TOPICS FROM CHEP A Closer Look: Renal Artery Stenosis On behalf of the Canadian Hypertension Education Program (CHEP), Dr. Tobe gives an overview of renal artery stenosis, including the prevalence, screening techniques, management and treatment options for this serious disease. Sheldon W. Tobe, MD, FRCPC; on behalf of the Canadian Hypertension Education Program Renal artery stenosis (RAS) is defined as a narrowing of the lumen of the renal artery. 1 Atherosclerotic renovascular disease is a combination of RAS and renal ischemia. 2 The disease may be unilateral or bilateral (or unilateral in the setting of one kidney). Atherosclerotic renovascular disease occurring in the elderly is most often due to atherosclerosis, which, because of its systemic nature, Copyright most often leads to disease of both large and small arteries of both kidneys. Progressive impairment in renal function occurs through ischemia of affected areas and hypertensive damage to the parts of the kidney perfused by relatively normal renal arteries. Fibromuscular disease, mostly found in younger female patients that smoke, responds well to angioplasty without stenting but is not reviewed here. Ischemic nephropathy describes the reduction in glomerular filtration rate (GFR) that is caused by hemodynamically significant RAS. Thus, a patient with atherosclerotic renovascular disease has both large and small vessel arterial disease and often has a loss of GFR due to ischemic nephropathy. Although renal artery atherosclerosis is common, as is atherosclerosis in the general adult population, renal perfusion is not reduced until there is > 50% stenosis and BP does not usually rise until the RAS is 60% to 70%. 2 Shawn s stenosis Shawn, 54, is transferred from a rural hospital for urgent renal artery revascularization after presenting in a hypertensive crisis. Magnetic resonance (MR) angiography identified a critical stenosis of the left renal artery as well as an 80% stenosis in the right renal artery. Diffuse atherosclerosis was noted. Shawn had not had his BP measured in decades, his ECHO showed evidence of left ventricular hypertrophy (LVH) and he had a long history of smoking. On arrival, Shawn was on four antihypertensives and: his BP was controlled to < 140/90 mmhg, his creatinine was 135 µmol/l and he was comfortable. Not for Sale or Commercial Distribution Unauthorised use prohibited. Authorised users can download, display, view and print a single copy for personal use Shawn wants to know the following: Could he have been diagnosed earlier? What medical therapy is necessary? What is the natural history of this disease without medical or radiological intervention? What should his target BP be? Can percutaneous revascularization procedures allow him to reduce his medications and bring his BP under better control? Which of these revascularization procedures would be best for him? Will these procedures help preserve his renal function and/or prevent cardiovascular disease? For the answers to these questions, turn to page 29... Perspectives in Cardiology / September 2007 27
In most patients with atherosclerotic renovascular disease, there is disease in both kidneys. Risk factors for atherosclerotic RAS include: long-standing hypertension, diabetes, smoking and dyslipidemia. These are also risk factors for premature coronary artery disease. Table 1 Factors associated with lower likelihood of response to renal revascularization Urinary protein excretion >1 g/d Hyperuricemia GFR < 40 ml/min Age > 65 years Pulse pressure of at least 70 mmhg Diastolic BP < 80 mmhg, systolic BP < 160 mmhg Male gender No abrupt elevation in BP Duration of hypertension > 10 years Diabetes mellitus No history of smoking Coronary artery disease Cerebrovascular disease Peripheral arterial disease The prevalence of atherosclerotic renovascular disease is approximately 1% of the hypertensive population. Prevalence The prevalence of atherosclerotic renovascular disease is approximately 1% of the hypertensive population. 2 In a group of people > 65-years-ofage, atherosclerotic renovascular disease diagnosed by Doppler ultrasound was found in 6.8%. 3 In patients with hypertension resistant to two medications, the prevalence was found to be 20%. 4 While RAS is prevalent in hypertension particularly in patients complicated by other atherosclerotic disease, the presence of the anatomical renal artery narrowing is not always associated with hypertension. This may explain one of the reasons why renal revascularization does not lower BP in all patients with atherosclerotic renovascular disease. Screening The ideal single screening test for atherosclerotic renovascular disease would: be accurate, have low technical failure, have high sensitivity and specificity and be non-invasive as well as inexpensive. 5,6 Magnetic resonance angiography (MRA) and CT angiography are non-invasive and have a high sensitivity and specificity, but have high costs and carry a risk for acute renal dysfunction related to the dyes that are used (contrast media for CT scan and radiation exposure or gadolinium for MRA). MRA is also contraindicated for patients with claustrophobia, metallic implants, obesity or for the seriously ill. The captopril-enhanced renal scan has lower sensitivity and specificity in patients with reduced renal function. 7 Doppler ultrasonography has been demonstrated 28 Perspectives in Cardiology / September 2007
