Renal Artery Stenosis

Epidemiology and Etiology

Epidemiology

• Renal artery stenosis (RAS) accounts for < 2% of all cases of hypertension.
• 2 main types of RAS:
  • Atherosclerotic type: 
    • 80% of all RAS cases
    • Strong association with atherosclerosis in other parts of the body
    • Most patients > 45 years of age, males > females
    • More common in Whites than in Blacks
    • Present in 10%–40% of patients with acute, severe, or refractory hypertension 
    • Bilateral disease is present in 23%–54% of patients (rarely do both sides show the same degree of stenosis).
  • Fibromuscular dysplasia (FMD) type:
    • 20% of all RAS cases
    • 90% of adult cases are in women.
    • Most patients are women < 50 years but all ages can be affected.
    • May be associated with FMD of the carotid and vertebral arteries

Etiology

• Atherosclerosis type: diffuse atherosclerosis usually present, but can be isolated
• FMD type: unknown etiology but genetics believed to play an important role
• Rare causes of RAS (approximately 1% of cases):
  • Extrinsic compression: usually by tumor
  • Intimal dissection: caused by trauma or endovascular intervention
  • Thromboembolism: caused by local sources (e.g., trauma, vasculitis) or by distant emboli (e.g., from left atrium or fat emboli from fractures)
  • Iatrogenic causes: migration and/or placement of endovascular aortic stent over the renal orifices 

Pathophysiology

• Pathogenesis of all RAS cases:
  • Significant decrease of lumen ≥ 70% (less than 30% patent) with poststenotic gradient → blood pressure is affected
  • Renal hypoperfusion → activation of the renin-angiotensin-aldosterone system (RAAS) → increased renin, angiotensin, and aldosterone → increased sodium (Na) retention and peripheral vascular resistance
  • Renovascular (secondary) hypertension (RVH) is the final result → affects both kidneys and other target organs
• RAS caused by atherosclerosis:
  • Usually involves the aortic orifice or the proximal main renal artery
  • Without treatment, 50% of cases progress, sometimes to complete obstruction.
• RAS caused by fibromuscular dysplasia:
  • Medial fibroplasia represents the most common dysplastic lesion, but intima fibroplasia and fibrous hyperplasia of the adventitia also occur.
  • Typically, involves the mid- or distal main renal artery or the intrarenal branches 
  • Focal loss of the internal elastic lamina, with intervening fibromuscular hyperplasia, produces the typical “string of beads” appearance on an angiogram.
  • Rarely leads to complete obstruction

Clinical Presentation and Diagnosis

Clinical signs and medical history

• Most patients are asymptomatic, with only mild hemodynamic effects, if the lumen is < 70% occluded.
• RVH should be suspected, and investigation for RVH initiated, if there are any of the following findings:
  • Diastolic hypertension develops abruptly in a patient < 30 years or > 50 years.
  • New or previously stable hypertension rapidly worsens.
  • Very severe hypertension: systolic ≥ 180 and/or diastolic ≥ 120 mm Hg
  • Hypertension with worsening renal function or refractory to drug treatment
  • Elevated serum creatinine within 1 week of starting an angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), or a direct renin inhibitor
  • Abdominal bruit on 1 side
  • History of trauma to the back or flank or acute pain in the back or flank region with or without hematuria (suggestive of arterial injury) 
  • Asymmetric renal size (> 1 cm difference) discovered incidentally by imaging 
  • Recurrent episodes of unexplained acute pulmonary edema or heart failure 
• Atherosclerotic-type RAS:
  • > 50 years of age
  • Strong association with other cardiovascular pathologies
  • Often presents with concurrent small-vessel disease in kidneys
  • Bilateral renal arterial stenosis is associated with more widespread atherosclerotic disease, higher serum creatinine levels, and higher mortality than the unilateral disease.
• FMD-type RAS:
  • Mostly in premenopausal women 15–50 years of age
  • Strongly suspect if hypertension occurs in a child
  • Typically, found incidentally on imaging
  • A systolic-diastolic bruit in the epigastrium is present in only 50% of FMD cases.

Diagnostic procedures

Additional diagnostic tests can be used in the following cases:

• Once other causes of secondary hypertension have been excluded
• If confirmation is needed, due to diagnostic uncertainty
• If therapeutic revascularization procedures are indicated

However, the tests are expensive and may have serious side effects, especially if renal insufficiency is present.

