Hypertension Journal

Show Contents

Renovascular Hypertension
  JOHTN
SECONDARY HYPERTENSION
Renovascular Hypertension
1Ashish Nandwani, 2Vijay Kher
1Consultant, 2Chairman
1Department of Nephrology and Renal Transplantation, Medanta -The Medicity, Gurgaon, Haryana, India
2Department of Nephrology and Renal Transplantation, FortisEscorts Hospital, New Delhi, India
Correspondence Author: Vijay Kher, Chairman, Department ofNephrology and Renal Transplantation, Fortis Escorts HospitalNew Delhi, India
Phone: +919811054118
e-mail: vijaykher51@yahoo.com
 
ABSTRACT
Renovascular disease caused by renal artery stenosis leadingto reduced renal perfusion can produce a range of clinicalconditions ranging from incidental finding on angiographywithout any hemodynamic significance to renovascularhypertension (RVH) with or without ischemic and hypertensiverenal injury. A fall in renal perfusion pressure is sufficient toinitiate RVH that only occurs when 70 to 80% of artery lumenis occluded. Atherosclerosis, fibromuscular dysplasia, andvasculitis involving the renal arteries are the leading causesof renovascular disease. With improvement in imaging studies,significant renal artery stenosis is detected more often thanbefore. Management includes medical therapy aiming at bloodpressure control and cardiovascular risk factor management.Renal revascularization is considered in patients withdeteriorating renal functions and resistant hypertension.
Keywords: Atherosclerotic renovascular disease,Fibromuscular dysplasia, Percutaneous transluminal renalangioplasty, Renin-angiotensin-aldosterone system,Renovascular hypertension.
How to cite this article: Nandwani A, Kher V. RenovascularHypertension. Hypertens J 2016;2(2):86-95.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Hypertension is the leading risk factor for coronaryartery disease, cerebrovascular disease, and renal failure.Various randomized controlled trials have shown thebenefit of antihypertensive drug therapy in decreasingthe morbidity and mortality due to hypertension. In 90 to95% of cases with hypertension, the cause of hypertensionis unknown. Patients with no identifiable cause forhypertension are classified as primary hypertensionor essential hypertension. Patients with identifiablecauses of hypertension are designated as secondaryhypertension. The commonest causes for secondary hypertension are renal parenchymal diseases (2-6%),renovascular hypertension (RVH) (1-4%), and endocrineabnormalities (1%). Coarctation of aorta, inflammatoryarteritides, obstructive sleep apnea, and obesity arethe other rare causes of secondary hypertension.Approximately 1% of cases are drug induced, and theyare caused by sympathomimetic drugs, decongestants,oral contraceptives, and steroids.1,2 It is important toevaluate the patients for secondary causes, as some ofthese conditions can be cured, leading to withdrawal orreduction of antihypertensive medication.3,4 The clinicalclues that suggest the likely presence of secondaryhypertension are:
  • Age < 30 years with no family history of hypertensionand other risk factors.
  • An acute rise in blood pressure (BP) in an individualwith documented normal BP in recent past.
  • Resistant hypertension, which is not controlled onadequate doses of more than three antihypertensivedrugs including a diuretic.
  • Malignant or accelerated hypertension with papilledema,neurological disturbances, acute kidney injury,or heart failure.
  • Flash pulmonary edema and labile BP.
  • Episodic headaches, diaphoresis, and palpitations.
 
RENOVASCULAR HYPERTENSION

The clinical consequences of renovascular disease withimpaired perfusion of the kidneys can lead to rise inarterial pressures designated as RVH with or withoutischemic injury to kidney causing irreversible loss ofkidney function designated as ischemic nephropathy orazotemic renovascular disease. It is an important andpotentially curable cause of secondary hypertension.Majority of patients with RVH have main renal arterystenosis leading to activation of various hormonal andneuronal responses, which causes rise in systemic arterialpressure. The leading causes of renal artery stenosisare atherosclerotic renovascular disease, fibromusculardysplasia, and vasculitis involving the renal arteries5(Tables 1 and 2).

Renovascular hypertension accounts for less than1%of patients with mild to moderate hypertension.6Atherosclerotic renal artery stenosis usually coexists withother manifestations of atherosclerosis, such as coronaryartery disease (10-14%) and peripheral arterial andaortic diseases (24-35%).6 The prevalence of renal artery stenosis in high-risk patients with severe or refractoryhypertension is 27 to 45% in whites when compared with8 to 19% in blacks.7 In another prospective study, RVHwas present equally in blacks and whites.8
 
86

Renovascular Hypertension

Table 1: Artherosclerosis or fibromuscular renal artery disease
Renovascular Hypertension

CLINICAL CLUES FOR RVH

The clinical findings associated with likelihood of RVHsecondary to significant renal artery stenosis are:
  • New onset of severe/resistant hypertension in patientsaged > 55 years.
  • Severe hypertension in patients with diffuse atherosclerosis,particularly those aged > 50 years.
  • Deterioration in renal function as defined by rise inserum creatinine by more than 50% within 1 weekof starting therapy with an angiotensin-convertingenzyme (ACE) inhibitor or angiotensin II receptorblocker (ARB).
  • Severe hypertension in patients with asymmetricalrenal sizes with difference of > 1.5 cm or unilateralunexplained atrophic kidney.
  • Abdominal bruit that lateralizes to one side. Abdominalrenal bruit has a sensitivity of approximately 40% buthas specificity as high as 99%.9
  • Recurrent episodes of flash pulmonary edema inpatients with severe hypertension or refractory heartfailure with impaired renal function.10

Heart Association guidelines on Peripheral ArteryDisease proposed that diagnostic testing for renal arterystenosis should be done in these settings, and correctiveprocedure may be considered if renovascular disease isdetected.11

ETIOLOGY OF RVH

The most common causes of RVH are stenosis of themain vessel supplying the kidney. The two majorcauses of main renal artery stenosis are atheroscleroticrenovascular disease (ASRVD) and fibromusculardysplasia (FMD). The latter may be caused by medial,perimedial, intimal fibroplasias, or medial hyperplasia.Atherosclerosis mainly affects male patients above theage of 45 years and usually involves the aortic orifice or the proximal main renal artery. This is particularlycommon in patients with diffuse atherosclerosis but canoccur as a relatively isolated renal lesion. Fibromusculardysplasia most often affects women below the age of50 years and typically involves the distal main renalartery or the intrarenal branches. Other causes includeinvolvement of renal arteries in systemic vasculitis, suchas Takayasu arteritis (TA) and polyarteritis, renal arteryaneurysm, atheroembolic disease, aortic coarctation,vascular occlusion due to endovascular aortic graft, andexternal compression by metastatic tumors.

