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BRIEF ANSWERS TO SPECIFIC CLINICAL Q: Does stenting of severe renal QUESTIONS improve outcomes compared with medical therapy alone?

AMJAD KABACH, MD but bilateral disease has also been reported. Department of Medicine, Creighton University, Omaha, NE The prevalence of atherosclerotic renal vas- OSAMA QASIM AGHA, MD cular disease in the US Medicare population is Department of Internal Medicine, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 0.5%, and 5.5% in those with chronic kidney disease.1 Furthermore, is MOTAZ BAIBARS, MD, FACP 2 Department of Hospital Medicine, Peninsula Regional Medical Center, found in 6.8% of adults over age 65. The preva- Salisbury, MD lence increases with age and is higher in patients ABDUL HAMID ALRAIYES, MD with hyperlipidemia, peripheral arterial disease, Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, and . The prevalence of renal ar- Cleveland Clinic, Cleveland, OH tery stenosis in patients with atherosclerotic dis- M. CHADI ALRAIES, MD, FACP ease and renal dysfunction is as high as 50%.3 Department of Medicine, Cardiovascular Division, University of Minnesota, Minneapolis Patients with peripheral artery disease may be five times more likely to develop renal ar- tery stenosis than people without peripheral Renal artery No. In patients with severe athero- artery disease.4 Significant stenosis can result A: sclerotic renal artery stenosis and hy- in resistant arterial hypertension, renal insuf- stenting added pertension or chronic kidney disease, renal ar- ficiency, left ventricular hypertrophy, and con- to drug therapy tery stenting offers no additional benefit when gestive .5 added to comprehensive medical therapy. Nephropathy due to renal artery stenosis is can modestly See related editorial, page 495 complex and is caused by hypoperfusion and improve blood chronic microatheroembolism. Renal artery pressure In these patients, renal artery stenting in stenosis leads to oxidative stress, , addition to antihypertensive drug therapy can fibrosis in the stenotic kidney, and, over time, control, improve control modestly but loss of kidney function. Hypoperfusion also but has no has no significant effect on outcomes such as leads to activation of the renin-angiotensin- adverse cardiovascular events and death. And aldosterone system, which plays a role in de- significant because renal artery stenting carries a risk of velopment of left ventricular hypertrophy.5,6 effect on complications, medical management should Adequate blood pressure control, goal- outcomes continue to be the first-line therapy. directed lipid-lowering therapy, smoking ces- sation, and other preventive measures are the ■■ RENAL ARTERY STENOSIS foundation of management. Renal artery stenosis is a common form of pe- ripheral artery disease. is the ■■ RENAL ARTERY STENOSIS most common cause, but it can also be caused AND HYPERTENSION by or (eg, Renal artery stenosis is a cause of secondary Takayasu ). It is most often unilateral, hypertension. The stenosis decreases renal per- fusion pressure, activating the release of renin doi:10.3949/ccjm.82a.14076 and the production of angiotensin II, which in

