Renal artery stenosis is a vascular lesion most commonly found in people with atherosclerosis and fibromuscular dysplasia.
The narrowing of the artery stimulates the renin-angiotensin-aldosterone system, which produces the main manifestation, hypertension.
To diagnose this condition, a complete physical exam and complementary exams, such as ultrasound, Magnetic resonance, and computerized tomography, are performed.
Treatment options include noninterventional therapy with medication and interventional therapy that can be performed surgically or endovascularly.
Definition of Renal Artery Stenosis
References: (1, 2)
Renal artery stenosis (RAS) refers to any vascular lesion causing the narrowing of the renal artery, thereby preventing enough oxygen-rich blood from reaching the kidney, decreasing kidney tissue perfusion, and increasing blood pressure. This disease encompasses a broad range of pathophysiologies, the two most common forms are fibromuscular dysplasia (FMD) and atherosclerotic renal artery disease. (3)
RAS is associated with ischemic nephropathy, hypertension, and destabilizing cardiac syndromes.
FMD is a collection of vascular diseases that affects the intima, media, and adventitia (3). Atherosclerotic renal artery disease is a combination of renal artery stenosis and renal ischemia (4). Both pathologies will be discussed further in the next section.
References: (2, 3, 5)
The Pathophysiology of Hypertension Secondary to RAS
Hypertension due to RAS is classified as either renin-dependent or primarily a result of volume overload. When renal hypoperfusion occurs due to a stenotic renal artery, it activates the renin-angiotensin system by releasing renin from juxtaglomerular cells, which leads to increased production of angiotensin II by angiotensin-converting enzyme in the lung vasculature.
GFR is increased via vasoconstriction of the efferent arteriole, mediated by angiotensin II. Antidiuretic hormones are released from the pituitary gland, causing water conservation, further increasing pressure diuresis, and aldosterone promotes a rise in sodium retention. In addition, this process intensifies the sympathetic nerve activity, intrarenal prostaglandin concentrations, and nitric oxide production, causing renovascular hypertension. (6, 7)
When hypertension is sustained chronically, renin activity reverses (reverse tachyphylaxis), making the measurement of renin in the diagnosis of patients with renovascular hypertension and RAS obsolete.
Etiology of RAS
The different etiologies related to RAS can be primary, usually affecting large renal arteries, or secondary, affecting small vessels and producing intrarenal vascular disease. In addition, RAS could be an isolated finding, or it could be associated with other pathologies. Consequently, patients are prone to other vascular issues, like hypertension or ischemic nephropathy.
The two main causes of RAS are atherosclerosis and fibromuscular dysplasia. Rarely, the etiology could be a vasculitis process or an abdominal tumor that compresses the kidney arteries.
Atherosclerosis usually involves the ostium and proximal third of the main renal artery and the perirenal aorta, accounting for 90% of cases of RAS (3). In severe cases, segmental and diffuse intrarenal atherosclerosis may also be observed in patients with ischemic nephropathy.
Atherosclerotic renal artery stenosis (ARAS) is more common in elderly people, patients with comorbidities like diabetes, hyperlipidemia, aortoiliac occlusive disease, coronary artery disease, or hypertension. It is a progressive illness that can happen alone or in combination with hypertension and ischemic kidney disease. (3)
Epidemiology of ARAS
The prevalence of ARAS varies from 30% in patients with coronary artery disease identified by angiography (8) to 50% among elderly people or those with diffuse atherosclerotic vascular diseases. (9)
Atherosclerotic renal artery stenosis is potentially reversible when treated early, and the absence of hypertension does not rule out RAS. Two important ischemic renal syndromes are acute renal failure and unexplained chronic or progressive azotemia. (3)
Among patients with ARAS, progressive stenosis was reported in 51% of renal arteries five years after diagnosis (6, 7), with 3-16% becoming totally occluded (10) and renal atrophy developing in 21 % of cases with more than 60% of stenosis.
Pathophysiology of Ischemic Nephropathy
Ischemic nephropathy is defined as an obstruction of renal blood flow that causes a decreased perfusion, leading to tissue ischemia and excretory dysfunction. Many mechanisms have been proposed; one of them is recurrent local ischemia that causes tubulointerstitial injury and microvascular damage. Another one is global renal hypoperfusion, leading to altered endothelial and epithelial factors and activation of the renin-angiotensin-aldosterone system with subsequent vasoconstriction. Both of them increase the production of fibrogenic cytokines and inflammation, leading to atrophy and fibrosis.
This renal dysfunction is less common in FMD than in ARAS, suggesting that atherogenic factors worsen renal injury.
Fibromuscular Dysplasia as a Cause of RAS
Fibromuscular dysplasia is a collection of non-inflammatory vascular diseases that affect the intima, media, and adventitia, where arterial wall muscle develops dysfunctionally, often starting in childhood. This results in the renal artery having narrow sections alternating with wider ones, giving a bead-like appearance on arterial images. The narrowing can be severe enough to decrease renal perfusion, leading to high blood pressure in young people.
FMD is more frequent in premenopausal women between 15 and 50 years old and may be congenital, although there are theories around the influence of smoking, hormones, genetics, and disorders of the vasa vasorum in disease development.
