as a treatable cause of hypertension.

Frequency

United States

RVHT is the most common type of secondary hypertension, accounting for less than 1% of cases in unselected populations and as many as 30% of cases in selected populations. Studies suggest that ischemic nephropathy may be responsible for 5-22% of advanced renal disease in all patients older than 50 years. FMD accounts for approximately 25% of all cases of RVHT, and it is a common cause of hypertension in children. RVHT occurs in approximately 6 of 100,000 people.

International

The international prevalence of RVHT is not known, but no data suggest that the incidence differs from that in the United States.

Mortality/Morbidity

Race

Sex

Age

The age of onset depends on the cause of the damage to the renal blood vessels. The average age range is 30-40 years. RVHT tends to occur in patients younger than 30 years or older than 50 years. The youngest patient with fibromuscular dysplasia (FMD) of the renal artery was reportedly 6 months of age.

Anatomy

Although classified as dorsal branches, the renal arteries usually arise as lateral aortic branches slightly below the disk between L1 and L2. Rarely, the renal arteries arise below the inferior aspect of D12 or below the lower border of L2.

The position of the kidney is variable, and although most renal arteries arise between L1 and L2, the length of the renal arteries and the angle between the aorta and the renal arteries vary. The lower the kidneys are, the longer and more acutely angulated are the renal arteries.

The right renal artery may originate slightly anterior to the coronal plane. Supplemental renal arteries may be problematic for the angiographer because they may be difficult to find and the catheter tip may obstruct the orifice. The origin of the renal arteries may vary; these arteries may arise from D11 down to the iliac vessels. Furthermore, supplemental branches may arise from visceral arteries.

Cadaveric studies have shown that single renal arteries are bilaterally present in 72% of cases. The kidney may be divided into dorsal and ventral segments, and the arteries to these segments may be identified on angiograms. The intrarenal branches of renal arteries taper uniformly. The intralobar branches repeatedly branch to give rise to arcuate arteries. The interlobular arteries arise from the arcuate arteries, where they extend into the renal cortex in a parallel fashion.

AD may affect the main renal arteries and the intralobar arteries. With severe RAS, extensive collateral circulation develops via the capsular, peripelvic, and periureteric systems. These collaterals involve the capsular, lumbar, internal iliac, lower intercostal, and gonadal arteries. The collateral channels are coiled, tortuous, and enormously lengthened in comparison to normal arteries.

Clinical Details

Risk factors associated with the development of atherosclerotic RAS include the following:

Preferred Examination

The preferred imaging method for a patient suspected of having RAS is controversial. Accurate identification of patients with correctable RVHT can be difficult with use of standard noninvasive techniques, such as sonography, because they provide only indirect evidence of the presence of RAS. On the other hand, some invasive techniques that are much more accurate have the potential of nephrotoxicity. In such cases, invasive methods can cause deterioration of renal function and procedure-related complications at the site of arterial puncture or catheter-induced embolism.

Gilfeather et al evaluated conventional angiography versus gadolinium-enhanced magnetic resonance angiography (MRA) in 54 patients and 107 kidneys. The study showed that in 70 kidneys (65%), the average degree of stenosis reported for both modalities differed by 10% or less.¹⁸

In 22 cases (21%), MRA caused overestimation of the stenosis by more than 10% relative to the results of conventional angiography. In 15 cases (14%), MRA caused underestimation of the stenosis by more than 10%. MRA produces excellent contrast-enhanced angiograms without the risk of iodinated compounds and radiation exposure. MRA provides accurate information about the number of renal arteries, the size of the kidneys, and the presence of anatomic variants. The obvious advantages of conventional angiography are its usefulness in determining the clinical importance of suspicious lesions and the ability to concurrently perform endovascular intervention.

Hypertensive urography is of historical interest and is no longer used as a screening technique for RAS. CO₂ angiography is also obsolete because of MRA and gadolinium imaging. CT angiography (CTA) with maximum intensity projection (MIP) and the quantitative measurement of stenosis is an accurate, noninvasive technique in the diagnosis of visceral artery stenosis; this is fast becoming the diagnostic tool of choice, with angiography being reserved for cases in which vascular intervention is planned.

Doppler sonography can be used to measure the velocity of blood flow. It is a noninvasive technique, and it has high sensitivity in expert hands. Color-flow Doppler may demonstrate disorganized flow patterns and high-velocity flow stream associated with hemodynamically significant stenosis. Radionuclide renography technetium-mercaptoacetyltriglycine (MAG3)-captopril has a high sensitivity and specificity, and it adds a physiologic element to the diagnosis of RAS.^{19, 20}

Limitations of Techniques

The acceptance of radionuclide renography as a primary screening tool for RAS has been hindered by the lack of standardized protocols.

