Atherosclerotic Renal Artery Stenosis: Overtreated but Underrated?
Stephen C. Textor
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
Correspondence: Dr. Stephen C. Textor, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905. Phone: 507-284-4083; Fax: 507-284-1161; E-mail: textor.stephen{at}mayo.edu
Despite evidence of only moderate clinical benefit, applicationof renal endovascular stent procedures has increased at leastfour-fold in the past decade. Medicare is reviewing nationalcoverage regarding reimbursement, questioning whether outcomedata warrant many of these procedures. Several prospective,randomized trials are now in progress to compare outcomes withoptimized medical therapy with and without stenting. Currentimaging methods establish primarily the presence and severityof vascular occlusive disease. Optimal treatment for individualpatients remains in flux and is reviewed here. Most important,nephrologists await development of tools to predict reliablywhen renal parenchymal injury is beyond recovery and/or whenrevascularization can produce meaningful salvage of kidney function.
A remarkable drama unfolded in 2007 regarding renovascular disease.The Center for Medicaid and Medicare Services (CMS) conveneda meeting of its medical advisory group regarding treatmentof renovascular disease, specifically atherosclerotic renalartery stenosis (RAS). The introductory statement read as follows:"In view of the uncertainty regarding optimal strategies forevaluation and management of atherosclerotic RAS, as well asthe controversy about the risks and benefits of treatment, theCMS internally generated in February 2007 a national coverageanalysis to examine the best treatment of RAS."
That CMS is reviewing its payment coverage for atheroscleroticRAS undoubtedly reflects the increase in endovascular stentingprocedures for Medicare beneficiaries, rising from 7660 in 1996to 18,520 in 2000.1 Estimates at the meeting suggested thisincreased further to more than 35,000 in 2005. The largest portionof this increase derives from procedures undertaken by cardiologists.1Recent guidelines from professional organizations based on admittedlyweak data lend support to the application of interventionalvascular procedures into the renal arteries and inclusion ofrenal arteriography as part of coronary angiographic procedures.2,3As part of their review, CMS commissioned an analysis of publishedinformation regarding the benefits of revascularizing the kidneyfor atherosclerotic RAS by the Agency for Healthcare Researchand Quality. The results of this analysis were published inDecember 2006. The authors of this review concluded that availableinformation was insufficient to support benefits regarding mortality,progressive kidney disease, or cardiovascular events.4 Thus,the published literature cannot support the observed, massiveexpansion of endovascular intervention.
During the same time interval, at least four prospective, randomizedtrials for atherosclerotic RAS were started to examine the roleof medical therapy alone as compared with medical therapy plusstent revascularization. In the United States, the NationalHeart, Lung, and Blood Institute of the National Institutesof Health is funding the Cardiovascular Outcomes for Renal AtheroscleroticLesions (CORAL) trial. This trial seeks to randomly assign 1080patients to "optimal medical therapy" with or without renalartery stenting and evaluate clinical events including death,stroke, coronary artery disease events, congestive heart failure,kidney failure, and uncontrolled hypertension.5 A central premiseof CORAL is that neurohormonal activation (mainly of the renin-angiotensinand sympathoadrenergic system) largely determines the morbidityfrom RAS. This trial has had difficulty meeting enrollment goalsdespite the increasing application of stent procedures. Thatthe National Institutes of Health and more than 70 institutionalreview boards accept that management of atherosclerotic RASis currently in "equipoise" regarding the added value of renalrevascularization again challenges the expanding use of interventionaltherapy. How CMS will ultimately cover reimbursement for renalartery stenting has yet to be settled.
How did we reach this divergence between medical subspecialties,and how does it affect clinical nephrology? Renovascular diseasehas always presented troublesome issues, different in fundamentalrespects from vascular occlusive disease affecting the heart,brain, or extremities. The interactions between vascular diseaseand kidney function, arterial pressure, and volume control arecomplex. Clinical syndromes associated with RAS now arise morefrequently than ever for patients who have other vascular diseaseinvolving the coronary and peripheral vascular beds.6 Some estimatethat up to 5% of patients who reach ESRD may have renal arterystenosis as their primary kidney disorder.7 This lingering concernmeans that for any single patient with worsening hypertensionand declining kidney function, nephrologists are forced to considerthe potential role of large-vessel atherosclerotic disease.Although many patients can be treated effectively and safelywith current medical therapy, selection of individuals who willbenefit from renal revascularization and for whom its risksare warranted poses a major clinical challenge.
In some respects, these developments reflect stunning successesof basic and clinical research. Diagnostic imaging and therapeuticoptions have advanced rapidly in the past two decades. Majormilestones in the evolution of our understanding of renovascularhypertension and ischemic nephropathy are summarized in Figure 1.Early observations that placement of a renal artery clip producesa rise in systemic arterial pressure was among the first evidencefirmly linking the kidney to cardiovascular control.8 For manyyears, patients with severe hypertension were examined for thepresence of renovascular hypertension with the goal of eitherremoving the offending kidney or revascularizing the kidneyusing surgical techniques. Available antihypertensive drug therapy(mainly sympatholytic agents such as methyldopa, reserpine,or guanethidine) often fail to control dangerous, sometimes"malignant phase" hypertension in such individuals. In extremecases, patients underwent bilateral nephrectomy as a life-savingmeasure to prevent episodes of recurrent hypertensive encephalopathyor pulmonary edema.6 These reports coincide with the introductionof renal replacement therapy with dialysis.