 
Table 2: Types of renal artery disease
Renovascular Hypertension

ATHEROSCLEROTIC RENOVASCULAR DISEASE

Atherosclerotic renovascular disease refers to theatherosclerotic narrowing of the renal arteries that mayrange from focal stenosis to complete occlusion of oneor both renal arteries leading to renal ischemia andsubsequent renal atrophy. These luminal atheroscleroticnarrowing of the renal arteries is often present inconjunction with macrovascular disease in other organsystems, such as coronary, peripheral, and cerebralarteries. Atherosclerotic plaques are commonly presentin the first or the second centimeter of renal artery andmay extend into the aorta.

The prevalence of ASRVD is increasing, although thismay partly be due to improved imaging and selectionbias. United States Renal Data System data from 1991 to2001 revealed prevalence of ASRVD of 0.54% in elderlypopulation, and an estimated incidence of new casesbetween 2000 and 2001 was 3.7 cases per 1000 patientyears.12,13 In patients undergoing peripheral or coronaryangiography, ASRVD was found in 11 to 42% of cases.Renal artery stenosis may be bilateral in 20 to 40% ofsuch cases.14 Risk factors include age > 50 years, smoking,diabetes mellitus, hyperlipidemia, and hypertension.A positive relationship has been shown in univariateanalysis between ASRVD and high-sensitivity C-reactiveprotein, lipoprotein and homocysteine levels.

Clinically, ASRVD may be detected incidentallywhile doing coronary or peripheral angiography. This isusually of no significance. Renovascular hypertensionis the most common clinical manifestation and may be associated with other target organ damage. Patientswith RVH have abnormal circadian rhythm with lossof nocturnal pressure fall. Patients may have resistanthypertension requiring three or more antihypertensivemedication. Renin-angiotensin-aldosterone system(RAAS) inhibition with ACE inhibitor or ARBs may leadto acute kidney injury in patients with ASRVD. Patientswith advanced disease present with renal impairmentprogressing to end-stage renal disease (ESRD) or flashpulmonary edema due to rapid volume expansion15-17(Figs 1A and B and 2A and B).

Hypertension Journal, April-June, Vol 2, 2016 87

Ashish Nandwani, Vijay Kher

Renovascular Hypertension
Figs 1A and B: (A) Magnetic resonance angiography showing atherosclerotic right renal artery stenosis, and (B) renalangiography showing atherosclerotic right renal artery stenosis (postangioplasty)


FIBROMUSCULAR DYSPLASIA

Fibromuscular dysplasia is an idiopathic noninflammatory,nonatheromatous arteriopathy associated withproliferation of medial smooth muscle cells and fibroustissue leading to renal artery stenosis. The prevalence ofrenovascular FMD is estimated at 4 in 1,000.18 The mostcommon age group is 15 to 50 years and 90% of casesare reported in females. Fibromuscular dysplasia may be associated with disorders, such as Marfan syndrome,tuberous sclerosis, Ehlers-Danlos syndrome, and cysticmedial necrosis. The vascular distribution of FMD involvesmainly renal and cerebral vessels. Renal arteriesare involved in 65 to 70% of cases and cerebrovascularinvolvement is seen in 25 to 30% of cases. It may alsoinvolve the coronary, mesenteric, and peripheral extremityvessels.19,20 Histologically, medial fibroplasia is thecommonest variety, and the other rare forms includeperimedial fibroplasias and medial hyperplasia.21 Angiographically,the characteristic appearance is that of stringof beads, with bead diameter larger than lumen22 (Fig. 3).

Renovascular Hypertension
Figs 2A and B: (A) Three-dimensional reconstruction image ofCTA showing left renal artery stenosis, and (B) renal angiographyshowing left renal artery stenosis (postangioplasty)
 
Commonest clinical presentation of FMD is RVH,headaches, dizziness, and pulsatile tinnitus. Whilehypertension is the leading manifestation of renovascularFMD, some patients may have flank pain due to renalinfarction either from dissection of renal artery orembolism from the proximal aneurysm. Flank pain mayalso be due to the rupture of a renal artery aneurysmwith retroperitoneal bleed. Bruits may be present in flanks over carotids and femorals.23-25 Progression ofFMD has been documented in approximately 27% caseson serial angiographic examination. Fibromusculardysplasia rarely causes ESRD unless hypertension isuncontrolled or thrombosis of renal artery results in therenal infarction.

Renovascular Hypertension
Fig. 3: Renal angiography showing fibromuscular dysplasia ofleft renal artery
 
88

Renovascular Hypertension

CONGENITAL ARTERITIS

Renovascular hypertension can also be caused by thecongenital abnormalities of vascular development, suchas coarctation of aorta and middle aortic syndrome.Congenital coarctation involving abdominal aortaleading to middle aortic syndrome is rare and accountsfor 2% of all coarctation. Proximal renal artery stenosisis present in 80% of cases and mesenteric arteries may beinvolved in 25% of cases. The common clinical featuresare hypertension, lower limb claudication, headaches,and stroke. Most patients do not live beyond 40 years, ifleft untreated. Surgical revascularization is required inmost cases.26,27

INFLAMMATORY ARTERITIS

Takayasu arteritis (TA) is the commonest inflammatoryarteritis leading to RVH. Other rare causes include polyarteritisnodosa, giant cell arteritis, Kawasaki disease, andidiopathic aortitis. Takayasu arteritis is an inflammatorygranulomatous arteritis involving aorta and its first-orderbranches. The prevalence is as high as 1 in 3,000 peoplein Japan in comparison to only 2.6 cases per million inthe USA. It has been reported as the commonest cause ofRVH in parts of Asia, especially India.28,29

Takayasu arteritis usually presents in the 25 to 40years age group. The common clinical presentation isfatigue and discomfort in the muscles of one or moreextremities, especially upper limbs. There is decreasedpulsation of one or both brachial arteries with differencein systolic BP in both arms. Bruit may be heard onabdominal aorta or subclavian arteries. Hypertensiondue to proximal renal artery stenosis may be the solemanifestation in some cases. Diagnosis is usually basedon angiographic findings of narrowing or occlusion ofaorta and its primary branches30 (Figs 4A and B).

