Recognition of important clinical clues for RVHT is paramount in the clinical diagnosis of this condition. RVHT probably occurs in less than 1% of unscreened patients with mild hypertension. By comparison, 10–30% of white patients with severe or refractory hypertension may have renal artery disease. Pertinent clinical clues for RVHT are summarized in Table 42–1.
Table 42–1. Clinical Clues to Renovascular Hypertension. ||Download (.pdf)
Table 42–1. Clinical Clues to Renovascular Hypertension.
Severe or refractory hypertension
Age of onset younger than 30 years or older than 55 years
Abrupt acceleration of stable hypertension
Severe hypertension in the setting of generalized atherosclerosis
Systolic–diastolic bruit in the epigastrium
Flash pulmonary edema
ACE inhibitor- or ARB-induced renal dysfunction
Essential or primary hypertension is the most common form of Hypertension, occurring in >90% of the more than 50 million Americans with elevated BP (Table 42–2). Of the 5–10% of hypertensive patients with secondary hypertension, RVHT accounts for 0.2–3%. However, at autopsy the prevalence of anatomic RAS attributable to atherosclerosis (ASO) in the elderly is quite common. Clinically, RAS may coexist in 20–25% of patients undergoing cardiac catheterization for coronary artery disease (CAD). Similarly, approximately 6% of patients with end-stage renal disease (ESRD) have a concomitant diagnosis of RAS. However, it is unclear whether the occlusive RAS was etiologic in the development of end-stage kidney failure.
Table 42–2. Classification of Hypertension. ||Download (.pdf)
Table 42–2. Classification of Hypertension.
Essential (primary) hypertension
90 to 95
5 to 10
2.6 to 6.0
0.2 to 3.0
Endocrine (primary aldosteronis, pheochromocytoma, thyroid disease, etc.)
1 to 2
The etiology of RAS is usually attributable to ASO or fibromuscular disease (FMD). As can be seen in Table 42–2, ASO accounts for over 70% of RAS. It is generally seen in an older hypertensive population with concomitant diffuse ASO in other vascular beds (eg, coronary, carotids, and peripheral circulation). The RAS lesion due to ASO occurs at the ostium or in the proximal 2 cm of the renal artery. In contrast, FMD accounts for 20–25% of RAS and is typically seen in younger female hypertensive patients. Table 42–3 lists other less common causes of RAS.
Table 42–3. Etiology of Renovascular Hypertension. ||Download (.pdf)
Table 42–3. Etiology of Renovascular Hypertension.
Older patients (>55 years of age)
Concomitant diffuse ASO in other vascular beds
Ostial or proximal (2 cm) renal artery lesions
Fibromuscular dysplasia (FMD)
Extrinsic compression by tumor
The pathophysiology of renovascular hypertension is best explained by the sentinel animal experiments by Goldblatt. These animal models consist of occluding one or both renal arteries with constricting clips. The two-kidney one-clip (2K-1C) model represents unilateral RAS whereas the two-kidney two-clip (2K-2C) model represents bilateral RAS. Unilateral stenosis in a solitary functioning kidney, such as in renal transplant patients, is represented by the one-kidney one-clip (1K-1C) model. Both the 2K-2C and 1K-1C models share similar features.
The mechanism of development of hypertension is mediated via the renin–angiotensin–aldosterone system (RAAS) with salt and water retention. In unilateral RAS (2K-1C model), renal perfusion pressure is decreased in the kidney distal to the stenosis, which leads to increased renin production, which in turn forms angiotensin II (AT II). AT II causes vasoconstriction directly and also stimulates aldosterone production, which causes salt and water retention. The normal contralateral kidney undergoes a pressure natriuresis, which maintains volume status. Due to the constantly elevated levels of renin in the 2K-1C model, this form of RAS is referred to as renin-mediated hypertension.
On the other hand, in the 2K-2C or 1K-1C models representing bilateral RAS or RAS to a solitary kidney, there is an initial increase in renin, which in turn causes an increase in AT II and aldosterone. As in the model described, resultant salt and water retention occurs, but the absence of a normal contralateral kidney prevents pressure natriuresis. Suppression of renin occurs due to volume expansion attributed to the increases in salt and water retention. This form of hypertension is considered volume mediated, whereas the 2K-1C model of unilateral RAS is renin mediated.
