lit review in renal artery stenosis

8/10/2019 lit review in renal artery stenosis

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3.1.Historical Background

As early as in 1836, Richard Bright reported the first potential association betweenhypertension and renal disease when he associated autopsy findings of kidney

disease and cardiac hypertrophy to an increased peripheral resistance .7

In 1898 Tigerstedt and Bergman discovered that extract from the renal cortex of

rabbits caused a marked increase in AP when injected intravenously (i.v.) tonormotensive rabbits 8. They hypothesized that the renal cortical tissue extract

contained a hypertensive factor and hence named it renin 8. The first successful

experimental model of arterial hypertension caused by manipulation of the kidneywas developed in 1934 when Goldblatt et al. showed that clamping of renal arteries

in dogs produced a reproducible and persistent rise in AP.9Clamping other large

arteries as splenic or femoral arteries had no effect on AP, indicating thathypertension resulted specifically from renal ischemia caused by renal artery

stenosis (RAS) 4. In 1938, Leadbetter and Burkland reported the first successfultreatment of hypertension by nephrectomy in a patient with RAS 9. Treatment of

RAS changed with the introduction of surgical revascularization in 1954 6 andlater on, in 1978, with the introduction of percutaneous transluminal renal

angioplasty (PTRA)9.

3.2.Renal Circulation Anatomy and Physiology

The kidneys play an essential role in maintaining a stable internal milieu for

optimal cellular function (homeostasis) through the excretion of metabolic wasteproducts and adjustment of urinary excretion of water and electrolytes. To achievethis homeostatic function, a high proportion of cardiac output (20-25%) passes

through the renal circulation producing about 180 liters of glomerular filtrate(primary urine) per day. In the tubular system the reabsorption of water and

electrolytes is adjusted to match the prevailing needs while waste products areretained in the urine and excreted. Almost all ( 99%) of the filtered water and

sodium is normally reabsorbed in the tubules. The kidneys receive their blood

supply from the main renal arteries which arise from the abdominal aorta. Before

reaching the hilum of the kidney, the renal artery generally divides into anteriorand posterior branches which in turn give rise to four or five segmental arteries.

The segmental arteries divide into interlobar arteries, which progress towards thecortex. At the junction between the cortex and medulla, interlobar arteries change

course and become arcuate arteries that run in parallel to the kidney surface. These,

in turn, give rise to interlobular arteries which radiate into the cortex and divide

into afferent arterioles supplying blood to the glomeruli. Each afferent arteriole


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supplies blood to a glomerulus, a tuft of capillaries attached to the mesangium and

enclosed in Bowmans capsule. Glomeruli are drained by efferentarterioles that inthe cortex give rise to the peritubular capillary plexus . Efferent arterioles from

juxtamedullary glomeruli form vasa recta capillaries that form long hair-pin loops

that turn in the medulla . Thus, the renal circulation consists of two capillary bedsconnected in series by the efferent arteriole. The first in the series is the glomerular

capillary bed which is the site of filtration and formation of primary urine and thesecond is the peritubular capillary bed which transports reabsorbed water and

solutes back to the systemic circulation. Total renal blood flow (RBF) in a healthyadult is approximately 1.2 L/min which corresponds to about 20-25% of cardiac

output. The high RBF is required to maintain a high GFR and effective excretion

of waste products. Consequently, oxygen delivery to the kidneys is very high andrenal oxygen extraction low. However, there is a marked regional difference in

blood flow distribution in the kidney . About 90% of total RBF is distributed to the

cortex where the partial pressure of oxygen (pO2) is high ( 50 mmHg), whereasapproximately 10% of RBF goes to the medulla where the pO2 is low ( 10-20mmHg). In addition, oxygen consumption in the outer medulla (OM) is high due to

active transport of sodium in the thick ascending loop of Henle making the OM

vulnerable to ischemic injury . However, low local blood flow in the medulla alsoplays important physiological roles in preventing washout of the medullary

hyperosmotic gradient which is necessary for effective water reabsorption and

urine concentration.10,11

3.3.Etiology of renal artery stenosis

RAS can be caused by a variety of lesions. In Western populations atherosclerosis

and fibromuscular dysplasia (FMD) are the main two causes of RAS.

