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De lo nuevo ... lo mejor |
Atherosclerotic
renal artery stenosis: how big is the problem, and what
happens if nothing is done?
Textor, Stephen C
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De lo nuevo ... lo mejor |
Textor, Stephen C
Renal artery stenosis is a common problem, particularly for patients with other manifestations of atherosclerosis. Wide practice variations are apparent regarding how best to manage this disorder. Part of this variation is based on a broad range of clinical presentation, from incidentally identified disease of no clinical importance to rapidly progressive hypertension, renal failure, and refractory congestive heart failure. Advances in antihypertensive therapy, particularly as a result of angiotensin-converting enzyme inhibition and angiotensin receptor blockade, have led to improved blood pressure control and delayed recognition of renal artery disease. As a result, patients now sent for revascularization are older than before and have high comorbid disease risk, primarily related to cardiovascular events. Clinicians need to be vigilant for evidence of unsuspected renal artery stenosis as a cause of treatment-resistant hypertension and/or renal failure. Renal revascularization should be considered in viable individuals before the development of advanced renal insufficiency.
Recent improvements in diagnostic imaging have increased our understanding of the prevalence of renovascular disease. Numerous techniques, using both invasive and non-invasive methodologies, have been developed to visualize and characterize the renal vasculature. These techniques demonstrate that the more you look for renovascular disease, the more you will find it. The real issues facing clinicians are deciding when to evaluate a particular patient, determining the true significance of any abnormalities found, and ascertaining the most appropriate therapeutic regimen and follow-up.
The etiology of the renovascular disease must be considered. The risks for disease progression and renal dysfunction are quite different for atherosclerotic and fibromuscular disorders . Most renovascular disease is atherosclerotic in nature, and the treatment of this form of the disease is most in question. Fibromuscular disease is far less common. It is typically bilateral and, as a clinical entity, usually occurs in younger women with hypertension. There is significantly less debate about the appropriate management of fibromuscular disease. Since it responds reasonably well to interventional therapy, most experts favor this therapy without much hesitation.
Atherosclerotic renal artery stenosis is a function of aging – the older the patient, the greater the likelihood of high-grade stenosis. In a recent multicenter, longitudinal cohort evaluation of cardiovascular risk factors, 870 free-living adults aged > 65 years underwent renal duplex sonography; 834 of the scans (96%) were technically adequate for renal artery evaluation [1]. High-grade renovascular disease, defined as >= 60% diameter-reducing renal artery stenosis or occlusion, was detected in 6.8% of the study cohort [1]. In univariate analyses, this prevalence was unaffected by race (Caucasian or other racial background, 6.9%; African American, 6.7%; P = 0.933); however, there was a trend for an increased prevalence in men (9.1%) versus women (5.5%; P = 0.053) [1]. In multivariate analysis, only increasing age (P = 0.028), high-density lipoprotein cholesterol levels < 40 mg/dl (P = 0.003), and increasing systolic blood pressure (P = 0.007) were independently associated with the prevalence of high-grade renovascular disease [1].
Atherosclerotic renovascular disease is one component of a generalized disease process. Consequently, the prevalence of this disease is more common in patients with other forms of atherosclerosis. In one evaluation, 47% of hypertensive patients referred for coronary angiography for ischemic heart disease had at least some degree of atherosclerotic renovascular disease detected when screened with abdominal aortography at the time of catheterization [2]. Moreover, 19.2% of these patients had >= 50% renal artery stenosis, 7% had high-grade stenosis (> 70%), and 3.7% had bilateral disease [2]. In multivariate analysis, systolic blood pressure (P = 0.02), history of stroke or transient ischemic attack (P = 0.01), and cancer (P = 0.04) independently correlated with the presence of >= 50% renal artery stenosis [2]. Remarkably, all of these cases were unsuspected. These were patients with hypertension and symptoms limited to coronary disease; there was no primary search for renovascular disease.
The prevalence of renovascular disease is even greater in patients with aortoiliac disease. In a retrospective review, some degree of renal artery stenosis was detected in 96 of 201 patients (48%) who underwent abdominal aortography for aortoiliac disease; 26% had >= 50% stenosis; and 21% had >= 70% stenosis [3]. In addition, 40 patients (20%) had bilateral stenoses, including four with bilateral stenoses >= 70% [3]. Similar findings are seen in other evaluations [3].