What Is Significant Stenosis?
Stenosis that causes hemodynamic changes with a reduction in renal perfusion pressure is called critical stenosis. In Goldblatt's experimental models, 80–85% renal artery constriction induces significant hemodynamic changes. In humans, a >75% degree of RAS is thought to cause critical hemodynamic changes. Clinically, this is of importance as modest RAS may be present in many older patients, but may not be sufficient to produce hemodynamically significant lesions.
Stages of Experimental Renovascular Hypertension
There is an immediate rise in BP as a result of increased levels of renin. This initial rise in BP, whether in the 2K-1C or in the 1K-1C model, is renin–angiotensin mediated. Removal of the stenosis reverses the hypertension.
Phase 2: Transition Phase
This phase lasts for few days to many weeks in the experimental model. Salt and water retention occur, along with a subsequent fall in plasma renin. Nevertheless, in this phase, removal of the stenosis may reverse the hypertension.
Over time, vascular changes and renal parenchymal disease may develop due to the hemodynamic and nonhemodynamic effects of AT II. The importance of this phase is that removal of the stenotic lesion fails to correct the hypertension. In this phase, blockade of RAAS may not decrease the BP.
The two major goals of the evaluation of the hypertensive patient are to recognize clinical clues for secondary forms of hypertension and to identify evidence of target-organ damage (TOD) from the hypertension. The clinical clues suggestive of RVHT are listed in Table 42–1
RVHT should be suspected in patients presenting with severe, sudden-onset hypertension prior to 30 years of age or after 55 years of age. For reasons that are not well understood, RVHT is relatively less common in African-Americans in whom severe hypertension is most frequently essential. Because fibromuscular dysplasia occurs in younger patients (mainly women), those presenting with hypertension before 30 years of age should be suspected of having RVHT. However, RVHT due to ASO is likely to present in older patients with significant hypertension in the setting of generalized ASO in other vascular beds. Malignant hypertension with neurologic symptoms and advanced fundoscopic changes with papilledema should raise the possibility of RVHT. Similarly, severe or refractory hypertension defined as hypertension requiring three or more drugs as well as severe hypertension with heart failure/flash pulmonary edema may also be one of the presenting features of RVHT. Importantly, this sudden onset of worsening azotemia after the institution of an angiotensin-converting enzyme (ACE) inhibitor or AT II receptor blockers (ARB) should suggest RVHT, especially bilateral RAS or RAS with a solitary functioning kidney. In such patients, with all of their functioning kidney mass distal to a critical RAS, maintenance of the glomerular filtration rate (GFR) is dependent upon efferent arteriolar vasoconstriction mediated by AT II. Once this preservation of function is lost after administration of an ACE or ARB, a decline in renal function is seen.
The presence of severe stage II hypertension (greater than 160–100 mm Hg) may be a critical clue to the presence of RVHT. The presence of an abdominal bruit in the setting of increased BP is also a strong clinical clue to RAS. The bruit is systolic–diastolic in nature and is located near the epigastrium. This is seen more commonly in fibromuscular dysplasia and, in fact, correlates with surgical outcomes. The absence of such a bruit does not exclude RAS. The presence of stage III or IV hypertensive retinopathy on fundus examination is highly suggestive of RVHT. Evidence of diffuse ASO in the peripheral vascular, coronary, and cerebral vascular beds may be suggestive of RVHT due to ASO renal artery disease in the older hypertensive population.
By definition RVHT requires an elevation of BP due to the activation of the renin–angiotensin system in the setting of renal artery occlusive disease. The diagnosis of RVHT can be made only if BP improves after a correction of RAS, thereby making RVHT a retrospective diagnosis. The primary goal in screening for RVHT is to identify a subset of patients who may have a reversible hemodynamic cause of their hypertension and/or renal dysfunction. Table 42–4 summarizes the specificity and sensitivity of these diagnostic modalities
Table 42–4. Specificity and Sensitivity. ||Download (.pdf)
Table 42–4. Specificity and Sensitivity.
