Atherosclerotic renal artery stenosis and reconstruction

http://www.kidney-international.org & 2006 International Society of Nephrology mini review Atherosclerotic renal artery stenosis and reconstruction B Krumme 1 and J Donauer 2 1 Deutsche Klinik für Diagnostik, Division of Nephrology and Hypertension, Wiesbaden, Germany and 2 University of Freiburg, Department of Medicine, Freiburg, Germany Renal artery stenosis is common especially in patients with generalized atherosclerosis. It is frequently associated with difficult-to-treat hypertension and with renal failure. There is an ongoing debate about the appropriate screening and treatment of atherosclerotic renal artery stenosis. Advances in imaging and interventional devices offer new opportunities, however, clinicians still have to decide individually in every patient to treat or not to treat stenosis with revascularization. This review evaluates the current literature in order to help the physician to find the right decision in this challenging clinical issue. Kidney International (2006) 70, 1543 1547. doi:10.1038/sj.ki.5001836; published online 20 September 2006 KEYWORDS: renal artery stenosis; renovascular disease; renovascular hypertension; ischemic nephropathy Correspondence: B Krumme, Division of Nephrology and Hypertension in Deutsche Klinik für Diagnostik, Von Leyden-Str. 23 D-65191 Wiesbaden, Germany. E-mail: Krumme@nephrologie-wiesbaden.de Received 28 April 2006; revised 17 June 2006; accepted 21 July 2006; published online 20 September 2006 Atherosclerosis is the main cause of renal artery stenosis. The lesions mostly occur in ostial segments of the renal artery and represent extension of adjacent aortic atherosclerotic plaque. 1 Renovascular disease may induce renovascular hypertension as well as ischemic nephropathy, an increasingly recognized cause of end-stage renal failure in the US. 2 This article will focus on the management and treatment of patients with atherosclerotic renal artery stenosis (ARAS) rather than on patients with fibromuscular dysplasia, which was recently reviewed in depth. 3 Despite extensive research there is still a controversy concerning the appropriate treatment of patients with ARAS. Physicians have to balance for their patients the chances of improvement regarding blood pressure and renal function versus risks and costs of intervention. Efforts have focused on finding reliable clinical parameters as well as improved diagnostic techniques for predicting the outcome of ARAS, 4 8 however, ideal solutions have not yet been found. It is of note, that ARAS may occur alone (isolated anatomical renal artery stenosis) or in association with hypertension, renal insufficiency (ischemic nephropathy), or both. 9 Hence screening tests for ARAS as well as interventional procedures have to be discussed in the light of the outcome of renovascular hypertension and ischemic nephropathy. Additionally it is worth taking in consideration the high cardiovascular mortality of patients with ARAS and its potential pathophysiological background. At present it is uncertain, whether renovascular reconstruction can improve the high mortality of these patients. Patients with ARAS are mainly older than 60 years and frequently suffer from widespread coexistent vascular disease. Five-year-survival has been found to be as low as 45% in patients with bilateral ARAS, 10 decreasing to only 18% in those requiring dialysis therapy. 11 SCREENING FOR ARAS In clinical practice it is essential to select patients with a high likelihood of ARAS for the further screening. A clinical score, developed by Krijnen et al., 4 may help in patient selection. However, it is of note, that this score was evaluated in a preselected population with a high probability of ARAS, because only those patients with refractory hypertension or an increase of creatinine after therapy with angiotensin-converting enzyme inhibitors were included into the study. 4 This bias Kidney International (2006) 70, 1543 1547 1543

m i n i r e v i e w B Krumme and J Donauer: Atherosclerotic renal artery stenosis may have influenced the prevalence of ARAS, evaluated with this score. Nevertheless, it seems useful to rely on several clinical parameters, which increase the likelihood for patients to have ARAS (Table 1). It is of note, that smoking as well as a low body mass index less than 25 kg/m 2 are predisposing factors for ARAS. 4 Meanwhile several non-invasive tests, such as captopril test, color duplex sonography, captopril scintigraphy, computed tomography angiography, and magnetic resonance (MR) angiography are available, most with excellent accuracy. Intra-arterial angiography including the measurement of the pressure gradient is still the gold standard for the diagnosis of ARAS, however, the diagnostic accuracy of even this invasive procedure is also operator dependent. 