Renal Artery Disease: Facts and Myths
Before developing an appropriate strategy for evaluating and treating RAS, you should understand the sound beliefs and common misconceptions surrounding it.
To view the figures and tables related to this article, please refer to the print version of our November/December issue, page 52.
SThere are three generally accepted clinical indications for renal artery revascularization with a hemodynamically significant renal artery stenosis (RAS) present. The first is poorly controlled hypertension on adequate medical therapy (two or more antihypertensive drugs), or in a patient intolerant of hypertensive medications. The second indication is to preserve renal function. The third is to treat cardiac disturbance syndromes, such as acute coronary ischemia or congestive heart failure (“flash” pulmonary edema), which are exacerbated by renovascular hypertension.
The treating physician should have a high clinical suspicion that the target stenosis is causally related to the clinical symptoms. This determination should be based upon both functional and anatomic assessments of the RAS. In developing an appropriate strategy for evaluation and treatment, there are several facts that should be understood and myths that should be explained (Table 1).
FACTS ABOUT RENAL ARTERY REVASCULARIZATION
Fact #1: RAS is more common in patients with atherosclerotic cardiovascular disease than previously thought.
The incidence of secondary causes of hypertension in the general hypertensive population is approximately 4%, and the most common secondary cause of hypertension is RAS.1 Atherosclerosis is a systemic disease, and patients with clinical atherosclerosis involving the coronary or peripheral vascular arteries are more likely to have renal artery involvement.
Incidental RAS has been documented in almost one-third of patients undergoing diagnostic cardiac catheterization and coronary angiography.2 Obstructive RAS (>50% diameter stenosis) has been documented in 11% to 19.2% of catheterization patients.3-5 Coronary artery disease (CAD) has been shown to be an independent predictor for the presence of RAS.3,4
Jean et al studied 196 consecutive patients at the time of diagnostic catheterization for suspicion of CAD. One-third had evidence of RAS and 18% had obstructive disease (Figure 1). Of the patients who had angiographically proven coronary disease, 22% had significant (>50% diameter stenosis) RAS. The presence of coronary disease and renal insufficiency independently correlated with the presence of RAS, whereas hypertension did not.3
In a European study, 177 consecutive patients with serum creatinine <2 mg/dL were screened for unsuspected or incidental RAS. Significant RAS was detected in 11% of patients. Patients with RAS tended to be older, have higher blood pressure, and have a lower glomerular filtration rate (GFR) than those without RAS. Using multivariate analysis, the presence of multivessel CAD (OR=2.227; 95% CI, 1.204 to 4.119; P=.011) and a lower GFR (OR=0.961; 95% CI, 0.925 to 0.998; P = .038) independently correlated with the presence of RAS. These investigators that the presence of CAD in two or more vessels has a sensitivity of 84% and a specificity of 77% for RAS.4
In a series of 297 hypertensive patients undergoing cardiac catheterization with abdominal aortography at the Mayo Clinic, the prevalence of RAS was 28%, including 19.2% with hemodynamically significant RAS.5 There were no adverse events attributable to the renal angiography in this series. The investigators concluded that the incidence of RAS was significant and justified screening abdominal angiography in these patients.
Prevalence studies have demonstrated that significant RAS is commonly found in patients with malignant, accelerated or resistant hypertension, patients with unexplained renal insufficiency, patients with azotemia when treated with angiotensin-converting enzyme inhibitors, patients with sudden onset, unexplained (flash) pulmonary edema, and patients with an atrophic kidney.6-9 The incidence of unsuspected RAS was 28% in a group of patients with documented aneurysmal or occlusive vascular disease.10 RAS is often bilateral, and is frequently described in &Mac179;30% of patients.11,12
Given the excellent yield and absence of risk attributed to angiographic screening for RAS in patients undergoing cardiac catheterization, it seems reasonable to recommend angiographic screening, if not in every patient, then certainly in those considered at increased risk for the presence of RAS (Table 2).
