Renovascular Hypertension

Etiology

It is important to realize that any condition that compromises blood flow to the kidneys can contribute to renovascular hypertension.[3] The most common causes of renovascular hypertension include:

• Renal artery stenosis (RAS), mostly secondary to atherosclerosis
• Fibromuscular dysplasia (FMD)
• Arteritides such as Takayasu’s, antiphospholipid antibody (APLA), or mid aortic syndrome[4][3]
• Extrinsic compression of a renal artery
• Renal artery dissection or infarction[3]
• Radiation fibrosis
• Obstruction from aortic endovascular grafts[3]

Epidemiology

Providing care for uncontrolled hypertension costs $48.6 billion each year.[5] Although the majority of these cases are due to essential hypertension, around 10% of these patients have secondary hypertension.[6] Studies have shown renovascular hypertension to be the underlying etiology in about 75% of the cases of secondary hypertension.[7]

Renovascular hypertension affects people of all ages. Renal artery stenosis secondary to atherosclerosis is the most common cause and is mostly seen in older adults (>65 years). It has a higher prevalence in patients with known atherosclerotic disease (such as those with coronary artery disease, peripheral artery disease, or carotid artery stenosis) and autopsy studies have revealed that "greater than 25% of all patients who die of cardiovascular disease have some degree of RAS.”[8] Fibromuscular dysplasia (FMD) is usually seen in young women and accounts for around 10% of renovascular hypertension and 5.8% of secondary hypertension.[9] FMD can affect any arterial bed but most commonly affects the distal two-thirds of the renal artery.[10]

Pathophysiology

The underlying mechanism in renovascular hypertension involves decreased perfusion to the kidney and activation of the renin-angiotensin-aldosterone (RAAS) pathway. This was first explained by Goldblatt et al. in the 1930s. His model studied the effect of decreased blood supply to the kidneys in dogs and found that ischemic kidneys contribute to persistent hypertension. He also proposed the presence of a substance that “may affect a pressor action like that of a hormone.” The hormone he was referring to was 'renin,' which is secreted by juxtaglomerular cells of the kidney. Renin secretion by the kidneys is stimulated by three main pathways, 1) renal baroreceptors that sense decreased perfusion to the kidney, 2) low sodium chloride levels detected by the macula densa and 3) beta-adrenergic stimulation. Prolonged ischemia also increases the number of renin expressing cells in the kidney in a process called ‘JG recruitment.’[11] When renin is secreted into the blood, it acts on angiotensinogen (produced by the liver). Renin cleaves angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) that is primarily found in the vascular endothelium of lungs and kidney. Angiotensin II raises blood pressure by multiple mechanisms, which include: 

• Vasoconstriction, mostly in the heart, kidney, and vascular smooth muscle[12]
• Sympathetic nervous stimulation causing a presynaptic release of norepinephrine
• Stimulates secretion of aldosterone by the adrenal cortex, which in turn causes sodium and water retention, thereby raising blood pressure.
• It also causes the increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis
• It has been shown to have a growth effect on renal cells, which has been implicated in the development of glomerulosclerosis and tubulointerstitial fibrosis

Though atherosclerotic renal artery stenosis (ARAS) and FMD are the two most common conditions causing this cascade, any pathology leading to decreased blood flow to the kidneys can essentially trigger this and lead to high blood pressure.

History and Physical

Salient points in the history that suggest the presence of renovascular hypertension include:

• Resistant hypertension: Uncontrolled blood pressure necessitating the use of 2 or 3 antihypertensive agents of different classes, one of which is a diuretic
• Trial of multiple medications to control blood pressure
• History of multiple hospital admissions for hypertensive crisis
• Elevation in creatinine of more than 30% after starting an angiotensin-converting enzyme inhibitor (ACE-I)
• Patients with renal artery stenosis secondary to atherosclerosis are usually older and might have the presence of other atherosclerotic diseases such as carotid artery stenosis, peripheral artery stenosis, or coronary artery disease
• A premenopausal female (15-50 years) with hypertension is most likely to have FMD[4]
• Long term history of smoking
• Patients with systemic vasculitis can develop vasculitis of renal arteries and present with renovascular hypertension
• Recurrent episodes of flash pulmonary edema and/or unexplained congestive heart failure
• Unexplained azotemia
• Elevation in serum creatinine upon starting ACE-I, which occurs due to interference with autoregulation and post glomerular arterial tone
• Unexplained hypokalemia and metabolic alkalosis 
• Unilateral small or atrophic kidney

Physical examination may reveal an abdominal bruit, indicating the presence of renal artery stenosis.