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Angiotensinogen

Decreased perfusion Renin caused by renal artery stenosis Angiotensin I

Angiotensin-converting enzyme

Angiotensin II

Increased vasoconstriction Increased aldosterone

Increased vascular resistance Increased sodium reabsorption

Hypervolemia

FIGURE 1. Pathophysiology of hypertension in renal artery stenosis. turn raises the blood pressure by two mecha- lines of the American College of Cardiology nisms (Figure 1): directly, by causing general- and the American Heart Association11 con- ized vasoconstriction, and indirectly, by stimu- sidered percutaneous revascularization a rea- Renal artery lating the release of aldosterone, which in turn sonable option (level of evidence B) for pa- stenosis raises increases the reabsorption of sodium and causes tients who meet one of the following criteria: hypervolemia. These two mechanisms play a • Hemodynamically significant stenosis and blood pressure major role in renal vascular hypertension when accelerated, resistant, or malignant hyper- both directly renal artery stenosis is bilateral. In unilateral tension, hypertension with an unexplained and indirectly renal artery stenosis, pressure diuresis in the unilateral small kidney, or hypertension unaffected kidney compensates for the reab- with intolerance to medication sorption of sodium in the affected kidney, keep- • Renal artery stenosis and progressive chron- ing the blood pressure down. However, with ic kidney disease with bilateral stenosis or time, the unaffected kidney will develop hy- stenosis in a solitary functioning kidney pertensive nephropathy, and pressure diuresis • Hemodynamically significant stenosis and will be lost.7,8 In addition, the activation of the recurrent, unexplained congestive heart renin-angiotensin-aldosterone system results in failure or sudden, unexplained pulmonary structural heart disease, such as left ventricular edema or unstable .11 hypertrophy,5 and may shorten survival. However, no randomized study has shown a direct benefit of renal artery stenting on ■■ STENTING PLUS ANTIHYPERTENSIVE rates of cardiovascular events or renal func- DRUG THERAPY tion compared with drug therapy alone. Because observational studies showed im- provement in blood pressure control after ■■ TRIALS OF STENTING endovascular stenting of atherosclerotic re- VS MEDICAL THERAPY ALONE nal artery stenosis,9,10 this approach became a Technical improvements have led to more treatment option for uncontrolled hyperten- widespread use of diagnostic and interven- sion in these patients. The 2005 joint guide- tional endovascular tools for renal artery re-

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vascularization. Studies over the past 10 years more stringent definitions and longer follow- examined the impact of stenting in patients up. It randomized 947 patients to either stent- with uncontrolled hypertension. ing plus medical therapy or medical therapy alone. Patients had atherosclerotic renal ar- The STAR trial tery stenosis, defined as stenosis of at least In the Stent Placement and Blood Pressure 80% or stenosis of 60% to 80% with a gradi- and Lipid-lowering for the Prevention of Progression of Renal Dysfunction Caused by ent of at least 20 mm Hg in the systolic pres- Atherosclerotic Ostial Stenosis of the Renal sure), and either while Artery (STAR) trial,9 patients with creati- taking two or more antihypertensive drugs or 2 stage 3 or higher chronic kidney disease (glo- nine clearance less than 80 mL/min/1.73 m , 2 renal artery stenosis greater than 50%, and merular filtration rate < 60 mL/min/1.73 m well-controlled blood pressure were random- as calculated by the Modification of Diet in ized to either renal artery stenting plus medi- Renal Disease formula). cal therapy or medical therapy alone. The au- Participants were followed for 43 months to thors concluded that stenting had no effect on detect the occurrence of adverse cardiovascu- the progression of renal dysfunction but led to lar and renal events. There was no significant a small number of significant, procedure-relat- difference in primary outcome between stent- ed complications. The study was criticized for ing plus drug therapy and drug therapy alone including patients with mild stenosis (< 50% (35.1% and 35.8%, respectively; P = .58). How- stenosis) and for being underpowered for the ever, stenting plus drug therapy was associated primary end point. with modestly lower systolic pressures compared with drug therapy alone (−2.3 mm Hg, 95% The ASTRAL study confidence interval −4.4 to −0.2 mm Hg, P = The Angioplasty and Stenting for Renal Ar- 13 10 .03). This study provided strong evidence that tery Lesions (ASTRAL) study was a similar renal artery stenting offers no significant benefit comparison with similar results, showing no to patients with moderately severe atheroscle- benefit from stenting with respect to renal rotic renal artery stenosis, and that stenting may function, systolic blood pressure control, car- Complications actually pose an unnecessary risk. diovascular events, or death. of renal artery HERCULES ■■ COMPLICATIONS stenting are a OF RENAL ARTERY STENTING The Herculink Elite Cobalt Chromium Renal limiting factor Stent Trial to Demonstrate Efficacy and Safety Complications of renal artery stenting are a 12 (HERCULES) was a prospective multicenter limiting factor compared with drug therapy compared with study of the effects of renal artery stenting alone, especially since the procedure offers drug therapy in 202 patients with significant renal artery no significant benefit in outcome. Procedural alone stenosis and uncontrolled hypertension. It complication rates of 10% to 15% have been showed a reduction in systolic blood pressure reported.9,10,12 The CORAL trial reported arte- from baseline (P < .0001). However, follow-up rial dissection in 2.2%, branch-vessel occlusion was only 9 months, which was insufficient to in 1.2%, and distal embolization in 1.2% of show a significant effect on long-term cardio- patients undergoing stenting.13 Other reported vascular and cerebrovascular outcomes. complications have included stent misplace- The CORAL trial ment requiring an additional stent, access- The Cardiovascular Outcomes in Renal Ath- vessel damage, stent embolization, renal artery erosclerotic Lesions (CORAL) trial13 used or occlusion, and death.10,12 ■

