Epidemiology of atherosclerotic renal artery stenosis as a mirror of prospective trials
Authors: Bernd Krumme
Journal: Kidney International (2009)

Diagnosis and treatment of atherosclerotic renal artery stenosis (ARAS) in the elderly is a never-ending challenge for every nephrologist. Kalra et al. report that adjusted hazard ratios for ARAS increased threefold from 1992 to 2004 in 16 million United States Renal Data System participants aged 66 years or older. However, numbers of revascularizations showed a biphasic pattern with a declining number since 1999. These exciting data have to be discussed with the knowledge of recent prospective trials. Diagnosis and treatment of atherosclerotic renal artery stenosis (ARAS) in the elderly is a never-ending challenge for every nephrologist. Kalra et al. report that adjusted hazard ratios for ARAS increased threefold from 1992 to 2004 in 16 million United States Renal Data System participants aged 66 years or older. However, numbers of revascularizations showed a biphasic pattern with a declining number since 1999. These exciting data have to be discussed with the knowledge of recent prospective trials. The significance of atherosclerotic renal artery stenosis (ARAS) for the clinical outcome of patients with hypertension and/or chronic kidney disease is still a matter of debate between nephrologists, interventional cardiologists, and radiologists.1.Levin A. Linas S. Luft F.C. et al.Controversies in renal artery stenosis: a review by the American Society of Nephrology Advisory group on Hypertension.Am J Nephrol. 2007; 27: 212-220Crossref PubMed Scopus (65) Google Scholar There is no doubt about the increasing number of renal artery interventions over the past two decades in the United States as well as in Europe; however, the benefit of these interventions remains a mystery.2.Murphy T.P. Soares G. Kim M. Increase in utilization of percutaneous renal artery interventions by Medicare beneficiaries, 1996–2000.Am J Roentgenol. 2004; 183: 561-568Crossref PubMed Scopus (108) Google Scholar Meanwhile, stenting of ARAS has been the treatment of choice since the first long-term results were presented by our group in 19973.Blum U. Krumme B. Flügel P. et al.Treatment of ostial renal-artery stenosis with vascular endoprostheses after unsuccessful balloon angioplasty.N Engl J Med. 1997; 336: 459-465Crossref PubMed Scopus (520) Google Scholar (Figure 1) and confirmed by a randomized prospective study by van de Veen et al.4.Van de Veen P.J. Kaatee R. Betler J. et al.Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial.Lancet. 1999; 353: 282-286Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar At the beginning of this century, three randomized prospective trials with a limited number of patients in each single study did not show per se any benefit of intervention either for blood pressure outcome or for renal function. It is of note that meta-analysis of the three trials detected beneficial effects of angioplasty on blood pressure, rather than on renal function.5.Nordmann A.J. 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.Am J Med. 2003; 114: 44-50Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Additionally, there was a trend toward a higher cardiovascular-event rate in the group of patients who were treated exclusively by medication versus those who received angioplasty.5.Nordmann A.J. 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.Am J Med. 2003; 114: 44-50Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar However, since the publications of the three studies, many nephrologists favor a nihilistic approach of ‘no screen, no treat,’ although up to now the number of preventable cardiovascular and renal events is unknown.6.Cooper C.J. Murphy T.P. Is renal artery stenting the correct treatment of renal artery stenosis? The case for renal artery stenting for treatments of renal artery stenosis.Circulation. 2007; 115: 263-270Crossref PubMed Scopus (45) Google Scholar The report on atherosclerotic renovascular disease by Kalra and co-workers7.Kalra P.A. Guo H. Gilbertson D.T. et al.Atherosclerotic renovascular disease in the United States.Kidney Int. 2010; 77: 37-43Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar (this issue), derived from the United States Renal Data System, mirrors the above-described process in a brilliant manner. Hazard ratios for the diagnosis of ARAS increased threefold from 1992 to 2004 in patients aged 65 years or older. The reasons for this increasing incidence can be manifold. Most likely, the growing use of noninvasive imaging techniques, such as magnetic resonance angiography, computer tomography angiography, and Doppler ultrasound, may be responsible for a better rate of detection of ARAS. Since the beginning of the 1990s, sensitivities and specificities of the imaging modalities have improved continuously, whereas functional tests, such as the captopril test or captopril scintigraphy, showed less accuracy.8.Vasbinder C. Boudewijn G. Nelemans P.J. et al.Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: a meta-analysis.Ann Intern Med. 2001; 135: 401-411Crossref PubMed Scopus (340) Google Scholar It seems plausible that physicians look less frequently for ARAS in patients aged 85 years or older with higher comorbidity, because of the lack of therapeutic consequences. This might be the reason for the reduced adjusted hazard ratio of these patients suffering ARAS in comparison with the general population in the study of Kalra et al.7.Kalra P.A. Guo H. Gilbertson D.T. et al.Atherosclerotic renovascular disease in the United States.Kidney Int. 2010; 77: 37-43Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar It is of note that the number of renal artery revascularizations presented in this study increased steadily from 1995 to 1999, whereas it has decreased continuously since 2000.7.Kalra P.A. Guo H. Gilbertson D.T. et al.Atherosclerotic renovascular disease in the United States.Kidney Int. 2010; 77: 37-43Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar If one keeps in mind the data of the above-mentioned publications about renal artery intervention,3.Blum U. Krumme B. Flügel P. et al.Treatment of ostial renal-artery stenosis with vascular endoprostheses after unsuccessful balloon angioplasty.N Engl J Med. 1997; 336: 459-465Crossref PubMed Scopus (520) Google Scholar, 4.Van de Veen P.J. Kaatee R. Betler J. et al.Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial.Lancet. 1999; 353: 282-286Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar it is likely that initial enthusiasm, derived from the primary study results, drove the rise of angioplasties with stenting during the end of the 1990s. However, after publication of the prospective randomized DRASTIC trial in 2000,9.van Jaarsfeld B.C. Krijnen P. Pieterman H. et al.The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis.N Engl J Med. 2000; 342: 1007-1014Crossref PubMed Scopus (811) Google Scholar in which medical treatment was shown to be as effective as angioplasty in patients with ARAS greater than 50%, the number of interventions decreased continuously until now in the United States.7.Kalra P.A. Guo H. Gilbertson D.T. et al.Atherosclerotic renovascular disease in the United States.Kidney Int. 2010; 77: 37-43Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar It will be of great interest in the near future to observe how the recently published prospective randomized studies—such as the ASTRAL and STAR trials, both comparing the best medical plus interventional treatment of ARAS with the best medical treatment alone—will impact the therapeutic behavior of physicians.10.Bax L. Woittiez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (537) Google Scholar, 11.Cooper C.J. Murphy T.P. Matsumoto A. et al.Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial.Am Heart J. 2006; 152: 59-66Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar Although the ASTRAL trial, with 806 patients, is still ongoing, initial results have been published as an abstract at the American Society of Nephrology Renal Week 2008. The authors could not find any effect of renal artery stent placement on mortality, renal function, or blood pressure in patients with ARAS greater than 70%. However, those patients who urgently needed renal artery revascularization because of malignant hypertension, fluid lung, or rapidly developing renal failure were excluded from the study by their treating physicians (K. Wheatley et al., 2008, abstr. F-FC206; Renal Week, 41st Annual Meeting and Scientific Exposition, Philadelphia, Pennsylvania, USA, 4–9 November 2008 (http://www.asn-online.org/press/Renal%20Week-08/14b-Atherosclerosis-Wheatley.pdf)). The STAR trial randomly assigned 140 patients with ARAS greater than 50% and impaired renal function (glomerular filtration rate >15 and <80 ml/min) for stent placement or medical treatment alone. After 2 years there was no difference between the two groups in the number of patients whose glomerular filtration rate fell by more than 20%, which was the primary end point of the study. Cumulative survival was similar in the two groups. Again, patients with malignant hypertension were excluded from the study.10.Bax L. Woittiez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (537) Google Scholar Now the epidemiological analysis of more than 16,000,000 patients in the United States, published by Kalra et al.,7.Kalra P.A. Guo H. Gilbertson D.T. et al.Atherosclerotic renovascular disease in the United States.Kidney Int. 2010; 77: 37-43Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar shows significantly lower adjusted hazard ratios for death of patients with ARAS who underwent renal revascularization compared with the total group of patients with ARAS. Although this retrospective analysis contains a bias toward selection of healthier patients for revascularization, it is important to ask the authors of the recent prospective randomized trials some questions—for example, whether patient selection was representative in their trials. I feel that, because of ethical problems, both studies did not include patients with clinically significant ARAS. Therefore interventional treatment did not differ from medical treatment. Finally, we have to wait for the results of the CORAL trial,11.Cooper C.J. Murphy T.P. Matsumoto A. et al.Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial.Am Heart J. 2006; 152: 59-66Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar the greatest study ever performed in the field of renal artery intervention, which is currently testing medical treatment versus stent placement in 1080 patients with ARAS greater than 60% (pressure gradient >20 mm Hg). The primary end point of this study will be cardiovascular mortality. If this study presents significant results, it is likely that epidemiological data might change in five years. Considering the recent results of the prospective trial, nephrologists must be careful to select those patients for interventional treatment of ARAS who urgently need revascularization of the renal artery.