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Atherosclerotic Renal Artery : Overtreated but Underrated?

Stephen C. Textor

Division of Nephrology and , Mayo Clinic, Rochester, Minnesota

ABSTRACT amine the role of medical therapy alone Despite evidence of only moderate clinical benefit, application of renal endovas- as compared with medical therapy plus cular stent procedures has increased at least four-fold in the past decade. Medi- stent revascularization. In the United care is reviewing national coverage regarding reimbursement, questioning States, the National Heart, Lung, and whether outcome data warrant many of these procedures. Several prospective, Blood Institute of the National Institutes randomized trials are now in progress to compare outcomes with optimized of Health is funding the Cardiovascular medical therapy with and without stenting. Current imaging methods establish Outcomes for Renal Atherosclerotic Le- primarily the presence and severity of vascular occlusive disease. Optimal treat- sions (CORAL) trial. This trial seeks to ment for individual patients remains in flux and is reviewed here. Most important, randomly assign 1080 patients to “opti- nephrologists await development of tools to predict reliably when renal parenchy- mal medical therapy” with or without re- mal injury is beyond recovery and/or when revascularization can produce mean- nal artery stenting and evaluate clinical ingful salvage of function. events including death, stroke, coronary artery disease events, congestive heart J Am Soc Nephrol 19: 656–659, 2008. doi: 10.1681/ASN.2007111204 failure, , and uncontrolled hypertension.5 A central premise of CORAL is that neurohormonal activa- A remarkable drama unfolded in 2007 cedures undertaken by cardiologists.1 tion (mainly of the -angiotensin regarding renovascular disease. The Recent guidelines from professional or- and sympathoadrenergic system) largely Center for Medicaid and Medicare Ser- ganizations based on admittedly weak determines the morbidity from RAS. vices (CMS) convened a meeting of its data lend support to the application of This trial has had difficulty meeting en- medical advisory group regarding treat- interventional vascular procedures into rollment goals despite the increasing ap- ment of renovascular disease, specifically the renal arteries and inclusion of renal plication of stent procedures. That the atherosclerotic renal artery stenosis arteriography as part of coronary angio- National Institutes of Health and more (RAS). The introductory statement read graphic procedures.2,3 As part of their re- than 70 institutional review boards ac- as follows: “In view of the uncertainty re- view, CMS commissioned an analysis of cept that management of atherosclerotic garding optimal strategies for evaluation published information regarding the RAS is currently in “equipoise” regard- and management of atherosclerotic RAS, benefits of revascularizing the kidney for ing the added value of renal revascular- as well as the controversy about the risks atherosclerotic RAS by the Agency for ization again challenges the expanding and benefits of treatment, the CMS inter- Healthcare Research and Quality. The use of interventional therapy. How CMS nally generated in February 2007 a na- results of this analysis were published in will ultimately cover reimbursement for tional coverage analysis to examine the December 2006. The authors of this re- renal artery stenting has yet to be settled. best treatment of RAS.” view concluded that available informa- How did we reach this divergence be- That CMS is reviewing its payment tion was insufficient to support benefits tween medical subspecialties, and how coverage for atherosclerotic RAS un- regarding mortality, progressive kidney doubtedly reflects the increase in endo- disease, or cardiovascular events.4 Thus, Published online ahead of print. Publication date vascular stenting procedures for Medi- the published literature cannot support available at www.jasn.org. care beneficiaries, rising from 7660 in the observed, massive expansion of en- Correspondence: Dr. Stephen C. Textor, Division of 1996 to 18,520 in 2000.1 Estimates at the dovascular intervention. Nephrology and Hypertension, Mayo Clinic, Roch- ester, MN 55905. Phone: 507-284-4083; Fax: 507- meeting suggested this increased further During the same time interval, at least 284-1161; E-mail: [email protected] to more than 35,000 in 2005. The largest four prospective, randomized trials for Copyright © 2008 by the American Society of portion of this increase derives from pro- atherosclerotic RAS were started to ex- Nephrology

