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Atherosclerotic Renal Artery Stenosis and Hypertension: Pragmatism, Pitfalls, and Perspectives

Published:October 29, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.10.010

      Abstract

      For many years and even decades, a diagnostic work-up to look for a secondary form of hypertension, particularly of renovascular origin, has been a central tenet in medicine. Atherosclerotic renal artery stenosis is considered the most common cause of renovascular hypertension. However, advances in understanding the complex pathophysiology of this condition and the recently documented futility of renal revascularization bring into question whether atherosclerotic renal artery stenosis truly causes “renovascular hypertension.” From a clinical point of view, a clear distinction should be made between hypertension associated with atherosclerotic renal artery stenosis and hypertension caused by renal artery stenosis-induced activation of the renin-angiotensin-aldosterone system. Most patients with atherosclerotic renal artery stenosis do not have a form of hypertension that is remediable or improved by angioplasty; to expose them to the cost, inconvenience, and risk of a diagnostic work-up add up to little more than a wild goose chase. However, with very few exceptions, medical therapy with antihypertensives and statins remains the cornerstone for the management of patients with atherosclerotic renal artery stenosis and hypertension.

      Keywords

      Clinical Significance
      • Atherosclerotic renal artery stenosis is considered the most common cause of “renovascular hypertension.”
      • From a clinical point of view, a clear distinction should be made between hypertension associated with renal artery stenosis and hypertension caused by renal artery stenosis-induced activation of the renin-angiotensin-aldosterone system.
      • Renal revascularization does not improve blood pressure, cardiovascular, or renal outcomes.
      • With few exceptions, medical therapy with antihypertensives and statins remains the cornerstone for management.
      For many years and even decades, a diagnostic work-up to look for a secondary form of hypertension, particularly of renovascular origin, has been a central tenet in medicine. Atherosclerotic renal artery stenosis is considered the most common cause of renovascular hypertension. However, recent advances in understanding the complex pathophysiology of this condition and the futility of renal revascularization question whether or not atherosclerotic renal artery stenosis truly causes renovascular hypertension. More recently, clinicians have become increasingly reluctant to spend time and effort to look for renal artery stenosis in patients with newly diagnosed uncomplicated hypertension. The main reason for refraining from doing so has been increasing uncertainty as to whether diagnosis and subsequent treatment of atherosclerotic renal artery stenosis by revascularization has a positive effect on outcome. A recent meta-analysis of 8 studies (2223 patients), including the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, found that renal revascularization was not associated with either improvement in systolic blood pressure or reduction in cardiovascular or renal outcomes, compared with medical therapy.
      • Bavry A.A.
      • Kapadia S.R.
      • Bhatt D.L.
      • Kumbhani D.J.
      Renal artery revascularization: updated meta-analysis with the CORAL trial.
      In the accompanying editorial, the question was asked whether the kidney connection was the Holy Grail or a wild goose chase.
      • Safley D.M.
      • Chhatriwalla A.K.
      The kidney connection: holy grail or wild goose chase?.
      The available data in aggregate now seem to suggest that the diagnostic search for atherosclerotic renal artery stenosis, whether positive or negative, confers no incremental benefit to the patient. This begs the question as to why clinicians should spin their wheels in pursuing diagnostic strategies that, even if positive, will have virtually no therapeutic consequences other than what would have been done anyway.
      • de Leeuw P.W.
      • Postma C.T.
      • Kroon A.A.
      Treatment of atherosclerotic renal artery stenosis: time for a new approach.
      With this seminal question in mind, we reviewed some pertinent clinical aspects of atherosclerotic renal artery stenosis and hypertension.

      Search Strategy and Selection Criteria

      Data for this concise review were identified by searches of MEDLINE and references of relevant articles using the following keywords and Medical Subject Headings terms: “renovascular hypertension,” “renal artery stenosis,” “atherosclerotic renal artery stenosis,” “medical therapy,” “surgical revascularization,” “renal angioplasty,” and “renal artery stenting.” We screened the title and abstract of possibly relevant citations and reviewed all the randomized control trials evaluating treatment strategies for atherosclerotic renal artery stenosis.

      Do Patients with Atherosclerotic Renal Artery Stenosis Have “Renovascular Hypertension”?