• Noninvasive tests: less reliable for FMD, related to distally located lesions:
  • Duplex Doppler ultrasonography
  • Computed tomographic angiography (CTA)
  • Magnetic resonance angiography (MRA)
  • Captopril renogram: radionuclide renography using captopril, an ACEI, mainly used to determine the relative function of each kidney
• Invasive testing: intra-arterial angiography:
  • Gold standard for assessing RAS
  • Perform only after non-invasive testing has been done.
  • Carries risk of atheroembolism

Laboratory testing

• Routine testing to evaluate kidney function by estimated glomerular filtration rate (GFR, from serum creatinine) and urinalysis
• Other labs:
  • Complete blood count (CBC)
  • Serum electrolyte levels (sodium, potassium, chloride, and total carbon dioxide)
  • Blood urea nitrogen (BUN)
  • Lipid panel and fasting glucose 
• Findings:
  • In mild RAS, insufficient to affect blood pressure → no abnormal labs
  • If RAS is severe enough to affect blood pressure (decrease of lumen ≥ 70%, with poststenotic gradient), specific testing is of limited value (poor sensitivity or specificity):
    • Plasma renin activity (PRA) is elevated in only 50%–80% of patients with renovascular hypertension.
    • Renal vein renin measurements have many false positives and negatives.

Management

Medical therapy

• Blockade of the renin-angiotensin system (ACEIs, ARBs)
• Blood pressure control (calcium channel blockers, diuretics, beta blockers)
• Lifestyle changes: cessation of tobacco
• Statins in atherosclerotic RAS
• Antiplatelet therapy

Invasive procedures

• Revascularization is usually reserved for cases in which medical therapy has failed.
• Major complications occur in 5%–9% of cases, even with experienced operators.
• Procedures include percutaneous transluminal renal angioplasty or aortorenal bypass surgery.
• Therapeutic nephrectomy is advised in patients with uncontrolled hypertension and unilateral renovascular occlusion, especially if the kidneys are poorly functioning (< 15% of total GFR).

Differential Diagnosis

Primary (“essential”) hypertension

The most common type of hypertension, with an unknown etiology. In 2017, the American College of Cardiology/American Heart Association (ACC/AHA) revised their definitions, which may vary among different countries:

• Normal blood pressure: systolic < 120 mm Hg and diastolic < 80 mm Hg
• Elevated blood pressure: systolic 120–129 mm Hg and diastolic < 80 mm Hg
• Hypertension stage 1: systolic 130–139 mm Hg or diastolic 80–89 mm Hg
• Hypertension stage 2: systolic at least 140 mm Hg or diastolic at least 90 mm Hg

Secondary causes of hypertension

Five to ten percent of all cases of hypertension include the following conditions:

• Primary kidney disease: suspected with elevated serum creatinine concentration and/or abnormal urinalysis. Chronic kidney disease typically has a persistent and progressive reduction in GFR, but differential diagnosis from RVH can be difficult.
• Primary aldosteronism: usually caused by an aldosterone-producing adenoma in the adrenal gland or bilateral adrenal hyperplasia. Clues include hypokalemia and increased plasma aldosterone to plasma renin activity.
• Sleep apnea syndrome: characterized by repeated apneic episodes at night due to passive collapse of the pharyngeal muscles during inspiration. Usually occurs in obese men who snore loudly while asleep. Can have hypertension, headache, cardiac arrhythmias, daytime somnolence and fatigue, confusion, personality changes, and depression.
• Oral contraceptives: normally, can elevate the blood pressure to hypertensive levels
• Pheochromocytoma: a catecholamine-secreting tumor from chromaffin cells of the adrenal medulla or the sympathetic ganglia. Paroxysmal elevations in blood pressure occur, with the classic symptom triad of pounding headache, palpitations, and sweating. 
• Cushing’s syndrome: caused by excess corticosteroid, which may be exogenous or endogenous, usually from a benign adrenal adenoma. Presents with Cushingoid facies, central obesity, proximal muscle weakness, and ecchymoses. 
• Coarctation of the aorta: a major cause of secondary hypertension in young children but may be diagnosed initially in adulthood. Causes hypertension in the upper extremities, low blood pressure in the lower extremities, and diminished or delayed femoral pulses (“brachial-femoral delay”). May auscultate a “machinery murmur” from the aorta over the posterior thorax. 
• Hypothyroidism: symptoms of hypothyroidism (fatigue, sensitivity to cold, weight gain, constipation, depression, muscle aches, and cramps) with an elevated serum thyroid-stimulating hormone (TSH) level.
• Primary hyperparathyroidism: due to parathyroid adenoma and associated with hypercalcemia, elevated levels of parathyroid hormone
• Renal atheroemboli: also called cholesterol crystal emboli, usually affects older patients with diffuse erosive atherosclerosis. Renal atheroemboli occur when portions of an atherosclerotic plaque break off and embolize distally. Can affect kidneys or other organs.
• Chemotherapeutic agents: agent-related kidney injury by a thrombotic microangiopathy pathway or by inhibiting vascular endothelial growth factor (VEGF) signaling pathways