Acs0621 Renovascular Hypertension And Stenosis

© 2007 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
6 VASCULAR SYSTEM 21 RENOVASCULAR HYPERTENSION AND STENOSIS — 1

21 RENOVASCULAR HYPERTENSION
AND STENOSIS
Michael T.Watkins, M.D., F.A.C.S., and Marvin D. Atkins, M.D.

Approach to Suspected Renovascular Disease
Vascular disease that affects the renal arteries is an increasingly imaging, renal artery stenosis (RAS) is frequently diagnosed in
common clinical scenario encountered by general and vascular hypertensive patients. However, the precise contribution RAS
surgeons. As a result of heightened clinical awareness and makes to hypertension and renal dysfunction is not always clear,
advances in vascular imaging, more patients than ever before are and therefore, the patient’s response to treatment may not be read-
being identified as having some degree of atherosclerotic or fibro- ily predictable.
muscular renovascular disease. The vast majority of these lesions The natural history of RAS consists of continued narrowing of
cause no symptoms, are hemodynamically insignificant, or both. the renal artery. Studies in which duplex ultrasonography (DUS)
Some, however, are severe enough to alter renal perfusion pres- was employed to follow untreated patients with greater than 60%
sure, leading to changes in blood pressure regulation and renal renal artery stenosis documented a 20% progression of disease per
function. Symptomatic renovascular disease can have a variety of year, with 11% of patients progressing to renal occlusion within 2
manifestations, ranging from mild renovascular hypertension to years.3 RAS is associated with loss of renal mass, which is a surro-
congestive heart failure and ischemic nephropathy. gate marker for renal function. Occlusion of a renal artery is asso-
Our purpose in this chapter is to outline an approach to the ciated with substantial loss of renal size and function. Historical
diagnosis and management of renovascular disease that is based studies of the clinical course of RAS suggested that chronic renal
on an understanding of the relevant pathophysiology [see Discus- failure developed within 6 years in as many as 27% of patients
sion, Pathophysiology of Renovascular Hypertension, below]. The with RAS.4
procedures employed for surgical and endovascular treatment of The two main conditions associated with RAS are atherosclero-
renovascular disease are described in greater depth in other chap- sis and fibromuscular dysplasia. The former accounts for the vast
ters [see 6:22 Open Procedures for Renovascular Disease and 6:23 majority of renovascular lesions. Atherosclerotic RAS is typically
Endovascular Procedures for Renovascular Disease]. located at the aortic orifice or the proximal renal artery and prob-
ably represents spillover of aortic atherosclerotic disease [see Figure
1]. It is most commonly found in patients older than 50 years who
Incidence and Risk have signs of atherosclerosis in other vascular beds. RAS associat-
Factors
In the United States,
hypertension affects approx- Table 1—Screening Tests for Secondary Causes
imately 24% of the entire of Hypertension
population and 50% of per-
sons over the age of 60 years.1 It is an independent risk factor for
increased cardiovascular morbidity and mortality: cardiovascular Diagnosis Diagnostic Study
risk doubles for every 20/10 mm Hg increase in blood pressure.2
In fact, it is the number-one modifiable risk factor associated with Chronic renal disease and salt
Serum creatinine, GFR
retention
increased cardiovascular morbidity and mortality. Data from the
National Health and Nutrition Examination Survey (NHANES) Renal artery stenosis DUS, MRA, CTA
revealed that 30% of hypertensive persons in the United States
Primary hyperaldosteronism 24-hr urinary aldosterone
were unaware that they had hypertension, that more than 40% of
hypertensive persons were not being treated for their condition, Pheochromocytoma
24-hr urinary metanephrine,
and that in two thirds of hypertensive patients who were being normetanephrine
treated, blood pressure was not maintained below the recom- Cushing syndrome or chronic History, cortisol, dexamethasone
mended target level of 140/90 mm Hg. steroid use suppression test
An estimated 90% to 95% of cases of hypertension are classi- Thyroid or parathyroid disease TSH, calcium, serum PTH
fied as essential or idiopathic, with the remaining 5% to 10% con-
sidered to be secondary to another cause. Secondary hypertension Coarctation of aorta CTA
is sometimes refractory to usual medical treatment, the reason Sleep apnea Sleep study with oxygen saturation
being that the underlying pathophysiologic state must be identi-
fied and treated in addition to the hypertension itself. There are Effect of medication History, drug screen
many possible causes of secondary hypertension [see Table 1], and CTA—computed tomographic angiography DUS—duplex ultrasonography GFR—
it can be difficult to determine which one is operative in a given glomerular filtration rate MRA—magnetic resonance angiography PTH—parathyroid
clinical situation. As a result of the increasing use of diagnostic hormone TSH—thyroid-stimulating hormone
1


Renal artery stenosis is suspected on clinical grounds

No limitations on the performance of duplex
ultrasonography exist

Perform renal artery DUS (RADUS).