      In medicine, we should preferably define a disease or clinical entity in a prospective way. In other words, based on certain signs and symptoms, we should be able to make a diagnosis first and then start treatment to cure the disease or alleviate symptoms. If treatment fails, it is likely that we made either the wrong diagnosis or that other patient-related factors precluded recovery. With so-called renovascular hypertension, the situation is different. True renovascular hypertension, that is, hypertension caused by stenosis of the renal artery and allegedly related to activation of the renin-angiotensin-aldosterone system (RAAS), is said to have been present when blood pressure falls to normal levels after successful revascularization. It therefore remains a post hoc diagnosis. If blood pressure does not normalize after revascularization, it is still possible that the patient suffered from renovascular hypertension but that structural vascular changes prevented blood pressure from falling. However, it is equally possible that the patient had essential hypertension with atherosclerotic renal artery stenosis, with or without a renovascular component. Indeed, for renovascular hypertension to occur, the presence of a stenosis is a sine qua non, whereas renal artery stenosis can be present without renovascular hypertension.
      • Safak E.
      • Wilke C.
      • Derer W.
      • et al.
      Long-term follow-up of patients with atherosclerotic renal artery disease.
      Moreover, renal revascularization for atherosclerotic renal artery stenosis improves neither the blood pressure nor cardiovascular or renal endpoints. It follows that we should seriously consider whether the working hypothesis that atherosclerotic renal artery stenosis and renovascular hypertension are synonymous is tenable. Some experts have clearly stated that patients with atherosclerotic renal artery stenosis and hypertension should not be classified as having “renovascular hypertension.”
      • Safian R.D.
      • Madder R.D.
      Refining the approach to renal artery revascularization.

      Goldblatt's Hypothesis and Emerging Concepts

      In the 1930s, Goldblatt et al
      • Goldblatt H.
      • Lynch J.
      • Hanzal R.F.
      • Summerville W.W.
      Studies on experimental hypertension: I. The production of persistent elevation of systolic blood pressure by means of renal ischemia.
      noted that clamping of both renal arteries resulted reliably in hypertension in all the dogs studied in the experiment. However, clamping of a single renal artery resulted in only mild elevation of blood pressure, which subsequently decreased to normotensive levels. Goldblatt et al
      • Goldblatt H.
      • Lynch J.
      • Hanzal R.F.
      • Summerville W.W.
      Studies on experimental hypertension: I. The production of persistent elevation of systolic blood pressure by means of renal ischemia.
      hypothesized that “afferent impulses from the ischemic kidneys may, in some way, bring about increased output of some internal secretion which, by peripheral or central action, may effect general vasoconstriction, and thus raise the blood pressure.” Unilateral severe renal artery stenosis is associated with activation of RAAS, promoting vasoconstriction and increase in peripheral arterial resistance. If the nonstenotic kidney is normal, intravascular volume expansion is limited by the salt and water excretion leading to normalization of blood volume, which in itself tends to normalize the blood pressure. In contrast, with bilateral renal artery stenosis, peripheral artery resistance and blood volume remain high and patients are prone to severe hypertension and volume overload. The experimental studies showed that for the occurrence of a significant hemodynamic change leading to hypertension, the renal artery lumen should be obliterated by at least 75%-80%.
      • May A.G.
      • De Weese J.A.
      • Rob C.G.
      Hemodynamic effects of arterial stenosis.
      When obstruction is severe enough, renal hypoperfusion and sympathetic and neurohormonal changes in the affected kidney lead to activation of the RAAS. However, a critical value for renal artery stenosis in humans is not well defined. Generally a cut-off of >50% or 70% stenosis, with hemodynamic compromise, is used to characterize a significant renal artery disease,
      • Parikh S.A.
      • Shishehbor M.H.
      • Gray B.H.
      • White C.J.
      • Jaff M.R.
      SCAI expert consensus statement for renal artery stenting appropriate use.
      but this does not take into account the factor time. Indeed, in the animal experiments, the stenosis due to clamping of the renal artery is instantaneous and the kidney is forced to mobilize its compensatory systems acutely. In humans, on the other hand, atherosclerotic stenosis of the renal artery develops gradually over a prolonged period.
      • Schreiber M.J.
      • Pohl M.A.
      • Novick A.C.
      The natural history of atherosclerotic and fibrous renal artery disease.
      • Zierler R.E.
      • Bergelin R.O.
      • Isaacson J.A.
      • Strandness Jr., D.E.
      Natural history of atherosclerotic renal artery stenosis: a prospective study with duplex ultrasonography.
      Thus, the kidney can adapt to the insidious decrease in flow by various autoregulatory pathways. Moreover, several other mechanisms such as increased activity of the sympathetic nervous system,
      • Johansson M.
      • Elam M.
      • Rundqvist B.
      • et al.
      Increased sympathetic nerve activity in renovascular hypertension.
      • Pradhan N.
      • Rossi N.F.
      Interactions between the sympathetic nervous system and angiotensin system in renovascular hypertension.
      endothelial dysfunction,
      • Higashi Y.
      • Sasaki S.
      • Nakagawa K.
      • Matsuura H.
      • Oshima T.
      • Chayama K.
      Endothelial function and oxidative stress in renovascular hypertension.
      oxidative stress,
      • Higashi Y.
      • Sasaki S.
      • Nakagawa K.
      • Matsuura H.
      • Oshima T.
      • Chayama K.
      Endothelial function and oxidative stress in renovascular hypertension.
      presence of ischemic nephropathy,
      • Textor S.C.
      • Wilcox C.S.
      Ischemic nephropathy/azotemic renovascular disease.
      or hypertensive end-organ damage are implicated in the pathogenesis of hypertension in patients with renal artery stenosis. Accordingly, the available animal data cannot serve as an adequate model for human renal artery stenosis. Particularly in atherosclerotic renal artery stenosis, the slow evolution of the stenotic process could explain why some patients with well-documented severe renal artery stenosis are not hypertensive.
      • Bazemore T.C.
      • Meredith D.
      • Bumgarner J.M.
      • Stouffer G.A.
      Relation of pulse and systolic and mean blood pressure to severe renal artery stenosis in patients undergoing concurrent coronary and renal angiography.
      Furthermore, patients with atherosclerotic renal artery stenosis and hypertension show similar blood pressure control compared with patients without atherosclerotic renal artery stenosis on long-term follow-up.
      • Safak E.
      • Wilke C.
      • Derer W.
      • et al.
      Long-term follow-up of patients with atherosclerotic renal artery disease.
      It may simply be that these individuals are still able to compensate for the effects of the impediment in flow. In a nutshell, it appears that hypertension is not always an obligatory sequel of renal artery stenosis.