656 ISSN : 1046-6673/1904-656 J Am Soc Nephrol 19: 656–659, 2008 www.jasn.org CLINICAL COMMENTARY

reserpine, or guanethidine) often fail to ACE inhibitor Rx TIME LINE OF MILESTONES control dangerous, sometimes “malig- Calcium blockers RELATED TO RENOVASCULAR nant phase” hypertension in such indi- HYPERTENSION PTRA introduced viduals. In extreme cases, patients under- Improved surgery Cooperative study of went bilateral nephrectomy as a life- renovascular hypertension Small, randomized trials saving measure to prevent episodes of Urgent bilateral nephrectomy for Med Rx vs PTRA treatment resistant, malignant HTN recurrent hypertensive encephalopathy Prospective trials: 6 Functional tests: Med Rx vs Stent therapy or pulmonary edema. These reports co- Blood flow, sodium excretion CORAL ASTRAL incide with the introduction of renal re- Renal artery clip Surgery for renal STAR hypertension reconstruction RAVE placement therapy with dialysis. Studies of the mechanisms by which a 1930 1940 1950 1960 1970 1980 1990 2000 renal artery clip produces hypertension

Nephrectomy for Early imaging: Advanced ARB Rx paved the way to define the renin-angio- hypertension with Intravenous imaging: a small kidney pyelography, scan MRA, CTA Statin therapy tensin-aldosterone system (RAAS) and Stents were fundamental to development of pharmacologic tools to block this system. Figure 1. Milestones in identification and treatment of renovascular hypertension and The first agents available (Sar-1-Ala-8- ischemic nephropathy: Renal revascularization was possible first in the 1960s and was the angiotensin, or saralasin) to block the only effective antihypertensive therapy for severe renovascular disease. The introduction angiotensin receptor were targeted pri- of agents that block the renin-angiotensin system (angiotensin-converting enzyme [ACE] marily at renovascular hypertension. inhibitors and angiotensin receptor blockers [ARB]) changed the landscape dramatically. Surgery has been mostly replaced by endovascular stent therapy for atherosclerotic Since then, many studies have identified disease. The introduction of intensive medical therapy including ACE/ARB and calcium complex interactions between angioten- channel blockers, plus statins, aspirin, and diabetes management, has allowed effective sin and kidney function, vascular remod- therapy for many patients considered untreatable before. Recent small, short-term, pro- eling, recruitment of additional pressor spective trials have failed to identify major benefits of revascularization as compared with mechanisms, and neurohormonal acti- medical therapy (see text). Larger, prospective trials are enrolling higher risk patients who vation.9 Studies of genetic knockout will be followed for longer periods of time. HTN, hypertension; STAR, STent placement models free of the angiotensin receptor and BP and lipid-lowering for progression of renal dysfunction caused by Atherosclerotic (AT1a knockout) extend these observa- ostial stenosis of the Renal artery; RAVE, Renal Athersosclerotic reVascularization Evalu- tions to demonstrate critical roles for ation; PTRA, Percutaneous Transluminal Renal Angioplasty. both kidney and systemic receptor acti- vation for angiotensin II–dependent hy- does it affect clinical nephrology? Reno- who will benefit from renal revascular- pertension.10 The development of oral vascular disease has always presented ization and for whom its risks are war- agents that interrupt the RAAS provided troublesome issues, different in funda- ranted poses a major clinical challenge. for the first time well-tolerated drugs mental respects from vascular occlusive In some respects, these developments that improved BP control and reduced disease affecting the heart, brain, or ex- reflect stunning successes of basic and cardiovascular risk for patients with re- tremities. The interactions between vas- clinical research. Diagnostic imaging and novascular hypertension. Wider applica- cular disease and kidney function, arte- therapeutic options have advanced rap- tion of renin-angiotensin system block- rial pressure, and volume control are idly in the past two decades. Major mile- ade now provides hope that many forms complex. Clinical syndromes associated stones in the evolution of our under- of progressive kidney injury, congestive with RAS now arise more frequently than standing of renovascular hypertension heart failure, and vascular disease may be ever for patients who have other vascular and ischemic nephropathy are summa- relieved to a degree never imagined by disease involving the coronary and pe- rized in Figure 1. Early observations that those first studying renovascular hyper- ripheral vascular beds.6 Some estimate placement of a renal artery clip produces tension. that up to 5% of patients who reach a rise in systemic arterial pressure was RAAS blockade, statins, and anti- ESRD may have renal artery stenosis as among the first evidence firmly linking therapy are now bedrocks for the their primary kidney disorder.7 This lin- the kidney to cardiovascular control.8 clinical management of atherosclerotic gering concern means that for any single For many years, patients with severe hy- disease, including RAS.11 Although the patient with worsening hypertension pertension were examined for the pres- benefits of restoring blood flow to the and declining kidney function, neph- ence of renovascular hypertension with kidney may seem to be obvious, vascular rologists are forced to consider the po- the goal of either removing the offending stenting carries well-recognized risks of tential role of large-vessel atherosclerotic kidney or revascularizing the kidney us- atheroembolic disease, restenosis, and disease. Although many patients can be ing surgical techniques. Available antihy- local complications, such as vessel dis- treated effectively and safely with current pertensive drug therapy (mainly sympa- section and thrombosis, that remain medical therapy, selection of individuals tholytic agents such as methyldopa, problematic12; therefore, whether endo-