Atherosclerosis accounts for about 90% of all cases of RAS. These lesions arecommonly ostial and are in many cases extensions of atheromatous aortic plaques

that involve the proximal 1-2 cm of the renal artery 23, 24. Patients with ARAS aretypically over the age of 50 years and males are more commonly affected than

females. ARAS is usually a manifestation of generalized atherosclerosis and hence

these patients frequently have coronary artery disease (about 20 %) and peripheral

vascular disease (about 35 %) 23, 24. FMD accounts for about 10% of all cases ofRAS. Medial fibroplasia is the most common subtype of FMD (7580%) . Theright renal artery is more commonly affected and the disease is most prevalent in

25- to 50- year old females . 12,13FMD may involve other major arteries, commonly internal carotid arteries, andless often the vertebral, iliac, subclavian, visceral and coronary arteries. The


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etiology of FMD is unknown although a number of factors have been suggested,

including: a) genetic predisposition, b) hormonal influence, in view of thepredominance in females, c) mechanical factors, such as stretching and trauma to

the blood vessel wall and d) ischemia of the vascular wall due to fibrotic occlusion

of the vasa vasorum.1

3.4. Pathophysiology of Renovascular Hypertension

Critical stenosis of a renal artery (i.e., 70% luminal narrowing) increasesrenin production from the ischemic kidney. Renin acts on circulating renin

substrate to produce angiotensin I, which is converted to angiotensin II (a potent

vasoconstrictor) by ACE in the lung and other tissues. In addition tovasoconstriction, angiotensin II directly increases renal sodium reabsorption and

also stimulates aldosterone production, resulting in extracellular volume

expansion. Angiotensin II also stimulates the sympathetic nervous system,contributing further to increased vascular resistance, and stimulates thirst and the

release of vasopressin, contributing further to increased extracellular volume. Inunilateral disease, the nonischemic kidney is subjected to increased perfusion,

resulting in higher sodium excretion and suppression of renin release. These effectslessen the degree of hypertension but perpetuate underperfusion of the ischemic

kidney, which, in turn, perpetuates excess renin production. In bilateral disease,

initial increases in renin cause extracellular volume expansion and volume-

dependent hypertension, which persists because there is no contralateral normalkidney to excrete more sodium. In persons with bilateral disease, the hypertension

is volume dependent but becomes renin dependent with extracellular volumedepletion. Correcting renal ischemia eliminates the stimulus for excess rennin

release and can cure or lessen hypertension. In unilateral renal artery stenosis,

prolonged hypertension eventually causes nephrosclerosis in the nonischemic

kidney (in combination with other cardiovascular risk factors) or ischemic injury tothe involved kidney. If either occurs, relieving renal arterial stenosis may not cure

hypertension. The longer the duration of hypertension before diagnosis, the greaterthe likelihood of these untoward renal outcomes and the less the likelihood of cure

of hypertension with intervention.1

3.5.Clinical Clues of Renovascular Hypertension

Clues suggesting renovascular hypertension include lack of a family history ofhypertension, onset of hypertension before age 30 (consider fibromuscular

dysplasia, especially in a woman), onset of hypertension after age 50 (consideratherosclerotic renovascular disease, especially in a smoker or a person with


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coronary or peripheral arterial disease), presentation with accelerated or malignant

hypertension, or sudden worsening of preexisting hypertension in a middle-aged orolder person (renovascular hypertension superimposed on essential hypertension).

Persons with cardiovascular risk factors (tobacco use, hyperlipidemia, or diabetes)

are at increased risk of atherosclerotic renal artery stenosis. The most importantphysical finding is an abdominal bruit, especially a high-pitched systolic-diastolic

bruit in the upper abdomen or flank. However, 50% of persons with renovascularhypertension do not have this finding. Other physical clues are severe retinopathy

of accelerated or malignant hypertension (hemorrhages, exudates, andpapilledema) or evidence of atherosclerotic occlusive disease in other vascular

beds (atherosclerotic renal artery stenosis of >50% is observed in up to 20% of

persons with coronary artery disease and in up to 50% of persons with peripheralarterial disease). Laboratory abnormalities are hypokalemia (due to secondary

aldosteronism), an increased serum level of creatinine, proteinuria (rarely in the

nephrotic range), and a small kidney seen on an imaging study. Underlyingbilateral renal artery stenosis may be indicated by an acute decline in renal function(20% increase in serum creatinine)either after the initiation of therapy with an

ACEI or an ARB or after a drug-induced, sudden decrease in blood pressure. Other

signs in patients presenting with bilateral renal artery stenosis (i.e., ischemicnephropathy) include the sudden development of pulmonary edema accompanied

by severe hypertension (flash pulmonary edema), frequent episodes of

symptomatic congestive heart failure accompanied by increases in blood pressure,or a subacute decline in renal function with or without worsening hypertension.