Doppler ultrasonography is operator dependent, time consuming, and cumbersome. Doppler sonography examination is affected by anatomic, technical, patient-related, and pathologic factors.

CTA or MRA may cause the clinician to overlook mild cases of FMD that are detectable with digital subtraction angiography (DSA). Most of the false-negative and false-positive findings of RAS arise from accessory renal arteries. MRI is expensive, and its availability is limited.

Measurements of the size of RAS on angiograms (an important clinical consideration) are imprecise, and angiograms do not permit assessment of the cross-sectional area or, more importantly, the flow through the stenotic segment. The various histologic types of FMD are difficult to distinguish on angiograms; this limitation has important clinical implications from a prognostic point of view.

All techniques do not relate to the predictive value of the cure aspect in reestablishing renal perfusion.

Other Problems to Be Considered

Systemic necrotizing vasculitis
Binswanger disease
Grange syndrome
Acute renal failure
Albuminuria
Atherosclerosis
Renal failure
Chronic glomerulonephritis
Essential hypertension and hypertension of other causes
Malignant hypertension
Nephropathy
Atherogenesis

Standing waves in the renal arteries appear as multiple serrated indentations, symmetrically distributed at evenly spaced intervals. These waves are of no pathologic significance and may represent arterial spasm. They may also affect intrarenal branches.

A fibrous musculotendinous band may cause extrinsic compression of the renal artery.

Klippel-Trenaunay syndrome is a congenital angiodysplasia consisting of a triad of angiomas, osteohypertrophy, and venous varicosities. Visceral involvement is not uncommon and may cause life-threatening complications.²¹

Findings

Degree of Confidence

Hypertensive urography is of historical interest only. It is no longer used as a screening technique for RAS because of its inconsistent results. The urogram may be normal in the presence of established RAS.

Findings

CTA with MIP and quantitative measurement of stenosis is an accurate noninvasive technique in the diagnosis of RAS. The advent of spiral and multisection CT scanning has made CTA feasible. Continuous scanning through an area of interest during a single breath-hold provides sufficient data to reconstruct 3-dimensional (3D) images (see Images 2, 14-18).

Many scanning protocols are available. The general consensus is that both a timed bolus and rapid injection rate improve image quality. No positive oral contrast material should be used because it results in severe degradation of the image quality. Immediately before the procedure, the patient ingests water, and glucagon is then given intravenously to diminish bowel movement and maximize bowel distention. The 3 most common techniques used for 3D reconstruction are MIP, shaded-surface display (SSD), and volume rendering. MIP is often the single most useful technique for 3D reconstructions.

Accessory renal arteries are reliably identified by means of CTA. In either the mainstem artery or its intrarenal branches, RAS is detected with a high degree of accuracy.^{22, 23, 24, 25}

Degree of Confidence

The sensitivity and specificity of spiral CT in detecting RAS are approximately 98% and 94%, respectively. In patients with a plasma creatinine concentration higher than 1.7 mg/dL, the accuracy is lower (93% sensitivity, 81% specificity), possibly because of reduced renal blood flow. Because most of the false-negative and false-positive findings arise from accessory renal arteries, the accuracy in detecting RAS of the main renal artery may be as good as that of angiography.

False Positives/Negatives

Andreoni et al raised concerns that CTA or MRA may cause clinicians to overlook mild cases of digital subtraction angiography (DSA)-detectable AD.²⁶ Most of the false-negative and false-positive findings of RAS are related to accessory renal arteries.

Findings

MRA is fast becoming a clinical standard for the safe and noninvasive detection of RAS, aneurysms, and occlusions. A comprehensive examination includes both 3D dynamic gadolinium-enhanced and 3D phase-contrast MRA techniques, which allow an evaluation of the renal arteries and other visceral arteries. The 3D phase-contrast technique is flow based and subject to dephasing in the presence of significant arterial stenosis. The 3D gadolinium-enhanced MRA method produces excellent contrast angiograms without the risk of iodinated compounds or radiation exposure (see Images 3-9, 11-12).

