eMedicine Specialties > Radiology > Genitourinary

Renal Artery Stenosis/Renovascular Hypertension

Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, Consultant Radiologist and Honorary Professor, North Manchester General Hospital Pennine Acute NHS Trust, UK
Coauthor(s): Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute; Muhammad Sohaib, MBBS, MSc, Principal Medical Officer, Associate Professor, Department of Medical Sciences, Pakistan Institute of Engineering and Applied Sciences; Shabana Saeed, MBBS, MSc, Head, Department of Medical Sciences, Pakistan Institute of Engineering and Applied Sciences; Consulting Staff, Department of Nuclear Medicine, Pakistan Institute of Engineering and Applied Sciences
Contributor Information and Disclosures

Updated: Oct 2, 2009

Introduction

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

Development of RVHT

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.¹²

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.

Evolution of RVHT

RVHT evolves in 3 stages.

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.

Atherosclerosis

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.¹³

Arterial dysplasia

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.^14,15 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.¹⁶ 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.¹⁷ 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.¹⁸ 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

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

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

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.¹⁹

Mortality/Morbidity

• In patients with hypertension, atherosclerotic renal artery disease is a strong predictor of increased mortality relative to the general population. In the setting of renal dysfunction, RVHT is associated with the greatest mortality rate.
• Major complications of RVHT include end-organ damage resulting from chronically uncontrolled hypertension and progressive renal insufficiency, which is an important sequel of chronic renal ischemia. (See also Pathophysiology.)
• The prognosis of patients with RVHT is difficult to ascertain because it varies with the degree of RAS, the response of the patient to antihypertensive therapy, and the effectiveness of revascularization procedures.

Race

RVHT is less common in African Americans than in persons of other races.

• In 2 studies of patients with severe hypertension, the incidence was 27-45% in white Americans, compared with 8-19% in African Americans.
• RVHT occurs more often in white men and in blacks of both sexes.

Sex

• All types of AD, except intimal fibroplasia, more commonly affect women than men. For intimal fibroplasias, the male-to-female distribution is 1:1. For FMD, the male-to-female ratio is 1:3-5.
• RVHT is most common in younger women and older men. In younger women, RVHT most commonly develops as a result of FMD affecting the distal two thirds of the renal arteries and their branches. In older men, RVHT most often develops as a result of atherosclerotic disease that affects the proximal third of the main renal artery.
• Although the incidence of atherosclerotic RVHT is independent of sex, Crowley et al showed that female sex is an independent predictor of renovascular disease progression. Other such predictors are older age, elevated serum creatinine level, coronary artery disease, peripheral vascular disease, hypertension, and cerebrovascular disease.²⁰

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.

• RVHT often occurs in men older than 45 years with atherosclerosis and in women younger than 45 years with AD.
• Approximately 10% of children with AD also have RVHT. FMD generally affects young to middle-aged adults, mostly women; however, it can affect children as well. FMD is an important cause of RVHT in children.
• In 1964, Holley et al reported data from 295 consecutive autopsies.²¹ The mean age at death was 61 years. The prevalence of RAS was 27% among 256 patients identified as having a history of hypertension, whereas 56% had significant stenosis (>50% luminal narrowing). Among normotensive patients, 17% had severe RAS (>80% luminal narrowing). Among those older than 70 years, 62% had severe RAS. Another, similar autopsy study showed that 5% of patients older than 64 years had severe stenosis; this rate increased to 18% in patients aged 65-74 years and to 42% for patients older than 75 years.

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.

Presentation

Clinical criteria for the presence of RVHT include the following:

• Difficult-to-control hypertension despite adequate medical treatment
• Hypertension with renal failure or progressive renal insufficiency
• Accelerated or malignant hypertension
• Severe hypertension (diastolic blood pressure >120 mm Hg) or resistant hypertension
• Hypertension with an asymmetric kidney
• Paradoxical worsening of hypertension with diuretic therapy
• Hypertension refractory to standard therapy
• Onset of hypertension occurring in patients younger than 30 years or older than 50 years
• Abrupt onset of hypertension
• Symptoms of atherosclerotic disease elsewhere
• Negative family history of hypertension
• Cigarette smoking or use of other tobacco products
• Renal failure with ACE inhibition
• Recurrent pulmonary edema (flash edema)
• Advanced funduscopic changes
• Clear abdominal bruit (This is heard in 46% of patients with RVHT. Bruit is also heard in 9% of patients with essential hypertension; however, innocent bruits are common in younger individuals.)
• Systolic-diastolic bruits (In combination with hypertension, these are suggestive of RVHT.)

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

• Carotid artery disease
• Coronary artery disease
• Diabetes mellitus
• Hypertension (high blood pressure)
• Obesity 
• Older age
• Peripheral vascular disease (vascular disease in the extremities)
• Smoking 
• Familial history of AD RAS (often present)

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.²²

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.^23,24

Limitations of Techniques

The acceptance of radionuclide renography as a primary screening tool for RAS has been hindered by the lack of standardized protocols.²⁵

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.

Differential Diagnoses

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.

Atheroma, FMD, thrombus, embolus, or arteritis may cause branch RAS.

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.²⁶

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