Fact #2: Restenosis is a function of acute gain at the time of stent placement.
Restenosis after renal stent placement is more dependent on procedural variables than on clinical variables. When quantitative measurements have been performed, indices that reflect acute gain after stent placement correlate with patency (Figure 2). In 100 consecutive patients that received renal stents with quantitative vascular angiography (QVA), we have shown that the post-stent minimal lumen diameter (MLD) correlates with patency.12 Quantitative angiographic data from Duke University confirm the validity of post-stent MLD in predicting patency.13 Furthermore, lesions were stratified by reference vessel diameter and found that the smallest arteries, those <4.5 mm had a restenosis rate of 36% compared to 15.8% for vessels 4.5 mm to 6.0 mm (P=.068) and compared to 6.5% for vessels >6% (P<.01).
Clearly, this has a significant impact on our clinical practice. If the operator is conservative in his choice of stent diameter, there will be a higher incidence of late restenosis. These data argue strongly for routine QVA measurements of the reference segment to optimize stent diameters.
Fact #3: Stents are superior to balloons for atherosclerotic RAS.
Primary versus provisional stenting continues to be an issue for debate. Primary stenting is characterized by the placement of a stent regardless of the result following balloon angioplasty. Provisional stenting requires that balloon angioplasty stand alone when an arbitrary endpoint is reached (eg, such as &Mac178;30% residual diameter stenosis). Stenting is reserved for “failed” or “unsatisfactory” balloon angioplasty.
Dorros et al compared the results of renal artery balloon angioplasty results to stenting results.14 They were able to show that compared to baseline results, stenting produced significantly better results for stenosis reduction and pressure gradient reduction compared to balloon angioplasty (Figure 3).
Only one randomized trial, conducted by van de Ven et al, of balloon angioplasty versus stenting for RAS has been published.15 The investigators confirmed the superiority of renal stent placement over balloon angioplasty in hypertensive patients. A total of 42 patients and 51 arteries were randomized to balloon angioplasty (with bail-out stenting), and 42 patients and 52 arteries were randomized to receive primary stent therapy. Procedure success and long-term patency markedly favored the stent group (Figure 4).
Over the course of the study, 29% of the patients in the balloon group crossed over to the stent group. This large percentage of crossover patients confounded the analysis of the clinical endpoint at 1 year. This trial demonstrated that a provisional stent strategy allowed for the avoidance of stent placement 40% of the time. However, 45% of these patients will ultimately require a second procedure with a stent associated with additional complications during this second treatment, thereby making a strategy of primary stent placement much more efficient.
For the provisional stent group to achieve a 90% patency rate at 6 months, 62% of the patients would ultimately require a stent and 57% of all patients would need a second or third procedure. The advantage for the primary stent group is that only 12% would need a second procedure to achieve a 90% 6-month patency rate. This randomized controlled trial clearly demonstrated superiority of a primary renal stent strategy over a provisional strategy in hypertensive RAS patients.15
A meta-analysis, comparing renal stent placement to balloon angioplasty, for atherosclerotic RAS confirmed van de Ven’s study by showing a significantly higher procedural success rate for stents (98%) than for balloon angioplasty (77%, P<.001) and a lower restenosis rate for stents (17%) than for balloon angioplasty (26%, P<.001).16
MYTHS ABOUT RENAL ARTERY REVASCULARIZATION
Myth #1: Medical therapy is equal to balloon angioplasty for renovascular hypertension.
The origin of this myth is the DRASTIC trial, in which patients with renovascular hypertension were randomized to best medical therapy and balloon angioplasty.17 RAS was not employed in this study due to operator limitations. Patients were evaluated at 3 months, and if deemed a “failure” of medical therapy, they were permitted to receive balloon angioplasty. Of the 50 patients randomized to medical therapy, 44% failed to respond to medical therapy at 3 months and received balloon angioplasty. At the 3-month crossover point, three of the 50 patients treated with medical therapy had progressed to renal artery occlusion, 14 patients had refractory hypertension, and eight patients had worsening renal function.