Patients with atheroembolic renal disease may also present with a sudden onset or

worsening of hypertension and a subacute decline in renal function. Historicalclues (e.g., occurrence after angiography or vascular surgery), physical findings

(distal livedo reticularis and peripheral emboli), and laboratory abnormalities(increased erythrocyte sedimentation rate, anemia, hematuria, eosinophilia, and

eosinophiluria) help identify this disorder. In young persons who have

hypertension (even if not severe) of short duration and suggestive clinical features,

evaluation for renovascular disease is indicated. Renal artery stenosis in thesepersons can be identified and corrected with a low risk of morbidity and mortality

and a high probability of cure. Older persons should be evaluated for renovascular

hypertension on a selective basis. In general, selection should be restricted topersons who have suggestive clinical features and blood pressure that cannot be

controlled medically or who have an unexplained, observed decline in renal

function or a cardiorenal syndrome (recurrent flash pulmonary edema or resistantheart failure) and who are considered reasonable risks for (and are willing to

undergo) interventional therapy.1


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3.6.Screening Tests

Duplex Ultrasonography will be discussed later.

3.6.1.Magnetic Resonance AngiographyMagnetic resonance angiography (MRA) visualizes the main renal arteries without

use of a radiocontrast agent or exposure to radiation. Its usefulness extends topersons with renal insufficiency or those with a history of radiocontrast allergy.

Also, it is a reasonable choice for persons with a high likelihood of the disorderwho have concomitant severe, diffuse atherosclerosis and, thus, are at high risk of

atheroembolization with angiography. Field limitations may decrease the ability to

see lesions in the distal main renal arteries or lesions in branch vessels (commonsites of fibromuscular disease). Accessory renal arteries may not be identified, the

degree of arterial stenosis may be overestimated, and persons prone toclaustrophobia may not tolerate being placed in the magnetic resonance equipment.

Renal stents cause imaging artifacts, and persons with cardiac pacemakers,metallic artificial cardiac valves, or cerebral artery aneurysm clips cannot be

imaged. Sensitivity is 80% to 90% (less for fibromuscular dysplasia), and

specificity is 90%. This is an expensive screening test.1

3.6.2.Spiral Computed Tomographic Angiography

Spiral CT angiography offers excellent three-dimensional images but requires aconsiderable amount of radiocontrast agent and patient cooperation. This is an

option for persons with normal renal function who do not have a contrast allergyand in whom MRA is contraindicated. Renal stents do not cause imaging artifacts.Sensitivity and specificity are similar to those for MRA. This is also an expensive

test. Other noninvasive tests are available to screen for renal artery stenosis;however, they are used less often because the test characteristics are inferior

compared with those of duplex ultrasonography, MRA, and spiral CT angiography.Historically, the intravenous pyelogram (IVP) was the mainstay screening

test for renovascular hypertension. For screening, radiographs that are taken at 1-

minute intervals for the first 5 minutes after injection of contrast medium are used

to identify a delay in the appearance of contrast medium in the renal collectingsystem on the side of a renal artery stenosis. This is referred to as the hypertensiveIVP. Characteristic findings on a hypertensive IVP suggesting renal artery stenosis

are 1) unilateral reduction in renal size (1.5-cm decrease in pole-to-pole diameterof the smaller kidney); 2) delayed appearance of contrast medium in the collecting

system of the ischemic kidney; 3) hyperconcentration of contrast medium in the


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ischemic kidney; 4) ureteral scalloping by collateral vessels; and 5) cortical

thinning or irregularity. Sensitivity is 70% to 75%, and specificity is 85%.1

3.6.3.Captopril Radionuclide Renal Scan

Some still consider the captopril radionuclide renal scan to be a useful screeningtest. However, recent reviews suggest a lower test sensitivity than was reported