MRA provides accurate information about the number of renal arteries, the size of the kidneys, and the presence of anatomic variants.^{27, 28, 29}

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

As of late December 2006, the FDA had received reports of 90 such cases of NSF/NFD. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Degree of Confidence

Gadolinium-enhanced MRA has been proven to have high sensitivity for detecting stenosis in the main and accessory renal arteries. At presentation, MRA provides anatomic information regarding a vascular stenosis, but it provides little information about the functional significance of a stenosis. Studies have shown that 3D MRA with gadolinium-based contrast agents (which have a low potential for nephrotoxicity) has a sensitivity of 96-100% and a specificity of 71-96% for the detection of a main RAS of greater than 50%.

When combined with cardiac synchronization, 3D MRA can sharply delineate the entire length of the major renal arteries. However, MRA remains suboptimal for the detection of hemodynamically significant lesions of distal, intrarenal, and accessory renal arteries, which may cause physiologically significant RAS.

Limitations of MRA include its cost and lack of availability. Contraindications to MRA include claustrophobia and the presence of metallic implants, such as a pacemaker or surgical clip.

False Positives/Negatives

Andreoni et al raised concerns that CTA or MRA may cause clinicians to overlook mild cases of digital subtraction angiography (DSA)-detectable AD.²⁶ Although false-negative studies in RAS are rare, a tendency to overestimate stenoses occurs, and this overestimation may lead to a false-positive diagnosis. To some extent, this tendency to overestimate stenoses can be compensated for by performing phase-contrast MRA, a type of MRA that utilizes accumulated phase differences.

Findings

The diagnosis of RAS is made on the basis of systolic and diastolic velocity changes throughout the length of the renal artery (see Image 1). Renal artery flow patterns can be classified into 4 categories: (1) normal, (2) diameter-reducing stenosis of less than 60%, (3) diameter-reducing stenosis of more than 60%, and (4) renal artery occlusion.

The peak systolic velocity in normal renal arteries averages 120 cm/s ±12, with an average peak systolic aortic velocity of 60 m/s ±15. Both velocities decrease with age.

The kidneys have a low-resistance vascular bed; thus, the Doppler spectral waveform from the normal kidney is that of a constant forward diastolic flow. In renal parenchymal disease, there is increased vascular resistance, which causes a decrease in the diastolic flow component and an increase in the pulsatility of the Doppler spectral waveform. Parenchymal diastolic flow velocities of less than 20% of the peak systolic velocities are consistent with renal parenchymal disease.

In RAS, the peak systolic velocity increases by more than 150 cm/s for angles less than 60° and by more than 180 cm/s for angles greater than 70°. Poststenotic spectral broadening may be present with or without flow reversal. Flow may be absent during diastole in a stenosis of more than 50%. A ratio of the peak systolic renal artery velocity to the aortic peak systolic velocity of 3.5 or more is said to be predictive of a stenosis of more than 60%.

Certain indirect Doppler sonographic signs have been described for RAS. One such sign is the presence of tardus-pavus pulse, which is demonstrated by a gradual slope of Doppler waveform during systole (pulse time increase of greater than 0.07-0.12 s) and an attenuation of Doppler waveform amplitude (peak systolic velocity less than 20-30 cm/s). The acceleration index is determined by dividing the slope of the systolic upstroke (in kilohertz per second) by the carrier Doppler frequency. The acceleration time is the interval between the onset of systole and the initial peak. The acceleration index in RAS is greater than 3 m/s². The resistive index in RAS is usually less than 0.56. The early systolic peak may be absent in RAS.

Color-flow Doppler imaging may demonstrate disorganized flow patterns and a high velocity flow stream associated with hemodynamically significant stenosis. A false-negative diagnosis may occur with an accessory renal artery, whereas a false-positive diagnosis may be made with coarctation of the aorta.

In about 10% of patients who undergo renal transplantation, RAS occurs in the transplanted kidney. This raises the question of whether RAS is the cause of post-transplant hypertension. The site of stenosis is not an anastomotic site in most patients; this suggests the possibility of focal rejection (with edema/fibrosis) as the cause of the hypertension. Duplex and color-Doppler sonography have greatly affected the diagnosis of RAS. The most reliable Doppler criteria for stenosis are a high-velocity jet and distal turbulence.³⁰

Degree of Confidence

Doppler sonography has several limitations in the diagnosis of RAS. These include patient-related factors, anatomic factors, technical factors, and pathologic factors.

Patient-related factors include bowel gas, obesity, respiratory renal movements, and poor patient compliance.

Anatomic factors include multiple renal arteries (16-28%), variation of renal veins (used as imaging landmarks), horseshoe kidneys, and crossed ectopia.