RADIATION-INDUCED RENOVASCULAR
DISEASE


Renovascular hypertension is the uncommon complicationof the abdominal radiation. Hypertension develops evendecades following abdominal radiation for lymphomaor seminoma. Clues for radiation-induced renovasculardisease include segmental renal atrophy along withhepatic and retroperitoneal fibrosis and focal aorticcalcification.31

 
Renovascular Hypertension
Figs 4A and B: (A) Three-dimensional reconstruction image of CTAin the case of TA showing aneurysmal dilatation of descending aorta,right renal artery stenosis with collateral formations, narrowing ofinfrarenal aorta, and iliac arteries with complete occlusion of leftinternal iliac artery, and (B) Computed tomographic angiographyin the case of TA postangioplasty with stenting

PATHOPHYSIOLOGY AND MANIFESTATIONS
OF RENOVASCULAR DISEASE


The presence of renal vascular abnormalities may beincidental, and it can be identified in patients undergoingvascular imaging for other reasons, such as coronaryangiography or peripheral vascular angiography. Theseincidental stenoses are usually of little or no hemodynamicsignificance. Renovascular hypertension refers to rise in arterialpressure secondary to hemodynamically significantrenal artery stenosis leading to reduced renal perfusion.Luminal occlusion of 70 to 80% is usually present beforechanges in blood flow or pressure across the lesion can bedetected. The presence of critical stenosis with reductionin renal perfusion pressure leads to activation of pressorpathways, notably release of renin from juxtaglomerularapparatus leading to activation of RAAS. The rise in angiotensinII and aldosterone increases the systemic arterialpressure to restore the renal perfusion. Additional mechanismscontributing to the elevation of the arterial pressureinclude activation of sympathetic nervous system, releaseof endothelin, and decrease in nitric oxide generation.32

Underlying mechanisms responsible for the RVH inhumans depend on whether renal artery stenosis is unilateralor bilateral. The nomenclature used for these conditionsare two-kidney-one-clip hypertension (Goldblatt),in which one clip is present with normal contralateralkidney and one-kidney-one-clip hypertension, in whichentire kidney mass is affected as in bilateral renal arterystenosis or stenosis of the solitary kidney. In the former,due to renal hypoperfusion, there is activation of RAASleading to sodium retention due to rise in angiotensin IIand aldosterone levels. However, presence of normal contralateralkidney allows pressure natriuresis to eliminateexcess of sodium. This leads to continuous activation of RAAS in the stenotic kidney. These sequences of eventsare responsible for the angiotensin II-dependent hypertensionand secondary hyperaldosteronism.

Hypertension Journal, April-June, Vol 2, 2016 89

Ashish Nandwani, Vijay Kher

In one-kidney-one-clip hypertension, entire renalmass is hypoperfused leading to RAAS activation withsodium and water retention; however, there is no contralateralor normal kidney to counteract these changes.With sodium retention and volume expansion, there isnegative feedback to inhibit the RAAS activation resultingin decrease in angiotensin II levels. Thus, under this situation,the hypertension is not angiotensin II dependent.33,34

DIAGNOSIS OF RVH

The diagnosis of the RVH depends on demonstratingboth critical stenosis of renal artery and activation ofRAAS. These include both invasive and noninvasiveimaging modalities. The goal of these diagnostictechniques is to establish the presence of renal arterystenosis, its location, and type, whether fibromusculardysplasia or atherosclerotic lesion. The lesion may beunilateral or bilateral. It is also important to establishthe hemodynamic severity of stenotic lesion. If anyendovascular intervention is planned, it is importantto know the location and degree of the lesion. The goldstandard for diagnosing renal artery stenosis is renalangiography. However, it is associated with risk ofcontrast-induced nephrotoxicity, i.e., more commonlyin patients with already compromised renal functions.

Common noninvasive modalities include duplexDoppler ultrasonography (USG), computed tomographicangiography (CTA), and magnetic resonance angiography(MRA). The choice of test depends upon institutionalexpertise and patient factors. If the noninvasive test isnot conclusive and the clinical suspicion remains high,conventional renal angiography is recommended.

Functional studies to assess renal function includecaptopril renal scintigraphy, which is also useful to determinethe relative function of each kidney. Physiologicstudies to assess the renin-angiotensin system includeselective renal vein renin measurements and plasmarenin activity (PRA). These tests are not useful as initialdiagnostic tests for renal artery stenosis.

DUPLEX DOPPLER ULTRASONOGRAPHY

Doppler USG is used for renal vascular anatomy and functionalstatus. Apart from direct visualization of main renalarteries via B-mode imaging, variety of hemodynamic factorsincluding renal blood flow can be measured via DopplerUSG. The narrowing of renal artery will cause velocitychange and waveform change commensurating with thedegree of the stenosis. The waveform becomes dampeneddownstream the stenosis site. Parameters measured using Doppler USG include peak systolic velocityat various sitesalong the aorta and renal arteries, acceleration time andindex, and intrarenal resistive index. Doppler USG is usedto obtain the renal resistive index, which is calculated fromthe following formula:
 
(Peak systolic velocity - end diastolic velocity) ÷
Peak systolic velocity


Lesions can also be detected by comparing the systolicflow velocity in the renal artery to that in the aorta sincethe velocity of flow increases as the artery narrows;end diastolic velocity may also be increased distal to astenotic lesion.
Features of significant renal artery stenosis are:
  • Elevated peak systolic velocity: Velocities in thestenotic segment > 1.8 to 2.0 m/s correlate well withstenosis of > 60% diameter reduction.
  • Renal artery/aorta ratio (RAR): An RAR > 3.5correlates with stenosis > 60%
  • Acceleration time (AT): An AT > 0.07 s correlates witha stenosis > 60%
  • Loss of the early systolic peak (ESP): Proximal stenosisresults in changes to the intrarenal waveform withloss of the ESP and a "tardus parvus" appearance.Using these criteria, sensitivity and specificity with
    angiographic estimation of lesions exceeding > 60% are90 and 96% respectively.