FMD accounts for less than 10% of cases of RAS, and 90% of FMD cases involve de media, involving the distal two-thirds of the renal artery and its branches. Intimal and periarterial FMD is usually associated with progressive dissection and thrombosis.
Fibromuscular dysplasia rarely leads to renal artery occlusion as in ARAS and has a good prognosis with appropriate treatment.
Other Causes of RAS
Other nonatherosclerotic renal artery disease that can cause RAS apart from FMD includes:
- Congenital or traumatic arterial vascular fistulas;
- Congenital bands;
- Post-radiation therapy;
Epidemiology of Renal Artery Stenosis
References: (1, 11, 12)
In the past, studies have not been able to determine the true prevalence of RAS in the general population. A recent study found that 6.8% of elderly patients enrolled in the Cardiovascular Health Study had >60% stenosis or occlusion as determined by renal duplex sonography (13). There was no difference in ethnicity, and it was associated with age, hyperlipidemia, and hypertension, particularly in elderly patients with comorbidities like diabetes, aortoiliac occlusive disease, coronary artery disease, or hypertension (3).
As previously mentioned, the more common etiologies of RAS are atherosclerosis and FMD. People at risk of atherosclerosis are patients with high blood pressure, high blood cholesterol levels, insulin resistance or diabetes, overweight/obese, sedentary, tobacco smoking, men older than 45 or women older than 55, with a family history of heart disease and patients that consume a high fat, sodium, and carbohydrate diet.
It has been recognized that patients with atherosclerotic vascular disease have 26-50% of risk of concurrent RAS (14). There is also a relationship between the severity of vascular occlusion and the increased incidence of RAS, being higher risk when moderate or severe the narrowing. (15)
The incidence of RAS in patients with angiographically significant coronary artery disease (CAD) is 15% with mild RAS (<50% stenosis) and 18% with significant RAS (>50% stenosis) (16). The prevalence of RAS tends to increase with the number of coronary vessels involved. In fact, the presence of significant CAD with greater than two vessel involvement was found to be an independent predictor of RAS with a sensitivity of 0.84 and specificity of 0.77 (17). In short, RAS is frequent in patients with CAD, more so in patients with renal insufficiency.
In a group of patients that underwent a routine angiographic evaluation of vascular pathology, RAS of more than 50% was found in 38% of patients with abdominal aortic aneurysm, 33% with aorto-occlusive disease, and 39% with lower-extremity occlusive disease (18). Another study observed a trend for patients with increasing degrees of renal artery disease to have increasing degrees of lower extremity arterial disease (19).
Fibromuscular dysplasia accounts for less than 10% of cases of RAS. It tends to affect younger women at the distal half of the renal arterial trunk or at the side branches. It also rarely leads to vessel occlusion or ischemic nephropathy.
Signs and Symptoms of Renal Artery Stenosis
References: (2, 11, 12)
Renal artery stenosis is usually asymptomatic until it becomes severe. It is usually discovered incidentally during routine assessment.
The early signs of RAS could be either high blood pressure or otherwise unexplained kidney dysfunction.
High blood pressure caused by renal artery stenosis develops suddenly or worsens without explanation. It usually starts before 30 or after 50 years of age without a family history and can frequently be unresponsive to 3 or more high blood pressure medications.
As RAS progresses, kidney function deteriorates, and symptoms may include:
- Increase or decrease urinary volume;
- Lower limb edema;
- Flash pulmonary edema in bilateral RAS;
- Fatigue and asthenia;
- Generalized itching or numbness;
- Dry mucosae;
- Anorexia or hyporexia;
- Weight loss;
- Nausea and vomiting;
- Muscular cramps;
- Darkened skin.
Diagnosis of Renal Artery Stenosis
References: (1, 3, 11, 20)
Some findings that can suggest RAS are:
- Treatment-resistant heart failure.
- Worsening kidney function during treatment of high blood pressure.
- A bruit on abdominal auscultation (the absence of this sound does not exclude the possibility of RAS).
Laboratory tests can assess:
- Renal function;
- Physiological studies to assess renin-angiotensin system;
- Perfusion studies to assess differential renal blood flow.
Evaluation of renal function:
- Serum creatinine concentration;
- Creatinine clearance;
- Inverse creatine slopes;
- The Cockcroft-Gault formula for estimating GFR.
Methods of measuring the renin-angiotensin system response:
- Renin-sodium profiling;
- Assessment of plasma renin activity before and after administration of captopril;
- Assessment of the effect on blood pressure and renal function of an angiotensin-converting-enzyme (ACE) inhibitor.
These studies are used for identifying patients with FMD since this disorder is frequently renin-dependent (21). However, this test lacks specificity.
Imaging Tests for the Diagnosis of Renal Artery Stenosis
Duplex ultrasound: Permits assessing the artery while measuring the velocity and other aspects of how blood flow, providing information about the degree of stenosis, kidney size, and characteristics. This test can show occlusion of the renal artery or arteries with a lower-than-normal blood flow velocity. Additionally, it is also used after the implantation of stents for follow-up (22).