earlier. Currently, sensitivity is estimated at 75% and specificity at 85%. Pretesttreatment of patients with captopril (25-50 mg given 1 hour before isotope

injection) increases the sensitivity of the scan compared with that of standard

renography. The rationale is that glomerular filtration in an ischemic kidneydepends on the vasoconstricting effect of angiotensin II on the efferent arteriole of

the nephron to maintain effective transglomerular filtration pressure. Treatment

with an ACEI causes efferent arteriolar dilatation, with loss of filtration pressure inthe nephron. This causes a decline of glomerular filtration in the ischemic kidney,with less of an effect on renal blood flow. These changes are identified with the

scanning technique. The radionuclides used most commonly are iodine 131

orthoiodohippuric acid (OIH) and Tc-99m mercaptoacetyltriglycine (MAG3),which are markers for renal blood flow (they are excreted primarily by renal

tubular secretion), and Tc-99m diethylenetriamine pentaacetic acid (DPTA), which

is a marker for glomerular filtration rate (it is excreted primarily by glomerularfiltration). Criteria for a positive test with DPTA are time to peak activity in the

kidney of 11 minutes or more and a ratio of the glomerular filtration rate between

the kidneys of 1.5 or more. The criterion for a positive test with OIH or MAG3 isresidual cortical activity at 20 minutes of 30% or more of peak activity. The renal

scan is safe for persons with a history of contrast allergy. The interpretive value isreduced by renal insufficiency (creatinine >2.0 mg/dL) or by bilateral or branch

renal artery disease. Urinary outflow obstruction may mimic renal artery stenosis.1

3.6.4.Captopril Test

Acute blockade of angiotensin II formation by ACEIs induces a reactive increase

in PRA. The magnitude of this increase is usually greater in renovascular

hypertension than in essential hypertension and is the basis for the captopril test.The use of antihypertensive drugs that influence the renin-angiotensin-aldosterone

axis must be discontinued for several days before the test. PRA is measured at

baseline and at 60 minutes after administering captopril orally. Criteria for apositive test are 1) PRA of more than 12 ng/mL per hour after administration of

captopril, 2) absolute increase in PRA over baseline of at least 10 ng/mL per hour,and 3) increase in PRA of 150% or more if the baseline PRA is more than 3 ng/mL


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per hour or 400% or more if the baseline PRA is less than 3 ng/mL per hour. The

results are compromised if the person has renal insufficiency. Sensitivity is 39% to100%, and specificity is 72% to 100%. Because the results can be influenced by

many factors that are difficult to identify and control, predictive accuracy is low.1

3.6.5.Renal Vein Renins

Lateralization of renal vein renins is a good predictor of a favorable outcome afterintervention for unilateral renal artery stenosis; however, because many factors that

influence renin secretion are difficult to identify and control (as noted for thecaptopril test), the predictive value of the test is low. It is invasive and expensive.

Lateralization is present if the ratio of renin activity on the affected side compared

with that on the normal side is 1.5:1.0 or more. Sensitivity is 63% to 77%, andspecificity is 60% to 95%.1

3.6.6.Digital Venous Subtraction AngiographyDigital venous subtraction angiography uses contrast media, but access to thecirculation is through a peripheral vein. With the advent of newer screening tests, it

is used less often. This technique provides adequate visualization of the proximal

portion of the main renal arteries (usual location of atherosclerotic disease) in 90%of persons but less effective visualization of the distal portions of the main renal

arteries or branches (the usual location of fibromuscular dysplasia). This technique

is expensive, and in 20% to 30% of persons, neither renal artery is identifiedbecause of superimposition of abdominal vessels or patient motion. Both the

sensitivity and the specificity are 85% to 90%.1

3.6.7.Renal Ar ter iography

Conventional renal arteriography is the diagnostic standard test to identify renalartery stenosis. In clinical situations in which the pretest likelihood is high (50%),

a negative result from a screening test still leaves a significant posttest probability

of disease (20%). Thus, in these settings, consideration should be given to

performing renal angiography without first performing screening tests. Exceptionsmay be when patients have diabetes or severe generalized atherosclerosis with

concomitant renal insufficiency and use of a noninvasive test initially, such as

MRA or duplex ultrasonography, may be reasonable. This is because in thesesettings, the risk of contrastinduced acute renal failure or atheroembolism is

significant. Contrast toxicity from angiography can be reduced with the use of

gadolinium or carbon dioxide as the contrast agent. However, these techniques donot reduce the risk of atheroembolism.1