Plasma renin activity (PRA)
Duplex ultrasound scanning
Spiral (helical) computed tomography scanning
Magnetic resonance Angiography
Hypokalemia may be a surrogate marker of hemodynamically significant renal artery occlusive disease secondary to stimulation of the renin–angiotensin system with secondary hyperaldosteronism. The hyperaldosteronism results in urinary sodium retention and kaliuresis, which may be responsible for the development of hypokalemia.
RVHT may be seen in patients with or without renal dysfunction. RVHT and possible ischemic nephropathy may be suspected in patients with unexplained azotemia occurring in the setting of generalized ASO and asymmetric kidney sizes (possibly due to the occlusive RAS). As noted previously, azotemia following the administration of an ACE inhibitor or ARB is a strong clinical clue suggestive of hemodynamically significant renal artery disease.
Plasma Renin Activity and Direct Renin
Historically, plasma renin activity (PRA) was measured to evaluate patients with RVHT. PRA was determined indirectly by measurement of AT I because the amount of AT I produced from angiotensinogen is proportional to the renin enzyme concentration. This reaction is dependent on the amount of angiotensinogen present and can underestimate the renin concentration in patients with severe heart or liver failure who have markedly low levels of angiotensinogen. Direct renin measurements are now determined by specific monoclonal antibodies to renin. Direct renin assays are now available clinically and may offer clinical advantages in terms of accuracy and more rapid reporting of results (a prior PRA level of 1 ng/mL/hour converts to a direct renin level of 8.4 mU/L).
Unfortunately, PRA has been an insensitive method of screening with elevated levels present in only 50–80% of patients with RVHT. Moreover, up to 15% of patients with essential hypertension have elevated PRA levels, making PRA a nonspecific determinant of RVHT. Although infrequently used in usual medical practices today due to its low sensitivity and specificity, a very low PRA (if plasma renin activity is very low, <1 ng/mL/hour, in the absence of drugs known to suppress renin) can strongly argue against RVHT as the cause of elevated BP. Captopril-stimulated PRA testing may be preferable to PRA determination alone in the evaluation of the patient with RVHT.
Commonly used radionuclide agents include technetium-99m diethylenetriaminepentaacetic acid (DTPA), which is used as a marker of GFR because it is exclusively excreted by glomerular filtration, and technetium-99m-labeled mercaptoacetyltriglycine (MAG3), which is used to approximate the renal plasma flow rate and, in contrast to DTPA, is excreted both by glomerular filtration and tubular secretion.
Since the ischemic kidney is dependent upon the effects of AT II to induce efferent artery vasoconstriction to maintain the GFR, the introduction of captopril is expected to lower the GFR of the affected kidney distal to the stenosis. The results after captopril are demonstrated by a decreased uptake of DTPA (decreased GFR) with little change in MAG3 uptake (preserved renal plasma flow rate), but a delayed excretion phase of MAG3 compared to renal scans without captopril provocation (Figure 42–1). Limitations of this technique for screening include decreased sensitivity in patients with renal dysfunction. A positive finding provides clear evidence that the occlusive disease is hemodynamically significant and that intervention is likely to improve BP control.
Captopril scintigraphy/renography. A Tc-DTPA time–activity curve at baseline (A) and after captopril (B) in a patient with stenosis of the right renal artery. The diagnosis of renal artery stenosis is based on asymmetry of renal size and function, as well as a delayed time to maximal activity (>11 minutes), significant asymmetry of the peak activity of each kidney, marked cortical retention of the radionuclide, and marked reduction in calculated glomerular filtration rate of the ipsilateral kidney. (Adapted with permission from Nally JV et al: Advances in noninvasive screening for renovascular hypertension disease. Cleve Clin J Med1994;61:328.)
Atherosclerotic Renal Artery Stenosis
Atherosclerotic lesions are ostial or proximal within the first 2 cm of the renal artery, and typically do not occur in the distal portion of the renal arteries.
Medial fibroplasia will appear as a “string of beads”(the beads are of larger caliber than the artery), and is often located at the mid to distal portion of the renal artery.