      Characteristics of Atherosclerotic Renal Artery Stenosis

      Atherosclerotic renal artery stenosis is considered one of the manifestations of systemic atherosclerosis rather than an individual disease entity. Its prevalence increases with age, and it affects 30% of patients with coronary artery disease and up to 50% of patients with peripheral arterial disease.
      • Harding M.B.
      • Smith L.R.
      • Himmelstein S.I.
      • et al.
      Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization.
      • Olin J.W.
      • Melia M.
      • Young J.R.
      • Graor R.A.
      • Risius B.
      Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere.
      • Buller C.E.
      • Nogareda J.G.
      • Ramanathan K.
      • et al.
      The profile of cardiac patients with renal artery stenosis.
      It usually involves the ostium and proximal third of the main renal artery and the perirenal aorta. Atherosclerotic renal artery stenosis is commonly encountered in the elderly and in patients with multiple cardiovascular risk factors.
      • Harding M.B.
      • Smith L.R.
      • Himmelstein S.I.
      • et al.
      Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization.
      • Conlon P.J.
      • O'Riordan E.
      • Kalra P.A.
      New insights into the epidemiologic and clinical manifestations of atherosclerotic renovascular disease.
      It is a progressive disease characterized by worsening stenosis,
      • Zierler R.E.
      • Bergelin R.O.
      • Isaacson J.A.
      • Strandness Jr., D.E.
      Natural history of atherosclerotic renal artery stenosis: a prospective study with duplex ultrasonography.
      • Kumar S.K.
      • MacGinley R.
      • Mantha M.
      • et al.
      The CARI guidelines. Natural history and progression of atherosclerotic renal vascular stenosis.
      • Crowley J.J.
      • Santos R.M.
      • Peter R.H.
      • et al.
      Progression of renal artery stenosis in patients undergoing cardiac catheterization.
      and hence, often presents with ischemic nephropathy. Based on the criteria and imaging modality, 12% to 44% of the patients having renal artery stenosis have bilateral stenosis.
      • Rimmer J.M.
      • Gennari F.J.
      Atherosclerotic renovascular disease and progressive renal failure.
      • Derkx F.H.
      • Schalekamp M.A.
      Renal artery stenosis and hypertension.
      The increased cardiovascular risk associated with atherosclerotic renal artery stenosis seems to be associated with the presence of atherosclerosis in other vascular beds, as well as with chronic kidney disease. More often than not, atherosclerotic renal artery stenosis is simply a marker of extensive vascular disease, which, not uncommonly, is a sequence of longstanding essential hypertension. Based on the experimental data (see above), atherosclerotic renal artery stenosis is usually considered hemodynamically significant only when the luminal diameter is reduced by 70% (according to some, 50%) or more. However, given the recruitment of compensatory mechanisms during the gradual development of stenosis, this is not a very convincing criterion. Less advanced stenosis may equally have relevance for kidney function or blood pressure. Several epidemiologic studies have failed to show a direct relationship between the severity of atherosclerotic stenosis lesions and the degree of renal dysfunction.
      • Cheung C.M.
      • Wright J.R.
      • Shurrab A.E.
      • et al.
      Epidemiology of renal dysfunction and patient outcome in atherosclerotic renal artery occlusion.
      • Wright J.R.
      • Shurrab A.E.
      • Cheung C.
      • et al.
      A prospective study of the determinants of renal functional outcome and mortality in atherosclerotic renovascular disease.
      • Suresh M.
      • Laboi P.
      • Mamtora H.
      • Kalra P.A.
      Relationship of renal dysfunction to proximal arterial disease severity in atherosclerotic renovascular disease.
      Conceivably, the intrarenal injury, probably secondary to long-standing hypertension and predating renal artery stenosis development, is the major factor responsible for renal dysfunction in the majority of patients with atherosclerotic renal artery stenosis.
      • Cheung C.M.
      • Hegarty J.
      • Kalra P.A.
      Dilemmas in the management of renal artery stenosis.
      The advantages, limitations, and salient features of routinely performed diagnostic tests for atherosclerotic renal artery stenosis are presented in Table 1.
      Table 1Common Imaging Modalities for Atherosclerotic Renal Artery Stenosis
      TestAdvantagesLimitationsSalient Features
      Doppler ultrasoundNoninvasive, radiation-free, affordable.