The balloon angioplasty group demonstrated a significant improvement in blood pressure from baseline to 3-month follow-up; this trend was not, however, seen in the medical therapy group. After more than 40% of the medical group received balloon angioplasty, there was significant improvement in their blood pressure at 1 year. The problem with this study is that the investigators chose to analyze their data using “intention to treat.” Because almost half of the medical group received balloon angioplasty, it should not have been surprising to find no treatment difference. Had the data been analyzed by “treatment received,” there would have been a definite benefit for the balloon angioplasty group.
At the end of 1 year, 16% of the medical therapy group had suffered irreversible loss of renal function due to occlusion of a renal artery. No renal artery in the balloon angioplasty group progressed to occlusion. There was also a threefold worsening of renal function in the medical therapy group compared to the balloon angioplasty group.
Balloon angioplasty is not an attractive therapy for aorto-ostial RAS and is clearly inferior to primary stent therapy as shown previously.15,16 In the DRASTIC study, however, there is no question that balloon angioplasty was superior to medical therapy, a benefit that was obscured by a disingenuous analysis that allowed a huge crossover group to confuse the outcome.
Myth #2: Elevated resistive indices are a contraindication to renal artery revascularization.
This myth is based upon a small retrospective series of patients reported on by Radermacher et al.18 They screened 5,950 patients with renal duplex ultrasound and identified 131 patients who had either unilateral or bilateral RAS of more than 50% narrowing with clinical manifestations of renovascular hypertension and who had been revascularized.
An arbitrary resistive index (RI) value of &Mac179;80 was used to segregate the groups. There were 35 patients with an RI &Mac179;80 who failed to show a response to revascularization compared to the 96 patients with an RI <80 who did show a favorable response to revascularization. Treatment received included balloon angioplasty (62%), balloon plus stent (32%), or surgery.8 The study, although interesting and certainly useful for generating hypotheses, cannot be considered to be conclusive for several reasons. First, the choice of the cutpoint (RI &Mac179;80) was arbitrary and not predetermined. Only 35 patients were treated in the elevated RI group. Finally, many of the lesions were of questionable importance (<70%), and most of the patients were treated with balloon angioplasty alone. Balloon angioplasty is associated with a higher restenosis rate than stent therapy, which limits its effectiveness.
A more recent study by Zeller et al described prospective results of renal stent placement in &Mac179;70% diameter stenosis RAS in patients with diabetes mellitus and nephrosclerosis.19 In contradistinction to the Radermacher et al article,18 they found that patients with elevated RIs responded favorably to renal stent placement (Figure 5). In fact, patients with moderate (RI=70 to 80) and severe (RI >80) nephrosclerosis demonstrated a statistically significant improvement at 1-year follow-up for mean blood pressure. More interestingly, patients with nephrosclerosis had greater improvement in serum creatinine levels after stent placement than did normal RI patients (Figure 6).
It seems that the article by Zeller et al much more clearly reflects current treatment methods and strategy. Conservative lesion selection (>70% diameter stenosis) is appropriate in diabetic and nephrosclerosis patients, but elevated RIs should not be a reason to exclude an otherwise good candidate from renal stent therapy.
Myth #3: Captopril renography is a good noninvasive screening tool for RAS.
This myth arises from the early trials investigating radionuclide imaging to detect RAS. Initially, the test was applied to patients with a high likelihood of disease, and as predicted by Bayes theorem, it appeared to be an excellent screening tool. In clinical practice, however, many clinicians have not found the Captopril Renogram to be a helpful screening test for RAS.
Recently, Huot et al from the Yale University Veterans Affairs hospital reported a prospective trial comparing Captopril renography to angiography to determine the sensitivity and specificity of the test.20 They screened 90 consecutive patients who had both renal angiography and a Captopril renogram within 6 months of each other. The sensitivity of the Captopril renogram was 74%, and the specificity was 59% (Table 3).