to have high sensitivity and specificity in experienced hands for the diagnosis of anatomical lesions. 5 It can also detect unilateral and bilateral lesions, accessory renal arteries, is noninvasive and inexpensive. Obesity, excessive bowel gas or poor blood flow in the main renal artery can interfere with direct visualization. The renal resistance index (RRI) performed as part of a Doppler ultrasound exam is a powerful tool for identifying patients that may not benefit from revascularization. It is easy to learn and can effectively be applied to all patients referred for a simple abdominal ultrasound as part of the initial investigation for atherosclerotic renal arterial disease. Predicting patient outcomes Simple measurements of serum renin levels have been investigated to predict the potential success of surgical revascularization, but the frequency of false-negative and false-positive results make this screening test unhelpful. 8 Even when the accuracy of the serum renin test is enhanced by the addition of an ACE inhibitor, the test still has insufficient specificity and sensitivity to be recommended. 9 Also, renin-based diagnostic tests are limited by antihypertensive drugs that interfere with plasma renin activity. The best determinant of patient outcome is not the degree of RAS but the degree of renal function. Damage to the nephrons has been found to be more important in the pathogenesis of renal dysfunction than the degree of the renal artery stenosis. 10 Renal revascularization has not been shown to be associated with improved patient survival or even renal survival compared to medical therapy alone. 11 However, with medical management alone, the progression to total renal artery occlusion occurs at about 3% to 5% per year, but only in those with > 60% stenosis. 12 Table 2 Clues suggesting the need for assessment of renovascular hypertension Patients presenting with 2 of the clinical clues listed below, suggesting renovascular hypertension, should be investigated. Sudden onset or worsening of hypertension and age > 55 or < 30 years The presence of an abdominal bruit Hypertension resistant to 3 drugs A rise in creatinine associated with the use of an ACE inhibitor or ARB Other atherosclerotic vascular diseases, particularly in patients who smoke or have dyslipidemia Recurrent pulmonary edema associated with hypertensive surges Shawn s case cont d... Shawn recognizes that renovascular disease is a marker for cardiovascular risk and focuses on risk reduction strategies, including lifestyle, modification and medication changes. His target systolic BP is < 140 mmhg, if tolerated. He is started on high-dose statin therapy. Although his BP is controlled and his renal function is stable, he elects to have revascularization and bilateral renal stents are put into place. He is able to stop one of his antihypertensives. On return home, he remains on his medications and his BP remains well controlled. Dr. Tobe is an Associate Professor of Medicine, University of Toronto and the Director of Home Dialysis, Division of Nephrology, Sunnybrook Health Science Centre, Toronto, Ontario. Perspectives in Cardiology / September 2007 29
Table 3 Recommendations for the management of hypertension in atherosclerotic renovascular disease Renovascular hypertension should be treated in the same manner as uncomplicated hypertension, except for caution in the use of ACE inhibitors or ARBs due to the risk of acute renal failure in bilateral disease or unilateral disease with a solitary kidney Close follow-up and early intervention (angioplasty and stenting or surgery) should be considered for patients with: - uncontrolled hypertension despite therapy with 3 drugs, - deteriorating kidney function, - bilateral atherosclerotic renal artery lesions (or tight atherosclerotic stenosis in a single kidney), or - recurrent episodes of flash pulmonary edema Alternatives to surgery Angiographic endovascular procedures are increasingly replacing surgery for the revascularization of atherosclerotic renovascular disease. 13 A meta-analysis of these studies of renal revascularization without stenting was able to show an 8 mmhg reduction in BP but could not show improvement in renal function compared to conservative strategies. 14 For factors associated with a lower likelihood of response to revascularization see Table 1. Percutaneous renal angioplasty (PTRA) with stenting has led to higher rates of successful revascularization (> 80%) and lower restenosis rates (< 20%) than revascularization without stenting. 15 In general, studies of PTRA for atherosclerotic renovascular disease have shown that renal function in patients is improved in about 25%, stabilizes in approximately 40%, but worsens in about 25%. 