      Can readily be used in patients with renal failure or contrast allergy.

      Allows anatomic assessment of the renal arteries and hemodynamic measurements through Doppler.
      Time consuming, highly operator based, technically challenging in obese patient and in presence of distended bowel gas.

      Accessory renal arteries may not be adequately visualized or identified on ultrasound.

      High operator variability could drastically influence the accuracy of the test.
      Several indices were devised based on peak systolic velocity, renal-aortic ratio, renal resistive index to determine significant RAS.
      Computed tomography angiographyExcellent special and temporal resolution of renal arteries and surrounding structures.

      Time-efficient, can better visualize stented arteries and less amenable to motion artifact.
      Use of iodinated contrast and ionized radiation.

      Unable to perform physiologic assessment of RAS.

      Severe renal artery calcification may obscure luminal narrowing limiting evaluation of stenosis.
      High sensitivity and specificity to detect RAS.
      Magnetic resonance angiographyHigh-quality noninvasive anatomic images of the renal arteries and surrounding structures.

      Less operator dependence.
      High cost.

      Contraindicated in patients with ferromagnetic implants and renal dysfunction with eGFR <30 mL/min/1.73 m2 (risk of gadolinium-related nephrogenic systemic sclerosis).

      Cannot be used to evaluate in-stent stenosis.
      High sensitivity and specificity to detect RAS.

      Functional assessment can be done using various “pulse sequences”.
      Catheter renal angiographyDirect hemodynamic measurements and if needed, revascularization could be performed immediately.

      Digital subtraction angiography improves contrast resolution and limits contrast use.
      Use of iodinated contrast and ionized radiation.

      Invasive modality.

      Associated risks of sedation, access related complications, atheroembolic disease, bleeding, dissection, and vascular injury sometimes requiring surgery to repair.
      “Gold standard” for diagnosis of RAS.
      eGFR = estimated glomerular filtration rate; RAS = renal artery stenosis.

      Management of Atherosclerotic Renal Artery Stenosis

      The management of atherosclerotic renal artery stenosis focuses on control of hypertension and preservation of renal function with a long-term aim of reducing cardiovascular and renal outcomes. Treatment options include medical therapy, surgical reconstruction, and revascularization with or without stenting.