Doppler USG is an inexpensive, noninvasive testand is widely available, and it is also suitable for serialmeasurements to determine disease progression. Thismodality can also be used to detect recurrent stenosisin patients previously treated with endovascular angioplastyor stenting.

However, limitations include that this is operatordependent and may be difficult to perform in obesepatients. It may not identify the small accessory vessels.Further, Doppler USG will not be able to differentiatebetween fibromuscular dysplasia and atheroscleroticlesion.

A meta-analysis of 88 studies involving 8,147 patientsassessed the ability of the various USG parameters to detectrenal artery stenosis. Of these parameters, peak systolicvelocity, with a sensitivity and specificity of 85 and92% respectively, was more accurate than the renal-aorticratio and acceleration index. The positive predictivevalue was 84% and the false-positive rate was 8%.35,36

The utility of the resistive index was evaluated in 138patients with renal artery stenosis. The outcomes werepoor among the patients with a resistive index above0.8. A high resistance index may indicate irreversibleintrarenal vascular disease.37-39 Determination of theresistive index is operator dependent and can be obscuredby patient factors, such as obesity.
 
90

Renovascular Hypertension

COMPUTED TOMOGRAPHIC ANGIOGRAPHY

A spiral computed tomography (CT) scan with intravenouscontrast injection is a highly accurate noninvasivediagnostic test, which provides excellent images of bothkidneys and the vascular tree. It can identify small as wellas accessory vessels. Computed tomographic angiographycontinues to evolve technically and provide excellentsensitivity (96%) and specificity (97%) in small groups ofpatients. The performance of CTA was less favorable thanmagnetic resonance angiography in a series of 356 hypertensivepatients, out of whom 72 patients had some degreeof renal artery stenosis. The sensitivity and specificity ofCTA were 64 and 92% respectively. The poor sensitivity ofCTA was probably due to the high proportion of patientshaving FMD, as fibromuscular disease usually involvesdistal arterial segments that are difficult to image.40,41

The risk of contrast-induced nephrotoxicity is highespecially in patients with impaired renal functions dueto underlying ischemic nephropathy. Computed tomographyimaging with three-dimensional reconstructionand higher resolution with less contrast use continue toimprove the value of CTA as a diagnostic tool for renovasculardisease.

MAGNETIC RESONANCE ANGIOGRAPHY

Magnetic resonance angiography with gadolinium contrastgives excellent vascular imaging of the renal arteries.This technique is useful in patients who cannot be giveniodinated contrast agent due to either allergic reactions orimpaired renal functions due to risk of contrast-inducednephrotoxicity. There are concerns about gadoliniumassociatedcomplications, especially nephrogenic systemicfibrosis in patients with glomerular filtration rate (GFR)< 30 mL/min/1.73 m2. Magnetic resonance angiographyis a highly sensitive technique for detecting proximalrenal artery stenosis with sensitivity of 83 to 100% andspecificity of 92 to 97%. Limitations of MRA include overestimationof luminal narrowing and limited sensitivityfor middle and distal vascular lesions.40 Patients withmetallic stents are not candidates for MRA.

Using arteriography as the gold standard, MRA had asensitivity of 100% and specificity of 96% for the detectionof stenosis of the main renal arteries.42 The use of breathholdMRA with paramagnetic contrast material improvesthe ability to visualize small accessory arteries. Bloodoxygen level-dependent magnetic resonance imagingis a noninvasive method that detects local levels of thedeoxyhemoglobin without requiring contrast.

INVASIVE IMAGING - RENAL ANGIOGRAPHY

Renal angiography remains the gold standard for definingthe stenotic lesions of renal vasculature. It can identify whether stenosis is unilateral or bilateral, atheroscleroticor fibromuscular dysplasia, and poststenotic dilatation.Angiography provides important anatomic and functionalinformation including delayed perfusion andcollateral and accessory renal vessels. It is also usefulfor planning the endovascular procedure, such as angioplastyand stenting.

 
Contrast-induced nephrotoxicity and catheter-relatedcomplications are main issues associated with renal angiography.Atherosclerotic disease, diabetes mellitus, oldage, impaired renal functions, and dehydration are mainrisk factors for contrast-induced nephrotoxicity. Althoughrenal angiography is the gold standard for diagnosing renalartery stenosis, its invasive nature, cost, and potentialcomplications make it suitable only for those patients inwhom renal vascular intervention is planned.

CAPTOPRIL RENOGRAM

Radionuclide imaging provides a functional assessment ofthe kidneys allowing the comparison of blood flow and GFRbetween two kidneys. Diethylenetriaminepentaacetic acidand MAG3 are the commonly used radiopharmaceuticalsused for radionuclide renography. MAG3 may be morereliable in patients with renal insufficiency. MAG3 alsohas clearance characteristic similar to hippuran andrepresents the renal blood flow. Change in the GFR afterACE inhibition allows inferences regarding the presenceof renal artery stenosis. When this test is completelynegative, it has a high negative predictive value.

Nonstimulated radionuclide scans have a false-negativerate of 20 to 5%. The predictive value can be increasedby administration of oral captopril (25-50 mg) 1 hourbefore the isotope is injected. The interpretation of captoprilrenogram is based upon the ACE inhibitor-induceddecline in GFR in the stenotic kidney, accompanied by anincrease in GFR in the contralateral kidney due to removalof angiotensin II-mediated vasoconstriction. The net resultis that the difference between the two kidneys is enhanced.