RADUS is positive for RAS RADUS is negative for RAS

Treat stenosis, either medically or If study is technically accurate and results
surgically. Consider percutaneous are reliable, no further workup is required.
angioplasty and stenting. If accuracy of study is in doubt and index
of suspicion for RAS is high, perform CTA,
conventional angiography, or MRA.

CTA is positive for RAS

Treat stenosis, either medically
or surgically. Consider
percutaneous angioplasty
and stenting.


Approach to Suspected Renovascular Disease

Patient is obese, or institution lacks sufficient
ultrasonographic expertise and experience

Examination of aorta for other pathologic Patient has renal insufficiency or failure
conditions (e.g., aneurysm) is desired, or
quality of MRA is poor Perform magnetic resonance angiography.

Perform computed tomographic angiography.

MRA is positive for RAS MRA is negative for RAS

CTA is negative for RAS Treat stenosis, either medically or surgically. If study is technically accurate and
Consider percutaneous angioplasty and results are reliable, no further workup
If study is technically accurate and stenting. is required.
results are reliable, no further workup If accuracy of study is in doubt and
is required. index of suspicion for RAS is high,
If accuracy of study is in doubt and perform conventional angiography.
index of suspicion for RAS is high,
perform conventional angiography.


of RAS. These studies make the points that cardiovascular risk is
high in RAS patients and that blood pressure control may be a
poor surrogate for clinical outcome. At present, it is not known
whether the higher cardiovascular morbidity and mortality associ-
ated with RAS are attributable to the effects of renal ischemia or
to the systemic effects of activation of the renin-angiotensin-aldos-
terone system (RAAS) [see Discussion, Pathophysiology of
Renovascular Hypertension, below] or whether RAS is simply a
marker of more advanced atherosclerotic disease.
Ischemic nephropathy may be defined as a progressive decline
in renal function secondary to global renal ischemia. It is estimat-
ed that for 5% to 15% of the patients in whom end-stage renal dis-
ease necessitating dialysis develops each year, ischemic nephro-
pathy is the underlying cause of the decline in renal function.8,9

Investigative Screening Studies

Figure 1 Shown is severe bilateral RAS with poststenotic dilation Screening for suspected RAS is performed to identify those
in a severely diseased aorta. patients who are most likely to benefit from renal artery interven-
tions aimed at managing hypertension or renal insufficiency. The
decision regarding which screening test or tests to perform is not,
ed with fibromuscular dysplasia is usually seen in patients younger however, a simple and obvious one. All of the noninvasive studies
than 40 years and usually affects the middle and distal segments currently in use have their strengths and weaknesses, many of
of the renal artery. These lesions have a characteristic “string of which are institution dependent. Constant improvements in tech-
beads” appearance. nology and institutional variations in reporting standards, tech-
Population-based studies indicate that hemodynamically signif- niques, and published results have further complicated the process
icant atherosclerotic RAS is present in approximately 6% of per- of determining the optimal first-line screening method. A variety
sons older than 65 years, with a somewhat higher incidence in of physiologic tests have been employed to screen for RAS and
men (9.1%) than in women (5.5%). Incidental RAS is seen in assess the contribution of RAS to hypertension or ischemic
approximately 20% of patients undergoing coronary angiography nephropathy. Peripheral plasma renin assays, rapid-sequence
and in 35% to 50% of patients undergoing peripheral vascular intravenous pyelography (for indirect assessment of differences in
angiography for occlusive disease of the aorta and the lower renal filtration), and isotope renography have all proved insuffi-
extremity. The prevalence of renovascular disease corresponds to ciently sensitive to be useful for screening purposes. Catheter-
the overall atherosclerotic burden. In the vast majority of patients, based angiography has been widely used to screen for RAS, but
no direct causal relation between significant RAS and hyperten- technical improvements in DUS, computed tomographic angiog-
sion or ischemic nephropathy can be identified. Efforts to define raphy (CTA), and magnetic resonance angiography (MRA) have
such a relation are confounded by the fact that the same popula- caused many physicians to prefer one or another of these imaging
tion in which renovascular disease is prevalent is also at risk for modalities for this purpose. A thorough understanding of the
essential hypertension, diabetes, and baseline renal insufficiency. strengths and limitations of all of the screening tests, as well as an
Other risk factors associated with renovascular disease include informed awareness of specific institutional limitations, is required
smoking, increased age, and hyperlipidemia. to define the place of each test in one’s preferred diagnostic
RAS is believed to be the cause of hypertension in only 3% to approach.
5% of the 90 million hypertensive persons in the United States. In
IMAGING
those with mild hypertension (the vast majority), it plays only a
negligible role; however, it plays a significantly larger role in those
Contrast Arteriography
with severe systemic hypertension. (The severity of a case of
hypertension is related to the patient’s blood pressure without Of the several noninva-
medication, not necessarily to the difficulty or ease with which sive or functional studies
blood pressure can be controlled medically.) At the extremes of that are used to diagnose
age (i.e., in the very young and the elderly), severe hypertension is RAS and renovascular hypertension, none has displaced catheter-
substantially more likely to be renovascular than essential in origin based contrast arteriography from its role as the diagnostic gold
[see Table 2]. standard. In many institutions, however, CTA is now considered
Patients with RAS are at higher risk for cardiovascular morbid- preferable to formal catheter-based arteriography as an easily
ity and mortality than similar patients without RAS are. One reproducible screening test for RAS. The obvious drawback of
series, in which patients underwent renal angiography after coro- CTA, as compared with the other imaging modalities, is the neces-
nary angiography, found that 4-year survival was significantly sity of administering iodinated contrast material and the conse-
decreased in patients with incidentally discovered RAS.5 Several quent risk of contrast-induced nephropathy (CIN). We frequently
series have suggested that the risk of adverse cardiovascular events use CTA for the diagnosis of RAS in cases where concomitant aor-
is high in this population and exceeds the risk that might have toiliac aneurysmal or occlusive disease is suspected [see Figure 2].
been expected on the basis of the severity of hypertension.6,7 Blood
pressure control—measured by the number of antihypertensive “Drive-by” renal arteriography In a 1992 study of
medications used, as well as by systolic and diastolic pressures—is screening renal angiography (the largest such study published to
the most commonly used end point in series examining treatment date), 1,235 consecutive patients underwent renal arteriography at