      Medical Therapy

      Medical therapy is the cornerstone in the treatment of atherosclerotic renal artery stenosis. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • et al.
      ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
      provide a Class I indication to angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), calcium channel blockers, and beta-blockers for the treatment of hypertension associated with renal artery stenosis. However, no randomized controlled trial has evaluated the efficacy of different medical regimens in patients with atherosclerotic renal artery stenosis. Experimental and clinical studies have shown that ACEI effectively reduces blood pressure in patients with unilateral renal artery stenosis.
      • Hodsman G.P.
      • Brown J.J.
      • Cumming A.M.
      • et al.
      Enalapril (MK421) in the treatment of hypertension with renal artery stenosis.
      • Schwietzer G.
      • Oelkers W.
      The antihypertensive effect of captopril in severe essential, renovascular, renal and transplant renovascular hypertension.
      • Hackam D.G.
      • Spence J.D.
      • Garg A.X.
      • Textor S.C.
      Role of renin-angiotensin system blockade in atherosclerotic renal artery stenosis and renovascular hypertension.
      Blockade of the renin-angiotensin cascade with ACEI/ARB not only serves to control blood pressure but also confers survival benefit on patients with atherosclerotic renal artery stenosis. In a cohort study of 195 patients, renal revascularization did not affect mortality, but ACEI was associated with decreased long-term mortality.
      • Losito A.
      • Errico R.
      • Santirosi P.
      • Lupattelli T.
      • Scalera G.B.
      • Lupattelli L.
      Long-term follow-up of atherosclerotic renovascular disease. Beneficial effect of ACE inhibition.
      In a prospective single-center study of 621 atherosclerotic renal artery stenosis patients, ACEI/ARB was associated with decreased mortality at a median follow-up of 3.1 years.
      • Chrysochou C.
      • Foley R.N.
      • Young J.F.
      • Khavandi K.
      • Cheung C.M.
      • Kalra P.A.
      Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease.
      Similarly, in a population-based cohort of 3570 elderly patients with renovascular hypertension, patients who received ACEI/ARB had a lower incidence of death and cardiovascular events and a higher incidence of acute renal failure, but a lower incidence of long-term dialysis than patients who did not receive such therapy.
      • Hackam D.G.
      • Duong-Hua M.L.
      • Mamdani M.
      • et al.
      Angiotensin inhibition in renovascular disease: a population-based cohort study.
      Tullis et al
      • Tullis M.J.
      • Caps M.T.
      • Zierler R.E.
      • et al.
      Blood pressure, antihypertensive medication, and atherosclerotic renal artery stenosis.
      showed that only ACEIs, and not other antihypertensive drugs, were associated with reductions in systolic and diastolic blood pressure in this setting. Based on the available data, ACEI/ARB is the preferred therapy unless there are any contraindications for its use. Most patients with unilateral renal artery stenosis tolerate RAAS inhibition with little, if any, change in renal function; nevertheless, renal function and serum potassium levels must be monitored closely.
      • van de Ven P.J.
      • Beutler J.J.
      • Kaatee R.
      • Beek F.J.
      • Mali W.P.
      • Koomans H.A.
      Angiotensin converting enzyme inhibitor-induced renal dysfunction in atherosclerotic renovascular disease.
      • Bicket D.P.
      Using ACE inhibitors appropriately.
      There are no robust data for calcium channel blockers and beta-blockers in patients with renal artery stenosis. Their utility is largely based on the extrapolation of results from essential hypertension studies. However, patients with renal artery stenosis often have resistant hypertension and require multiple antihypertension agents. Calcium channel blockers and beta-blockers could be instrumental in patients not tolerating ACEI/ARBs or as additive therapy in resistant hypertension. In addition, the use of dual calcium channel blockers (dihydropyridine and nondihydropyridine) and mineralocorticoid receptor antagonists (spironolactone and eplerenone) have been proposed when existing multidrug regimens were inadequate to control hypertension.
      • Alviar C.L.
      • Devarapally S.
      • Nadkarni G.N.
      • et al.
      Efficacy and safety of dual calcium channel blockade for the treatment of hypertension: a meta-analysis.
      • Calhoun D.A.
      • Jones D.
      • Textor S.
      • et al.
      Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
      Management strategies should be on an individual basis, with the primary aim of blood pressure control but using fewer medications and a regimen that minimizes adverse effects.
      For patients with atherosclerotic renal artery stenosis, aspirin, lipid-lowering drugs, smoking cessation, weight, and diabetes control are essential to limit progression of atherosclerosis. While no randomized control trial has specifically looked into the role of statins in patients with renal artery stenosis, the cardiovascular benefits of statin seen in patients with coronary artery disease, hypertension, or renal dysfunction are most likely applicable in management of atherosclerotic renal artery stenosis. Statins were an important part of medical therapy in the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL),
      • Wheatley K.
      • Ives N.
      • et al.
      ASTRAL Investigators
      Revascularization versus medical therapy for renal-artery stenosis.
      Stenting in Renal Dysfunction Caused by Atherosclerotic Renal Artery Stenosis (STAR),
      • Bax L.
      • Woittiez A.J.
      • Kouwenberg H.J.
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL)
      • Cooper C.J.
      • Murphy T.P.
      • Cutlip D.E.
      • et al.
      Stenting and medical therapy for atherosclerotic renal-artery stenosis.
      trials. In the STAR trial,
      • Bax L.
      • Woittiez A.J.
      • Kouwenberg H.J.
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      patients were given 10-20 mg of atorvastatin as tolerated, regardless of lipid levels. In the CORAL trial,
      • Cooper C.J.
      • Murphy T.P.
      • Cutlip D.E.
      • et al.
      Stenting and medical therapy for atherosclerotic renal-artery stenosis.
      statin was prescribed as a combination agent amlodipine–atorvastatin, with the dose adjusted based on blood pressure and lipid status.