The implications of these results are enormous. By simply evaluating patients with other forms of vascular disease, unsuspected renal artery disease will be discovered in a large percentage of patients. The corollary, however, is equally important. The risk of other atherosclerotic disorders is significantly increased in patients with atherosclerotic renovascular disease, and systemic atherosclerosis may complicate the endovascular or surgical repair of the renal artery stenosis. depicts a patient with bilateral renal artery stenosis and diffuse vascular disease. The expected risks and benefits of intervention should be carefully evaluated before determining whether renal revascularization in such a patient should even be considered. Clearly, this intervention should not be undertaken lightly.
Considering the variety of clinical situations in which renovascular disease may be suspected and identified, it should not be surprising that different subspecialists sometimes reach different conclusions regarding appropriate indications for revascularization. Interventional radiologists and cardiologists tend to be enthusiastic about endovascular repair; they view it as an opportunity to protect the kidney, preserve kidney function, improve blood pressure control, and reduce the tendency for refractory heart failure. They argue that the approach to renal artery stenosis should be the same as for most other vascular lesions. In other major arteries, physicians would try to eliminate a symptomatic obstruction.
About 10 years ago, nephrologists experienced a surge of enthusiasm for interventional therapy for ‘preservation of renal function’. However, most have since become more conservative in their management approach. Now, nephrologists commonly first meet the patient after the vascular intervention, often after complications of the procedure are fully manifest. Instead of an improvement, they see patients with a substantial loss of kidney function, some of which may be a direct result of the intervention. They argue that restenosis of the renal artery may develop, that an implanted stent may thrombose, and that absolute levels of improvement in blood pressure, heart failure, or renal function may be arguable at best.
When different groups of clinicians reach different conclusions from the same data, it is likely that the data are inconclusive. The use of peripheral angioplasty procedures varies significantly depending on geographic region. Medicare claim data from 1996 were used to derive ratios of peripheral angioplasty rates in each of the 306 United States hospital referral regions to the average rate in the entire United States [4]. In total, > 37 000 procedures were performed with a 14-fold variation in the angioplasty rate by region (median 12/10 000 beneficiaries; 10th-90th percentile, 4.1-57.9) [4]. Moreover, in regions where cardiologists performed >= 50% of the procedures, the mean angioplasty rate was almost double that in regions where they performed none (21.9 vs. 12.1 procedures/10 000 beneficiaries; P < 0.001) [4].
Evaluating therapeutic options for renal artery stenosis involves several factors. First, it is important to remember that the clinical manifestations of renovascular disease cover a broad range . It is likely, perhaps even probable, that many of the lesions seen are truly incidental. They do not produce symptoms and may have little, if anything, to do with the clinical issues facing the patient. These lesions must be distinguished from lesions that produce renovascular hypertension or threaten the viability of the kidney. It is important for clinicians, and especially primary care physicians, to recognize when renovascular disease begins to accelerate cardiovascular events. When a patient with stable hypertension suddenly develops accelerated hypertension and/or suffers a stroke, it should raise the possibility that unsuspected renal artery stenosis has reached a critical level. Physicians need to recognize where their patients fit on the spectrum of clinical manifestations of renovascular disease, monitor for a change in status, and determine when intervention should be considered.
The demographics of patients undergoing renovascular intervention have changed considerably over the past 50 years (Fig. 4) [5]. When revascularization of the kidneys first became practical, the patients undergoing this procedure had mean reported ages in the 40s and 50s, much younger than patients who are now undergoing interventional procedures. Angioplasty has allowed older, higher-risk patients to be treated without surgery, and subsequent improvements in surgical technique, as well as the introduction of stents, have further contributed to a shift in this mean age. Today patients are typically in their late 60s or early 70s at the time of intervention, and frequently have comorbid diseases and risks that are much more substantial than those of patients in their 40s and 50s. The data from earlier evaluations, therefore, cannot be automatically extended to the current patient population.
The predictive effect of renovascular disease on survival must also be considered. There is a steady attrition rate in patients managed both with and without renal revascularization. Patients with high-grade, bilateral renal artery stenosis have reduced survival as compared with those with unilateral disease, regardless of whether renal revascularization is performed [6]. This increased mortality is related to cardiovascular mortality and other cardiac events associated with this disorder. Renal insufficiency, through a variety of mechanisms, contributes to both generalized atherosclerosis and left ventricular hypertrophy. In a prospective evaluation of 261 patients with renal artery stenosis who were treated with percutaneous transluminal renal artery angioplasty with renal artery stenting and followed for a mean of 21 months, the baseline renal status, determined by creatinine clearance, was a significant predictor of major cardiovascular events, including cardiovascular, renal, and all-cause mortality [7]. Moreover, even in patients with pre-intervention and post-intervention creatinine clearance > 40 ml/min, cumulative event-free survival was only approximately 50% at 50 months [7]. Thus, even with successful intervention, cardiovascular risk remains elevated. Intervention, however, did influence this risk to some degree. Patients with normal or mildly impaired renal function, whose renal function worsened post-intervention, had a greater risk of adverse events than patients whose renal function remained stable post-intervention (31% vs. 19%; P < 0.05) [7]. Conversely, patients with moderate to severe renal impairment, whose renal function improved post-intervention, had a trend for event reduction compared with patients whose renal dysfunction remained unchanged (50% vs. 23%; P = 0.06) [7].