12,13 Usually renal arteriography is only indicated, if angioplasty or stenting is intended. Recently in a meta-analysis Vasbinder et al. 6 compared color duplex sonography with other non-invasive tests by analyzing the area under the receiver operator curve of these screening tests. They found computed tomography angiography and MR angiography with higher diagnostic accuracy than color duplex sonography for the diagnosis of ARAS. Captopril scintigraphy and captopril test were less accurate than color duplex sonography in this metaanalysis. However, diagnostic accuray may be only one of several arguments, which lead the clinician to his favorite screening method. Other criteria may be local availability of the test and personal experience with it, as well as aspects of cost benefit. There are some clear advantages for using color duplex sonography as the first screening test of ARAS. Sonography is an economic test, giving information about the hemodynamic significance of stenosis and avoiding nephrotoxic contrast media. In addition it is useful for the follow-up after renal artery stenting. 14,15 If direct visualization of the renal arteries (Figure 1) is combined with intrarenal scanning of the kidney, both accessible within Table 1 Clinical findings compatible with atherosclerotic renal artery stenosis Hypertension Abrupt onset of hypertension at or after the age of 50 years Accelerated or malignant hypertension Refractory hypertension (not responsive to therapy with X3 drugs) Renal abnormalities Unexplained azotemia Azotemia induced by treatment with an ACE inhibitor Sonographic length of the kidney o8 cm Other findings Unexplained congestive heart failure or acute pulmonary edema Abdominal bruit, flank bruit, or both Systemic atherosclerotic vascular disease Severe retinopathy Current or former smoker Low body mass index (o25 kg/m 2 ) ACE, angiotensin-converting enzyme. 0.64 T1/ 1/ 3/VV:3 1/2 CD:2.5 MHz CD Verst = 50 0.64 4.0 m/s 1.0 TAMX = 2.23 m/s Max = 3.36 m/s Min = 1.64 m/s PI = 0.77 RI = 0.51 S/D = 2.05 PW: 2.5 MHz θ=31 HPRF 11:37:05 am 4V2 49 H4.0 MHz R11 mm 48 ABDOMEN NEU ABDOMEN2 47 45 Speichert 46 Geschw.= 50 mm/s Figure 1 Color duplex sonography of right-sided ostial renal artery stenosis. High peak systolic velocity of 3.36 m/s is obtained within in the stenosis. The green color indicates high blood flow velocity with turbulences near the stenosis. Low mean resistive index (RI ¼ 47) of the right kidney is an indirect sign of significant stenosis. 30 min of examination time, color duplex sonography has a sensitivity and specificity of 90%, respectively, which is appropiate for a single screening test for ARAS. 16 Currently, it is at issue whether or not color duplex sonography is useful to predict the outcome of revascularization of ARAS. 17,18 A single study showed a high predictive value of resistive index, obtained in the segmental renal arteries with color duplex sonography, 8 however, subsequent studies could not confirm these results. 19 21 High operator dependency of color duplex sonography is often felt to argue against this diagnostic tool in the screening for ARAS. This argument, however, is referring to data of the older literature, when high-end sonographic machines with better penetration of the Doppler beam and faster hardware were not available. 22,23 Thus in recent years the success rate of sonographic visualization of the renal arteries has improved owing to further technical improvements as well as owing to broader operator experience. Additionally it is of note, that other renal imaging techniques, such as computed tomography angiography, and MR angiography, also show substantial operator dependency including the gold standard, as mentioned above. 12,13 Recently Vasbinder et al. 24 prospectively assessed the diagnostic validity of computed tomography angiography and MR angiography with two panels of three observers in 356 hypertensive patients who underwent digital subtraction angiography for detection of renal artery stenosis. Moderate interobserver agreement was found, with K values ranging from 0.59 to 0.64 for computed tomography angiography and 0.40 to 0.51 for MR angiography. Owing to the lack of clear evidence in the literature for diagnostic superiority of one technique, the physician, who has to screen patients for ARAS, will choose this technique, he is either performing himself (e.g., color duplex sono- 1544 Kidney International (2006) 70, 1543 1547

