Scoble J.E.: The epidemiology and clinical manifestations of atheroscle- rotic renal disease. In: Renal Vascular. Disease. Novick A., Scoble J.,. Hamilton G. W.B. ...
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JBR–BTR, 2004, 87 (1)
RENOVASCULAR HYPERTENSION: DIAGNOSTIC AND THERAPEUTIC CHALLENGES J.L. Bosmans, M.E. De Broe1 Atherosclerotic renal artery stenosis (ARAS) is associated with two common clinical syndromes: renovascular hypertension and ischemic nephropathy, which often coexist. The ensuing renovascular disease constitutes the fastestgrowing etiology of end-stage renal disease. Diagnostic work-up for hemodynamical significant renal artery stenosis should be restricted to patients suspected to be at moderate or high risk for renovascular disease. Patients at moderate risk should first undergo a screening test, like Doppler ultrasonography or captopril-enhanced scintigraphy. In case of a positive screening test, renal artery imaging with either spiral computed tomography angiography or magnetic resonance angiography with Gadolinium is indicated. Patients at high risk for renovascular disease may be directly referred for intra-arterial renal artery angiography, the golden standard diagnostic procedure. A renal artery stenosis with narrowing of > 50-60% of the lumen, is considered hemodynamically significant, and may be suitable for treatment with angioplasty or angioplasty plus stent placement (in case of osteal renal artery stenosis). The therapeutic approach of the hypertensive patient with a hemodynamically significant renal artery stenosis is currently a matter of great debate. In any case optimal medical therapy with antihypertensive, lipid-lowering, and platelet-inhibiting drugs should be instituted, since such approach may not only prevent the progression to endstage renal disease, but may also prevent the progression of extra-renal vascular disease, which affects the majority of these patients. Current evidence suggests that angioplasty (with additional stent placement in case of osteal renal artery stenosis) may benefit a subset of patients with significant RAS, i.e. patients with a resistance index < 80% at the level of the segmental renal arteries, and patients with bilateral RAS or patients with unilateral RAS with a unique functioning kidney. Prospective, randomized and controlled studies with clearly defined clinical endpoints are needed to better define the absolute and relative indications of angioplasty (plus stenting) in the setting of renal artery stenosis. Key-words: Hypertension, renovascular – Renal angiography – Magnetic resonance (MR), treatment planning – Computed tomography (CT), treatment planning.
Renovascular disease constitutes the fastest growing etiology of endstage renal disease in Western countries (1), and is frequently associated with extensive atherosclerosis, affecting the carotid, coronary and peripheral arteries (2). It is present in 10-40% of the patients with endstage renal disease (3, 4). Renovascular disease is associated with renovascular hypertension and ischemic nephropathy, two dis-
tinct clinical entities, which often coexist in the same patient (5). Renovascular hypertension refers to an elevation of the arterial pressure, precipitated by a hemodynamically significant stenosis of a renal artery or arteries, and is mediated by an activation of the renin-angiotensin system in the affected kidney(s) (6). Although the degree of luminal narrowing at renal angiography, corresponding to a
From: 1. Department of Nephrology and Hypertension, University Hospital Antwerp, Belgium.
hemodynamical significant stenosis, is currently not well defined, several data point out that narrowing of more than 50-60% of the lumen, or a pressure gradient greater than 15 mm Hg within the vessel, may induce renovascular hypertension (6, 7). The diagnosis of renovascular hypertension is usually retrospective, since it involves the demonstration of a cure or considerable improvement in high blood pressure level after correction of a narrowed renal artery (7). The two main causes of renovascular hypertension are fibromuscu-
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lar dysplasia, which affects mainly Caucasian women between 20 and 50 years and is often bilateral and situated in the more distal portion of the renal artery and atherosclerosis, which accounts for more than two thirds of cases of renovascular hypertension, most commonly involving the renal ostium and/or the proximal third of the artery, which develops in older people, with a male/female ratio of 2/1. Ischemic nephropathy develops at a later stage of atherosclerotic renal disease, when both kidneys are involved (5). The majority of these patients have also extensive atherosclerotic disease of extrarenal arteries. The present review intends to discuss which patients may benefit from a diagnostic work-up for renovascular disease, and when revascularization should be considered in patients with significant renal artery stenosis. Patients at risk for renovascular disease Although the prevalence of atherosclerotic renal artery stenosis is steadily increasing in the general population (8), renovascular hypertension still accounts for only 1 to 5% of all the cases with arterial hypertension (9). In contrast, the prevalence of renovascular hypertension may increase to values between 20 and 50%, when considering patients with severe or refractory hypertension (10). It therefore appears that diagnostic work-up for renovascular hypertension may only benefit a selected subpopulation of hypertensive patients, i.e. those patients at moderate or high risk for renovascular