This high intrinsic mortality rate is partly a function of the pathophysiology of this disorder. The presence of high-grade renal artery stenosis causes the activation of a number of key pressor systems [8]. The renin–angiotensin–aldosterone system (RAAS) is central to initiating this pathophysiology. Over the past decade, we have learned that angiotensin has numerous other detrimental effects in addition to its effects on blood pressure regulation, including remodeling of both blood vessels and the myocardium.
The benefits of RAAS inhibition are greater than would have ever been predicted, with implications for the diagnosis and management of renovascular disease. Before the development of angiotensin-converting enzyme (ACE) inhibitors, approximately 50% of patients did not achieve blood pressure control with medical therapy [9]. These patients could not be protected from malignant hypertension; bilateral nephrectomies were sometimes performed as a life-saving measure. Since the introduction of ACE inhibitors and other classes of drugs that block the RAAS, reasonable blood pressure control can be obtained in most patients with pharmacologic therapy. In multiple studies, ACE inhibitor-based regimens are 80–96% effective in controlling blood pressure in patients with renovascular hypertension [8–10]. Intervention is rarely required now primarily for controlling blood pressure. Other factors must be considered in deciding when and in whom interventional therapy is appropriate.
Renal failure is one such potential factor. In the Heart Outcomes Prevention Evaluation trial, a significant mortality benefit was seen with RAAS inhibition in patients with vascular disease [11]. This trial excluded patients with severe renal insufficiency (baseline serum creatinine > 2.3 mg/dl); however, approximately 11% of patients had mild renal insufficiency (baseline serum creatinine >= 1.4 mg/dl) [11]. Compared with subjects with normal renal function, this mild degree of renal insufficiency significantly increased both all-cause and cardiovascular mortality (both P < 0.001), and this effect was independent of known cardiovascular risk factors and treatment [11]. ACE inhibition with ramipril attenuated this high cardiovascular risk. In fact, the beneficial effects of ramipril were greater in these patients than in patients with normal renal function [11]. As the authors suggest, renal dysfunction not only does not preclude ACE inhibitor use, it may be an indication for using it.
These findings have changed the landscape of renovascular disorders. Patients with renovascular hypertension are now treated with medical regimens even though most cases are never identified. Drugs, including ACE inhibitors, effectively treat hypertension, and since kidney function remains reasonably stable, no further testing is done. A small group of patients with resistant hypertension syndromes, more common than currently believed, needs further evaluation and attention.
The likelihood of disease progression needs to be considered when evaluating treatment options. Natural history data demonstrate that atherosclerotic renal artery disease can be a progressive disorder [12]. In one prospective study using Doppler ultrasound, the overall cumulative incidence of progression was 35% at 3 years and 51% at 5 years [12]. Although these data are frequently cited to support the concept of disease progression, they also show that approximately 50% of patients will not have disease progression over a 5-year period. Moreover, the risk of disease progression is directly related to the degree of stenosis at baseline. In the preceding evaluation, the 3-year cumulative incidence of progression was 18%, 28%, and 49% for patients with normal renal arteries, < 60% renal artery stenosis, and >= 60% renal artery stenosis at baseline, respectively (P = 0.03; [12].
Renal atrophy can be viewed as a consequence of progression. Its risk is greatest in patients who have the most severe lesions at baseline, and even in these patients only a small subset develops atrophy. In an evaluation of 122 subjects followed for a mean of 33 months, the 2-year cumulative incidence of renal atrophy, defined as a reduction in renal length >= 1 cm, was 5.5%, 11.7%, and 20.8% for kidneys with normal renal arteries, < 60% renal artery stenosis, and >= 60% renal artery stenosis at baseline, respectively (P = 0.009) [13].
