Article Update

Thursday, July 9, 2020


Renal artery stenosis (RAS) is an uncommon but important cause of secondary hypertension. It is unclear what fraction of hypertension is related to this problem; however, it is currently estimated that 1% to 2% of patients with mild to moderate hypertension have clinically significant RAS. Establishing whether the RAS is the primary cause of hypertension in such patients is difficult.

In addition to its effects on blood pressure, RAS can also lead to impaired renal function, a phenomenon known as ischemic nephropathy.


A substantial portion of the aging population has some degree of RAS, which may be discovered as an incidental finding during color Doppler ultrasound or other vascular imaging studies. Indeed, roughly 20% to 45% of the patients who undergo angiography for any indication will be found to have RAS. Once the stenosis occludes more than approximately 50% to 70% of the arterial lumen, a significant drop in pressure distal to the lesion produces a series of pathophysiologic events that lead to a fall in renal blood flow and rise in systemic arterial pressure.
First, reduced perfusion pressure to the affected kidney decreases hydrostatic pressure in the glomeruli and thereby reduces tubular flow rates, triggering release of renin and synthesis of angiotensin II and aldosterone. These hormones increase systemic pressure and promote volume retention, leading to secondary hypertension.
If the contralateral kidney is normal, it will be exposed to these circulating hormones and initially contribute to volume expansion. As its perfusion pressure increases above normal, however, the contralateral kidney will begin to excrete sodium and water. This phenomenon, known as “pressure natriuresis,” relies on mechanisms that are incompletely understood. Although autoregulation generally prevents increased perfusion pressure from reaching the glomerular capillaries, it has been hypothesized that increased shear stress in the preglomerular vessels, as well as increased renal interstitial hydrostatic pressure, may activate local natriuretic mechanisms. As a result, the nonstenotic kidney prevents effective volume expansion, and the persistently underperfused stenotic kidney continues to secrete renin. At least in the early stages, the hypertension is thus angiotensin-dependent; however, later in the disease course, renin levels fall as alternate pressor mechanisms, such as endothelin and oxidative stress, are recruited.
If, in contrast, the contralateral kidney is absent or dysfunctional, or if both kidneys are affected by RAS, renin secretion will lead to unopposed expansion of fluid volume. Once there is enough volume to achieve normal perfusion pressure in the stenotic kidney (or kidneys), renin secretion ceases.
During these processes, the affected kidney may itself become dysfunctional, a phenomenon known as “ischemic nephropathy.” The kidney as a whole does not become “ischemic” per se because its blood supply generally continues to exceed overall metabolic requirements. Nonetheless, the decline in pressure causes autoregulation to become ineffective, leading to focal areas of tissue injury and ischemia. In addition, the hemodynamic changes lead to altered expression of endothelium-derived substances, such as nitric oxide and endothelin, and promoters of fibrogenic injury, such as transforming growth factor β. As a result, the kidney may exhibit a variable degree of tubulointerstitial fibrosis. If there is bilateral disease, overall filtration may become impaired.
The RAS itself reflects the presence of either atherosclerotic disease, which accounts for approximately 90% of cases, or fibromuscular dysplasia, which accounts for most of the remainder.
Atherosclerosis is a common problem, especially among individuals over 50 years of age. It is associated with risk factors including smoking, diabetes mellitus, and hypercholesterolemia. Because hypertension is also a well-known risk factor for atherosclerosis, many patients with atherosclerotic RAS may also have essential hypertension. Atherosclerosis typically affects the proximal region of the renal artery and the perirenal aorta.
Fibromuscular dysplasia comprises a group of angiopathies that typically occur in women of child-bearing age. Their etiology is unknown. These disorders can lead to fibroplasia in all layers of the arterial wall, but most cases involve the media. A smaller number of cases may feature intimal hyperplasia, which typically leads to dissection and eventual thrombosis. Unlike atherosclerosis, fibromuscular dysplasia typically affects the distal two thirds of the renal arteries.

