The ESC Textbook of Cardiovascular Medicine (3 edn)
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This chapter provides the background information and detailed discussion of the data for the following current ESC Guidelines on: 
Diagnosis and Treatment of Peripheral Arterial Diseases - academic.oup.com/eurheartj/article/39/9/763/5033666#117577060
This section was reviewed and edited by The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Authors/Task Force Members: Helmut Baumgartner (ESC Chairperson) (Germany), Volkmar Falk (EACTS Chairperson) (Germany), Jeroen J. Bax (The Netherlands), Michele De Bonis (Italy), Christian Hamm (Germany), Per Johan Holm (Sweden), Bernard Iung (France), Patrizio Lancellotti (Belgium), Emmanuel Lansac (France), Daniel Rodriguez Muñoz (Spain), Raphael Rosenhek (Austria), Johan Sjögren (Sweden), Pilar Tornos Mas (Spain), Alec Vahanian (France), Thomas Walther (Germany), Olaf Wendler (UK), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain)
Summary
Atherosclerotic renal artery disease (RAD) is the most common cause of “renovascular hypertension”. In clinical situations with high suspicion, the use of DUS, usually as first-line imaging, followed by MRA and/or CTA are recommended for the establishment of RAD diagnosis. Renal revascularization does not generally improve blood pressure, renal or cardiovascular outcomes in patients with atherosclerotic RAD. With few exceptions, medical therapy with antihypertensive agents, antiplatelet drugs and statins remain the cornerstone for management of patients with RAD.
Atherosclerotic renal artery disease (RAD) is the most common cause of ‘renovascular hypertension’.
In clinical situations with high suspicion, the use of duplex ultrasound, usually as first-line imaging, followed by magnetic resonance angiography (MRA) or computed tomography angiography (CTA), or both, are recommended for the establishment of RAD diagnosis.
Renal revascularization does not generally improve blood pressure, renal, or cardiovascular outcomes in patients with atherosclerotic RAD.
With few exceptions, medical therapy with antihypertensive agents, antiplatelet drugs, and statins remain the cornerstone for management of patients with RAD.
Introduction
RAD is generally considered when renal artery stenosis (RAS) is 60% or greater, although additional functional assessment by haemodynamic criteria is advisable. The prevalence of RAD increases with advancing age and is mostly related to atherosclerosis. It is associated with male gender, hypertension, smoking, diabetes mellitus, chronic kidney disease (CKD), aorto-iliac occlusive disease, and coronary artery disease.1 It may be present in 5–10% of the general population, with a higher prevalence in high-risk populations.2 Approximately 20% have bilateral disease or a single functioning kidney is affected. Less frequent causes of RAD are fibromuscular dysplasia (FMD)3 and arteritis. The former is the most frequent cause of RAD in young hypertensive patients (especially in women).
Clinical presentation
Clinical signs include resistant hypertension, unexplained renal failure, and, uncommonly, flash pulmonary oedema (Box 49.8.1). RAD promotes hypertension and subsequent cardiovascular disease, while atherosclerotic disease may in turn cause RAD. The filtration capacity loss in the ischaemic kidney may be due to hypoperfusion or recurrent microembolism, or both. Renal hypoperfusion causes an increase in blood pressure (BP) secondary to activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS), which may be important in the risk of cardiovascular complications.4 With unilateral RAS, the contralateral kidney will increase sodium excretion and there is no sodium retention or volume overload. In patients with severe bilateral RAS or unilateral RAS in a single functioning kidney, renal failure and flash pulmonary oedema can occur.5
Onset of hypertension before the age of 30 years.
Onset of severe hypertension after the age of 55 years, when associated with CKD or heart failure.
Hypertension and abdominal bruit.
Rapid and persistent worsening of previously controlled hypertension.
Resistant hypertension (i.e. other secondary form unlikely and target not achieved despite four drug classes including a diuretic and a mineralocorticoid-receptor antagonist in appropriate doses).
Hypertensive crisis (i.e. acute kidney injury, acute heart failure, hypertensive encephalopathy, or grade 3–4 retinopathy).
New azotaemia or worsening of renal function after treatment with RAAS blockers.
Unexplained atrophic kidney or discrepancy in kidney size, or unexplained renal failure.