Technical factors include false-positive examination results associated with suboptimal angles, variation in operator experience, incomplete examination (because complete renal evaluation is cumbersome), the need to visualize the entire length of artery, transmitted cardiac and/or aortic pulsation (which may obscure renal waveforms), and different emphases on variable parameters.

Pathologic factors include false tracings (which may be recorded from large collateral vessels and a reconstituted main renal artery) and the presence of disorders that are associated with RAS and that affect different sites (eg, atheroma, fibromuscular hyperplasia, vasculitis, arteriovenous fistula, retroperitoneal fibrosis, neurofibromatosis).

False Positives/Negatives

A false-negative diagnosis may occur with accessory renal artery, whereas a false-positive diagnosis may be made with coarctation of the aorta.

Findings

Standard renography with iodine-131 (¹³¹I)–labeled ortho-iodohippurate (OIH) is of historical interest and is no longer performed in the investigation of RAS.

The effect of the ACE inhibitor captopril on RAS was first described by Majd et al in 1983.³¹ They observed virtually no radionuclide uptake on diethylene triamine pentaacetic acid (DTPA) images in a patient with hypertension receiving captopril therapy. A repeat DTPA renogram performed in the same patient after cessation of captopril therapy revealed normal, bilateral DTPA uptake.

A number of mechanisms have been proposed to explain the effects Majd et al observed,³¹ although none explain the entire observed phenomenon. Normally, a balance maintains glomerular filtration in vascular tone between the preglomerular and postglomerular arterioles. With significant RAS, this balance is disturbed, because the pressure in the preglomerular arteriole is decreased and the filtration pressure can be maintained only by the postglomerular arteriolar vasoconstriction mediated by the renin-angiotensin system.

The administration of an ACE inhibitor such as captopril prevents the conversion of angiotensin I to the active vasoconstrictors angiotensin II and angiotensin III. By inhibiting the compensatory increase in vascular tone at the postglomerular arteriole, ACE inhibitors decrease glomerular filtration in the setting of RAS. The administration of ACE inhibitors in conjunction with radionuclide renography provides a noninvasive method for the detection of functionally significant RAS.^{32, 33}

Several radiopharmaceuticals with different clearance mechanisms are available, although all show a degree of clearance via glomerular filtration. In particular, DTPA is primarily cleared by means of glomerular filtration. The decreased clearance of DTPA induced by ACE inhibitors in RAS, as Majd et al observed, is readily shown on renograms as a decrease in function in the affected kidney and a deterioration in the renogram curve.³¹

In patients with RAS, effective renal plasma flow (ERPF) is shown to increase after the administration of an ACE inhibitor because of the efferent arteriolar vasodilatation, which increases blood flow through the renal parenchyma and decreases blood flow through the glomerulus. ¹³¹I-labeled OIH also closely estimates ERPF. Technetium (Tc)-labeled mercaptoacetyltriglycine (MAG3) has also been used to qualitatively assess ERPF (see Image 10).

Since the introduction of captopril renography, various modifications have been made. Some centers use only 1 agent, either DTPA or MAG3. A positive result on ACE inhibition radionuclide scanning indicates that RVHT is present; it also implies the existence of hemodynamically significant RAS (>60-75% of the lumen).

It is important to understand that the criteria for interpreting a result as being positive depend upon the tracer used. If DTPA is used, there should be a change in split function if RVHT is present (since DTPA is dependent upon GFR for uptake, the initial uptake in the affected kidney will be decreased). If MAG3 is used, split function will usually not change, but there will be an increase in cortical retention (usually measured as 20 minute to maximum ratio) in the affected kidney. This is because initial MAG3 uptake is primarily dependent upon tubular secretion rather than GFR. However, later clearance of MAG3 is dependent upon GFR (therefore, decreased excretion is the primary finding). Rarely, the split function will change when MAG3 is used in cases of severe RVHT.

Preliminary data suggest that aspirin renography may be as sensitive as captopril renography for detecting RAS. Considering that, compared with captopril, aspirin reduces renal blood flow and thus tubular tracer delivery in poststenotic kidneys, aspirin renography is expected to be more useful, particularly if tubular tracers are used.^{34, 35, 36, 37, 38}

Degree of Confidence

Standard renography with ¹³¹I-labeled OIH has low specificity and low sensitivity in the diagnosis of RAS.

For RAS greater than 50%, Tc-MAG3 captopril renography has a sensitivity of 90%, a specificity of 91%, a positive predictive value of 70%, and a negative predictive value of 97%.