Few, if any, clinical features can distinguish patents with renovascular hypertension from those with essential hypertension. Although some features are suggestive, none is particularly sensitive or specific.
In the clinical history, suggestive features include the onset of hypertension before age 30 or after age 50 (which favor fibromuscular dysplasia or atherosclerosis, respectively); an acute rise in blood pressure in patients with previously well-controlled essential hypertension; refractory hypertension despite multiple treatments; accelerated or malignant hypertension; and the presence of other vascular disease.
On physical examination, an abdominal bruit may be noted. On laboratory studies, suggestive features include hypokalemia (reflecting increased potassium secretion secondary to aldosterone release), an increased BUN : creatinine ratio (reflecting increased proximal tubule reabsorption secondary to angiotensin II release); a significant elevation in serum creatinine concentration after starting an ACE inhibitor or ARB; and a lack of evidence for intrinsic renal disease (e.g., benign urine sediment). On abdominal imaging, one kidney may also appear markedly smaller than the other in the setting of unilateral disease.
If the index of suspicion is high, more specific tests may be performed, but these should be performed mainly if an interventional procedure would be undertaken in the event that RAS were confirmed.
Noninvasive tests include measurement of plasma renin (including after administration of captopril, which removes the negative feedback from angiotensin II), as well as nuclear scanning of renal function after captopril administration. These tests, however, are not highly sensitive or specific in many populations because, for the reasons discussed previously, renin secretion varies widely.
Imaging studies may be performed to directly evaluate the renal vasculature, including Doppler ultrasound (US), computed tomographic angiography (CTA), or magnetic resonance angiography (MRA). US may reveal increased flow velocities across the narrowed vessel, and calculation of the resistive index (which indicates small-vessel disease and parenchymal fibrosis) may indicate the potential benefit of intervention. US, however, is operator-dependent and varies widely between institutions.
CTA and MRA, in contrast, are highly sensitive tests that are widely available; however, these sometimes fail to detect lesions associated with fibromuscular dysplasia, which affect the more distal segments of the renal artery. In addition, these tests require the use of iodinated contrast or gadolinium, which limits their availability to patients with reduced kidney function. Because of its risks and costs, invasive angiography is generally not performed unless an intervention is planned for the same procedure.
For patients with ambiguous degrees of vascular occlusive disease, demonstrating lateralization of renal vein renin levels reliably predicts the role of the affected kidney in sustaining hypertension and the likely effect of revascularization on arterial pressure.

ACE inhibitors or ARBs should be offered to patients with RAS, either alone or in combination with other antihypertensives, to lower systemic blood pressure. In unilateral disease, the nonstenotic kidney is typically able to compensate for the reduced filtration that these agents cause in the affected kidney. In bilateral disease, however, some patients will experience a clinically significant decline in overall glomerular filtration rate in response to these agents. Thus, in all patients, serum creatinine and potassium concentrations should be measured shortly after these agents are initiated.
In patients with atherosclerotic disease, measures should be taken to limit the progression of plaque formation, including smoking cessation and administration of statins.
The indications for renal revascularization are controversial, particularly for patients with satisfactory blood pressure control and stable kidney function. In general, interventions should be considered in patients who have drug-resistant or malignant hypertension. In addition, intervention should be considered in patients who have either bilateral stenosis or stenosis to a solitary kidney along with normal or mildly impaired renal function and no evidence of intrinsic renal disease. Although it is difficult to predict which patients with renal dysfunction will benefit the most from revascularization, some evidence suggests that patients with high resistance indices on ultrasound are unlikely to regain much function because they are more likely to have chronic, irreversible renal disease.
Endovascular repair is generally the preferred method of intervention. It consists of balloon angioplasty and, in patients with atherosclerosis, stent placement. Surgical bypass of the renal artery may be indicated in patients with complex lesions.

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