B mode with a Doppler angle of less than 60°.The ratios between
Table 2 Clinical Clues to Diagnosis of Renal the velocities in the renal artery and those in the aorta are deter-
Artery Stenosis mined, and the Doppler spectral waveform is recorded [see Figure
3]. The normal Doppler spectral waveform of the low-resistance
Onset of hypertension at extremes of age (< 30 or > 60 yr) renal vascular bed shows continuous diastolic flow.
Severe hypertension at > 55 yr
Accelerated, resistant, or malignant hypertension
Unexplained renal insufficiency or failure
Renal dysfunction associated with initiation of ACE inhibitor or ARB
therapy
Unexplained congestive failure, pulmonary edema, or both
Unexplained atrophic kidney or size discrepancy between kidneys
Abdominal bruit

the conclusion of coronary angiography.10 Approximately 30% of
these patients were found to have evidence of RAS, and 15% had
greater than 50% stenosis. A 2001 study confirmed that RAS is
associated with an increased risk of myocardial infarction, stroke,
and death and that its presence in patients with coronary disease
doubles the risk of mortality even when coronary revascularization
is performed.5 This same study found that the severity of RAS was
also predictive of mortality: 4-year survival was significantly lower
(47%) in patients with bilateral RAS than in those with unilateral
RAS (59%). The addition of nonselective renal arteriography in
cases where the patient’s serum creatinine concentration was lower
than 2.0 mg/dl was associated with minimal additional cost and
no clinically significant deterioration in renal function.
In 2006, on the basis of the findings from these studies, the
American Heart Association (AHA) published a science advisory
that made recommendations concerning routine renal arteriogra-
phy in patients undergoing coronary angiography.11 The AHA
concluded that screening renal arteriography can reasonably be
performed at the time of cardiac catheterization in patients at
increased risk for RAS who are candidates for revascularization;
however, it made no recommendation regarding concomitant
treatment of RAS discovered during cardiac catheterization. In
most cases, such a combined intervention is not feasible, whether
because of the lack of preprocedural informed consent about renal
artery endovascular intervention, the risk of CIN, or both.
Duplex Ultrasonography
In many institutions,
including our own, renal
artery duplex ultrasonogra-
phy (RADUS) is currently
used as the first-line screen-
ing test for RAS. Compared with other imaging modalities,
RADUS has several unique advantages. In B mode, it provides
direct images of the renal arteries, as well as a clear picture of con-
tralateral kidney size (see below). It allows ongoing surveillance of
lesions and interventions. It also achieves excellent imaging
through renal stents, which on MRA appear only as flow voids.
Finally, unlike CTA or even gadolinium-enhanced MRA,
RADUS carries no risk of CIN.
Before RADUS is performed, the patient should fast overnight,
should be given simethicone (to minimize interference on the images
caused by bowel gas), or both. The study is done from both the
anterior approach and the oblique flank approach; the latter is
particularly helpful in obese patients, whose body habitus may
severely limit the accuracy of the study.The renal arteries are imaged Figure 2 CTA in a woman with a 7 cm infrarenal abdominal aor-
at their aortic origin and in their middle and distal segments.The tic aneurysm and chronic renal insufficiency shows severe bilater-
peak systolic and end-diastolic arterial velocities are measured in al stenosis of the renal artery origins and small, atrophic kidneys.