The sensitivity and specificity of the captopril renogramvary substantially in different studies and has a poorcorrelation with the benefit obtained from angioplasty. Thesensitivity and specificity range from 65 to 96% and 62 to100% respectively, in several series. Sensitivity furtherdecreases in the presence of the renal insufficiency with reducedGFR (serum creatinine > 2.0 mg/dL).43,44 As a resultof these limitations, captopril renography is not broadlyhelpful in diagnosing renal artery stenosis, and the majoruse is to determine the relative function of each kidney.

PLASMA RENIN ACTIVITY

Peripheral venous PRA demonstrates the activation ofrenin-angiotensin system as a marker of underlying RVH. Plasma renin activity is elevated in only 50 to 80%of patients with RVH. Levels of PRA may be suppressedby a high dietary sodium intake, bilateral renal arterialdisease, volume expansion related to intrinsic kidneydisease, and various antihypertensive drugs. It haslimited value for the diagnosis of RVH as both sensitivityand specificity are low.
Hypertension Journal, April-June, Vol 2, 2016 91

Ashish Nandwani, Vijay Kher

The predictive value of the PRA can be increased bymeasuring the rise in PRA 1 hour after the administrationof 25 to 50 mg of captopril. Patients with renal arterystenosis have an increase in the PRA as compared withnormal individuals due to the removal of the normalsuppressive effect of high angiotensin II levels on reninsecretion in the stenotic kidney.45

MEASUREMENTS OF RENAL VEIN RENIN

Measurement of renal vein renin levels helps to lateralizethe stenotic kidney (> 1.5:1 stenotic-nonstenotic kidneyratio). This discrepancy in renin secretion betweenthe two kidneys is present in less than 10% of normalindividuals. Thus, the presence of highly lateralizing renalrenin values indicates the presence of physiologicallysignificant renal artery stenosis. The accuracy of thesemeasurements may be enhanced by administration ofan ACE inhibitor and/or diuretics, which will increaserenin secretion on the affected side.

The overall sensitivity of renal vein rennin measurementis 65% and positive predictive value is 18.5%.Renal vein renins have a limited role in estimating thephysiologic significance of a stenotic lesion. Exceptionsmay include patients with bilateral renal artery stenosisin whom renal vein renin measurements can be usedto determine which side contributes most to the hypertensionor in patients considered for nephrectomy of apressor kidney.46

These noninvasive tests, peripheral PRA, stimulatedPRA, renal vein renin level, and the captopril renogramare no longer considered suitable for initial testingpatients with suspected renovascular disease because oftheir poor sensitivity and specificity, and thus, they haveno meaningful role.

MANAGEMENT OF RVH

Once a patient is diagnosed with renal artery stenosisleading to RVH, it is important to know whether the lesionis unilateral or bilateral and likely cause of renal arterystenosis, that is, atherosclerotic or FMD or inflammatory.The main therapeutic options available are:
  • Medical therapy
  • Percutaneous angioplasty with or without stenting
  • Surgical revascularization, or in some cases, resectionof a "pressor" kidney

 
Perhaps, the most difficult aspect of management ofRVH is whether to treat medically or proceed for revascularizationprocedure. General approaches in patientswith RVH include control of hypertension by medicaltherapy. Revascularization is reasonable in patients whohave short duration of BP elevation prior to the diagnosisof renovascular disease or in patients who do not respondto optimal medical therapy or are intolerant to medicaltherapy. Patients with recurrent flash pulmonary edemaand/or refractory heart failure may also require revascularizationprocedure. In addition, revascularization maybe required in patients having progressive renal insufficiencydue to bilateral renal artery stenosis (or unilateralstenosis to a solitary functioning kidney).47

MEDICAL THERAPY

Angiotensin-converting enzyme inhibitors and ARBsare most effective drugs to control BP in patients withrenovascular disease. If BP goals are not achieved withangiotensin inhibition alone, other antihypertensivedrugs, such as a calcium channel blocker, thiazide diuretic,a mineralocorticoid receptor antagonist, or a betablocker, should be added as necessary. The potential concernsassociated with medical treatment are progressiveworsening of stenotic lesion over a period of time leadingto impaired renal functions due to ischemic damage.Angiotensin inhibition may lead to acute kidney injuryand hyperkalemia.48-50

The clinical characteristics associated with poorresponse to antihypertensive therapy include advancedage, advanced renal insufficiency (serum creatinine > 3.0mg/dL), atherosclerotic as opposed to FMD, and smallkidneys on imaging.

ENDOVASCULAR TREATMENT OF RENAL
ARTERY STENOSIS


For patients with renal artery stenosis with uncontrolledhypertension, deterioration in renal function, and cardiacfailure, revascularization may restore the renal bloodflow and stabilize the renal function. There is gooddata that stent placement is superior to angioplastyalone, especially in ostial stenosis. Patients with FMDare usually treated with angioplasty without stenting.The risks associated with the procedure are renal arterydissection, embolization into the kidney, rupture of renalartery, and contrast-induced nephrotoxicity.

REVASCULARIZATION VS MEDICAL
THERAPY ALONE


Multiple randomized trials have compared revascularizationusing percutaneous transluminal renal angioplasty(PTRA) with or without stent in combination with medical therapy in patients with atheroscleroticrenovascular disease.
 
92

Renovascular Hypertension

The largest and most recent of these was the CardiovascularOutcomes in Renal Atherosclerotic Lesions(CORAL) trial,51 which included 947 patients, who hadunilateral or bilateral atherosclerotic renal artery stenosis.These patients had systolic hypertension despite two ormore antihypertensive medications and/or an estimatedGFR (eGFR) < 60 mL/min/1.73 m2. All patients receiveda combination of antiplatelet therapy and standardizedmedical treatments for diabetes, hypertension, andhyperlipidemia. Candesartan was given as an angiotensinreceptor blocking agent to all the patients. Patients werethen randomly assigned to revascularization or to norevascularization.