The gold standard in detecting renal artery occlusive disease remains renal angiography/arteriography because it provides maximum information about the vascular architecture as well as an opportunity for intervention if hemodynamically significant lesions are found. With the advent of digital subtraction angiography, less contrast media can be given to obtain images, thus decreasing the risk of developing contrast-induced nephropathy. Techniques developed to avoid the use of contrast media include carbon dioxide (CO2) angiography, which lowers the risk of renal toxicity, but also lowers the resolution of the image. Other complications that can result from invasive renal angiography include renal artery dissection and generation of atheroemboli.
Magnetic Resonance Angiography
A noninvasive method of defining the renal artery vasculature includes magnetic resonance angiography (MRA), which modifies the magnetic resonance imaging (MRI) to examine patterns of blood flow. In renal vascular disease, there is reduced blood flow distal to a stenotic lesion that causes a loss of MRA signaling. Unfortunately, loss of MRA signaling is also commonly encountered in distal vessels of normal patients thereby exaggerating the amount of narrowing found, especially in the distal half of the artery. Gadolinium MRA has been shown to significantly improve the images of the distal arteries and accessory renal arteries. Although gadolinium-enhanced MRA has previously been suggested to be an alternative non-nephrotoxic method in defining the renal artery vasculature, its use should be avoided in those with renal dysfunction due to the well-described association between gadolinium and the development of nephrogenic fibrosing dermopathy (NFD) and systemic fibrosis (NSF). Contraindications to the use of MRA include patients with claustrophobia and those with metallic implants/foreign bodies. MRA may not be as useful in detecting FMD as compared to renal angiography due to the increased spatial resolution of MRA (1 mm versus 200 νm).
Spiral (Helical) Computed Tomography Scanning
High quality images, as well as three-dimensional images, of the renal arteries can be obtained using this technique. By using a continuously rotating tube and an advancing table, images can be obtained in less than 1 minute, thereby significantly reducing motion artifact. Unfortunately, as with conventional renal angiography, contrast media must be administered and therefore the concerns for nephrotoxicity exist.
Duplex Ultrasound Scanning
Over the years, the noninvasive renal ultrasound has replaced intravenous pyelography (IVP) as the preferred method of obtaining information regarding the assessment of kidney size. Direct visualization of the renal arteries can be obtained (by B-mode imaging) and measurement of hemodynamic factors can be achieved by pulse Doppler ultrasound. Duplex ultrasound scanning is generally reported as lesions causing 0–59% stenosis and those causing 60–99% stenosis. Areas that are 0–59% stenosed are unlikely to cause lesions that are hemodynamically significant, whereas lesions that are 60–99% stenosed indicate a further need for investigation. A drawback to duplex ultrasound scanning is that the procedure is operator dependent due to its high technical demands.
Renal resistive indices are also provided by duplex ultrasound. RI approximates the amount of renal arterial impedance. In patients with RAS, an increase in renal resistive index >80% is associated with poorer postrevascularization outcome as well as an increased risk of progressive renal dysfunction.
Captopril-Stimulated Plasma Renin Activity Test
By comparing PRA at baseline and at 1 hour after an oral dose of 25–50 mg of captopril (a short-acting ACE inhibitor), the predictive value of PRA may be increased and used to discriminate essential hypertension from RVHT. Studies have shown larger elevations in PRA and greater reductions in BP after captopril in patients with RVHT compared to those with essential hypertension (see Table 42–5). Major limitations to the widespread use of this screening method include decreased reliability of the test in patients with renal dysfunction, inability to determine unilateral versus bilateral disease, nonstandardized assay methodology of PRA between institutions, and improper patient preparation prior to testing. Ideally patients should ingest dietary salt ad libitum and hold antihypertensive medications for 2 weeks (especially ACE inhibitors, diuretics, and β-blocking agents) prior to the captopril PRA testing.
Table 42–5. Renin Criteria for Captopril Test that Distinguish Patients with Renovascular Hypertension from Those with Essential Hypertension. ||Download (.pdf)
Table 42–5. Renin Criteria for Captopril Test that Distinguish Patients with Renovascular Hypertension from Those with Essential Hypertension.