Figure 3 DUS focused on the proximal left renal artery reveals severe stenosis with markedly
elevated peak systolic velocity (PSV) and end-diastolic velocity (EDV).

The size of the contralateral kidney is a useful surrogate mark- enhanced MRA is the technique of choice, in that the presumably
er for kidney function. A significant discrepancy in size and mass less nephrotoxic gadolinium enhances visualization of the renal
between the two kidneys should prompt the ultrasonographer to arteries. Multiplanar reconstruction (MPR) and maximum-inten-
search for significant RAS or an occluded renal artery. sity projection (MIP) techniques provide three-dimensional
Doppler examination of the renal parenchyma is also employed anatomic detail that is superior to what can be obtained with con-
as a means of indirectly evaluating RAS. This technique, per- trast arteriography [see Figure 4]. On a two-dimensional arteri-
formed via a flank approach, is very useful with obese patients and ogram, vessel overlap can cause the examiner to miss a severe
with cases in which examination is hindered by the presence of stenosis; this problem rarely arises with three-dimensional images.
bowel gas.The acceleration time (the interval from the onset of the We find renal MRA to be especially helpful in evaluating patients
upstroke of the arterial waveform to the systolic peak), the accel- with RAS and ischemic nephropathy necessitating endovascular
eration index (the slope of the acceleration curve), and the resis- intervention.
tive index (a measure of the resistance within the renal circulation) Before the intervention is carried out, we review the axial MRA
are determined. There is evidence to suggest that a normal resis- images of the aorta and the origins of the renal vessels. Working
tive index (< 80) before renal revascularization (whether endovas- from these images, we rotate the image intensifier camera so as to
cular or surgical) predicts improvement with respect to blood obtain a perpendicular view of the renal orifice [see Figure 5].This
pressure, renal function, and freedom from dialysis.12 The resistive step allows us to use smaller quantities of contrast material and
index itself, however, is not useful in predicting the degree of cannulate the renal orifice more quickly during endovascular
stenosis, because it may already be elevated in elderly patients and intervention. It must be kept in mind that MPR and MIP postpro-
those with renal parenchymal disease. cessing techniques are well known to exaggerate or even create the
One disadvantage of RADUS is that the diagnostic value of the appearance of a stenosis and that the original source axial images
images can be limited by the patient’s body habitus or the pres- must therefore be evaluated.The three-dimensional data set is dig-
ence of overlying bowel gas. In addition, RADUS can be time con- itally subtracted from the precontrast source images to create the
suming to perform (requiring 30 to 60 minutes), and its accuracy contrast MRA images. Other signs of significant RAS include
is highly dependent on the experience of the ultrasonographer. poststenotic dilation, loss of cortical medullary differentiation, and
Finally, polar or accessory renal arteries can easily be missed on delayed renal enhancement or asymmetric filling of the collecting
RADUS, potentially leading to a false negative study result. system during contrast injection.
The utility of MRA can be limited by several factors that are
Magnetic Resonance capable of degrading the acquired data. The presence of nearby
Angiography metal (e.g., clips or stents) and air-tissue interfaces can lead to
Many practitioners pre- focal signal drop-out and simulate stenosis or obstruction. Move-
fer MRA as the initial ment by the patient during the scan (or even bowel peristalsis) can
screening test for RAS. One result in degraded, blurred images. The timing of the contrast
advantage of renal MRA in bolus must be right to ensure adequate visualization of the arteri-
this setting is that the quality of the results is less dependent on al vessels. A contrast bolus that is delivered too late will not opaci-
operator technique than is the case with RADUS. Gadolinium- fy the vessels and will appear as a stenosis, whereas a bolus that is