The primary outcomes were a composite of cardiovascularor renal death, stroke, myocardial infarction,hospitalization for heart failure, a reduction in eGFR bymore than 30%, or ESRD. After a median of 3.6 years,revascularization had no additional effect on the primaryoutcome as compared with medical therapy alone(35.1 vs 35.8%). Further, revascularization had no effecton any of the individual components of the primaryoutcome. The most frequent complication was renalartery dissection, which occurred in 11 (2.2%) revascularizedpatients.

The angioplasty and stenting for renal artery lesiontrial (ASTRAL)52 and stent placement in patients withatherosclerotic renal artery stenosis and impaired renalfunction trial (STAR)53 randomized patients to medicaltherapy or intervention. All classes of antihypertensiveswere used. Angiotensin-converting enzyme inhibitorswere used in two-thirds of patients in STAR and 38%patients in the ASTRAL trial. There were no significantdifferences in the BP control, number of antihypertensivemedications, renal functions, or cardiovascular outcomesin these patients.

A meta-analysis, including CORAL and ASTRAL,has been published.54 Patients treated with PTRAwith or without stent required an average of 0.2 lesserantihypertensive medications. However, there was nodifference with regard to change in renal function or theincidence of heart failure, stroke, myocardial infarction, ortotal mortality. Periprocedural complications associatedwith PTRA varied across these trials; procedure-relateddeaths occurred in 0.4% of patients and renal arteryperforations or dissections occurred in 2.5%. Apart fromslight reduction in antihypertensive medication, none ofthese studies demonstrated any significant clinical benefitfrom PTRA.51-53,55-58

Earlier studies by Van Jaarsveld et al56 and Plouinet al57 evaluated BP control in patients with medicaltherapy vs PTRA in patients who required two or more antihypertensive drugs for BP control and serum creatinine< 2.3 mg/dL. The study was unable to demonstrateany benefit in respect of renal function or event-freesurvival. They concluded that angioplasty had littleadvantage over antihypertensive therapy and final BPwas not different between the groups.

 
The main drawbacks of these studies are that highriskgroup patients were excluded, who may havebenefited most from the procedure, e.g., patients withbilateral RAS, recurrent pulmonary edema, and renaldysfunction.

In summary, these trials demonstrate that most of thepatients with ASRVD can be effectively managed withoptimal medical therapy with antihypertensive therapyas compared with PTRA with or without stent therapy. Nodifference in patient survival or renal function could beidentified. In most of these studies, ACE inhibitors or ARBswere used and were well tolerated without any significantside effects. Risk associated with revascularizationinclude contrast-induced nephrotoxicity and procedurerelatedcomplications including arterial dissection andsegmental renal infarction.

SURGICAL REVASCULARIZATION

Surgical revascularization carries a considerable risk, cost,and morbidity. It is reserved for patients who fail medicaland endovascular therapies or have associated aorticdisease, i.e., not amenable to endovascular therapy. Somepatients with total occlusion of renal artery resulting innonfunctioning kidney may require nephrectomy forcontrol of BP.

CONCLUSION

Renovascular hypertension caused by renal arterystenosis is an important cause of secondary hypertension,especially in elderly patients with other atheroscleroticdiseases. Most of the patients can be managed by medicalmeans by antihypertensive medications and measures toprevent atherosclerotic progression with statin therapy.These patients need to be reviewed at regular intervalsfor progression of disease. Development of resistanthypertension, deteriorating renal functions, and flashpulmonary edema despite medical and diuretic therapymay warrant revascularization therapy. Long-termfollow-up for BP control and renal functions is importantbecause of potential recurrent disease or restenosis afterrevascularization.

ACKNOWLEDGMENT

Authors would like to acknowledge Dr. Virender Sheorainfor providing images for the article.
Hypertension Journal, April-June, Vol 2, 2016 93

Ashish Nandwani, Vijay Kher

REFERENCES
  1. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD,White A, Cushman WC, White W, Sica D, et al. Resistanthypertension: diagnosis, evaluation, and treatment: a scientificstatement from the American Heart Association ProfessionalEducation Committee of the Council for High BloodPressure Research. Hypertension 2008 Jun;51(6):1403-1419.
  2. Faselis C, Doumas M, Papademetriou V. Common secondarycauses of resistant hypertension and rational for treatment.Int J Hypertens 2011;2011:236239.
  3. Lewin A, Blaufox MD, Castle H, Entwisle G, Langford H.Apparent prevalence of curable hypertension in the HypertensionDetection and Follow-up Program. Arch Intern Med1985 Mar;145(3):424-427.
  4. Borgel J, Springer S, Ghafoor J, Arndt D, Duchna HW, Barthel A,Werner S, Van Helden J, Hanefeld C, Neubauer H, et al.Unrecognized secondary causes of hypertension in patientswith hypertensive urgency/emergency: prevalence and coprevalence. Clin Res Cardiol 2010 Aug;99(8):499-506.
  5. Textor SC, Lerman L. Renovascular hypertension and ischemicnephropathy. Am J Hypertens 2010 Nov;23(11):1159-1169.
  6. Davis BA, Crook JE, Vestal RE, Oates JA. Prevalence ofrenovascular hypertension in patients with grade III or IVhypertensive retinopathy. N Engl J Med 1979 Dec 6;301(23):1273-1276.
  7. Novick AC, Zaki S, Goldfarb D, Hodge EE. Epidemiologic andclinical comparison of renal artery stenosis in black patientsand white patients. J Vasc Surg 1994 Jul;20(1):1-5.
  8. Svetkey LP, Kadir S, Dunnick NR, Smith SR, Dunham CB,Lambert M, Klotman PE. Similar prevalence of renovascularhypertension in selected blacks and whites. Hypertension1991 May;17(5):678-683.
  9. Turnbull JM. The rational clinical examination. Is listening forabdominal bruits useful in the evaluation of hypertension?JAMA 1995 Oct 25;274(16):1299-1301.
  10. Messerli FH, Banglore S, Makani H, Makani H, Rimoldi SF,Allemann Y, White CJ, Textor S, Sleight P. Flash pulmonaryoedema and bilateral renal artery stenosis: the Pickeringsyndrome. Eur Heart J 2011 Sep;32(18):2231-2235.
  11. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA,Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR,et al. 2011 ACCF/AHA Focused Update of the Guideline forthe Management of Patients With Peripheral Artery Disease(updating the 2005 guideline): a report of the AmericanCollege of Cardiology Foundation/American Heart AssociationTask Force on Practice Guidelines. J Am Coll Cardiol2011 Nov 1;58(19):2020-2045.
  12. Kalra PA, Guo H, Kausz AT, Gilbertson DT, Liu J, Chen SC,Ishani A, Collins AJ, Foley RN. Atherosclerotic renovasculardisease in United States patients aged 67 years or older: riskfactors, revascularization and prognosis. Kidney Int 2005Jul;68(1):293-301.
  13. Kalra PA, Guo H, Gilbertson DT, Liu J, Chen SC, Ishani A,Collins AJ, Foley RN. Atherosclerotic renovascular diseasein United States. Kidney Int 2010 Jan;77(1):37-43.
  14. Khosla S, Kunjummen SI, Manda R, Khaleel R, Kular R,Gladson M, Razminia M, Guerrero M, Trivedi A, Vidyarthi V,et al. Prevalence of renal artery stenosis requiring revascularizationin patients initially referred for coronary angiography.Catheter Cardiovasc Interv 2003 Mar;58(3):400-403.
  15. De Mast Q, Beutler JJ. The prevalence of atherosclerotic renalartery stenosis in risk groups: a systematic literature review.J Hypertens 2009 Jul;27(7):1333-1340.