Stimulated plasma renin activity of 12 ng/mL or more
Absolute increase in PRA of 10 ng/mL/hour or more
Percent increase in PRA
Increase in PRA of 150% if baseline PRA >3 ng/mL/hour
Increase in PRA of 400% if baseline PRA <3 ng/mL/hour
Differential Renal Vein Renin Determinations
Historically used to assess the functional significance of renal vascular stenosis, the determination of the renal vein renin ratio has fallen out of favor because of the invasive nature of the procedure, the associated technical difficulties, the inability to detect bilateral stenosis, and the high false-negative rate. The procedure is done by obtaining blood samples from each of the renal veins and the inferior vena cava (below the level of the renal artery). Lateralization of the renal vein renin ratio predicts substantial improvement in BP control after surgical intervention. Renal vein renin ratios are considered to be lateralized when the ratio is greater than 1.5 (ipsilateral to contralateral kidney).
The goals of therapy are optimal control of hypertension and preservation of renal function, which can be achieved either through medical therapy, percutaneous renal angioplasty (PTRA) with or without stenting, or renovascular bypass surgery. The optimal treatment of patients with RVHT remains an elusive goal because there are no randomized controlled trials comparing medical versus surgical versus renal angioplasty versus renal stents on BP control and/or the preservation of kidney function.
Medical therapy is often required either for short-term management prior to an intervention or for long-term management of unstable patients or those whose BP is easily controlled with preserved GFR. Long-term medical therapy is often recommended for patients who are not optimal surgical candidates, patients with multiple comorbidities, and those with technically difficult revascularization. The medical management of RVHT is similar to that of primary hypertension, yet three important distinctions exist: (1) Hypertension may be more difficult to control and often requires multiple medications from different classes, (2) vigilant attention must be given to preserving kidney function, and (3) coexistent atherosclerotic cardiac and carotid disease are more prevalent and may require specific intervention. The response to a specific drug may be variable and highly individualized. All patients with RVHT may not readily respond to antihypertensive therapy. Historically, early studies in the 1960s did not show much success when a thiazide diuretic and hydralazine were employed. Later, with the advent of β-blockers and agents that interrupt the renin–angiotensin system, major improvements in medical therapy were seen.
Angiotensin–Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers
In patients with unilateral RAS, ACE inhibitors are the preferred agent of choice. To achieve optimal control of hypertension, these agents are often combined with other antihypertensive agents, especially diuretics. Optimal control may be achieved in up to 96% of patients with an ACE inhibitor. The initial review of captopril therapy in 269 patients showed successful short-term control of BP in 74%. In a comparison study of Enalapril and a diuretic with standard triple drug therapy, control was seen in 96% of patients on an ACE inhibitor versus 62% on triple drug therapy. In unilateral RAS, the fall in GFR in the stenotic kidney due to AT II inhibition by an ACE inhibitor is not reflected, as the total GFR does not fall due to compensation of filtration in the contralateral kidney. In bilateral RAS, the GFR is maintained by AT II. Inhibition of AT II by an ACE inhibitor can cause hemodynamic changes causing a further reduction in GFR. A loss in the autoregulatory mechanism of efferent arteriolar constriction occurs in patients who are on an ACE inhibitor. This effect is also potentiated by volume contraction induced by a diuretic. Thus, in patients with bilateral RAS, a combination of an ACE inhibitor and diuretic should be used with caution. Despite the reduction of the potent vasoconstrictor AT II, medical control of hypertension is often difficult to achieve with these agents, especially if the hypertension has been present for over 3–5 years. Underlying severe ASO and/or the presence of chronic kidney disease (CKD) makes the hypertension difficult to manage.
Calcium channel blockers (CCBs) are effective in lowering the BP in patients with RVHT. They also maintain renal blood flow through vasodilation in the afferent arteriole. The benefit of using CCBs in RVHT is they have a more favorable effect on renal function compared to an ACE inhibitor. They can be used safely in patients with bilateral RAS without concern for a significant decline in the GFR. In one study, nifedipine produced a smaller reduction in GFR as compared to captopril. All three categories of CCBs, the dihydropyridines (nifedipine, felodipine, amlodipine), benzothiazipines (diltiazem), and phenylalkylamines (verapamil), have been used as antihypertensive medications for patients with or without RAS.