Evaluation

Patients with renovascular hypertension often undergo an extensive evaluation to find a cause for uncontrolled hypertension.

Laboratory Tests

1. Urine analysis: To check for proteinuria, hematuria, and casts. The presence of proteinuria indicates the presence of renal parenchymal disorder, whereas the presence of hematuria or red blood cell (RBC) casts indicates the presence of glomerulonephritis.
2. Blood urea nitrogen and serum creatinine: To assess baseline kidney function. 
3. Basal metabolic profile: To assess for electrolyte disturbances and acid-base balance. 
4. Complement levels and autoimmune profile: In suspected cases of autoimmune diseases affecting the renal vasculature.
5. Plasma free metanephrines or 24-hour urinary fractionated metanephrines and normetanephrine to rule out pheochromocytoma
6. Plasma renin-aldosterone ratio to rule out hyperaldosteronism
7. 24 hour urinary free cortisol or low dose dexamethasone suppression test to rule out Cushing's syndrome

Imaging

There are multiple imaging modalities available to evaluate renovascular hypertension. Since the most common cause of renovascular hypertension is renal artery stenosis, renal arteriography remains the gold standard diagnostic test.[10] However, catheter angiography is invasive, costly, time-consuming, and can lead to complications such as renal artery dissection or cholesterol embolization. Other imaging tests that can be done to evaluate the renal vessels include duplex ultrasonography, computed tomography with angiography (CTA), and magnetic resonance angiography (MRA). The type of imaging test used often depends on the suspicion for high-grade lesions, and the need for intervention.[4]

Duplex ultrasonography is the initial imaging test of choice to evaluate the renal arteries. It is relatively inexpensive, non-invasive, and does not involve administration of contrast or exposure to radiation. A duplex scan has been shown to have an excellent correlation with contrast-enhanced angiography.[13] Though there are several criteria to assess the presence of renal artery stenosis, the most important sign is peak systolic velocity (PSV). A PSV higher than 180 cm/s suggests the presence of stenosis of greater than 60%.[14]

Duplex ultrasonography can also measure the resistive index (RI), which is calculated as (PSV-End diastolic velocity)/PSV. A value of more than 0.7 indicates the presence of pathological resistance to flow, and studies have shown that a value >0.8 predicts poor response to revascularization treatments.[14] The most significant setbacks for duplex ultrasonography are its reduced sensitivity in obese patients, hindrance by overlying bowel gas, and operator dependence.

CT angiography involves the administration of intravenous contrast and acquiring detailed images of blood vessels or tissues by moving the beam in a helical manner across the area being studied. In a study by Wittenberg et al, the sensitivity and specificity for hemodynamically significant RAS (>50%) by CTA was found to be 96% and 99%. CTA also has a comparable negative predictive value to MRA in ruling out renal artery stenosis.[15] It can also diagnose extrinsic compression of renal arteries, FMD, arterial dissection, and help in evaluating surrounding structures. However, CTA can only provide an anatomical assessment of the lesion and is not able to evaluate the degree of obstruction to renal blood flow. Exposure to radiation, allergy to contrast, and acute kidney injury are other downfalls of CTA.

MRA uses a powerful magnetic field, pulses of radio waves, and intravenous gadolinium to evaluate the renal blood vessels and surrounding structures. Several studies have shown the sensitivity and specificity of MRA to be around 97% and 92% in diagnosing renal artery stenosis.[15] MRA does not involve radiation, and gadolinium contrast is less likely to cause an allergic reaction as compared to the iodine contrast used in CTA. However, MRA has been shown to overestimate the grade of stenosis and is often affected by motion artifacts or opacification of renal veins, leading to difficulty visualizing the renal arteries.[15] Also, gadolinium has been shown to induce a rare, progressively fatal disease called nephrogenic systemic fibrosis (NSF). NSF can affect the skin, joints, and multiple organs leading to progressive, irreversible fibrosis and eventual death. This occurs due to a transmetalation reaction that displaces gadolinium ion from its chelate, resulting in the deposition of gadolinium in the skin and soft tissues. The 1-year incidence of NSF has been reported to be around 4.6% and almost all cases occurred in patients with a glomerular filtration rate < 30 mL/min/1.73 m2.[16]