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3.7.Therapy for Renovascular Hypertension

Options for the management of renovascular hypertension include medical andinterventional therapies. Percutaneous balloon angioplasty, stent placement, and

surgical procedures to relieve renal ischemia are the interventional treatments.Goals of interventional therapy are to cure or improve hypertension or to preserve

renal function. Medical therapy is reserved for persons who are not considered

candidates for interventional therapy (because of the extent or location of thevascular lesions, high surgical risk, or uncertainty about the causative significance

of the lesion) or who are unwilling to undergo interventional therapy. As noted

earlier, selection of persons for screening excludes older persons with controlledhypertension and no evidence of progressive renal dysfunction even if

renovascular disease is suspected. Percutaneous transluminal angioplasty is thetreatment of choice for amenable lesions caused by fibromuscular dysplasia and is

an option with or without stent placement in some cases of atheroscleroticrenovascular disease. Hypertension is cured in 50% and improved in 35% of

persons with fibromuscular dysplasia. The failure rate is 15%. In contrast,hypertension is cured in 20% and improved in 50%, with a failure rate of 30%, in

persons with atherosclerotic renovascular disease. Complications of angioplasty

include groin hematoma, dye-induced azotemia, dissection of the renal artery, renal

infarction, and, rarely, rupture of the renal artery, with the potential for loss of the

kidney and the need for immediate surgery. Atheroembolization is a risk in olderpersons with diffuse atherosclerosis . Stent-supported angioplasty is an appropriateoption for some persons with atherosclerotic renal artery stenosis, especially for

orificial disease. In the presence of aneurysmal or severe atherosclerotic disease

of the aorta requiring concomitant aortic reconstruction, or in persons in whompercutaneous intervention has failed, surgical intervention is the treatment of

choice. Kidneys with a pole-to-pole length of 8 cm or less should be removednotrevascularizedif intervention is indicated and removal will not jeopardize overall

renal function. The role of interventional therapy for preservation of renal function

in ischemic nephropathy is uncertain. In most cases, the underlying disease is

atherosclerosis. Improvement in renal function, defined as a decrease in serumcreatinine, occurs in 30% of cases. In approximately 50% of cases, the creatininelevel does not decrease; however, benefit may be defined as stabilization of renal

function. Of concern is that in 20% of cases, renal function deteriorates rapidlyafter the intervention, most likely from a combination of several factors, includingcontrast toxicity, acute renal artery thrombosis, or atheroembolization. The medical


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treatment of renovascular hypertension is not different from that of essential

hypertension. Both volume retention (due to aldosterone) and vasoconstriction(due to activation of the sympathetic nervous system and angiotensin II) contribute

to the elevation of blood pressure. ACEIs and ARBs can precipitate acute renal

failure in the presence of bilateral renal artery stenosis. Medical treatment does notcorrect the underlying ischemia of the affected kidney, and decreases in systemic

blood pressure may further aggravate loss of renal function. Progression ofatherosclerotic renal artery disease can be slowed by control of all modifiable risk

factors, including the use of statin drugs for aggressive lowering of cholesterol. Inmedically managed persons, renal function should be followed carefully because

deterioration may be a sign of progressive disease .1

3.8.Duplex Ultrasound of the Renal Artery

Duplex ultrasonography is noninvasive and does not use contrast media. Itsusefulness extends to persons who have renal insufficiency or a history of contrast

allergy. Performance of the test does not require discontinuation of anyantihypertensive drug.therapy, and it provides information on kidney size, screens

for obstructive uropathy and aortic aneurysm, and identifies bilateralrenal arterystenosis. Overlying bowel gas or other technical problems limit the complete study

of both renal arteries in up to 50% of cases. Often, accessory or branch vessel

disease is not identified. The sensitivity and specificity are 75% to 80%.1

3.8.1.Examination TechniqueOne way of identifying the renal arteries at their origins just below the easily