■■ REFERENCES 1. Kalra PA, Guo H, Kausz AT, et al. Atherosclerotic reno- study. J Vasc Surg 2002; 36:443–451. in United States patients aged 67 years 3. Uzu T, Takeji M, Yamada N, et al. Prevalence and outcome or older: risk factors, revascularization, and prognosis. of renal artery stenosis in atherosclerotic patients with Kidney Int 2005; 68:293–301. renal dysfunction. Hypertens Res 2002; 25:537–542. 2. Hansen KJ, Edwards MS, Craven TE, et al. Prevalence of 4. Benjamin MM, Fazel P, Filardo G, Choi JW, Stoler RC. renovascular disease in the elderly: a population-based Prevalence of and risk factors of renal artery stenosis in

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patients with resistant hypertension. Am J Cardiol 2014; Revascularization versus medical therapy for renal-artery 113:687–690. stenosis. N Engl J Med 2009; 361:1953–1962. 5. Wu S, Polavarapu N, Stouffer GA. Left ventricular hyper- 11. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 trophy in patients with renal artery stenosis. Am J Med guidelines for the management of patients with periph- Sci 2006; 332:334–338. eral arterial disease (lower extremity, renal, mesenteric, 6. Lerman LO, Textor SC, Grande JP. Mechanisms of tissue and abdominal aortic): executive summary. J Am Coll injury in renal artery stenosis: ischemia and beyond. Prog Cardiol 2006; 47:1239–1312. Cardiovasc Dis 2009; 52:196–203. 12. Jaff MR, Bates M, Sullivan T, et al; HERCULES Investiga- 7. Black HR, Glickman MG, Schiff M Jr, Pingoud EG. Reno- tors. Significant reduction in systolic blood pressure vascular hypertension: pathophysiology, diagnosis, and following renal artery stenting in patients with uncon- treatment. Yale J Biol Med 1978; 51:635–654. trolled hypertension: results from the HERCULES trial. 8. Tobe SW, Burgess E, Lebel M. Atherosclerotic renovascu- Catheter Cardiovasc Interv 2012; 80:343–350. lar disease. Can J Cardiol 2006; 22:623–628. 13. Cooper CJ, Murphy TP, Cutlip DE, et al; CORAL Inves- 9. Bax L, Mali WP, Buskens E, et al; STAR Study Group. tigators. Stenting and medical therapy for athero- sclerotic renal-artery stenosis. N Engl J Med 2014; The benefit of stent placement and blood pressure and 370:13–22. lipid-lowering for the prevention of progression of renal dysfunction caused by atherosclerotic ostial stenosis of ADDRESS: M. Chadi Alraies, MD, FACP, Department of Medi- the renal artery. The STAR-study: rationale and study cine, Cardiovascular Division, University of Minnesota Medical design. J Nephrol 2003; 16:807–812. Center, 420 Delaware Street SE, MMC 508, Minneapolis, MN 10. ASTRAL Investigators; Wheatley K, Ives N, Gray R, et al. 55455; e-mail: [email protected]

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