      Surgical Revascularization

      Surgical revascularization includes aortorenal bypass, extra-anatomical bypass procedures, unilateral nephrectomy, extracorporeal microvascular reconstruction, endarterectomy, and atherectomy. Surgical revascularization techniques do not confer better outcomes than medical therapy or percutaneous revascularization
      • Uzzo R.G.
      • Novick A.C.
      • Goormastic M.
      • et al.
      Medical versus surgical management of atherosclerotic renal artery stenosis.
      • Weibull H.
      • Bergqvist D.
      • Bergentz S.E.
      • et al.
      Percutaneous transluminal renal angioplasty versus surgical reconstruction of atherosclerotic renal artery stenosis: a prospective randomized study.
      • Balzer K.M.
      • Pfeiffer T.
      • Rossbach S.
      • et al.
      Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD).
      (Table 2). Due to the risks and major complications associated with surgery, when intervention is contemplated, percutaneous revascularization is commonly preferred. Surgery may be indicated for fibromuscular dysplastic renal artery stenosis, in particular when hypertension is of recent onset or with worsening renal function.
      • Persu A.
      • Giavarini A.
      • Touze E.
      • et al.
      European consensus on the diagnosis and management of fibromuscular dysplasia.
      A surgical approach may also be considered in case of complex lesions such as aneurysms.
      Table 2Randomized Controlled Trials of Various Management Strategies in Patients with Atherosclerotic Renal Artery Stenosis
      TrialPatient CriterianComparisonPrimary EndpointsFollow-upResults
      Surgery vs medical therapy alone
       Uzzo et al, 2002
      • Uzzo R.G.
      • Novick A.C.
      • Goormastic M.
      • et al.
      Medical versus surgical management of atherosclerotic renal artery stenosis.
      RAS (>75% stenosis) with azotemia52Medical therapy (n = 27) vs medical therapy + surgery (n = 25)Poorly controlled hypertension, renal events, cardiovascular events74 moNo significant difference in mortality or incidence of renal and cardiovascular events between the 2 treatment groups
      Surgery vs PTA
       Weibull et al, 1993
      • Weibull H.
      • Bergqvist D.
      • Bergentz S.E.
      • et al.
      Percutaneous transluminal renal angioplasty versus surgical reconstruction of atherosclerotic renal artery stenosis: a prospective randomized study.
      Unilateral RAS (stenosis with a diameter ≤2 mm and a renal vein renin ratio ≥1.5)58Surgery (n = 29) vs PTA without stenting (n = 29)Technical success, primary and secondary patency, and effects on blood pressure and renal function2 yNo significant difference in restenosis, blood pressure, or renal function
       Balzer et al, 2009
      • Balzer K.M.
      • Pfeiffer T.
      • Rossbach S.
      • et al.
      Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD).
      Unilateral or bilateral, ostial RAS (>70% stenosis)50Surgery (n = 27) vs PTA with stenting (n = 23)Technical success, primary and secondary patency, and effects on blood pressure and renal function4 yNo significant difference in mortality, restenosis, improvement of blood pressure, or renal function
      PTA vs medical therapy
       Plouin et al, 1998 (EMMA)
      • Plouin P.F.
      • Chatellier G.
      • Darne B.
      • et al.
      Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group.
      Unilateral RAS (stenosis ≥75% or ≥60% with a positive lateralization test), DBP >95 mm Hg, Cr clearance <50 mL/min49PTA without stenting
      Stenting in 2 patients.
      (n = 23) vs medical therapy (n = 26)
      24-hour ambulatory blood pressure6 moNo significant difference in ambulatory blood pressure in both groups. Patients with angioplasty had higher complications, required fewer antihypertensive agents
       Webster et al, 1998
      • Webster J.
      • Marshall F.
      • Abdalla M.
      • et al.
      Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle Renal Artery Stenosis Collaborative Group.
      Unilateral or bilateral RAS (≥50 stenosis), DBP >95 mm Hg on ≥2 antihypertensives55PTA without stenting (n = 25) vs medical therapy (n = 30)Office blood pressure6 moPTA resulted in significant reduction in blood pressure in patients with bilateral RAS, but not in unilateral RAS. No difference in major cardiovascular events or renal function
       Van Jaarsveld et al, 2000 (DRASTIC)
      • van Jaarsveld B.C.
      • Krijnen P.
      • Pieterman H.
      • et al.
      The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N. Engl.
      Unilateral or bilateral RAS (≥50 stenosis), DBP >95 mm Hg on ≥2 antihypertensives, serum Cr <2.3 mg/dL106PTA without stenting (n = 56) vs medical therapy (n = 50)Office systolic and diastolic blood pressure1 yNo significant difference in systolic and diastolic blood pressure; PTA required fewer antihypertensive agents
      PTA vs PTA with stenting
       van de Ven et al, 1999
      • van de Ven P.J.
      • Kaatee R.
      • Beutler J.J.
      • et al.
      Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial.
      Unilateral or bilateral, ostial RAS (>50% stenosis) and positive renography or an increase in serum Cr ≥20% on ACE inhibitor84PTA alone (n = 42) vs PTA with stenting (n = 42)Restenosis6 moPTA with stenting showed higher success rates and lower restenosis rates. No difference in systolic and diastolic blood pressure or renal function
      PTA with stenting vs medical therapy
       Bax et al, 2009 (STAR)
      • Bax L.
      • Woittiez A.J.
      • Kouwenberg H.J.
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      RAS (>50% stenosis), impaired renal function140PTA with stenting (n = 64) vs medical therapy (n = 76)>20% decrease in Cr clearance2 yNo significant difference in renal function, blood pressure, cardiovascular mortality, and morbidity
       ASTRAL Investigators et al, 2009 (ASTRAL)
      • Wheatley K.
      • Ives N.
      • et al.
      ASTRAL Investigators
      Revascularization versus medical therapy for renal-artery stenosis.
      RAS806PTA with stenting (n = 403) vs medical therapy (n = 403)Change in renal function34 moNo significant difference in renal function, blood pressure, cardiovascular events, and mortality
       Cooper et al, 2014 (CORAL)
      • Cooper C.J.
      • Murphy T.P.
      • Cutlip D.E.
      • et al.
      Stenting and medical therapy for atherosclerotic renal-artery stenosis.
      RAS (stenosis >80% or >60% stenosis with a systolic pressure gradient >20 mm Hg)947PTA with stenting (n = 459) vs medical therapy (n = 472)Composite of death from cardiovascular or renal causes, stroke, MI, CHF hospitalization, renal insufficiency, or permanent RRT43 moNo significant difference in the occurrence of primary composite endpoint, any of the individual components of the composite endpoints, or all-cause mortality
      ACE = angiotensin-converting enzyme; ASTRAL = Angioplasty and Stenting for Renal Artery Lesions trial; CHF = congestive heart failure; CORAL = Cardiovascular Outcomes in Renal Atherosclerotic Lesions trial; Cr = serum creatinine; DBP = diastolic blood pressure; DRASTIC = Dutch Renal Artery Stenosis Intervention Cooperative trial; EMMA = Essai Multicentrique Medicaments vs Angioplastie trial; MI = myocardial infarction; n = total number of patients in the trial; PTA = percutaneous transluminal renal artery angioplasty; RAS = renal artery stenosis; RRT = renal replacement therapy; SBP = systolic blood pressure; STAR = Stenting in Renal Dysfunction Caused by Atherosclerotic Renal Artery Stenosis.
      Stenting in 2 patients.