Flash pulmonary oedema.
Natural history
Atherosclerotic RAD is progressive and the risk of progression is highest with high-grade stenosis, severe hypertension, and diabetes.6 Less than 10% of patients with RAS progress to high-grade stenosis or occlusion within 5 years,7 and renal function deterioration is rare with unilateral RAS, but more evident with bilateral RAS or with a single functioning kidney (3%, 18%, and 55%, respectively, at 2 years).8
Diagnostic strategy
Patients with a clinical suspicion of RAS (Box 49.8.1) should undergo a diagnostic evaluation including physical examination, exclusion of other potential causes of secondary hypertension, and ambulatory (or home) BP measurement (see Chapter 44.4).
Duplex ultrasound is the first-line imaging modality to screen for significant (≥60%) stenosis,2,4,7,9 although it may overestimate the degree of stenosis. It can be repeated to assess stenosis progression and its haemodynamic consequences (e.g. flow velocity and vascular resistance). Peak systolic velocity in the main renal artery shows the best sensitivity (85%) and specificity (92%) to identify angiographically significant stenoses.10 Thus, criteria other than peak systolic velocity should be used to support the diagnosis.9,10 The renal resistive index (RRI) may help to identify more severe RAS and provide additional information on patient response to intervention.4,9 It is measured by Doppler sonography in an intrarenal artery and is defined as the ratio of [peak systolic velocity − end diastolic velocity] to peak systolic velocity. The RRI can provide information on vascular and parenchymal renal abnormalities, but it can also be regarded as a marker of systemic vascular properties. Normal values range between 0.60 and 0.70 and RRI can be abnormal both when high and low. It can be influenced both by renal and extrarenal determinants. Therefore, a low (< 60) RRI can reflect RAS greater than 70% (intrarenal determinant) or valvular aortic stenosis, thoracic or suprarenal abdominal aortic stenosis, tachycardia, hypervolaemia, and parasympathetic activation (extrarenal determinants). A high RRI (>70) can reflect vasoconstriction, arteriolosclerosis, increased interstitial and increased venous pressure (intrarenal determinants) or adrenergic hyperactivity, bradycardia, and increased systemic pulse pressure (extrarenal determinants).11 The latter is the result of increased aortic stiffening.12
In the case of isolated renal diseases (i.e. acute kidney injury, hydronephrosis, renal vein thrombosis), RRI is a reliable index of renal damage. However, in the case of arterial involvement, both renal and systemic (i.e. CKD), RRI predicts renal and general outcomes as a marker of systemic atherosclerotic/arteriosclerotic burden rather than being a marker of renal damage.13 The latter notion is still a matter of investigation.
In the case of a significant RAS (>75–80%), the Doppler post-stenotic flow wave is characterized by a ‘tardus’ (slow) and ‘parvus’ (weak) pattern, and thus RRI is low (<0.60). This low RRI suggests that the ischaemic kidney is protected by a marked vasodilatation, modulated by the self-regulating intrarenal mechanisms. However, progression of chronic renal disease leads to an increase in RRI due to an increase in parenchymal vascular resistance, and this may mask the diagnosis and haemodynamic effects of significant artery stenosis. A low RRI (<0.60) may predict a successful outcome of revascularization in terms of renal function recovery and regulation of BP. A high RRI (>0.75–0.80), denoting parenchymal disease, is associated with an unsuccessful outcome post revascularization. Recently, an increased RRI (>0.73) measured in the kidney contralateral to RAS was found to be the best single predictor of worse renal function outcome after renal revascularization,14 possibly because it represented the state of the small parenchymal renal vessels not subject directly to large renal vessel disease.
Renal duplex ultrasound requires experience. It may be difficult in overweight subjects. Other limitations include failure to visualize the entire renal artery, and missing the highest peak systolic velocity tracing. Accessory renal arteries may be missed.