J Am Soc Nephrol 19: 656–659, 2008 Atherosclerotic Renal Artery Stenosis 657 CLINICAL COMMENTARY www.jasn.org

Table 1. Interactive mechanisms underlying hypertension and kidney injury in milieu produced by dyslipidemia (Table atherosclerotic RASa 1).15 It is unclear whether high-grade Tissue Underperfusion Recurrent Local vascular occlusion induces repeated epi- Activation of renin-angiotensin system ATP depletion sodes of transient kidney ischemia that Altered endothelial function (endothelin, NO, Tubulointerstitial injury activate profibrotic pathways similar to prostaglandins) other acute models. How to identify re- Sympathoadrenergic activation Microvascular damage gional “ischemia” in living animals is not Increased reactive oxygen species Immune activation yet certain. Recent studies using blood Cytokine release/ (NF-␬B, TNF, Vascular remodeling oxygen level dependent magnetic reso- TGF-␤, PAI-1, IL-1) nance indicate that poststenotic kidneys Impaired tubular transport functions Interstitial fibrosis have a range of metabolic activity and ox- / RAAS ygen consumption linked to active solute Sympathoadrenergic activation transport.16 Our initial studies suggest Endothelin Disturbances of Љoxidative stressЉ that total vascular occlusion and loss of Oxidized LDL filtration is associated with reduced lev- aNO, ; PAI-1, plasminogen activator inhibitor-1. els of deoxyhemoglobin and minimal change during administra- tion.17 By contrast, viable, functioning vascular stenting provides additional efit from renal artery revascularization to kidneys beyond an atherosclerotic lesion benefit beyond meticulous management a major degree. have relatively high levels of accumulated of BP, blockade of neurohormonal acti- Among the problematic features of deoxyhemoglobin, particularly in the vation, and management of other risk atherosclerotic RAS has been the poorly medulla. Such kidneys can respond factors is controversial. This is the basic defined relationship between the pres- briskly to reduce deoxyhemoglobin lev- question underlying current prospective ence of large-vessel occlusive disease and els after intravenous administration of treatment trials such as CORAL and AS- target injury in the kidney. Unlike fibro- furosemide to reduce solute transport. TRAL (Angioplasty and STent for Renal muscular disease, the degree of severity Whether elevations of deoxyhemoglobin Artery Lesions). Nephrologists have of vascular occlusion in and furosemide-suppressible oxygen moved toward a more conservative clin- bears little relationship to measured consumption induce cytokine release or ical stance in recent years, perhaps as a blood flow, kidney volume, degree of fi- toxic is an important 6 pragmatic counterweight to enthusiastic brosis, or GFR. These observations pro- question that warrants further study. interventional cardiologists and radiolo- vide the basis for experimental studies of It is almost certain that many, if not 7 gists. The challenge facing thoughtful interactions between vascular occlusion most, patients now being subjected to clinicians in this arena is to prevent such and other vectors of kidney injury, in- endovascular stenting of the renal arter- 13 conservatism from interfering with the cluding endothelial dysfunction, tissue ies have only limited benefit, regarding 14 best interests of patients who could ben- oxidative stress, and the atherosclerotic either BP response or improvement in kidney function.7 Equally important to Table 2. Issues central to determining role for renal revascularization in recognize is that a subset of patients with atherosclerotic RASa “critical” renal artery stenosis stand to Questions Tools for Evaluation have major clinical benefit from restor- Severity of vascular occlusion? Quantitative angiography, translesional gradients, ing kidney perfusion and major adverse 18 intravascular ultrasound outcomes if not detected and treated. Treatable? Vessel location, associated disease, accessory Summarized in Table 2 are a series of vessels, aneurysm, occlusion clinical issues that address whether pa- Responsible for disease? Evident activation of pressor systems (e.g., renin) tients are likely to warrant renal revascu- Duration of change (e.g., BP) renal function; larization. Most imaging procedures fo- other measures of tissue ischemia (e.g., BOLD cus on the first two items—the anatomic MR, PET energy consumption); activation of severity and approachability of renal vas- fibrogenic, inflammatory, or oxidative pathways cular lesions. It is likely that the third and Benefit from revascularization? Rapidity of evolution, preexisting injury (e.g., fourth items—diagnostic measures to hypertension, diabetes, other kidney disease), evaluate the role of vascular occlusive le- comorbid disease risk, associated procedural risk to kidney (e.g., atheroembolic potential), sions in generating disease and the likeli- response to other medical therapy hood of clinical benefit after restoration Risk for disease progression, salvageability of of vessel patency—are more important. kidney function (resistive index, BOLD MR) Further studies in the renal vasculature aBOLD MR, blood oxygen level dependent magnetic resonance; PET, positron emission tomography. should be aimed at defining these char-