B Krumme and J Donauer: Atherosclerotic renal artery stenosis m i n i r e v i e w graphy) or that is easily available, reliable, and valid in his personal experience. TREATMENT OF ARAS Potential consequences of conservative management Many nephrologists tend to be conservative towards reconstruction of ARAS as some disappointing results were published in three randomized prospective studies, which compared medical treatment with angioplasty in patients with ARAS. 25 27 In all three studies there is no evidence that angioplasty improves the outcome of blood pressure in comparison to medical treatment. However, if the clinician prefers medical treatment, the natural history of ARAS has to be considered. It is of note that the progression of ARAS depends on the grading of stenosis at the time of the initial diagnosis. Caps et al. 28 monitored patients with ARAS by color duplex sonography during a 3-year follow-up. Progressive narrowing was reported in 18, 28, and 49% for renal arteries that initially were classified as normal, o60% stenosis, and X60% stenosis, respectively. However, approximately half of the patients do not show disease progression. Therefore the initial screening test should enable the clinician to perform a reliable grading of the stenotic lesion. If the renal artery is narrowed by 70 80%, a 40% decline in renal perfusion pressure occurs, termed critical stenosis. 22 It is of note, that several studies dealing with the treatment of ARAS, included patients with the lower limit of X50% stenosis. 8,25,27 Therefore some negative results should be cautiously interpreted. If the clinician favors conservative treatment, regular monitoring (e.g., every 6 months) is recommended to detect those patients with progression of ARAS. Currently color duplex sonography seems to be the ideal tool for this monitoring. 16 In the Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study, the largest of the three randomized studies, eight occlusions of renal arteries occurred in the group of patients with medical treatment in contrast to no occlusion in the group of patients with interventional treatment. 25 Medical treatment of patients with ARAS should also include statins as well as low doses of acetyl-salicyl acid in addition to the cessation of smoking, although any evidence from prospective studies showing significant benefit for these patients is missing. It is clinical common sense that aggressive lipid lowering may have the same effect of atherosclerotic regression in the renal arteries as it has been shown for coronary arteries. 29 Antihypertensive treatment may also include angiotensin-converting enzyme inhibitors in patients suspected for ARAS, if renal function, for example, serum creatinine, is controlled in a close period of time. Van de Ven et al. 30 investigated the effects on renal function in 108 patients at risk for severe bilateral atherosclerotic renovascular disease. In 62 of the 108 patients serum creatinine increased within 4 days or 2 weeks, respectively, however, no case of acute renal failure was encountered, because medication was stopped in time. 30 Regarding patient survival Conlon et al. 31 have shown in 3987 patients, who underwent abdominal aortography immediately following coronary angiography, that 4-yearadjusted survival of patients with 50, 75, and X95% ARAS was 70, 68, and 48%, respectively. Some recent data from the literature may help to understand this obvious relationship between stenotic grading and patient survival. Higashi et al. 32 have shown that excessive oxidative stress is involved, at least in part, in impaired endotheliumdependent vasodilatation in patients with renovascular hypertension. Recently Wright et al. 33 found significantly more cardiovascular comorbidity in 79 patients with ARAS than in 50 control patients (78.5 versus 46%). Patients with ARAS had greater prevalence of left ventricular hypertrophy and left ventricular diastolic dysfunction, greater left ventricular mass index, and left ventricular end-diastolic volume index than control subjects. The higher levels of angiotensin II in patients with ARAS may explain several morphological and functional abnormalities in these patients. Further studies should reveal, whether renal artery reconstruction improves patient survival, which has not yet been clearly shown. A meta-analysis of the three randomized trials comparing medical treatment with balloon angioplasty in a total of 210 patients may give a hint in this direction. 34 The authors reported 10 major cardiovascular or renovascular complications in the balloon angioplasty group, compared with 26 in the medical therapy group, which might have been significantly different, if a larger group of patients would have been studied. 34 In summary of the current data it can be concluded that medical treatment of ARAS is not without risk for the patients. The choice of treatment In 1993 a randomized study compared the outcome of angioplasty with that of surgical reconstruction of ARAS in 58 patients less than 70 years. The primary and secondary patency rates of surgery were significantly higher than those of angioplasty, for example, 96 and 97% versus 75 and 90%, respectively. 