disease (11). Such selection of risk patients is imperative, since it not only improves the predictive value of screening tests, used in the setting of renovascular hypertension (12), but it also contributes to constrain the screening costs (13). Ideally, this selection should be based on rigorously defined and well-established clinical criteria. Although there is no unanimous agreement about the clinical selection criteria for screening for renovascular hypertension, most physicians agree with the criteria proposed by Mann and Pickering (14), which are summarized in Table I. Multiple criteria may co-exist in the same patient, thereby increasing the probability for renovascular disease. Diagnostic approach of the patient with suspected renovascular hypertension Patients with a low risk profile for renovascular hypertension, do not require a diagnostic work-up in the initial phase, but may benefit from antihypertensive treatment and regular follow-up. Diagnostic workup must be considered, when these patients present an evolutive risk profile during follow-up. In contrast, patients at moderate and high risk for renovascular disease may benefit from additional investigation for RAS. Although several tests were developed in the past, current evidence suggests that ACE-inhibition renal scintigraphy and Doppler ultrasonography are the two most suitable screening tests for the detection of renovascular hypertension (11). Patients at moderate risk for renovascular disease are most likely to benefit from scree-
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ning for renovascular hypertension, since these tests may not only enhance the likelihood for significant RAS, but may also predict the response to revascularization (15-17). ACE-inhibition renal scintigraphy is a functional test, providing information on renal function and size, with delayed uptake and prolonged parenchymal uptake of the radionuclide after ACE-inhibition in case of severe RAS (18). Sensitivity and specificity of this test vary among different laboratories and tracers from 45 to > 90% (11). While the negative predictive value of this test for RAS > 70% is as high as 90%, its positive predictive value is only around 70% (19). The predictive value of ACEinhibition renography regarding blood pressure improvement after revascularization was reported to be 92% in patients with normal renal function (15), but could not be confirmed in a more recent study (20). Moreover, ACE-inhibition renography has several limitations, such as the lack of direct visualization of the stenotic lesion, the need for interruption of ACE-inhibitors, ARB’s and diuretics 48 h prior to the study, and decreased accuracy in patients with GFR < 30 ml/min or bilateral renovascular disease (11). Doppler ultrasonography combines direct visualization of the renal arteries with measurement of various hemodynamic changes in the main renal arteries, providing both a structural and a functional assessment of renovascular hypertension (16). The combination of peak systolic velocity > 2 m/sec at the level of the renal artery, and a side-to-side difference of intrarenal resistive index > 5%, has a sensitivity of 89% and a specificity of 92% for the detection of unilateral RAS
Table I. — Clinical risk stratification for renovascular hypertension. Low Borderline and mild hypertension without hypertensive target-organ damage Moderate Severe hypertension (diastolic blood pressure > 120 mm Hg) Hypertension refractory to standard antihypertensive treatment Hypertension with abdominal or flank bruit Moderate hypertension in patients with occlusive vascular disease (abdomen or legs), and in patients with unexplained renal failure High Severe hypertension, with either progressive renal insufficiency, or refractoriness to combination therapy with 3 antihypertensive drugs Accelerated or malignant hypertension (severe retinopathy) Unexplained flash pulmonary edema Hypertension with an ACE-inhibitor or ARB-induced acute renal failure Moderate and severe hypertension with asymmetry of renal size
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> 70%. The reported positive predictive value of this test was 92%, and the negative predictive value 88% (16). However, Doppler ultrasonography has several limitations, such as interference of bowel gas and abdominal obesity with adequate visualization of the renal arteries, the operator-dependent accuracy of the measurements, and the timerequirement (21). In contrast, Doppler-ultrasonography has also many advantages, since it allows non-invasive follow-up of patients after revascularization (22), it is noninvasive, does not require discontinuation of antihypertensive drugs, and does not involve exposure to radiation or radiocontrast (21). Moreover, Doppler-ultrasonography was recently shown to predict the outcome of revascularization for renal-artery stenosis (17). According to this study, a renal resistanceindex value of at least 80 reliably identifies patients with renal-artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure, or kidney survival. The choice between ACE-inhibition scintigraphy and Doppler ultrasonography may not only depend on the local availability and expertise at each centre, but may also be determined by patient-characteristics, such as obesity or advanced renal failure. Patients at moderate risk for significant RAS with a negative screening test do not require additional diagnostic work-up, but need adequate antihypertensive treatment and regular