Computerized tomographic angiography (CTA) scan: A contrast medium is used to enhance arterial anatomy. Apart from providing improved visualization of the renal artery, it is useful to evaluate adjacent anatomic structures. However, it is not recommended for patients with impaired kidney function. It is a reliable test to identify RAS.
Magnetic resonance angiogram (MRA): MRI can provide a functional assessment of blood flow and organ function. It allows for the visualization of surrounding anatomical structures, including accessory renal arteries, and assessment of renal perfusion and glomerular filtration rate (GFR). Although gadolinium contrast is less nephrotoxic than iodine contrast used in CTA, it is also not advised for patients with kidney failure. MRA without contrast is nonspecific compared to catheter angiogram and results in overestimation of renal artery stenosis in almost one-third of the patients.
These noninvasive studies receive class I level B evidence (23).
This is why in experienced centers, high-quality digital-subtraction angiography with or without selective renal angiography may be performed with the use of small-diameter catheters and minimal amounts of contrast material in order to reduce the risk of vascular complications and contrast nephropathy (20), in patients with decreased renal function.
Catheter angiogram: This is an exam used when the clinical suspicion index is high and non-invasive studies are inconclusive or after a positive noninvasive test. A catheter is threaded through the femoral artery to the renal artery, and a contrast medium is injected to visualize the arterial anatomy. This test is the “gold standard” for diagnosing RAS. The goal is to confirm the diagnosis and evaluate the extent of the disease.
Receiving a class III level of recommendation is captopril renography and other tests used in the past and are not recommended as screening tests to diagnose RAS (23).
Treatment of Renal Artery Stenosis
References: (1, 3, 11, 20, 24)
The aim of the management of RAS is to prevent progression, treat hypertension, and reperfuse the stenotic renal artery(ies). If the RAS does not lead to hypertension or causes severe stenosis may not be treated. A RAS that needs intervention corresponds to a reduction of>60% in the lumen diameter of the renal artery, according to the American Heart Association (AHA). (1)
In all cases, lifestyle changes are the first step for managing RAS, promoting a healthy body weight, exercising, and limiting the intake of fats and sodium. Patients with kidney failure due to RAS should limit their intake of protein, cholesterol, sodium, and potassium. Patients should quit smoking as a measure of atherosclerosis management.
The main treatment of renal artery stenosis is divided into medical therapy and interventional therapy.
The major goals of treatment are glycemic control optimization, cholesterol reduction, and blood pressure management. In addition, smoking cessation and atherothrombotic primary prevention with aspirin are indicated.
For managing blood pressure, multidrug regimens are usually needed due to the activation of the renin-angiotensin-aldosterone system. ACE inhibitors (a mainstay in the treatment of RAS hypertension), angiotensin receptor blockers, calcium channel blockers, and beta-blockers receive a class I level of recommendation by the ACC/ACH guidelines (23). The use of a renin-angiotensin-aldosterone system inhibitor in bilateral severe stenosis may induce acute renal failure in some patients. However, in patients with high-grade stenosis in one kidney or advanced chronic kidney disease, this complication is less frequent (25).
Patients with FMD rarely have excretory dysfunction, and hypertension usually responds to ACE inhibitors.
In patients with ARAS with hypertension, baseline treatment is aspirin, cholesterol-lowering drugs, and smoking cessation. There are many case reports that describe a reduction in the severity of renal-artery stenosis in patients treated with statins (26).
To manage hypertension, ACE inhibitors and angiotensin-receptor blockers are effective in 86-92% of patients (27).
An extra-anatomical bypass (anastomosis from the celiac or mesenteric branches) accounts for 80% of renal bypass surgeries (28). Perioperative mortality rates range from 2.1% to 6.1% (28).
Factors that increase these rates are: (29)
- Early graft failure;
- Presence of coronary artery disease;
- Presence of uncontrolled hypertension;
- The need for abdominal aortic aneurysm repair.
There is no consensus on whether a patient should undergo revascularization treatment or which method should be used. The decision is made when the renal function is insufficient, and the stenosis is hemodynamically important. Several studies suggest that performing the procedure before the serum creatinine concentration becomes elevated is the best approach.
Percutaneous revascularization of renal-artery stenosis involves conventional balloon angioplasty, with or without stenting, with guiding-catheter techniques. The use of aspirin, low contrast medium, and heparin are advised for this procedure.
A randomized trial comparing balloon angioplasty with surgery showed similar rates of cure or improvement, making the nonsurgical approach the preferred one for patients with uncontrolled hypertension and FMD.
On the contrary, balloon angioplasty is less effective for ARAS since it is most likely to have complications (dissection of the artery) because of the poor elastic recoil and rigidity of the lesion. Stenting is an alternative to conventional balloon angioplasty for ARAS.
Predictors of a favorable outcome are: (30)
- Age younger than 40 years at diagnosis;
- Duration of hypertension of less than five years;
- A systolic blood pressure of less than 160 mm Hg.
After the RAS is corrected, follow-up studies (measurement of blood pressure, creatinine clearance, and ultrasonographic studies) should be performed 3, 6, and 12 months and yearly thereafter.
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