1Deutsche Klinik für Diagnostik, Fachbereich Nephrologie, Wiesbaden, Germany and 2VI Medizinische Abteilung, Städtisches Klinikum Schwabing, München, Germany
Introduction
Atherosclerotic renal artery stenosis (ARAS) may cause ischaemic nephropathy and renovascular hypertension. Nephropathy and hypertension may occur separately or together [1]. In clinical decision-making about screening for and therapy of ARAS, we have to balance the chance of improving renal function and blood pressure with the risks of interventional procedures. Recent randomized studies comparing percutaneous transluminal angioplasty (PTA) with medical treatment of hypertension in patients with ARAS suggested no real short-term benefit of PTA [24]. These new results may be an incentive to abandon invasive strategies in many centres. In those studies [24] some subgroups of patients benefited from intervention. Therefore, the mystery of identifying these subgroups by clinical clues in combination with non-invasive imaging procedures has to be solved. The rapid progress in this field necessitates an update.
Diagnosis of atherosclerotic renal artery stenosis
Screening
The prevalence of ARAS is low in a non-selected population of hypertensive patients. Clinical characteristics can help to increase the probability of ARAS and thus the cost-effectiveness of non-invasive screening in patients with hypertension. Recently Krijnen et al. [5] described a clinical prediction rule for renal artery stenosis, which has been derived from 477 hypertensive patients who underwent renal angiography.
All patients had drug-resistant hypertension or renal failure due to ACE-inhibitor treatment. A complex score was developed based on age, gender, presence of atherosclerotic vascular disease, onset of hypertension within 2 years, body mass index <25 kg/m2, presence of abdominal bruit, serum creatinine concentration as well as the serum cholesterol level [5]. Despite its complexity, this score had a sensitivity of only 68% and its specificity was 87%. This thorough analysis shows that clinical parameters can increase the pretest probability for ARAS but do not resolve the dilemma that even patients with a low score may have ARAS. Therefore, we need non-invasive testing for ARAS in drug-resistant hypertension and in unexplained renal insufficiency, as is indicated by a further large study on more than 1000 patients [6].
Non-invasive testing
We will focus on four non-invasive tools for the diagnosis of ARAS which are either morphological (magnetic resonance angiography (MRA) and spiral computer tomography angiography (CTA)) or functional (colour coded duplex sonography (CDS) and captopril renography (CR)) [7]. However, recently it has been shown that MRA with high-end-machines is able to obtain haemodynamic parameters of renal artery stenoses [8]. Moreover, in a swine model of renal artery stenosis, electron-beam CT could quantify intrarenal haemodynamics and tubular function [9]. If these pilot studies are confirmed, the morphological diagnostic tools may soon give haemodynamic information of ARAS. This could facilitate the non-invasive grading of the stenosis which is important for further work-up.
CDS is an elegant non-invasive method to obtain blood flow profiles in the main renal arteries and in the intrarenal vessels [1012]. In the past, a high inter-observer variability and technical failure due to obesity and bowel gas were frequent limits to this technique [13]. However, technical progress with better machines and operator technique have overcome these disadvantages. Intrarenal Doppler signals of segmental renal arteries can be obtained in almost every patient [14]. Intrarenal resistive index (RI), calculated from the signals of the segmental renal arteries, can detect ARAS with a sensitivity of 70% to 93% and a specificity of 90% to 96% [10,12]. CDS is also safe to diagnose intrarenal stenoses [14]. In a recent study, an intrarenal RI >0.8 of the contralateral kidney did predict interventional treatment failure in all patients with ARAS [11]. If those results stand the test of time, we have an excellent method to exclude screened patients from further invasive measures. It is of note that CDS is the most cost-saving tool to screen for ARAS [15] and allows non-invasive follow-up of patients after intervention, even after the placement of stents.
Renography without and with captopril has been used to screen for renovascular hypertension for many years. Sensitivity and specificity vary with different laboratories and tracers from 43% to >93% [7]. The hypothesis that CR detects renin-dependency and therefore treatable renovascular hypertension was not borne out by data. Insufficient sensitivity in patients with renal failure as well as renin-independent hypertension in patients with ARAS are reasons for some authors to refuse to use CR as a screening procedure [1].
Spiral CTA is a reliable test to image main and accessory renal arteries. Combining different modalities of reconstruction, the sensitivity and specificity are around 95% [16,17]. Aortorenal calcification can be better quantified and located by CTA than by any other method including intra-arterial angiography [18]. This information is important for stent placement because calcifications in the aortic wall necessitate longer stents [19]. Fast CT scanners are also able to quantify renal perfusion and segmental renal function [9,20]. This functional information may facilitate the decision for further work-up of patients with significant ARAS. However, the amount of contrast medium used for CTA is high. Patients at risk of ARAS often have pre-existing renal insufficiency and the potential nephrotoxicity of contrast agents limits the use of CTA.