Data reported by Imanishi et al suggest that iodine-123 OIH or MAG3 renography is more sensitive for the diagnosis of unilateral RVHT when aspirin is given.³⁶ Although Maini et al found that aspirin renography is superior to captopril renography,³⁴ results from van de Ven et al show that, for the identification of RAS, the usefulness of aspirin renography equals but does not surpass that of captopril renography.³⁵

False Positives/Negatives

With standard ¹³¹I-labeled OIH radionuclide renography, false-positive results may occur with all conditions that cause unilateral reduction in blood flow. These conditions include chronic pyelonephritis, renal outlet obstruction, renal vein thrombosis, compression of the renal hilum, perirenal abscess, perirenal hematoma, and ptosis of the kidney.

In patients with RVHT, a captopril renogram may yield false-negative results after the long-term administration of captopril despite adequately maintained blood pressure. Therefore, where possible, ACE inhibitors should be discontinued before captopril renography. Overhydration may lead to a false-negative result, and underhydration may lead to a false-positive result. Bilateral RAS may be difficult to diagnose. In patients with poor renal function, examinations are nondiagnostic. An asymmetric, small kidney with poor function is often unresponsive to a captopril renogram.

Findings

Conventional angiography remains the criterion standard for the detection of RAS, although CTA and MRA are increasingly being used. The severity of the stenosis and the presence of collateral circulation to the kidney may be assessed to determine the hemodynamic significance of RAS. Lesions occluding more than 50% of the diameter of the artery are considered significant. Both the angiographic and the nephrographic phases can be evaluated; the latter may better depict ischemic changes (see Image 13).

Epinephrine may further restrict blood flow to the kidneys and make the collateral circulation more obvious. Generally, flush aortography suffices for mainstem RAS, but if branch stenosis is suspected, selective renal angiography may better define the lesion. Digital subtraction angiography (DSA) does not address the hemodynamic significance of RAS.

RAS caused by AD generally affects the middle and distal renal artery in 79% of the patients, affects a branch renal artery in 4%, or affects a combination of the 2 in 17%. MFP is bilateral in approximately 65% of cases; the left-to-right ratio is 4:1.

Degree of Confidence

Renal angiography remains the criterion standard in the diagnosis of RAS. Angiography is essential when renovascular intervention is contemplated. The angiographic measurement of the size of RAS — an important parameter in assessing the significance of RAS — is inaccurate. Angiography provides only anatomic information; it does not enable the assessment of blood flow through the stenosis.

False Positives/Negatives

On DSA images, artifact from moving structures, such as occurs with peristalsis, may be mistaken for RAS. Standing waves may be confused with RAS.

Interventions appropriate for patients with RAS/RVHT include medical therapy, percutaneous transluminal angioplasty (PTA), vascular stent placement, intravascular ultrasonography-guided atherectomy, and surgical revascularization.^{39, 40}

Treatment with antihypertensive drugs is indicated, and optimal blood pressure control is essential. ACE inhibitors should be avoided. Other risk factors that should be addressed include atherosclerosis, smoking, and hyperlipidemia. Definitive therapy for the underlying cause should always be considered to prevent the development of ischemic nephropathy. In patients with diffuse atherosclerosis, the complication rate with both surgery and angioplasty is relatively high. Medical therapy may be preferred to other treatments.

PTA has become the procedure of choice for the treatment of symptomatic stenoses. Patency rates after PTA are strongly dependent on the size of the vessel treated and the quality of inflow and outflow through the vessel. RAS is an established cause of either RVHT or chronic renal insufficiency. Because of the excellent results obtained with renal angioplasty, it is the most commonly performed procedure for patients with symptomatic RAS.

Previously, angioplasty was considered to be contraindicated for patients with a solitary or transplanted kidney. This is no longer the case, and angioplasty is now considered the procedure of choice for treatment of RAS in these patients.

Technical success is achieved in more than 90% of patients; patency rates are 90-95% at 2 years for MFP and 80-85% for atherosclerosis. Restenosis requiring repeat angioplasty has been reported in fewer than 10% of patients with AD and in 8-30% with atherosclerotic stenosis. Improvement in blood pressure control with fewer antihypertensive medications is achieved in 30-35% of patients with fibromuscular lesions and in 50-60% of patients with atherosclerotic lesions. A success rate of 83% has been reported with PTA in RAS associated with renal transplantation.

Many vascular stents are now available. Some stents are metallic and are either self-expanding or balloon expandable. The US Food and Drug Administration (FDA) has approved a few of these for peripheral coronary procedures and for transjugular intrahepatic portosystemic shunt (TIPS) procedures.