 
  1. Appel RG, Bleyer AJ, Reavis S, Hansen KJ. Renovasculardisease in older patients beginning renal replacementtherapy. Kidney Int 1995 Jul;48(1):171-176.
  2. Keddis M, Garovic V, Bailey K, Wood CM, Raissian Y, Grande JP.Ischaemic nephropathy secondary to atherosclerotic renalartery stenosis-clinical and histopathology. Nephrol DialTransplant 2010 Nov;25(11):3615-3622.
  3. Olin JW, Froehlich J, Gu X, Bacharach JM, Eagle K, Gray BH,Jaff MR, Kim ES, Mace P, Matsumoto AH, et al. The UnitedStates Registry for Fibromuscular Dysplasia: results in thefirst 447 patients. Circulation 2012 Jun 26;125(25):3182-3190.
  4. Plouin PF, Perdu J, La Batide-Alanore A, Boutouyrie P,Gimenez-Roqueplo AP, Jeunemaitre X. Fibromuscular dysplasia.Orphanet J Rare Dis 2007 Jun 7;2:28.
  5. Olin JW, Gornik HL, Bacharach JM, Biller J, Fine LJ, Gray BH,Gray WA, Gupta R, Hamburg NM, Katzen BT, et al. Fibromusculardysplasia: state of the science and critical unansweredquestions: a scientific statement from the American HeartAssociation. Circulation 2014 Mar;129(9):1048-1078.
  6. Alimi Y, Mercier C, Pellissier JF, Piquet P, Tournigand P.Fibromuscular disease of renal artery: a new histopathologicalclassification. Ann Vasc Surg 1992 May;6(3):220-224.
  7. Meaney TF. Progression of renal artery fibromuscular dysplasiain 42 patients as seen on angiography. Radiology 1982Jan;142(1):252-253.
  8. Olin JW, Sealove BA. Diagnosis, management, and futuredevelopments of fibromuscular dysplasia. J Vasc Surg 2011Mar;53(3):826-836.
  9. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med2004 Apr 29;350(18):1862-1871.
  10. Persu A, Touze E, Mousseaux E, Barrel X, Joffre F, Plouin PF.Diagnosis and management of fibromuscular dysplasia: anexpert consensus. Eur J Clin Invest 2012 Mar;42(3):338-347.
  11. Rosenthal E. Coarctation of aorta from fetus to adult: curablecondition or life long disease process? Heart 2005 Nov;91(11):1495-1502.
  12. Kenny D, Polson JW, Martin RP, Paton JF, Wolf AR. Hypertensionand coarctation of aorta: an inevitable consequenceof developmental pathophysiology. Hypertens Res 2011May;34(5):543-547.
  13. Ishikawa K. Diagnostic approach and proposed criteria forthe clinical diagnosis of Takayasu's arteriopathy. J Am CollCardiol 1988 Oct;12(4):964-972.
  14. Sharma BK, Jain S, Suri S, Numano F. Diagnostic criteria forTakayasu arteritis. Int J Cardiol 1996 Aug; (Suppl 54):S141-S147.
  15. Tann OR, Tulloh RM, Hamilton MC. Takayasu disease: areview. Cardiol Young 2008 Jun;18(3):250-259.
  16. Fakhouri F, La Batide AA, Rerolle JP, Guery B, Raynaud A,Plouin PF. Presentation and revascularization outcome inpatients with radiation induced renal artery stenosis. Am JKidney Dis 2001 Aug;38(2):302-309.
  17. Martinez-Maldonado M. Pathophysiology of renovascularhypertension. Hypertension 1991 May;17(5):707-719.
  18. Navar LG, Zou L, Von Thun A, Tarng Wang C, Imig JD,Mitchell KD. Unraveling the mystery of Goldblatt hypertension.News Physiol Sci 1998 Aug;13:170-176.
  19. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R,Flannery PJ, Spurney RF, Kim HS, Smithies O, Le TH,et al. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin angiotensin system.J Clin Invest 2005 Apr;115(4):1092-1099.