In comparative studies, the positive predictive value of MRA was found to be higher than CTA due to increased false-positive rates with CTA. Negative predictive values are high for both CTA and MRA (>98% for both).[15] Both modalities can exclude significant renal artery lesions with a high degree of certainty. Both MRA and CTA have also shown to be effective for the diagnosis of FMD, with the sensitivity of CTA being the best (84.2%) when compared to angiography.[17]

Nuclear medicine ACE-inhibitor (ACE-I) renography is another non-invasive, relatively safe imaging method that uses radioactive material, a special camera, and a computer to evaluate for renovascular hypertension. It involves the administration of an ACE-I to determine if the cause of hypertension is due to the narrowing of the renal arteries. The sensitivity and specificity of this test have shown to be variable, with values between 74% - 94% for sensitivity and 59% - 95% for specificity.[18] It is a time-consuming procedure, and there is a risk of radiation exposure and irritation or pain from the injection of the radiotracer. The sensitivity of ultrasound has shown to be higher than captopril renography which makes it a better choice for an initial diagnostic test.[19]

Catheter angiography is the gold standard test to evaluate for renovascular hypertension and provides the best temporal and spatial resolution. Catheter angiography has the added advantage of measuring translesional pressure gradients to assess the hemodynamic significance of anatomically severe lesions.[20] It is most useful in:

• Patients with a disparity between imaging modalities
• Patients with a high index of suspicion and negative imaging findings
• Patients anticipated of needing an intervention

It can also evaluate anatomical abnormalities of the kidney, renal arteries, aorta, and can be followed by endovascular intervention for the treatment of significant lesions. Also, the surrounding tissues and bones can be removed or subtracted from the final image revealing only the arterial framework. This method is known as digital subtraction angiography (DSA). However, the radiation doses are higher than CTA, and because it is an invasive procedure, there are risks of complications such as arterial dissection, tear, rupture, or thromboembolic phenomenon.[20]

Treatment / Management

The management of renovascular hypertension aims to treat the underlying cause. Several options are available, which include pharmacological and invasive therapy.

Pharmacological therapy entails the use of antihypertensive medications to control blood pressure. The American College of Cardiology and the American Heart Association (ACC/AHA) advocates pharmacological therapy as the first-line treatment for renal artery stenosis.[21] Since RAAS is the most prominent pathway contributing to hypertension in these disorders, ACE-Is and angiotensin receptor blockers (ARBs) form the cornerstone of managing renovascular hypertension (Class 1a indication). Often more than one medication will be needed to control the blood pressure. Calcium channel blockers, thiazides, beta-blockers, and hydralazine have been shown to be effective to control blood pressure in patients with RAS.[22] Direct renin inhibitors such as aliskiren have been studied as monotherapy or in combination with ACEIs/ARBs to treat hypertension. Though it has been shown to be effective for the treatment of hypertension there is not enough data to prove its efficacy in treating renovascular hypertension.[23][24][25][26][27](A1)

ACEIs and ARBs inhibit the action of angiotensin II, thereby causing vasodilation and promote sodium and water excretion. However, these medications are contraindicated in patients with a single functioning kidney or bilateral lesions as they can cause efferent arteriolar vasodilatation leading to interruption in autoregulation and thereby decreasing glomerular filtration. While these medications are effective in controlling blood pressure, they can also lead to worsening renal function.

Percutaneous angioplasty is the treatment of choice for renovascular hypertension due to FMD and for patients with atherosclerotic renal artery stenosis that is not controlled with medications.[28] The ACC/AHA guidelines recommend revascularization for renal artery disease in the following scenarios:[22](B3)

1. Patients with hemodynamically significant RAS and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema (class Ia)
2. Hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension or hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication (Class IIa)
3. Patients with bilateral RAS and progressive chronic kidney disease or a RAS to a solitary functioning kidney (Class IIa)
4. Patients with hemodynamically significant RAS and unstable angina (class IIa)
5. Asymptomatic bilateral or solitary viable kidney with hemodynamically significant RAS (Class IIb)
6. Patients with RAS and chronic renal insufficiency with unilateral RAS (class IIb)
7. In addition to angioplasty, renal stent placement is indicated for patients with ostial atherosclerotic lesions (Class I).