35 However, renal artery stent placement was not routinely available at that time. ARAS typically occurs in elder patients (470 years) with an increased risk of cardiovascular and cholesterol-embolic complications during surgical repair of the renal artery. Nevertheless even younger patients with complex renovascular diseases, for example, renal artery aneurysm or failed endovascular procedures, still have a benefit from renal artery surgery. As the introduction of stents patients with ostial ARAS, frequently showing the problem of elastic recoil after angioplasty, should be treated by primary stent placement. 15 However, it is of note that a prospective randomized study comparing renal artery stenting with angioplasty alone at 6 months follow-up did not show any difference of blood pressure outcome between both groups, although the primary patency rate was significantly improved in the patients with stents (75 versus 29%, respectively). 36 Kidney International (2006) 70, 1543 1547 1545

m i n i r e v i e w B Krumme and J Donauer: Atherosclerotic renal artery stenosis Renovascular hypertension Three single randomized trials did not find any beneficial effect of angioplasty concerning the outcome of blood pressure in comparison to medical treatment. 25 27 However, two meta-analyses of these studies, each involving a total of 210 patients, both found a significantly better reduction of blood pressure with angioplasty, rather than with medical treatment. 34,37 It can be hypothesized that the number of patients in each randomized trial was to low to show any difference of both treatments. For the daily practice, perhaps, we can learn something from important details of the DRASTIC study. From 50 patients originally assigned for drug therapy 22 patients underwent angioplasty after 3 months, because diastolic blood pressure was 95 mm Hg or higher despite treatment with three or more antihypertensive drugs. 25 At this time, before angioplasty was performed in the 22 patients, systolic and diastolic blood pressure as well as the number of antihypertensives were statistically different from those of the 28 patients, who exclusively received medical treatment. After 12 months the final intention-to-treat-analysis of the entire group of 50 patients showed no difference of blood pressure, which may have been influenced by the changes of treatment. These data clearly demonstrate that even those patients with intractable hypertension may have a high likelihood of benefit from reconstruction of the renal artery. Ischemic nephropathy Significant ARAS potentially increases the risk of renal atrophy as well as progressive loss of renal function. In none of the three prospective randomized studies there was any consistent change in renal function between the angioplasty and medical-therapy groups. 25 27 However, evaluation of renal function was not the primary end point and probably the follow-up of the mentioned studies (6 12 months) was too short to detect any difference. Additionally it is noteworthy that patients with severe renal dysfunction were excluded in all three studies. The slope of decline of the glomerular filtration rate in the recent history of patients with ARAS seems to be more important rather than the level of renal function at the time of admission. Beutler et al. 38 prospectively studied the longterm effects of stenting on kidney function in patients with renal insufficiency and ostial ARAS. During a 1-year followup in 26 of 56 patients with previous stable renal dysfunction renal artery stenting did not improve serum creatinine levels. However, in the remaining 30 patients with previously deteriorating renal function serum creatinine significantly improved after stenting und remained stable during followup monitoring. In another group of patients with global renovascular obstruction (bilateral stenosis or ARAS in the presence of a solitary or single functioning kidney) the previously negative slope of reciprocal serum creatinine became positive in 18 of 33 patients and less negative in additional seven patients. 39 In conclusion the change of serum creatinine, especially in the recent patient s history, is rather more important for the physician than the absolute level of kidney function. CONCLUSION Atherosclerotic renovascular disease, commonly seen in clinical practice, is in part a progressive disorder associated with increased cardiovascular morbidity and mortality. Physicians have to distinguish patients with a high likelihood of treatment benefit from those with incidental ARAS. 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