The prevalence of RAS in the general population is unclear due the asymptomatic nature of the majority of cases. Most data are from autopsy series or patients undergoing angiography for evaluation of other atherosclerotic disease (e.g., cardiac catheterization or lower extremity angiography). In addition, methods and criteria for defining a significant stenosis vary across studies.

The prevalence of RAS does not equal the prevalence of RVHTN, because a causal relationship is not always clear. A large autopsy study noted RAS in 4.3% of cases, and if there was a history of type 2 diabetes mellitus, the incidence was as high as 8.3%. A combined history of type 2 diabetes and hypertension was associated with a 10% risk of RAS.²

Population-based studies using Doppler techniques in persons aged >65 years found RAS in 6.8% (males, 9.1%; females, 5.5%). RAS was unilateral in 88% of cases and bilateral in 12%.² Medicare claims from 1999 to 2001 showed an incidence of newly diagnosed ARAS of 3.7 per 1000 patient years. Follow-up of this group for another 2 years showed that cardiovascular events from atherosclerotic heart disease in the incident ARAS patients were higher than in the general population (304 vs. 73 per 1000 patient years).³

It stands to reason that patients with atherosclerotic disease of other vascular beds would be more likely to have ARAS. For instance, ARAS of >50% can be found incidentally in up to 20% of patients undergoing coronary angiography. A finding of
RAS of >75% in this setting is an independent predictor of all-cause mortality.⁴ In patients undergoing angiography for atherosclerotic disease in the aorta or legs, RAS of >50% can be seen in up to 50% of the cases.^5,6

Ischemic nephropathy is defined as the diminution of renal function due to low blood flow caused by an obstructive lesion in the renal artery. According to the U.S. Renal Data System report from 2000 to 2004, the incidence of ESRD from RAS was 1.8%.⁷ Other studies suggest that ischemic nephropathy may be the cause of ESRD in up to approximately 10% to 15% of cases. As the elderly population in the United States is steadily increasing, it is also expected that the incidence of RAS and ischemic nephropathy will rise.

FMD is most common in women with onset of hypertension below 30 years of age or in women under the age of 50 years with refractory or suddenly worsening hypertension. The most common form of FMD is medial fibroplasias, present with the classic string-of-beads appearance on the angiogram. Other arteries may also be affected in this disease.

In 1934, Goldblatt experimentally produced hypertension in dogs by clamping their renal arteries, demonstrating that decreasing perfusion to the kidney(s) could cause systemic hypertension.

The renal blood flow to the kidneys largely exceeds tissue metabolic needs. Hence, for a lesion to cause significant hemodynamic impairment of blood flow through the renal artery, it must occlude the luminal diameter of the artery by 75% to 80%. When this critical level of stenosis is reached, numerous mechanisms are activated in an attempt to restore renal perfusion. Fundamental to this process is the release of renin from the juxtaglomerular apparatus, which then activates the renin–angiotensin–aldosterone system (RAAS).

Subsequently, systemic arterial pressure increases until renal perfusion is restored or improved. By experimentally blocking the RAAS, medically or by genetic knockout in animal models for the angiotensin II 1A receptor, this rise in systemic arterial pressure can be prevented.⁸

Mechanisms of continued RVHTN depend on whether the RAS affects one or both kidneys. The terminology that has evolved from experimental animal models illustrates pathophysiologic concepts in human disease.

The Goldblatt 2-kidney, 1-clip (2K1C) model represents unilateral RAS in a patient with two functioning kidneys. Central to this concept is the fact that the kidney contralateral to the stenosis is normal and experiences increased perfusion pressure. This normal kidney adapts to the increased arterial pressure with local suppression of the RAAS and excretion of excess sodium and water. Because of normalization of volume status, poor perfusion to the stenotic kidney is maintained and persistent activation of the RAAS in this kidney occurs. This model is known as angiotensin II-dependent RVHTN.

The 1-kidney, 1-clip (1C1K) model means that the entire renal mass is distal to a hemodynamically significant stenosis, whether this is bilateral RAS in a patient with two functioning kidneys or unilateral RAS in a patient with a single functioning kidney. In the 1C1K model, the entire renal mass is under-perfused, leading to RAAS activation with sodium retention and volume expansion leading to increased renal perfusion pressure. Once this occurs, the RAAS is then suppressed and hypertension is thought to be more related to persistent volume expansion. This scenario is known as angiotensin-independent or volume-dependent RVHTN.⁹

The pathophysiology in Goldblatt models is true to the cases of isolated RAS with normal renal parenchyma, such as the case of FMD, or acute renal artery occlusion due to an aneurysm rupture. The pathophysiology underlying HTN in ARAS is more complicated.

The pathophysiology underlying hypertension in ARAS is multifactorial and does not result solely from the reduction in renal perfusion as seen in Goldblatt models. This is evident by the failure of angioplasty procedures to cure hypertension in many patients with ARAS.

The atherosclerotic milieu that results in the development of atherosclerotic plaques in the variable vascular beds, is part of a systemic inflammatory environment that does not only affect vascular beds but also several tissues and organs. In the kidneys, it results in renal parenchymal damage by means of endothelial injury, increased generation of reactive oxygen species and oxidative stress. This damage to the renal parenchyma is the primary culprit for hypertension and reduced renal function.¹⁰

ARAS may superimpose hypoxic injury upon the pre-existing atherosclerotic tissue injury in cases of severe luminal stenosis.

Unexplained malignant or accelerated hypertension with or without renal failure in patients with previously well-controlled blood pressure should raise suspicion for
acute severe renal ischemia such in the cases of renal artery plaque rupture or aneurysm dissection.

Increase in antihypertensive requirements in patient with previously stable blood pressure control that is not explained by medication or dietary noncompliance or worsening renal function could signify progression of underlying ARAS.

Rapid deterioration of renal function (>30% reduction in estimated glomerular filtration rate [eGFR] over ≤3 months) in patients with previously stable or slowly progressive renal disease and background of atherosclerotic milieu.

Episodes of recurrent flash pulmonary edema with accelerated hypertension should raise the suspicion of RVHTN and are more commonly found in patients with bilateral disease. This is related to the pathophysiology of the 1C1K model (see Pathophysiology) and the resultant tendency toward volume overload and to left ventricular hypertrophy with diastolic dysfunction.

A significant and persistent rise (>30%) in serum creatinine after initiation of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) suggests the presence of bilateral RAS or RAS in a patient with a single functioning kidney.