Patients with FMD and renovascular hypertension are also treated with percutaneous intervention with or without a stent.[28] Multiple studies have shown a decrease in baseline blood pressure after intervention for FMD.[29][30] However, there remains an ongoing debate about the benefit of revascularization when compared to medical management in patients with atherosclerotic renal artery stenosis (ARAS). Several studies have failed to show a significant decrease in blood pressure or the number of antihypertensive agents between angioplasty and medical treatment groups. A meta-analysis of 7 trials by Zhu et al. revealed that medical management is as effective as percutaneous revascularization in the treatment of RAS.[31] Three recent trials ASTRAL, CORAL, and STAR found no difference between stenting and medical therapy in patients with atherosclerotic renal artery stenosis.[32][33][34] Thus it can be established that revascularization does not reverse renal damage or decrease blood pressure in patients with atherosclerotic renal artery stenosis.(A1)

In the case of recurrent renal artery stenosis or blood pressure not controlled with medication and or/angioplasty, renal bypass surgery may be an option. In this procedure, the surgeon uses a vein or synthetic tube to connect the kidney to the aorta, to create an alternate route for blood to flow around the blocked artery into the kidney. This is a complex procedure and rarely used. The ACC/AHA guidelines recommend surgery for RAS in:[22](B3)

1. Patients with RAS secondary to FMD, especially those with complex disease and/or those having microaneurysms
2. Patients with atherosclerotic RAS involving multiple vessels or involvement of early primary branch of the main renal artery
3. Patients with atherosclerotic RAS who require pararenal aortic reconstructions (such as with aortic aneurysms or severe aortoiliac obstruction)

Several studies have also evaluated the role of unilateral nephrectomy in patients with renovascular hypertension and have shown improvement in blood pressure control, renal function, and a decrease in the use of anti-hypertensives.[35][36] However, this is an invasive procedure with inherent risks and the long-term consequences of such a procedure are unclear.(B2)

Differential Diagnosis

The differential diagnosis for renovascular hypertension includes potential causes of secondary hypertension, such as:

• Pheochromocytoma: Usually presents as a constellation of symptoms such as flushing, headache, tachycardia, and episodic uncontrolled hypertension. 
• Primary hyperaldosteronism: Presents with persistent hypokalemia and metabolic alkalosis. 
• Obstructive sleep apnea: Usually seen in obese males with increased neck circumference and a history of snoring. Diagnosed with polysomnography/sleep study.
• Coarctation of the aorta: Patients usually have a systolic murmur, radio-femoral delay, and upper extremity hypertension. The diagnosis is with MRA or CTA.
• Cushing syndrome: Associated with moon facies, buffalo hump, proximal myopathy, glucose intolerance, abdominal striae, and central obesity.

Prognosis

Atherosclerotic renal artery stenosis is a progressive disorder that can lead to worsening stenosis and, ultimately, renal failure. In previous studies, the 3-year cumulative incidence of disease progression was found to be 18%, 28%, and 49% for renal arteries classified as normal, <60% stenosis and >60% stenosis. High blood pressure (systolic >160 mm hg), diabetes mellitus, and high-grade stenosis (>60% obstruction) have been shown to be associated with an increased rate of progression. Untreated renovascular hypertension can also lead to end-stage renal failure with a median survival time of 25 months and a 4-year mortality rate of 35%. Primary management of renovascular hypertension should aim to correct the underlying cause. Renovascular hypertension due to atherosclerotic renal artery stenosis should be primarily managed medically as multiple studies have failed to show renal or cardiovascular benefits with invasive management.

Complications

Complications of Renovascular hypertension are mostly due to uncontrolled blood pressure and include:

1. Renal failure
2. Myocardial infarction
3. Stroke
4. Pulmonary edema
5. Retinopathy
6. Left ventricular hypertrophy
7. Congestive heart failure
8. Aneurysm
9. Vascular dementia