Figure 1. Milestones in identification and treatment of renovascular hypertension and ischemic nephropathy: Renal revascularization was possible first in the 1960s and was the only effective antihypertensive therapy for severe renovascular disease. The introduction of agents that block the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARB]) changed the landscape dramatically. Surgery has been mostly replaced by endovascular stent therapy for atherosclerotic disease. The introduction of intensive medical therapy including ACE/ARB and calcium channel blockers, plus statins, aspirin, and diabetes management, has allowed effective therapy for many patients considered untreatable before. Recent small, short-term, prospective trials have failed to identify major benefits of revascularization as compared with medical therapy (see text). Larger, prospective trials are enrolling higher risk patients who will be followed for longer periods of time. HTN, hypertension; STAR, STent placement and BP and lipid-lowering for progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery; RAVE, Renal Athersosclerotic reVascularization Evaluation; PTRA, Percutaneous Transluminal Renal Angioplasty.
Studies of the mechanisms by which a renal artery clip produceshypertension paved the way to define the renin-angiotensin-aldosteronesystem (RAAS) and were fundamental to development of pharmacologictools to block this system. The first agents available (Sar-1-Ala-8-angiotensin,or saralasin) to block the angiotensin receptor were targetedprimarily at renovascular hypertension. Since then, many studieshave identified complex interactions between angiotensin andkidney function, vascular remodeling, recruitment of additionalpressor mechanisms, and neurohormonal activation.9 Studies ofgenetic knockout models free of the angiotensin receptor (AT1aknockout) extend these observations to demonstrate criticalroles for both kidney and systemic receptor activation for angiotensinII–dependent hypertension.10 The development of oral agentsthat interrupt the RAAS provided for the first time well-tolerateddrugs that improved BP control and reduced cardiovascular riskfor patients with renovascular hypertension. Wider applicationof renin-angiotensin system blockade now provides hope thatmany forms of progressive kidney injury, congestive heart failure,and vascular disease may be relieved to a degree never imaginedby those first studying renovascular hypertension.
RAAS blockade, statins, and antiplatelet therapy are now bedrocksfor the clinical management of atherosclerotic disease, includingRAS.11 Although the benefits of restoring blood flow to thekidney may seem to be obvious, vascular stenting carries well-recognizedrisks of atheroembolic disease, restenosis, and local complications,such as vessel dissection and thrombosis, that remain problematic12;therefore, whether endovascular stenting provides additionalbenefit beyond meticulous management of BP, blockade of neurohormonalactivation, and management of other risk factors is controversial.This is the basic question underlying current prospective treatmenttrials such as CORAL and ASTRAL (Angioplasty and STent for RenalArtery Lesions). Nephrologists have moved toward a more conservativeclinical stance in recent years, perhaps as a pragmatic counterweightto enthusiastic interventional cardiologists and radiologists.7The challenge facing thoughtful clinicians in this arena isto prevent such conservatism from interfering with the bestinterests of patients who could benefit from renal artery revascularizationto a major degree.
Among the problematic features of atherosclerotic RAS has beenthe poorly defined relationship between the presence of large-vesselocclusive disease and target injury in the kidney. Unlike fibromusculardisease, the degree of severity of vascular occlusion in atherosclerosisbears little relationship to measured blood flow, kidney volume,degree of fibrosis, or GFR.6 These observations provide thebasis for experimental studies of interactions between vascularocclusion and other vectors of kidney injury, including endothelialdysfunction,13 tissue oxidative stress,14 and the atheroscleroticmilieu produced by dyslipidemia (Table 1).15 It is unclear whetherhigh-grade vascular occlusion induces repeated episodes of transientkidney ischemia that activate profibrotic pathways similar toother acute models. How to identify regional "ischemia" in livinganimals is not yet certain. Recent studies using blood oxygenlevel dependent magnetic resonance indicate that poststenotickidneys have a range of metabolic activity and oxygen consumptionlinked to active solute transport.16 Our initial studies suggestthat total vascular occlusion and loss of filtration is associatedwith reduced levels of deoxyhemoglobin and minimal change duringfurosemide administration.17 By contrast, viable, functioningkidneys beyond an atherosclerotic lesion have relatively highlevels of accumulated deoxyhemoglobin, particularly in the medulla.Such kidneys can respond briskly to reduce deoxyhemoglobin levelsafter intravenous administration of furosemide to reduce solutetransport. Whether elevations of deoxyhemoglobin and furosemide-suppressibleoxygen consumption induce cytokine release or toxic oxidativestress is an important question that warrants further study.
Table 1. Interactive mechanisms underlying hypertension and kidney injury in atherosclerotic RASa
It is almost certain that many, if not most, patients now beingsubjected to endovascular stenting of the renal arteries haveonly limited benefit, regarding either BP response or improvementin kidney function.7 Equally important to recognize is thata subset of patients with "critical" renal artery stenosis standto have major clinical benefit from restoring kidney perfusionand major adverse outcomes if not detected and treated.18 Summarizedin Table 2 are a series of clinical issues that address whetherpatients are likely to warrant renal revascularization. Mostimaging procedures focus on the first two items—the anatomicseverity and approachability of renal vascular lesions. It islikely that the third and fourth items—diagnostic measuresto evaluate the role of vascular occlusive lesions in generatingdisease and the likelihood of clinical benefit after restorationof vessel patency—are more important. Further studiesin the renal vasculature should be aimed at defining these characteristicsmore fully. A recognized drawback of clinical treatment trials,of course, is the intermixture of high-risk and low-risk patientsinto the "average" of the entire cohort.19 Although prospective,randomized trials are essential, clinicians remain in sore needof better tools to identify renal parenchyma at true risk for"ischemic injury" and to identify when kidney function can be(or can no longer be) improved with renal revascularization.
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Abstract
Introduction