MRA with gadolinium-based contrast is without risk of nephrotoxicity. Using two ways to analyse MRAtime-of-flight and phase-contrast-sequencesARAS can be diagnosed with a sensitivity and specificity of 90% to 100% [7,17]. Schoenberg and co-workers [21] recently introduced a haemodynamic grading of renal artery stenosis using flow signals with the phase-contrast-technique. The flow pattern of the MRA signals, with a post-stenotic parvus and tardus pattern is very similar to the flow pattern obtained with CDS in patients with higher grades of stenosis. The major drawback of MRA is the limited visualization of the intrarenal arteries which, in many cases, are not amenable to invasive therapy anyway. However, an intrarenal stenosis can be detected by intrarenal CDS via a lateral approach [14].
With present-day technology and experienced operators, CDS is the best available technique to screen for renovascular hypertension and to exclude patients with an RI >0.8 for further work-up because they are unlikely to benefit from invasive therapy. If CDS is not available, CR may be useful if an institution has a high success rate with that technique. If further morphological or haemodynamic information is required in patients, in whom intervention is intended, MRA or CTA (excluding patients with renal failure) should be performed as the new non-invasive gold standard. Intra-arterial angiography should be restricted for PTA and stenting and should not be used only to confirm a suspected ARAS.
Therapy
Over the last decades it was common practice to treat patients with ARAS by invasive therapy, initially by surgery and, since the 1980s, by percutaneous transluminal angioplasty (PTA) without or with stents (PTA-S). Despite a high level of technical achievement over the years, randomized trials that compared invasive with conservative therapy (i.e. with antihypertensive drug treatment) were published only very recently [3,4,22]. In contrast to observational studies, the randomized trials uniformly demonstrated that blood pressure control and renal function are not very different whether an invasive or a conservative approach is taken as the first step in managing a patient with renal artery stenosis. These challenging results, based on relatively small sample sizes (n=5576), were confirmed by the largest randomized trial done so far in 106 patients with renal artery stenosis who were followed for 1 year [2]. The latter trial, however, made it clear that a conservative approach is hampered by: (i) a higher number of antihypertensive drugs than there would be with invasive therapy; (ii) a surprisingly high number of patients (about 50%) that have to undergo PTA because of uncontrolled blood pressure; and (iii) a higher number of renal artery occlusion during 12 months follow-up. Also, the study showed [2] that more patients in the invasive than in the conservative group experienced improved blood pressure control while mean blood pressure, the primary outcome of that particular trial, was not different. A further critical aspect is the inclusion of patients with a stenosis of 50% likewise in other studies. The inclusion of low-grade stenosis (<70%) increases the risk of recruiting without haemodynamic effects.
The above cited controlled trials did not use stents, which provide a significant reduction of the restenosis rate to around 20% especially of the prevalent ostial type of ARAS [19,23]. Unfortunately, the much better technical success of PTA-S vs PTA did not correlate with the clinical outcome in a randomized comparison of 84 patients [23]. Others confirmed that the anatomic result of PTA, or PTA-S for that matter, did not predict clinical outcome [2]. Even progressive renal failure may not be prevented after successful and lasting dilatation of a stenosis [24] especially in patients with chronic renal insufficiency and GFR <30 ml/min [25].
Even though, finally, results of some randomized trials are available, the primary outcomes of those trials were blood pressure and change in serum creatinine. To answer more important questions, namely about prevention of cardiovascular complications and of end-stage renal disease, all above cited trials were underpowered, especially because follow-up was 1 year or less. In patients with ARAS, the common wisdom that lowering of blood pressure will reduce cardiovascular risk is not self-evident. Almost all of those patients exhibit extrarenal atherosclerotic disease, often severe, which predisposes them to a very high cardiovascular event rate [3,25]. These events may be largely independent of blood pressure control and some events, including cholesterol embolism, myocardial infarction or death, may even be provoked by invasive procedures. Therefore, we need a large outcome trial with several years of follow-up in patients with ARAS to gauge the real benefit and harm that invasive and conservative therapy offer.
Conclusion
We are slightly less confused, at present, about atherosclerotic renal artery stenosis. While waiting for randomized trials with long-term follow-up, we must treat patients with ARAS by all measures that may possibly reduce their atherosclerotic burden, including smoking cessation, LDL-cholesterol <100 mg/dl, blood pressure below 140/85 mmHg, ACE-inhibition if tolerated, possibly low-dose aspirin, and folate administration. If we achieve these goals and the patient has no history of worsening renal function or flash pulmonary oedema, we may stick to conservative therapy (Table 1). However, as will often happen, if blood pressure cannot be controlled by drugs, PTA-S should be offered to the patient without much ado, if the intrarenal RI is <0.80. If it is >0.80, invasive therapy should be administered as ultima ratio. If further studies confirm the outstanding predictive value of the RI we may totally abandon invasive therapy when the latter is >0.80.
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Notes
Correspondence and offprint requests to: Bernd Krumme MD, Deutsche Klinik für Diagnostik (DKD), Fachbereich Nephrologie, Aukammallee 33, D-65191 Wiesbaden, Germany. Email: Bkrumme{at}aol.com
References