Multidetector CTA and MRA (with or without gadolinium) show equally high sensitivities (64–100% and 94–97%) and specificities (92–98% and 85–93%) for detection of significant RAS.15,16 CTA provides higher spatial resolution but usual limitations should always be considered. Gadolinium-enhanced MRA provides excellent characterization of renal arteries, the surrounding vessels, renal mass, and even renal excretion function. It tends to overestimate the stenosis severity. It is less useful in patients with renal artery stents because of artefacts. Digital subtraction angiography remains the gold standard for the diagnosis of RAS.7,15 Since the correlation between the angiographic stenosis and the haemodynamic impact is poor, a major advantage of digital subtraction angiography is the possibility to measure the pressure gradient across the lesion, which is especially useful for moderate stenosis. A systolic pressure gradient greater than 20 mmHg or a resting pressure ratio distal to the stenosis less than 0.90 is considered to confirm significant stenosis in symptomatic patients.17 Renal artery fractional flow reserve measured during maximum hyperaemia, induced by papaverine, dopamine, or acetylcholine, is an alternative method to assess the stenosis severity, which might predict the clinical response to intervention.4 Due to the potential risks with invasive procedures, angiography is generally limited to visualization and quantification of the stenosis before vascular intervention. It is also indicated when clinical suspicion is high and the results of non-invasive examinations are inconclusive.2,15 Renal scintigraphy, plasma renin measurements before and after angiotensin-converting enzyme inhibitor (ACEI) provocation, and venous renin measurements are not considered anymore for the diagnosis of atherosclerotic RAD.1,2
See Table 49.8.1 for recommendations for diagnostic strategies for RAD.
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ACEI, angiotensin-converting enzyme inhibitor; CTA, computed tomography angiography; DSA, digital subtraction angiography; DUS, duplex ultrasound; eGFR, estimated glomerular filtration rate; MRA, magnetic resonance angiography.
a Class of recommendation.
b Level of evidence.
c When eGFR is ≥60 mL/min.
d When eGFR is ≥30 mL/min.
Prognosis
Life expectancy is reduced in patients with RAD without end-stage CKD, as they mostly die from an acute cardiovascular event.2,18 Patients who progress to end-stage CKD have even higher mortality rates.19
Treatment
Medical therapy
Risk assessment, lifestyle management, and medical treatment should follow current European Society of Cardiology Guidelines (see Chapter 44.7).20,21,22 Most antihypertensive drugs (ACEIs, angiotensin receptor blockers (ARBs), calcium channel blockers, beta blockers, and diuretics) are effective for treating hypertension and may lead to slowing of the progression of renal disease.23,24 Most patients with significant RAS tolerate ACEIs or ARBs without difficulty. In large observational studies, ACEIs and ARBs have shown benefits in reducing mortality and morbidity in patients with RAD.24,25,26 However, these drugs can reduce glomerular capillary hydrostatic pressure enough to cause a transient decrease in glomerular filtration rate and raise serum creatinine, warranting caution and close follow-up. These drugs may be introduced in the case of bilateral RAS and when the lesion affects a single functioning kidney, provided that the patients are very carefully monitored.23,25 Optimal BP in the setting of RAD is unknown. It has been hypothesized that severe RAS might require higher BPs to maintain adequate blood flow across the stenosis; however, very low rates of progressive renal failure in medically managed patients argue against such a strategy.
Statins are associated with improved survival, slower lesion progression, and reduced restenosis risk after renal stenting.27,28 Antiplatelet therapy should be part of best medical therapy (BMT).