      Percutaneous Revascularization

      Percutaneous transluminal renal angioplasty with or without stenting has yielded disappointing results.
      • Plouin P.F.
      • Chatellier G.
      • Darne B.
      • et al.
      Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group.
      • Webster J.
      • Marshall F.
      • Abdalla M.
      • et al.
      Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle Renal Artery Stenosis Collaborative Group.
      • van Jaarsveld B.C.
      • Krijnen P.
      • Pieterman H.
      • et al.
      The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N. Engl.
      • van de Ven P.J.
      • Kaatee R.
      • Beutler J.J.
      • et al.
      Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial.
      Randomized control trials published to date have failed to show any clinical benefit of renal artery stenting over medical therapy in the treatment of atherosclerotic renal artery stenosis (Table 2). While reviewing these trials, one has to equally consider the limitations of these trials that include an inadequate number of participants, nonstandardized inclusion criteria, exclusion of patients with “high-risk” features, use of only visual assessment of stenosis severity, patient enrollment delays, protocol revisions, high cross-over rates (in earlier trials), and low event rates. In a recent meta-analysis comparing all trials on revascularization vs medical therapy, renal artery revascularization was not associated with either an improvement in systolic blood pressure or a reduction in adverse cardiovascular or renal outcomes.
      • Bavry A.A.
      • Kapadia S.R.
      • Bhatt D.L.
      • Kumbhani D.J.
      Renal artery revascularization: updated meta-analysis with the CORAL trial.
      Although the need for antihypertensive medication was reduced by renal revascularization, it was not a practically meaningful reduction (number of medications was 3.2 vs 3.0). In addition, challenges still remain in terms of technical outcomes such as in-stent restenosis, with approximately 3.5% to 17% restenosis rates
      • Rastan A.
      • Krankenberg H.
      • Muller-Hulsbeck S.
      • et al.
      Improved renal function and blood pressure control following renal artery angioplasty: the renal artery angioplasty in patients with renal insufficiency and hypertension using a dedicated renal stent device study (PRECISION).
      • Rocha-Singh K.
      • Jaff M.R.
      • Rosenfield K.
      Aspire-2 Trial Investigators. Evaluation of the safety and effectiveness of renal artery stenting after unsuccessful balloon angioplasty: the ASPIRE-2 study.
      • Stone P.A.
      • Srivastava M.
      • Campbell J.E.
      • et al.
      A 10-year experience of infection following carotid endarterectomy with patch angioplasty.
      and vascular complications.
      • Steichen O.
      • Amar L.
      • Plouin P.F.
      Primary stenting for atherosclerotic renal artery stenosis.
      The indications for renal artery revascularization for hemodynamically significant renal artery stenosis per 2006 ACC/AHA guidelines
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • et al.
      ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
      are shown in Table 3. The ACC/AHA has not revised or updated the guidelines for renal artery revascularization since then. The guideline did not mention any criteria to define “hemodynamically significant” renal artery stenosis. Similarly, the 2011 ESC guidelines
      • Tendera M.
      • Aboyans V.
      • Bartelink M.L.
      • et al.
      ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC).
      on renal artery stenosis lack clarity (Table 3). The guideline recommends renal revascularization for renal artery stenosis with impaired renal function, however, it is unclear what constitutes “impaired renal function” amenable to revascularization in such patients.
      Table 3Various Guideline Recommendations for Renal Revascularization in Renal Artery Stenosis
      Hemodynamically significant RAS with:ACC/AHA Recommendations
       Recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edemaClass I (Level of evidence B)
       Unstable anginaClass IIa (Level of evidence B)
       Accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medicationClass IIa (Level of evidence B)
       Progressive chronic kidney disease with bilateral RAS or an RAS to a solitary functioning kidneyClass IIa (Level of evidence B)
       Chronic renal insufficiency with unilateral RASClass IIb (Level of evidence C)
       Asymptomatic unilateral, bilateral or solitary viable kidneyClass IIb (Level of evidence C)
      RAS with:ESC recommendations
       Symptomatic ARAS >60%Class IIb (Level of evidence A)
       Ostial ARAS, in the case for indication for angioplasty (PTA with stenting)Class I (Level of evidence B)
       Impaired renal functionClass IIb (Level of evidence B)
       Unexplained recurrent congestive heart failure or sudden pulmonary edema and preserved systolic left ventricular function (PTA with or without stenting)Class IIb (Level of evidence C)
      ACC/AHA = American College of Cardiology/American Heart Association; ARAS = atherosclerotic renal artery stenosis; ESC = European Society of Cardiology; PTA = percutaneous transluminal renal angioplasty; RAS = renal artery stenosis.