Percutaneous Renal Artery Intervention
Selected patients with RAS may benefit from percutaneous revascularization. Revascularization is often recommended when control of hypertension becomes difficult despite multiple antihypertensive medications. Patients with long-standing renal parenchymal disease may not benefit from PTRA. Nevertheless, a recent pronounced decline in GFR before PTRA may predict a favorable outcome. Renal angiography with and without renal artery stenting has become the major form of renal revascularization. The technical success rate is high, yet long-term studies reporting BP control or preservation of kidney function are either inconclusive or in progress. Recommendations vary as to whether the RAS is due to FMD or to ASO.
Percutaneous Renal Artery Intervention for Fibromuscular Dysplasia
PTRA is the initial choice in younger patients with fibromuscular disease. Correction is indicated to control hypertension and to prevent progressive renal disease. Results for percutaneous intervention in the majority of patients with FMD have been very good and comparable to surgical therapy. Indication for surgical intervention in these patients is due to branch renal artery involvement, which makes PTRA technically difficult. As many as 30% of FMD patients may have branch renal artery disease requiring surgical intervention.
Atherosclerotic Renal Artery Stenosis
There have been three randomized controlled trials comparing the merits of medical therapy versus percutaneous revascularization in terms of BP control and/or renal function in RAS attributable to atherosclerosis (ASO-RAS). Fifty-five hypertensive patients with sustained hypertension attributed to RAS with a minimum diastolic BP of 95 mm Hg on at least two antihypertensive drugs were randomized to either medical therapy or PTRA without stenting. In patients with bilateral RAS randomized to angioplasty, a significant fall in BP was observed at the latest follow-up (3–54 months). There was no clinically or statistically significant difference noted in either the medical or the angioplasty arm in patients with unilateral stenosis. No significant renal outcomes were noted in either unilateral or bilateral stenosis.
The largest randomized controlled trial of PTRA without stenting was conducted by the Dutch Renal Artery Stenosis Intervention Cooperative Study Group. They randomized 106 patients with ASO-RAS to medical therapy or PTRA. At the end of 12 months, there were no significant differences between the two groups in BP, renal function, and antihypertensive drug therapy. They concluded that angioplasty has little advantage over medical therapy. The limitation of the study was the high crossover rate from medical therapy to intervention and lack of stent use. Currently, studies examining medical therapy versus renal artery angioplasty with stenting are ongoing.
Renal Artery Bypass Surgery
Earlier reports had suggested a survival benefit for RAS patients who underwent renal artery bypass surgery versus medical therapy. However, these observations came from nonrandomized studies in which there was an inherent bias for healthier patients to undergo surgery. To date, there is a single randomized trial comparing medical therapy and renovascular surgery in patients with high-grade bilateral RAS or RAS to a solitary kidney. The primary endpoints were doubling of serum creatinine, uncontrolled hypertension, renal failure, or death. There were no significant differences between the medical and surgical groups in this randomized, controlled study. Given the lack of a clear mandate in the treatment of patients with hemodynamically significant renovascular disease, recent guidelines by the National Kidney Foundation suggest referral of such patients to an expert in the field of hypertension and kidney disease for specific medical and/or interventive therapy tailored to that individual. Currently, percutaneous angiography with stent placement is increasingly being used in the treatment of ASO-RAS. Although this form of intervention is more likely to maintain artery patency when clinically successful, there is a lack of clinical evidence from long-term trials that stenting has demonstrable benefits on BP control, preservation of kidney function, or patient morbidity and mortality from cardiovascular events. At present, three trials are ongoing in the United States and abroad comparing medical therapy to renal angioplasty with stenting in patients with ASO-RAS. Definitive recommendations regarding the management of RVHT awaits the conclusions of these important trials.
Izzo JL, Black HR, Eds.Hypertension Primer, 3rd ed. American Heart Association, 2003.