delivered too early will opacify the veins, resulting in so-called
venous contamination of the images. We have found that the
image quality attained with MRA is highly dependent on the insti-
tution where it is performed.
MRA is contraindicated in patients with pacemakers, automat-
ic implantable cardioverter defibrillators (AICDs), brain aneurysm
clips, cochlear implants, or metal fragments in the eyes. It is not
contraindicated in patients with vascular stents, coils, or inferior
vena cava filters, nor is it contraindicated in those with metal
orthopedic devices, heart valves, or dental devices and materials.
Captopril Renal Scintigraphy
Radionuclide imaging is a noninvasive and safe means of eval-
Figure 5 For optimal viewing of the right renal artery during
uating renal blood flow and excretory function.The addition of an endovascular intervention, the C arm should be set to a 30° left
angiotensin-converting enzyme (ACE) inhibitor, such as capto- anterior oblique position. Evaluation of axial MRA images before
pril, to isotope renography improves the sensitivity and specificity the procedure is begun facilitates cannulation and limits the
of the test. In the presence of unilateral RAS, administration of amount of contrast material used.
captopril is associated with a 30% reduction of the glomerular fil-
tration rate (GFR) in the affected kidney.The contralateral kidney
shows a rise in the GFR, an increase in urine flow, and enhanced function at baseline (serum creatinine concentration greater than
salt excretion, leading to marked retention of the isotope in the 2.0 mg/dl), bilateral RAS, or both adversely affects the sensitivity
cortex of the affected kidney.The presence of significant renal dys- and specificity of captopril renal scintigraphy, thereby limiting its
utility as a screening test. In addition, the necessity of discontinu-
a ing ACE inhibitors and angiotensin-receptor blockers (ARBs)
before the study may preclude the use of this test in patients with
severe hypertension. Improvements in DUS, CTA, and MRA
have now relegated captopril renal scintigraphy to secondary sta-
tus as a screening modality.
Contrast-Induced Nephrotoxicity
The increasing use of diagnostic imaging studies (e.g., CTA
and MRA) and catheter-based interventions in patients with sig-
nificant RAS has made treatment and prevention of CIN impor-
tant issues in this patient population. Current strategies for pre-
venting CIN have generally involved one of three approaches: (1)
providing hydration, (2) using low-osmolar or iso-osmolar iodi-
nated contrast agents, and (3) administering the free radical scav-
enger N-acetylcysteine.
Intravascular volume depletion is an important risk factor for the
development of CIN. Although to date, no randomized, controlled
trials comparing hydration with placebo have been published, it has
been standard practice for some time to institute hydration (usual-
ly intravenous) before administering a contrast agent. A small ran-
domized, controlled trial from 2003 that compared I.V. hydration
(0.9% saline, 1 ml/kg, starting 12 hours before infusion of contrast
material) with unlimited oral fluid intake found I.V. hydration to be
far superior for preventing CIN.13 In a subsequent study, 119
patients at a single center were randomly assigned to receive a 154
mEq/L infusion of either sodium chloride or sodium bicarbonate
b both before and after administration of contrast material (starting
with a 3 ml/kg bolus 1 hour before contrast administration and con-
tinued at a rate of 1 ml/kg/hr for 6 hours afterward).14 Sodium
bicarbonate hydration was found to reduce the incidence of CIN
from 13.6% to 1.7%. Although this study is probably underpow-
ered from a statistical perspective, the findings are suggestive.
Sodium bicarbonate hydration is inexpensive and well tolerated
and has become standard practice at most institutions.
The optimal choice of contrast media for preventing CIN has
also been a subject of debate.There is evidence that the use of iso-
Figure 4 (a) Gadolinium-enhanced MRA reveals signal dropout osmolar nonionic contrast agents (e.g., iodixanol [Visipaque; GE
(flow void) at the origin of the left renal artery, signifying severe Healthcare, Princeton, New Jersey]) yields significantly lower
stenosis. (b) Axial MRA image reveals severe right renal artery rates of CIN than the use of low-osmolar contrast agents (e.g.,
stenosis. iohexol [Omnipaque; GE Healthcare, Princeton, New Jersey]) in