      Pickering Syndrome

      Pickering Syndrome is a clinical conundrum comprising hypertension, flash pulmonary edema, and bilateral renal artery stenosis.
      • Messerli F.H.
      • Bangalore S.
      • Makani H.
      • et al.
      Flash pulmonary oedema and bilateral renal artery stenosis: the Pickering syndrome.
      In 1988, this clinical entity was first described by Thomas Pickering and colleagues in a series of 11 hypertensive patients with bilateral atheromatous renovascular disease, who presented with a history of multiple episodes of pulmonary edema.
      • Pickering T.G.
      • Herman L.
      • Devereux R.B.
      • et al.
      Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation.
      In the acute phase, Pickering Syndrome can be treated effectively by maintaining adequate oxygenation and reducing ventricular preload using diuresis. However, aggressive medical treatment of flash pulmonary edema in patients with bilateral renal artery stenosis usually will cause a decline in renal function, and hyperkalemia may ensue. Renal revascularization is the treatment of choice.
      • Messerli F.H.
      • Bangalore S.
      • Makani H.
      • et al.
      Flash pulmonary oedema and bilateral renal artery stenosis: the Pickering syndrome.
      Currently, Pickering Syndrome may be one of the few better-documented indications for renal revascularization.
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • et al.
      ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.
      • Tendera M.
      • Aboyans V.
      • Bartelink M.L.
      • et al.
      ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC).

      Why Does Revascularization Confer so Little Benefit?

      Even though revascularization may make hypertension a bit better treatable, the results of the trials do not live up to the expectations. Of course this could mean that our invasive treatments are not effective enough. However, an alternative explanation may be that the wrong type of patient has been included in the trials. For instance, no distinction was made between patients in whom “true” renovascular hypertension was present and patients in whom atherosclerotic renal artery stenosis developed secondary to long-standing hypertension. In addition, most trials enrolled patients in whom renal function was already significantly impaired. Once structural ischemic damage occurs to the kidneys, it is very unlikely that renal function will recover after restoration of flow.
      • Saad A.
      • Herrmann S.M.
      • Crane J.
      • et al.
      Stent revascularization restores cortical blood flow and reverses tissue hypoxia in atherosclerotic renal artery stenosis but fails to reverse inflammatory pathways or glomerular filtration rate.

      Clinical Implications: “Routine” Search for Atherosclerotic Renal Artery Stenosis

      Given the available information, the question arises as to whether or not the clinician should actively search for renal artery stenosis. In general, when there is no specific treatment option for a certain disease, there is no point in pursuing an extensive diagnostic work-up. In the case of difficult-to-treat hypertension, it is rather difficult to make an unequivocal recommendation. At least when there is an extensive atherosclerotic disease, one cannot expect cure from revascularization, although there is a chance that antihypertensive therapy can be slightly reduced. Thus, one has to weigh in each patient whether the potential small benefit from revascularization is worth the risk of diagnostic procedures and that of the revascularization itself. It is conceivable that in cases with less advanced disease, the restoration of flow confers a greater benefit, but so far there is no such evidence from trials.
      • Wheatley K.
      • Ives N.
      • et al.
      ASTRAL Investigators
      Revascularization versus medical therapy for renal-artery stenosis.
      • Bax L.
      • Woittiez A.J.
      • Kouwenberg H.J.
      • et al.
      Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.
      • Cooper C.J.
      • Murphy T.P.
      • Cutlip D.E.
      • et al.
      Stenting and medical therapy for atherosclerotic renal-artery stenosis.
      When there are no signs of atherosclerotic disease, it is still possible that a patient has fibromuscular dysplasia. In view of the positive results of revascularization in fibromuscular dysplasia, it is worthwhile to search for this condition when the clinical suspicion is high.
      • Olin J.W.
      • Gornik H.L.
      • Bacharach J.M.
      • et al.
      Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association.

      Conclusion and Perspective

      From a clinical point of view, a clear distinction should be made between hypertension associated with atherosclerotic renal artery stenosis and hypertension caused by renal artery stenosis through activation of the RAAS. The central tenet of many years, to search for renovascular hypertension in patients with new-onset or resistant hypertension, has crumbled. Most patients with atherosclerotic renal artery stenosis do not have a form of hypertension that is remediable or even improved by angioplasty; to expose them to the cost, inconvenience, and risk of a diagnostic work-up adds up to little more than a wild goose chase. The role of the hypertension specialists and nephrologists will be to identify the select subgroups of patients at risk of progressive ischemic nephropathy and end-organ damage (pulmonary edema, recurrent heart failure, refractory/accelerated/malignant hypertension) at a time when they still may benefit from revascularization. However, with very few exceptions, medical therapy with antihypertensives and statins remains the cornerstone for the management of patients with atherosclerotic renal artery stenosis and hypertension.

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