The ultimate role of stents in the treatment of vascular disease is not yet established, but these devices have already had a dramatic impact on the practice of interventional radiology. In studies from both the US and Europe, stenting of smaller vessels has resulted in an unacceptably high incidence of thrombosis. These problems are being addressed in the development of new stent materials and coatings.

Intravascular stents placed during angioplasty may be helpful in the prevention of restenosis and the management of RAS. Early results suggest that stenting may prove useful in patients with ostial disease, in those in whom restenosis occurs after PTA, and in those with complications (eg, renal artery dissection) resulting from PTA. Primary renal artery stenting in patients with atherosclerotic RAS has a high technical success rate and a low complication rate.

In a single reported case, hypertension secondary to AD was successfully diagnosed with intravascular sonography, and intravascular sonography-guided renal atherectomy was curative.

Currently, surgical revascularization is reserved for patients in whom the main renal artery appears completely occluded and in whom the surviving renal parenchyma is vascularized by collaterals. Surgical revascularization might also be used when an ostial stenosis is present with a buttressing atheroma on either side of the ostium. Some of these lesions may also be amenable to percutaneous vascular stent placement.

Several surgical options are available. The stenotic segment may be excised and the artery resutured directly onto either the aorta or surviving stump. A vein graft may be transplanted or the kidney resected and reimplanted in the iliac fossa with the renal artery anastomosed to the iliac artery. Another novel method involves a splenectomy and anastomoses of the splenic artery to the renal artery when RAS involves the left kidney. The underlying diagnosis determines the results of this surgery. With advanced diffuse atherosclerosis, surgery may become less feasible because the certainty that the RAS is the cause of the hypertension is less and the prognosis may be determined by comorbidities.

A potential complication is the release of cholesterol emboli during the surgery; however, 80-90% of patients undergoing operation for atherosclerotic RAS benefit with cure or improvement. The perioperative mortality rate is less than 5%. In patients with AD, the cure rate is as high as 80%, and morbidity rates are low. However, similar results can be achieved with the minimally invasive renal angioplasty technique, with considerably less morbidity, mortality, and expense. In patients with diffuse atherosclerosis, the complication rate with both surgery and angioplasty is relatively high.⁴¹

Antihypertensive therapy may increase or decrease plasma renin levels. Nonsteroidal anti-inflammatory drugs can also decrease plasma renin levels. The baseline plasma renin activity is elevated in 50-80% of patients with RVHT. Measuring the increase in the baseline plasma renin activity 1 hour after the administration of 25-50 mg of the ACE inhibitor captopril can increase the predictive value of baseline plasma renin activity. In patients with RAS, the baseline plasma renin activity is significantly increased, perhaps as a result of the cessation of the normal suppressive effect of high angiotensin II levels on renin secretion in the ischemic kidney.

The sensitivity and specificity of the captopril renin test are 75-100% and 60-95%, respectively. A major limitation is the need to discontinue antihypertensive therapy, including the use of ACE inhibitors, beta blockers, and diuretics, because these agents can affect the baseline plasma renin activity. The sensitivity of the test is also low, and its predictive value is lower than that of a captopril renogram.

Ischemic kidneys release higher levels of renin in their veins. Renal venous sampling can be used to measure renin levels so as to compare the venous drainage from each kidney; the resulting data can be used to predict the degree of renal ischemia and the potential success of surgical revascularization. A 1.5-fold increase in renin level in the ischemic kidney is a positive result and suggests that revascularization may be successful in the treatment of elevated blood pressure.

Renin secretion in the contralateral kidney is suppressed, as evidenced by the fact that the levels of renin in the renal artery, the infrarenal inferior vena cava, and the renal vein are similar. Approximately 10% of healthy patients have a ratio above 1.5, and fewer than 20% have a ratio below 1.1. The accuracy of the measurements may improve by prior administration of an ACE inhibitor, which increases renin secretion on the affected side.

False-negative and false-positive results occur frequently. Although more than 90% of patients with unilateral RAS and increased renin levels in the affected renal vein have a positive response to angioplasty or surgery, approximately 50% of patients with nondiagnostic findings also benefit from revascularization. As a result, most clinicians rely on the clinical index of suspicion rather than renin measurements in the renal vein to estimate the physiologic significance of RAS. However, these renin measurements may still be useful in patients with bilateral RAS, in whom measurements may determine the side that most contributes to the hypertension.