patients with diabetes or baseline renal insufficiency who undergo that appropriate cardiovascular risk factor modification measures are
cardiac or vascular angiography.15 being undertaken. After consultation with the patient’s primary care
N-acetylcysteine, a thiol-containing antioxidant, is believed to provider, we routinely provide prescriptions for a cholesterol-lower-
act as a free-radical scavenger to prevent toxic effects on the renal ing medication (e.g., a 3-hydroxy-3-methylglutaryl coenzyme A
tubular epithelium. Multiple clinical studies have examined the [HMG-CoA] reductase inhibitor) and an antiplatelet drug (e.g.,
question of whether administration of N-acetylcysteine is benefi- acetylsalicylic acid [ASA]) if the patient has not already been taking
cial in preventing CIN, but the results have been mixed. Although these agents.
pooled meta-analyses have recommended giving N-acetylcysteine It is worth remembering that although medical treatment may
to patients who are at high risk, the overall effect of this measure lead to significant reductions in cardiovascular morbidity and
is small in comparison with that of simple hydration. Never- mortality, no medical therapy has yet been shown to prevent the
theless, N-acetylcysteine is inexpensive and generally well tolerat- progression of ischemic nephropathy and renal failure. For
ed, and its use in those at high risk for CIN may reasonably be patients with these latter conditions, renal revascularization is like-
recommended. ly to be preferable to medical therapy.
On the basis of the existing evidence regarding prevention of
CIN, we routinely preadmit patients with baseline serum creati- Antihypertensive Agents
nine concentrations higher than 2.5 mg/dl for overnight hydration, Both ACE inhibitors and ARBs have proved to be safe and ef-
usually with saline; we then switch to sodium bicarbonate hydra- fective for the treatment of hypertension in the setting of renovas-
tion (see above) before administering the contrast agent. We also cular disease. In addition to their effects on the RAAS, these
use N-acetylcysteine (600 orally twice daily on the day before, the agents have been shown to reduce proteinuria and glomerular
day of, and the 2 days after contrast administration) in this high- scarring in patients with a variety of renal diseases. Close clinical
risk patient subset. Patients with serum creatinine concentrations supervision is necessary when ACE inhibitors or ARBs are given
between 1.5 and 2.5 mg/dl receive sodium bicarbonate hydration to patients with renal insufficiency or failure. In this population,
on the day of the procedure.We try to limit the amount of contrast serum creatinine and potassium levels should be obtained weekly
material given during the procedure, and we currently favor iodix- for 2 to 3 weeks after antihypertensive therapy with an ACE inhi-
anol over iohexol in patients with baseline serum creatinine con- bitor or an ARB is started. These patients are at increased risk for
centrations higher than 1.5 mg/dl or other risk factors for CIN acute renal failure (ARF); if ARF develops, the medications
(e.g., diabetes or a solitary kidney). Because of its substantial cost, should be promptly discontinued. Patients with significant RAS
we do not routinely use iodixanol in all patients. Well-hydrated who take ACE inhibitors or ARBs are also at risk for ARF when
persons with normal renal function receive I.V. saline before and severely dehydrated; accordingly, they should be instructed to
after the procedure. In such patients, we routinely use iohexol, refrain from taking these agents when affected by severe vomiting,
without other adjuncts. diarrhea, or dehydration. As a rule, ARF that occurs in this latter
setting responds rapidly to fluid rehydration and temporary sus-
LABORATORY TESTS
pension of the ACE inhibitor or ARB. Once renal function has re-
turned to baseline, the medications can usually be safely restarted.
Renal-Vein Renin Assay It is important to be aware that some antihypertensive drugs
When hemodynamically significant RAS is found, functional may be associated with lack of energy (e.g., beta blockers and cal-
studies may be indicated to determine the physiologic significance cium channel blockers) or chronic cough (ACE inhibitors), either
of the lesion. One such study involves measuring the renin concen- of which may have substantial effects on patient compliance.
tration in blood samples from the two renal veins to determine Several studies have shown that as many as 50% of such medica-
whether unilateral renin hypersecretion is occurring. If the ratio of tions are changed or discontinued within 6 months. Proponents of
the renin concentration in the affected side to that in the unaffect- renovascular revascularization have cited such studies as evidence
ed side is greater than 1.5, the assay is considered to have yielded favoring aggressive use of open or endovascular treatment of RAS
a positive result. The sensitivity and specificity of this test are over reliance on medical therapy alone.
diminished by the presence of bilateral RAS or RAS of a solitary
kidney. Other factors that may reduce the reliability of the results Lipid-Lowering Agents
include the inherent limitations of the renin assay itself and the Lipid-lowering therapy with HMG-CoA reductase inhibitors
potential for sampling errors. Because of the invasive nature of the (also referred to as statins) effectively reduces total and low-densi-
selective renin assay and the concerns about its accuracy, we do ty lipoprotein (LDL) cholesterol levels while increasing high-den-
not routinely use this test in RAS patients. sity lipoprotein (HDL) cholesterol levels.There is compelling level
1 evidence that this reduction of total and LDL cholesterol levels
markedly lowers the incidence of secondary cardiovascular events
Management and mortality.There is, however, no direct evidence that lipid con-
trol has an effect on the progression of renal artery disease, though
MEDICAL THERAPY
one might reasonably suspect that it would.
Given the known associa- Statins generally are well tolerated, but on occasion, they may
tion between RAS and sys- be associated with hepatic toxicity (0.5% to 3% of cases) or myosi-
temic cardiovascular disease, medical treatment aimed at preventing tis. Accordingly, liver function tests should be performed at base-
or retarding further progression of systemic atherosclerosis is clearly line and again 3 months after the start of therapy. If a threefold or
a paramount concern in the management of RAS patients. Measures greater increase in aminotransferase levels is noted, the statin
for modifying cardiovascular risk factors include effective blood pres- should be discontinued, and alternative therapy with another
sure control, weight reduction, smoking cessation, lipid-lowering lipid-lowering medication (e.g., a fibrate, a bile acid sequestrant, a
therapy, and antiplatelet therapy. It is the responsibility of the sur- cholesterol absorption inhibitor, or nicotinic acid) should be start-
geon evaluating a patient with RAS to use this opportunity to ensure ed in conjunction with diet modification.