Revascularization
Impact on blood pressure control, renal function, and survival
Uncontrolled trials reported improved BP control in resistant hypertensive patients following renal stenting,29,30 but previous31 and three recent major randomized controlled trials (Table 49.8.2; see also Chapter 44.4)) showed no difference between endovascular therapy and BMT other than a minor reduction of antihypertensive medications after revascularization (2.96 vs 3.18 drugs).32,33,34,35 Data do not support a benefit of stenting based on degree of stenosis, haemodynamic significance of the lesion, or higher pre-treatment BP.34
| Trial | Main selection criteria | Treatment group (n) | Control group (n) | Primary outcome | Main results | Renal outcome | Hypertension outcome | Intervention-related complication (%) |
|---|---|---|---|---|---|---|---|---|
STAR 10 centres; follow-up 2 years (2009) | Impaired renal function, ostial renal artery of ≥50%, stable BP | 64 | 76 | ≥20% eGFR decrease | No difference in GFR decline | No difference in GFR decline | No difference | 2 procedure-related deaths (3%), 1 late death secondary to an infected haematoma, and 1 patient who required dialysis secondary to cholesterol embolism |
ASTRAL 57 centres; follow-up 5 years (2009) | Uncontrolled/refractory hypertension or unexplained CKD with unilateral or bilateral RAS and clinician unsure of best treatment | 403 | 403 | 20% reduction in the mean slope of the reciprocal of the serum creatinine level | No difference in BP, renal function, mortality, CV events | No difference in renal function | No difference in BP | Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs |
CORAL 109 centres; follow-up 5 years (2014) | Hypertension on ≥2 anti-hypertensive drugs or CKD stage ≥2 with unilateral or bilateral renal stenosis (≥60%) | 467 | 480 | Major CV or renal event | No difference in the primary endpoint (HR 0.94; p =0.58) | No difference in renal function or events | Modest difference in systolic BP favouring the stent group (−2.3 mmHg; p =0.03) | Total 26 procedure-related complications (5.5%) |
| Trial | Main selection criteria | Treatment group (n) | Control group (n) | Primary outcome | Main results | Renal outcome | Hypertension outcome | Intervention-related complication (%) |
|---|---|---|---|---|---|---|---|---|
STAR 10 centres; follow-up 2 years (2009) | Impaired renal function, ostial renal artery of ≥50%, stable BP | 64 | 76 | ≥20% eGFR decrease | No difference in GFR decline | No difference in GFR decline | No difference | 2 procedure-related deaths (3%), 1 late death secondary to an infected haematoma, and 1 patient who required dialysis secondary to cholesterol embolism |
ASTRAL 57 centres; follow-up 5 years (2009) | Uncontrolled/refractory hypertension or unexplained CKD with unilateral or bilateral RAS and clinician unsure of best treatment | 403 | 403 | 20% reduction in the mean slope of the reciprocal of the serum creatinine level | No difference in BP, renal function, mortality, CV events | No difference in renal function | No difference in BP | Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs |
CORAL 109 centres; follow-up 5 years (2014) | Hypertension on ≥2 anti-hypertensive drugs or CKD stage ≥2 with unilateral or bilateral renal stenosis (≥60%) | 467 | 480 | Major CV or renal event | No difference in the primary endpoint (HR 0.94; p =0.58) | No difference in renal function or events | Modest difference in systolic BP favouring the stent group (−2.3 mmHg; p =0.03) | Total 26 procedure-related complications (5.5%) |
ASTRAL, Angioplasty and Stenting for Renal Artery Lesions; BP, blood pressure; CKD, chronic kidney disease; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HR, hazard ratio; RAS, renal artery stenosis; STAR, Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function.
Comments on the power of each trial:
STAR: the sample size calculation was based on an expected reduction in the incidence of progressive renal failure, defined as serum creatinine levels that increased by at least 20% in the previous 12 months, from 50% in the medication group to 20% in the stent group, with a power of 90%. To detect this difference at a significance level of 5140 patients were needed. The study had a lower rate of primary events than anticipated, which reduced the power of the trial to detect a difference between the two groups
ASTRAL: the trial was designed to detect a reduction of 20% in the mean slope of the reciprocal of the serum creatinine level. Assuming that there would be a mean slope of −1.6×10−3 l per mm per year (with a standard deviation of 1.5) in the medical-therapy group, we determined that achieving a mean slope of −1.28×10−3 l per mm per year in the revascularization group would require the enrolment of 700 patients, with a power of 80% and a two-tailed p-value of 0.05. Target recruitment was initially set at 1000 patients.
CORAL: 1080 participants would need to be enrolled for the study to have 90% power to test the hypothesis that stenting would reduce the incidence of the primary endpoint by 25% (HR 0.75) at 2 years, at a two-sided type I error rate of 0.05. Because the recruitment was slower than anticipated, the data and safety monitoring board recommended termination of recruitment on 30 January 2010 (at which point 947 participants had undergone randomization), and follow-up was extended through 28 September 2012 to preserve the statistical power.