follow-up. In contrast, patients at moderate risk with a positive screening test, and patients at high risk for RAS, should be referred for renal artery imaging. Two non-invasive radiologic techniques, i.e. spiral computed tomography and magnetic resonance angiography, allow to adequately visualize the ostium and the proximal segments of the renal arteries, which are affected in the majority of the patients with atherosclerotic renovascular disease (21). Spiral computed tomography allows to rapidly acquire volumetric images by moving the beam (or patient) continuously in a helical manner across a region of interest during a single bolus of contrast (23). Compared to conventional angiography, the golden standard diagnostic procedure, spiral computed tomography has a sensitivity of 98% and a specificity of 94% for the detection of renal artery stenosis
JBR–BTR, 2004, 87 (1)
(24). The requirement of 130-150 ml contrast is the major clinical drawback of spiral computed tomography angiography, and makes this diagnostic procedure less suitable for patients with impaired renal function (21). Magnetic resonance angiography with Gadolinium, a non-nephrotoxic contrast medium, allows to adequately visualize the proximal portion of the renal arteries (25). The sensitivity and specificity of MRA are between 90 and 100% (11). In contrast to the spiral computed tomography angiography and the renal angiography, MRA can be performed without any risk for nephrotoxicity in patients with impaired renal function (26). However, MRA is less accurate for the diagnosis of more distal lesions of the renal artery, such as in fibromuscular dysplasia, and MRA often fails to detect accessory renal arteries (11). Intra-arterial angiography remains the golden standard diagnostic procedure for the evaluation of renal artery lesions. The main limitations of this diagnostic procedure are its invasiveness, the potential for contrast-induced nephrotoxicity, and the risk of complications, such as bleeding at the puncture site and cholesterol embolism. Patients suspected for fibromuscular dysplasia and patients with normal renal function at high risk for RAS are good candidates for renal angiography. Therapeutic approach of the patient with suspected renovascular hypertension Theoretically, three therapeutical strategies could be considered in patients with hypertension and significant RAS, i.e. medical therapy, angioplasty (with or without stenting), and bypass surgery. However, due to the perioperative morbidity and mortality (ranging between 2.2 and 7.8%), surgical aorto-renal bypass is no longer considered as a first line therapy (27). Whether renal angioplasty (with or without stenting) provides a better outcome, in terms of blood pressure, renal function, and kidney survival, compared to optimal medical therapy remains a matter of intense debate. Although recent studies report excellent primary patency rates with stenting of 94-100%, with less than 20% restenosis over 2 years (28), there is currently insufficient evidence of a clear benefit of revascularization over medical
management of atheromatous renovascular disease in unselected patients. In uncontrolled studies, angioplasty (with or without stenting) cured hypertension in less than 20%, with improvement in around half of the patients (29, 30). Three prospective randomized controlled trials showed a small reduction in number of antihypertensive drugs, but no significant improvement of the blood pressure in patients treated with angioplasty (20, 31,32). The beneficial effects of angioplasty on the renal function is even less clear, since one randomized controlled study showed no improvement at all of the renal function (20), while another study reported renal function improvement in 40 to 55% of patients, and deterioration in 14 to 30% (33). Obviously, more prospective randomized controlled studies are needed to better define which patients with severe renal artery stenosis may benefit from renal angioplasty (with or without stenting). In any case, optimal medical therapy should be achieved, since such strategy may not only slow down the progression of the renovascular disease, but may also have beneficial effects on extra-renal vascular sites, which are often affected in patients with atherosclerotic disease. Such medical treatment should not only include antihypertensive drugs, but also lipid-lowering and platelet-inhibiting drugs. Angioplasty is currently the treatment of choice in patients with fibromuscular dysplasia, since success rates of 82-100% have been reported, and recurrence rates are as low as 10% with this technique (5). Angioplasty (with or without stenting) is likely to be beneficial in patients with RAS and a resistance index below 80% (17), in patients with RAS and medically uncontrolled hypertension, in patients with RAS and progressive renal failure, in patients with RAS and unexplained flash pulmonary edema, and in patients with bilateral significant RAS, or in patients with unilateral RAS on a unique functioning kidney (5). Conclusion Current evidence suggests that patients with significant renal artery stenosis represent a heterogeneous group in terms of response to revascularization. Doppler ultrasonography appears to be helpful to predict
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which subgroup of patients may benefit from angioplasty (with or without stenting). Since this test is highly observer-dependent, the current results need to be confirmed by larger, multicentric studies.
13.
14.
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