 
94

Renovascular Hypertension

  1. Williams GJ, Macaskill P, Chan SF, Karplus TE, Yung W,Hodson EM, Craig JC. Comparative accuracy of renal duplexsonographic parameters in the diagnosis of renal artery stenosis:paired and unpaired analysis. Am J Roentgenol 2007Mar;188(3):798-811.
  2. Radermacher J, Chavan A, Bleck J, Vitzthum A, Stoess B,Gebel MJ, Galanski M, Koch KM, Haller H. Use of Dopplerultrasonography to predict the outcome of therapy for renalarterystenosis. N Engl J Med 2001 Feb;344(6):410-417.
  3. Ikee R, Kobayashi S, Hemmi N, Imakiire T, Kikuchi Y, Moriya H,Suzuki S, Miura S. Correlation between the resistive indexby Doppler ultrasound and kidney function and histology.Am J Kidney Dis 2005 Oct;46(4):603-609.
  4. Krumme B, Hollenbeck M. Doppler sonography in renalartery stenosis - does the Resistive Index predict the successof intervention? Nephrol Dial Transplant 2007 Mar;22(3):692-696.
  5. Crutchley TA, Pearce JD, Craven TE, Stafford JM, EdwardsMS, Hansen KJ. Clinical utility of the resistive index in atheroscleroticrenovascular disease. J Vasc Surg 2009 Jan;49(1):148-155.
  6. Glockner JF, Vrtiska TJ. Renal MR and CT angiography:current concepts. Abdomen Imaging 2007 Jun;32(3):407-420.
  7. Olbricht CJ, Paul K, Prokop M, Chavan A, Schaefer-Prokop CM,Jandeleit K, Koch KM, Galanski M. Minimally invasive diagnosisof renal artery stenosis by spiral computed tomographyangiography. Kidney Int 1995 Oct;48(4):1332-1337.
  8. Vasbinder GB, Nelemans PJ, Kessels AG, Kroon AA, Maki JH,Leiner T, Beek FJ, Korst MB, Flobbe K, de Haan MW, et al.Accuracy of computed tomographic angiography and magneticresonance angiography for diagnosing renal arterystenosis. Ann Intern Med 2004 Nov 2;141(9):674-682.
  9. Setaro JF, Saddler MC, Chen CC, Hoffer PB, Roer DA, MarkowitzDM, Meier GH, Gusberg RJ, Black HR. Simplifiedcaptopril renography in diagnosis and treatment of renalartery stenosis. Hypertension 1991 Sep;18(3):289-298.
  10. Mann SJ, Pickering TG. Detection of renovascular hypertension.State of the art: 1992. Ann Intern Med 1992 Nov15;117(10):845-853.
  11. Vaughan ED Jr. Curable renal hypertension: renin, markeror cause? Question answered. Am J Hypertens 2014 Aug;27(8):1000-1003.
  12. Rossi GP, Cesari M, Chiesura-Corona M, Miotto D, Semplicini A,Pessina AC. Renal vein renin measurements accurately identifyrenovascular hypertension caused by total occlusion ofthe renal artery. J Hypertens 2002 May;20(5):975-984.
  13. Novick AC. Current concepts in the management of renovascularhypertension and ischemic renal failure. Am J KidneyDis 1989 Jun;13(6 Suppl 1):33-37.


 
  1. Hackam DG, Duong-Hua ML, Mamdani M, Li P, Tobe SW,Spence JD, Garg AX. Angiotensin inhibition in renovasculardisease: a population-based cohort study. Am Heart J 2008Sep;156(3):549-555.
  2. Hricik DE, Dunn MJ. Angiotensin-converting enzymeinhibitor-induced renal failure: causes, consequences, anddiagnostic uses. J Am Soc Nephrol 1990 Dec;1(6):845-858.50. Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM,Kalra PA. Dispelling the myth: the use of renin-angiotensinblockade in atheromatous renovascular disease. NephrolDial Transplant 2012 Apr;27(4):1403-1409.
  3. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W,Reid DM, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, et al.Stenting and medical therapy for atherosclerotic renal-arterystenosis. N Engl J Med 2014 Jan;370(1):13-22.
  4. ASTRAL Investigators, Wheatley K, Ives N, Gray R, Kalra PA,Moss JG, Baigent C, Carr S, Chalmers N, Eadington D, et al.Revascularization versus medical therapy for renal-arterystenosis. N Engl J Med 2009 Nov 12;361(20):1953-1962.
  5. Bax L, Woittiez AJ, Kouwenberg HJ, Mali WP, Buskens E,Beek FJ, Braam B, Huysmans FT, Schultze Kool LJ, Rutten MJ,et al. Stent placement in patients with atherosclerotic renalartery stenosis and impaired renal function: a randomizedtrial. Ann Intern Med 2009 Jun 16;150(12):840-848.
  6. Jenks S, Yeoh SE, Conway BR. Balloon angioplasty, with andwithout stenting, versus medical therapy for hypertensivepatients with renal artery stenosis. Cochrane Database SystRev 2014;(12):CD002944.
  7. Kumbhani DJ, Bavry AA, Harvey JE, de Souza R, Scarpioni R,Bhatt DL, Kapadia SR. Clinical outcomes after percutaneousrevascularization versus medical management in patientswith significant renal artery stenosis: a meta-analysis of randomizedcontrolled trials. Am Heart J 2011 Mar;161(3):622-630.
  8. Van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J,Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in 't Veld AJ,et al. The effect of balloon angioplasty on hypertension inatherosclerotic renal-artery stenosis. Dutch Renal ArteryStenosis Intervention Cooperative Study Group. N Engl JMed 2000 Apr 6;342(14):1007-1014.
  9. Plouin PF, Chatellier G, Darne B, Raynaud A. Blood pressureoutcome of angioplasty in atherosclerotic renal artery stenosis:a randomized trial. Essai Multicentrique Medicaments vsAngioplastie (EMMA) Study Group. Hypertension 1998Mar;31(3):823-829.
  10. Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R,Isles CG, Loose H, Main J, Padfield P, Russell IT, et al.Randomized comparison of percutaneous angioplasty vscontinued medical therapy for hypertensive patients withatheromatous renal artery stenosis. Scottish and NewcastleRenal Artery Stenosis Collaborative Group. J Hum Hypertens1998 May;12(5):329-335.

Hypertension Journal, April-June, Vol 2, 2016 95