There may be several reasons for the poor performance of this test as a screening tool. One reason could be the relatively high incidence of bilateral RAS (30%), which may confound a test that relies on the contralateral kidney as a control. A second reason is the difficulty in controlling a patient’s volume status and the need to withhold certain medications that can interfere with the test results. The investigators suggest that Captopril renography not be used as a screening test for RAS. In today’s clinical environment, there are better noninvasive tools for screening patients including Doppler ultrasound, CT angiography and MR angiography.
Christopher J. White, MD, is Chairman of the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, Louisiana. Dr. White may be reached at (504) 842-3717; email@example.com.
1. Scoble JE. The epidemiology and clinical manifestations of atherosclerotic renal disease. In: Novick AC, Scoble J, Hamilton G, eds: Renal Vascular Disease. London: WB Saunders Co., Ltd. 1996;303-314.
2. Harding MB, Smith LR, Himmelstein SI et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol. 1992;2:1608-1616.
3. Jean WJ, al-Bitar I, Zwicke DL, et al. High incidence of renal artery stenosis in patients with coronary artery disease. Cathet Cardiovasc Diagn. 1994;32:8-10.
4. Weber-Mzell D, Kotanko P, Schumacher M, et al. Coronary anatomy predicts presence or absence of renal artery stenosis. Eur Heart J. 2002;23:1684-1691.
5. Rihal CS, Textor SC, Breen JF, et al. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002;77:309-316.
6. Jacobsen HR. Ischemic renal disease: an overlooked clinical entity? Kidney Int. 1988;34:729-743.
7. Pickering TG, Devereux RB, James GD, et al: Recurrent pulmonary edema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revacularisation. Lancet. 1988;9:551-552.
8. O’Neil EA, Hansen KJ, Canzanello VJ, et al. Prevalence of ischemic nephropathy in patients with renal insufficiency. J Am Surg. 1992;58:485-490.
9. Olin JW, Melia M, Young JR, et al. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med. 1990;88:46N-51N.
10. Valentine RJ, Clagett GP, Miller GL, et al. The coronary risk of unsuspected renal artery stenosis. J Vasc Surg. 1993;18:433-440.
11. Rimmer J, Gennari FJ. Atherosclerotic renovascular disease and progressive renal failure. Ann Intern Med. 1993;118:712-719.
12. White CJ, Ramee SR, Collins TJ, et al. Renal artery stent placement: utility in difficult lesions for balloon angioplasty. J Am Coll Cardiol. 1997;30:1445-1450.
13. Lederman RJ, Mendelsohn FO, Santos R, et al. Primary renal artery stenting: characteristics and outcomes after 363 procedures. Am Heart J. 2001;142:314-323.
14. Dorros G, Prince C, Mathiak L. Stenting of a renal artery stenosis achieves better relief of the obstructive lesion than balloon angioplasty. Cathet Cardiovasc Diagn. 1993;29:191-198.
15. van de Ven PJ, Kaatee R, Beutler JJ, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomized trial. Lancet. 1999;353:282-286.
16. Leertouwer TC, Gussenhoven EJ, Bosch JL, et al. Stent placement for renal artery stenosis: where do we stand? A meta-analysis. Radiology. 2000;216:78-85.
17. van Jaarsveld BC, 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 J Med. 2000;342;1007-1014.
18. Radermacher J, Chavan A, Bleck J, et al. Use of Doppler ultrasonography to predict the outcome of therapy for renal artery stenosis. N Engl J Med. 2001;344:410-417.
19. Zeller T, Muller C, Frank U, et al. Stent angioplasty of severe atherosclerotic ostial renal artery stenosis in patients with diabetes mellitus and nephrosclerosis. Cath Cardiovasc Intervent. 2003;58:510-515.
20. Huot SJ, Hansson JH, Dey H, et al. Utility of captopril renal scans for detecting renal artery stenosis. Arch Intern Med. 2002;162:1981-1984.