Regarding renal function, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial reported no benefit from endovascular therapy over BMT.36 Progressive renal failure occurred in 16.8% in the endovascular therapy group versus 18.9% in the BMT group (p = 0.34), and permanent renal replacement therapy occurred in 3.5% versus 1.7%, respectively (p = 0.11). Renal artery dissection was reported in 2.4% of the endovascular therapy group. The two other randomized controlled trials showed similar findings even in the highest risk groups, including severe kidney ischaemia and impaired, or rapidly decreasing, kidney function. There was no advantage for revascularization with regard to cardiovascular morbidity and mortality.33,35,37
Revascularization in specific indications
With the low evidence of a potential benefit for revascularization over medical therapy, renal revascularization could only be considered in patients with anatomically and functionally significant RAS with the following particular aetiology or clinical scenarios.
RAD due to fibromuscular dysplasia
The prevalence of renal FMD is considered to be less than 1% in the general population,38 and more common in women than men by a ratio of 9:1 (see Chapter 44.4). Renovascular hypertension is the most common clinical presentation of FMD. Revascularization of FMD-related lesions should be recommended only in cases of symptomatic FMD with signs of organ ischaemia.3 Renal balloon angioplasty is the first-line revascularization technique and stenting should be considered in the management of dissection or balloon angioplasty failure.39,40,41 In a meta-analysis (47 studies for endovascular therapy, 1616 patients; 23 studies for open surgery, 1014 patients), major complication rates and mortality rates were lower in the case of endovascular therapy (6.3% and 0.9% vs 15.4% and 1.2%, respectively).41 Therefore, open surgery should be reserved for the management of stenosis associated with complex aneurysms, complex lesions (arterial bifurcation or branches), or endovascular therapy failure.3
RAD in flash pulmonary oedema or congestive heart failure
Patients with sudden-onset or ‘flash’ pulmonary oedema or congestive heart failure predominantly with preserved left ventricular function may be candidates for endovascular therapy,5,42,43,44 although a sub-analysis of the CORAL trial was not conclusive.33
RAD and acute oligo-/anuric renal failure
Patients with acute oligo-/anuric renal failure with kidney ischaemia may be candidates for revascularization in some rare cases of bilateral RAS without significant renal atrophy.
Technical considerations for revascularization
Endovascular therapy
In atherosclerotic RAD, stent placement has consistently proven superior to balloon angioplasty.45 Restenosis rates range from 4% to 20%46; drug-eluting stents have not demonstrated a better outcome.47,48 In one study, repeated stenting was associated with similar peri- and postoperative results with low complication rates compared to the primary procedure.49 The role of distal embolus protection devices was addressed in a small randomized trial, which showed no improved renal function outcome for distal filter protection during stent revascularization except with adjunctive glycoprotein IIb/IIIa receptor antagonist use.50
Surgery
Renal artery surgery appears to be superior to endovascular therapy in patients with complex disease of the renal arteries (e.g. aneurysms), failed endovascular procedures (i.e. dissection), and for patients undergoing surgical repair of the aorta with concomitant RAS (see Chapter 44.4).51,52 While truncal renal artery aneurysms can alternatively be treated with covered stents, aneurysms of the renal artery bifurcation and branches should be operated on, and ex situ renal artery revascularization may be recommended in expert centres.53,54 Thirty-day mortality rates range from 0% to 9%. After a follow-up of up to 5 years, 5–15% needed a reoperation, and survival was 65–81%.52,55,56,57
See Table 49.8.3 for recommendations for treatment strategies for RAD.
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ACEIs, angiotensin-converting enzyme inhibitor; ARBs, angiotensin-receptor blockers.
a Class of recommendation.
b Level of evidence.
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Further Reading
Persu A, Giavarini A, Touze E, Januszewicz A, Sapoval M, Azizi M, Barral X, Jeunemaitre X, Morganti A, Plouin PF, de Leeuw P.
Messerli FH, Bangalore S, Makani H, Rimoldi SF, Allemann Y, White CJ, Textor S, Sleight P.
Bavry AA, Kapadia SR, Bhatt DL, Kumbhani DJ.
Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KR, Shapiro JI, Rundback JH, Massaro JM, D’Agostino RB, Sr., Dworkin LD.
Olin JW, Gornik HL, Bacharach JM, Biller J, Fine LJ, Gray BH, Gray WA, Gupta R, Hamburg NM, Katzen BT, Lookstein RA, Lumsden AB, Newburger JW, Rundek T, Sperati CJ, Stanley JC.