A measurable change in renal function is less common than progression or atrophy. Chábová et al. [14] reported follow-up data on 68 patients with high-grade (> 70%) renal artery stenosis; the mean age at study entry was 72 years, and the mean duration of follow-up was 39 months. Although the average number of blood pressure medications did rise slightly from 1.6 to 1.9 (P = 0.02), blood pressures were unchanged during the follow-up period [14], demonstrating that blood pressure can be managed reasonably well in most of these patients. During this follow-up period, the mean serum creatinine increased from 1.4 to 2.0 mg/dl (P < 0.001) [14]. This increase resulted from deterioration in a small group of patients. Serum creatinine remained stable throughout the follow-up period in 58 of 68 patients (85%); in the remaining 10 patients, serum creatinine increased by > 50%, and six patients developed end-stage renal failure [14]. A subset of patients may benefit from revascularizing the kidney, but this subset is fairly small, probably <= 10%. Finally, although mortality in this group is quite high (28%), the mean age at the time of death was 78 years [14]. These patients are at high risk of mortality independently of their renal artery stenosis, and it is not known whether intervention would have significantly improved their chance of survival. This 3-year mortality rate compares favorably with published mortality rates following intervention [7,15,16].
Given these findings, it is hard to argue that every patient with incidental renal artery stenosis should undergo repair. Who are appropriate candidates? Several identifiable groups of patients are likely to benefit from renal revascularization. In most patients, renovascular hypertension is effectively controlled by RAAS inhibition. Patients who fail to respond to adequate medical therapy within a reasonable time period or who stop responding to this therapy are candidates for revascularization. depicts the blood pressure response of one such patient who had diabetes and coronary artery disease [17]. An incidental renal aortogram, performed as part of a cardiac catheterization 3 years before referral, revealed high-grade renal artery stenosis on the left and moderate stenosis on the right. Despite these lesions, his blood pressure was adequately controlled with atenolol, his kidney function was stable, and nothing further was done at that time. However, approximately 3 months before referral, enough progression had occurred to accelerate his hypertension. The patient's blood pressure began to rise, and he was no longer responsive to increasing medical therapy. He then underwent percutaneous transluminal renal angioplasty stent with a good technical result; effective blood pressure control was restored and subsequently maintained with no further change in medications. When following patients with hypertension, it is important that primary care physicians recognize that this blood pressure response pattern may be due to severe progressive renovascular disease. These patients should be referred for evaluation and possible vascular intervention.
Patients are also candidates for intervention when the entire renal mass is affected, either through bilateral disease or disease of a solitary kidney. Untreated, these patients are at high risk for morbidity and mortality. Antihypertensive therapy may lead to progressive renal failure, and renal failure may limit antihypertensive therapy. For example, the risk of acute functional renal failure may preclude the use of ACE inhibitors in these patients. In addition, these patients tend to have significant circulatory congestion and flash pulmonary edema, and are more likely to develop end-stage renal failure. depicts the beneficial effects of intervention in a 64-year-old man with a solitary functioning ischemic kidney due to total occlusion of the right renal artery and high-grade stenosis of the left renal artery [18]. This patient's blood pressure was poorly controlled, and his serum creatinine was > 6 mg/dl. Intervention was recommended, and his left renal artery was stented successfully. Within 1 month, renal function and blood pressure control significantly improved, and this improvement has been maintained for > 5 years. The improvement in renal function permitted the initiation and long-term use of ACE inhibitors. Intervention can be beneficial in these patients, if they are identified and treated before irreversible kidney disease develops.
An algorithm proposed for the initial evaluation and treatment of renovascular disease [6]. Patients with hypertension, with or without a drop in glomerular filtration rate, should receive vigorous antihypertensive therapy combined with aggressive lipid reduction and smoking cessation. In most patients, these treatments will be adequate. Patients need intermittent reevaluation and continuously optimized medical therapy. If at any time, blood pressure control or renal function stability becomes questionable, the possibility of high-grade renovascular disease must be considered. Based on appropriate diagnostic evaluations and the patient's comorbid risk, intervention may be necessary.
Renovascular disease is a component of the global atherosclerotic process and is commonly seen in clinical practice. Its manifestations are varied and range from asymptomatic ‘incidental’ renal artery stenosis to end-stage renal disease and/or accelerated cardiovascular disease. Clinicians must be able to recognize the range of manifestations of this disease and evaluate where their patients are on this disease spectrum. In addition, they must understand the risks for disease progression and the risks and benefits of renal revascularization. Renal revascularization is indicated whenever medical therapy is not successful.
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Journal of Hypertension - December2005