16 An approach to atherosclerotic renovascular disease must recognize that some patients have anatomical RAS with no functional effect, while others have both and still others have stenosis causing hypertension or loss of renal function renal disease. Because of microvascular disease within the affected kidney, even if the stenosis was repaired, these problems would not be resolved. Revascularization, by angioplasty and stent insertion, should be considered for patients with uncontrollable hypertension or deteriorating renal function (Table 2). For those with a high likelihood of atherosclerotic renovascular disease, the following tests are recommended, when available, to screen for renal artery stenosis: Renovascular disease Does not imply specific treatment choice Caution in the use of ACE inhibitor/arb in bilateral renal artery stenosis or unilateral disease with solitary kidney Figure 1. Treatment of hypertension in patients with renovascular disease. 30 Perspectives in Cardiology / September 2007
captopril-enhanced radioisotope renal scan (if GFR > 60 ml/minute), Doppler sonography, MRA and CT angiography. The optimal test for diagnosing renovascular hypertension depends on local radiological expertise and the underlying clinical situation. The prevalence of atherosclerotic renovascular disease is approximately 1% of the hypertensive population. Management of hypertension The management of hypertension in this condition involves the use of combinations of antihypertensive agents at doses sufficient to control BP. Blockers of the renin-angiotensinaldosterone system must be used with close monitoring of renal function and serum potassium levels, preferably with an existing baseline result and another within a week or so of initiating therapy. Diuretics and long-acting calcium channel blockers are common mainstays of therapy. Medical management also includes aggressive lipid-lowering therapy with high-dose statin therapy, or possibly, the combination of a lower dose statin in the setting of chronic kidney disease and a cholesterol absorption inhibitor drug such as ezetimibe, the use of antiplatelet therapy, smoking cessation, as well as diet and lifestyle counselling. The recommendations for the management of hypertension in atherosclerotic renovascular disease are found in Table 3. PCard References 1. Rundback JH, Sacks D, Kent KC, et al: Guidelines for the Reporting of Renal Artery Revascularization in Clinical Trials. J Vasc Interv Radiol 2002; 13(10):959-74. 2. Pickering TG, Blumenfeld JD: Renovascular Hypertension and Ischemic Nephropathy. In: Brenner BM (ed): Brenner and Rector s The Kidney. W.B Saunders Co, Philadelphia: 2000, pp. 2007-34. 3. Hansen KJ, Edwards MS, Craven TE, et al: Prevalence of Renovascular Disease in the Elderly: A Population-Based Study. J Vasc Surg 2002; 36(3):443-51. 4. van Jaarsveld BC, Krijnen P, Derkx FH, et al: Resistance to Antihypertensive Medication as Predictor of Renal Artery Stenosis: Comparison of Two Drug Regimens. J Hum Hypertens 2001; 15(10):669-76. 5. Radermacher J, Chavan A, Schaffer J, et al: Detection of Significant Renal Artery Stenosis with Color Doppler Sonography: Combining Extrarenal and Intrarenal Approaches to Minimize Technical Failure. Clinical Nephrology 2000; 53(5):333-43. 6. Radermacher J, Chavan A, Bleck J, et al: Use of Doppler Ultrasonography to Predict the Outcome of Therapy for Renal-Artery Stenosis. NEJM 2001; 344(6):410-17. 7. Taylor A: Functional Testing: ACEI Renography. [Review] [51 refs]. Seminars in Nephrology 2000; 20(5):437-44. 8. Radermacher J, Haller H: The Right Diagnostic Work-Up: Investigating Renal and Renovascular Disorders. [Review] [22 refs]. J Hypertens 2003; 21(Suppl2):S19-S24. 9. Lenz T, Kia T, Rupprecht G, et al. Captopril Test: Time Over? J Hum Hypertens 1999; 13(7):431-5. 10. Wright JR, Shurrab AE, Cheung C, et al: A Prospective Study of the Determinants of Renal Functional Outcome and Mortality in Atherosclerotic Renovascular Disease [comment]. Am J Kidney Dis 2002; 39(6):1153-61. 11. Losito A, Errico R, Santirosi P, et al: Long-Term Follow-up of Atherosclerotic Renovascular Disease. Beneficial effect of ACE Inhibition. Nephrol Dial Transplant 2005; 20(8):1604-9. 12. Caps MT, Perissinotto C, Zierler RE, et al: Prospective Study of Atherosclerotic Disease Progression in the Renal Artery. Circulation 1998; 98(25):2866-72. 13. Mackrell PJ, Langan EM III, Sullivan TM, et al: Management of Renal Artery Stenosis: Effects of a Shift from Surgical to Percutaneous Therapy on Indications and Outcomes. Ann Vasc Surg 2003; 17(1):54-9. 14. Nordmann AJ, Woo K, Parkes R, et al: Balloon Angioplasty or Medical Therapy for Hypertensive Patients with Atherosclerotic Renal Artery Stenosis? A Meta-Analysis of Randomized Controlled Trials. American J of Medicine 2003; 114(1):44-50. 15. Leertouwer TC, Gussenhoven EJ, Bosch JL, et al: Stent Placement for Renal Arterial Stenosis: Where Do We Stand? A Meta-Analysis. Radiology 2000; 216(1):78-85. 16. Textor SC, Wilcox CS: Renal Artery Stenosis: A Common, Treatable Cause of Renal Failure? [Review] [127 refs]. Ann Rev Med 2001; 52:421-42. Perspectives in Cardiology / September 2007 31