Muscle injury is uncommon with statin therapy alone: myalgias were unable to demonstrate any beneficial effect on blood pressure.16-
occur in 2% to 11% of patients, myositis in 0.5%, and rhabdomy- 18 Proponents of renal artery intervention have argued that these

olysis in fewer than 0.1%. Myositis associated with statin therapy three trials were flawed by their failure to include stenting and by the
is treated by switching to another HMG-CoA reductase inhibitor. fact that blood pressure control may be a poor surrogate clinical end
Routine measurement of serum creatine kinase levels in not rec- point.These studies were plagued by several other weaknesses as well,
ommended, but patients taking statins should be warned about including high rates of crossover to angioplasty and marked variations
the risk of myositis and weakness and instructed to stop statin in the medical therapy provided.The inclusion of stenting as a com-
therapy if such side effects occur. ponent of endovascular treatment of RAS is now considered the stan-
dard of care by many, in that it significantly improves technical suc-
Antiplatelet Agents cess rates and lowers the incidence of restenosis.
Antiplatelet therapy has been shown to reduce the risk of sec- Revascularization of RAS with stenting treats the root cause of
ondary events in patients with coronary artery disease and carotid the neurohormonal activation that leads to end-organ heart and
stenosis. The data currently available do not conclusively demon- kidney damage; best medical therapy, when adequately carried
strate that antiplatelet therapy has a beneficial effect on RAS, but out, yields substantial reductions in cardiovascular morbidity and
given that RAS is a manifestation of systemic atherosclerosis, mortality in and of itself. Consequently, it is difficult to detect sig-
antiplatelet therapy appears warranted on the same grounds that nificant differences between best medical therapy alone and best
statin therapy would be. After endovascular intervention to treat medical therapy plus renal artery stenting. Until sufficient evi-
RAS, we typically place patients on ASA, 81 mg/day, and clopido- dence (from adequately powered, well-designed, and unbiased tri-
grel, 75 mg/day, for 4 to 6 weeks while the stent is undergoing als) has been accumulated to confirm or rule out such differences,
endothelialization. After this period, patients are switched to ASA, the debate regarding the benefits of percutaneous renal artery
325 mg/day. Admittedly, there is no direct evidence supporting revascularization will continue.
this practice in patients with RAS who undergo endovascular To date, no trials comparing best medical therapy with best
intervention; however, data extracted from the coronary stenting medical therapy plus angioplasty and stenting have been complet-
literature suggest that such an approach may be reasonable. ed. Currently, however, patients are being recruited into a clinical
trial sponsored by the National Heart, Lung, and Blood Institute,
ENDOVASCULAR AND OPEN SURGICAL THERAPY
which is likely to answer several important questions about the
Despite the relatively high prevalence of RAS, especially in per- management of RAS that have not been answered by previous
sons who have atherosclerosis in other vascular beds, there is cur- studies. This study, known as the Cardiovascular Outcomes in
rently no consensus on diagnosis, therapy, or follow-up. In the Renal Atherosclerotic Lesions (CORAL) trial, is expected to yield
absence of well-designed, evidence-based studies, many practition- important information about which groups of RAS patients bene-
ers have adopted a “find it and fix it” approach to managing RAS. fit from endovascular intervention. A total of 1,080 patients will be
The endovascular and surgical interventions employed to treat enrolled in the trial and will be randomly assigned to receive either
RAS are described more fully elsewhere [see 6:22 Open Procedures best medical therapy or best medical therapy with angioplasty and
for Renovascular Disease and 6:23 Endovascular Procedures for Reno- stenting.The primary outcome evaluated will be adverse cardiovas-
vascular Disease]. We ourselves generally take an aggressive stance cular and renal events. Best medical therapy will be provided on
toward the application of renal artery stenting, especially in patients the basis of current evidence-based guidelines, which include tight
with evidence of ischemic nephropathy (who presumably would be control of blood pressure (< 140/90 mm Hg; <130/80 mm Hg in
the patients most likely to benefit from renal revascularization). patients with diabetes or proteinuria), treatment of hypercholes-
It must be admitted, however, that the current evidence for terolemia (LDL concentration < 100 mg/dl) and diabetes (glyco-
renal artery percutaneous intervention is circumstantial at best. sylated hemoglobin [HbA1c] level < 7 mg/dl), smoking cessation,
Clearly, there are three possible outcomes associated with renal and antiplatelet therapy (with ASA, clopidogrel, or ticlopidine). All
revascularization. Some patients derive tremendous benefit from patients will receive an ARB as the first-line antihypertensive agent,
the procedure, showing substantial improvements in blood pres- and a specific stepwise algorithm will be implemented for patients
sure and renal function. Others (a very small subset) experience a requiring combination antihypertensive therapy. All patients will
rapid decline in renal function, probably resulting from either undergo diagnostic angiography to assess the severity of their
atheroembolization or CIN associated with the procedure itself. lesions. Patients will be followed for as long as 5 years with an eye
Still others exhibit no changes in renal function, number of anti- to both primary end points (e.g., death, stroke, myocardial infarc-
hypertensive medications used, or blood pressure control. tion, ARF, and dialysis) and secondary end points (e.g., hyperten-
Unfortunately, there are, at present, no good methods of reliably sion, medication use, quality of life, and cost). It is expected that
predicting which patients will benefit from renal revascularization. enrollment in the CORAL trial will conclude in 2009, though
Several uncontrolled reports suggested that hypertension and renal interim data will probably be reported earlier.This important study
function may improve after successful renal artery stenting. However, should make a major contribution to determining the appropriate
three small trials evaluating angioplasty alone (i.e., without stenting) role of endovascular stenting in the management of RAS.