visualized superior mesenteric artery is to localize the latter in transverse

orientation and to then move the transducer 12 cm downward and look for the

renal arteries as they arise from the aorta to the left and right . A second landmarkis the left renal vein (hypoechoic, broader band) which overcrosses the aorta before

opening into the vena cava and along its route passes between the superiormesenteric artery and the aorta. The left renal artery typically arises some

millimeters below the right renal artery and both do not usually take a strictlyhorizontalcourse but move slightly downward. The right renal artery first courses

anteriorly in a slightly curved fashion and then arches underneath the vena cava.The origins as well as the first 3 cm of the renal arteries can be visualized and

evaluated in over 90% of cases while visualization of the middle third is oftenincomplete due to overlying bowel gas, especially on the left. The middle segment

of the renal artery is easier to scan on the right where the vena cava can serve as anacoustic window. Interfering bowel gas can be displaced by pressing the transducer


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use a variation of the Cleveland Clinic guidelines, using the same RAR as the

study but a higher PSV. We have done internal validation of our guidelines butcontinue to look for ways to improve them. False-Positive/False-NegativeResults. To obtain the highest accuracy, it is important to avoid relying solely on

the numerical data obtained. When a high velocity is seen or when the renal aorticratio is high, the interpreting radiologist must also actively look for secondary

signs of stenosis, such as a characteristic harsh audible signal at the site of stenosis,increased diastolic flow, color bruit, and post-stenotic turbulence. Without

ancillary findings, the interpreter must consider the possibility that the highvelocity or high RAR represents a false-positive result. False-negative findings are

most a risk when visualization is marginal and the entire artery has not been

adequately evaluated. In perhaps 5% to 10% of patients, accurate diagnosis cannotbe made because of inadequate visualization of one or both arteries. Attention tointrarenal waveforms is also of some importance. A highly abnormal waveform

can be a valuable indicator of stenosis. A delayed systolic peak (tardus, i.e.,tardy) and velocities that are greatly decreased (parvus, i.e., puny) can be astrong sign of a more proximal stenosis. The intrarenal waveform can be analyzed

quantitatively by calculating the systolic rise time and the acceleration . Although

we calculate these parameters, a qualitative assessment of the appearance of thewaveform usually serves just as well. We only rely on a tardus-parvus waveform

to make the diagnosis when the finding is pronounced. An acceleration time

greater than 0.07 second and a slope of systolic upstroke less than 3 m/s2 aresuggested as thresholds to assess for renal artery stenosis.Simple recognition of

the change in pattern may be adequate. Pharmacologic manipulation with captopril

may enhance the waveform abnormalities in patients with renal artery stenosis.Doppler sonography remains a controversial technique for the detection of native

renal artery stenosis. The use of intravascular contrast agents increases thetechnical success rate for the evaluation of renal artery stenosis.It may also play a

role in the assessment and follow-up of patients undergoing renal artery

angioplasty and stent placement.6

The examination is challenging to the uninitiated operator, but establishment of arenal artery duplex Doppler program can be rewarding. Because of the lower cost

versus other diagnostic tests, Doppler ultrasound lowers the threshold for the

diagnosis of renovascular hypertension. Hurdles mainly relate to the learning curveand the initial investment of time. Starting a program is more feasible in a large

center where demand will likely be higher than in a smaller facility. Once the

program is mature, the study is financially viable and can result in improvedpatient care .6


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3.9.Previous Comparative Studies

The average incidence of renovascular hypertension is 1 to 4%in an unselectedpopulation (von Bockel et al. 1989; Foster et al. 1973; Olbricht et al. 1991) but

incidences as low as 0.18% and as high as 20% have also been reported (Arlart andIngrisch 1984; Tucker and Lebbarthe 1977). These discrepancies are due to the use

of different screening methods and the investigation of different groups of the

normal population and patients (presence of vascular risk factors andaccompanying diseases, selected patient groups).V

Hansen et al, used ultrasonography to screen 870 people over age 65 and found a

lesion (a narrowing of more than 60%) in 6.8%.178A population based study about the prevalence of renal artery stenosis in subjects

with moderate to severe hypertension by Andersen UB , Borglykke A, andJorgensen T, examined 332 subjects aged 50-66 years using doppler ultrasound,

with blood pressure

lit review in renal artery stenosis

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