658 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 656–659, 2008 www.jasn.org CLINICAL COMMENTARY acteristics more fully. A recognized gery, Society for Vascular Surgery, Society giotensin system. J Clin Invest 115: 1092– drawback of clinical treatment trials, of for Cardiovascular Angiography and Inter- 1099, 2005 ventions, Society for Vascular Medicine and 11. Hackam DG, Spence JD, Garg AX, Textor course, is the intermixture of high-risk Biology, Society of Interventional Radiology, SC: Role of renin-angiotensin system block- and low-risk patients into the “average” and the ACC/AHA Task force on Practice ade in atherosclerotic renal artery stenosis of the entire cohort.19 Although prospec- Guidelines. J Vasc Interv Radiol 17: 1383– and renovascular hypertension. Hyperten- tive, randomized trials are essential, cli- 1397, 2006 sion 50: 998–1003, 2007 nicians remain in sore need of better 3. White CJ, Jaff MR, Haska ZJ, Jones DJ, Olin 12. Ivanovic V, McKusick MA, Johnson CM, Sa- JW, Rocha-Singh KJ, Rosenfield KA, Rund- bater EA, Andrews JC, Breen JF, Bjarnason tools to identify renal parenchyma at back JH, Linas SL: Indications for renal arte- H, Misra S, Stanson AW: Renal artery stent true risk for “ischemic injury” and to riography at the time of coronary arteriogra- placement: Complications at a single tertiary identify when kidney function can be (or phy: A science advisory from the American care center. J Vasc Interv Radiol 14: 217– can no longer be) improved with renal Heart Association Committee on Diagnostic 225, 2003 revascularization. and Interventional Cardiac Catheterization, 13. Chade AR, Rodriguez-Porcel M, Grande JP, Council on Clinical Cardiology, and the Coun- Krier JD, Lerman A, Romero JC, Napoli C, cils on Cardiovascular Radiology and Interven- Lerman LO: Distinct renal injury in early ath- tion and on Kidney in Cardiovascular Disease. erosclerosis and renovascular disease. Cir- ACKNOWLEDGMENT Circulation 114: 1892–1895, 2006 culation 106: 1165–1171, 2002 4. Balk E, Raman G, Chung M, Ip S, Tatsioni A, 14. Lerman LO, Nath KA, Rodriguez-Porcel M, Alonso A, Chew P, Gilbert SJ, Lau J: Effec- Krier JD, Schwartz RS, Napoli C: Increased Supported in part by NIH: HL16496 and tiveness of management strategies for renal oxidative stress in experimental renovascu- 1PO1HL085307. artery stenosis: A systematic review. Ann In- lar hypertension. Hypertension 37: 541–546, tern Med 145: 901–912, 2006 2001 5. Murphy TP, Cooper CJ, Dworkin LD, Hen- 15. Chade AR, Rodriguez-Porcel M, Grande JP, rich WL, Rundback JH, Matsumoto AH, Jam- Zhu X, Sica V, Napoli C, Sawamura T, Textor DISCLOSURES erson KA, D’Agostino RB: The Cardiovascu- SC, Lerman A, Lerman LO: Mechanisms of None. lar Outcomes with Renal Atherosclerotic renal structural alterations in combined hy- Lesions (CORAL) Study: Rationale and meth- percholesterolemia and renal artery steno- ods. 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