Discussion
Pathophysiology of Renovascular Hypertension ical role in this process. The RAAS maintains vascular tone, water
The seminal studies performed by Goldblatt and associates in the and salt balance, and cardiac function. It works through the sympa-
1930s demonstrated that reduction of renal perfusion can result in thetic nervous system and the actions of several hormones to main-
sustained elevation of arterial pressures.19 Later work revealed that tain hemodynamic stability.The RAAS is activated through several
the renin-angiotensin-aldosterone system plays an intricate and crit- mechanisms, including hypotension and decreased intravascular


volume.These mechanisms cause decreased renal perfusion and the Ischemic injury to the affected kidney, hypertensive nephro-
secretion of renin from the juxtaglomerular apparatus within the sclerosis of the contralateral kidney, and smooth muscle hypertro-
kidneys. Renin cleaves angiotensinogen in the liver to form angio- phy in the peripheral blood vessels may all contribute to sustained
tensin I; ACE then transforms angiotensin I into angiotensin II in hypertension independently of RAAS activity. In addition, both
the lung. Angiotensin II is a potent vasoconstrictor (considerably the sympathetic nervous system and the central nervous system
more potent than epinephrine) and is implicated in end-organ dam- contribute to hypertension associated with RAS.22 Several neu-
age to the heart and the kidney.20,21 Angiotensin II promotes the roendocrine systems activated by RAS have also been shown to
release of aldosterone from the adrenal cortex, and this release of have deleterious cardiovascular effects. Besides increasing periph-
aldosterone leads to the reabsorption of sodium in the distal convo- eral resistance, angiotensin II is thought to cause smooth muscle
luted tubules of the kidney, resulting in increased intravascular volume. hypertrophy (both in peripheral arteries and in cardiac myo-
In patients who have unilateral RAS with a normal contralater- cytes), plaque rupture, endothelial dysfunction, and inhibition of
al kidney, the elevation of blood pressure is renin dependent and fibrinolysis.23-25 An elevated angiotensin II level is believed to cause
is characterized by increased peripheral vascular resistance. Such left ventricular hypertrophy (LVH) on occasion, even in cases
patients are considered to have volume-independent hyperten- where blood pressure is well controlled.26 Angiotensin II also in-
sion, in that the normal contralateral kidney compensates for the teracts with tumor growth factor–β, platelet-derived growth fac-
unilateral RAS by increasing its excretion of fluid. In patients who tor, and endothelin, each of which has been implicated in the
have bilateral RAS or unilateral RAS with no contralateral kidney, development of vascular muscle hypertrophy, cardiac myocyte
intravascular volume increases and renin secretion decreases over hypertrophy, and renal parenchymal damage. Clearly, RAS and
time. Such patients are considered to have volume-dependent or activation of the RAAS have systemic effects that go beyond sim-
Goldblatt hypertension. ply causing hypertension.

References

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