Prevalence of atherosclerotic renal artery stenosis in patients starting dialysis

Jacobine M. A. van Ampting1, Erik L. Penne1, Frederik J. A. Beek2, Hein A. Koomans1, Walther H. Boer1 and Jaap J. Beutler1,

1 Department of Nephrology and Hypertension, and 2 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Atherosclerotic renal artery stenosis (ARAS) can lead to end-stage renal failure (ESRF). We determined the prevalence of ARAS in patients 45 years of age or older starting renal replacement therapy.

Methods. Forty-nine of 80 consecutive patients (37 males, 12 females) starting renal replacement therapy in our centre gave informed consent and underwent spiral computed tomographic angiography of their renal arteries. A renal artery diameter reduction of 50% or more assessed by two radiologists was considered as a significant stenosis.

Results. Twenty of 49 patients (41%) had an ARAS, and in eight cases (16%) this was bilateral or unilateral with a single kidney. Women were more likely to have an ARAS than men; 75 (9/12) vs 30% (11/37, P<0.01). However, relatively more women declined participation. Non-participants and participants did not differ in respect to other relevant clinical data. Nonetheless, findings in these patients would be negative, the prevalence of ARAS would still be 31% in women and 22% in men (NS). In 13 patients with ARAS the registered diagnosis of ESRF either was hypertension, renovascular disease or unknown. Assuming that in these patients atherosclerotic renovascular disease was the cause of renal failure, a total of 13 patients (13/49, 27%) entered the dialysis programme because of this problem.

Conclusions. These results suggest that ARAS is an important cause of ESRF.

Keywords: atherosclerosis; renal artery stenosis; renal failure; renal replacement therapy



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Atherosclerotic renal artery stenosis (ARAS) is a progressive disorder, which may damage renal function with end-stage renal failure (ESRF) as ultimate manifestation [1,2]. Early detection and treatment possibly prevents progressive loss of renal function [3,4].

Studies in Europe and in the USA suggest that renal artery stenosis is a frequent cause of ESRF [59]. In the elderly it is probably the most common cause and the incidence is increasing faster than other causes of ESRF [911]. However, the true prevalence is still unknown: most data are based on uncontrolled local registries [5,6,9]. Only two studies were specifically designed to investigate the prevalence of ARAS in patients starting dialysis. Both were relatively small, and suffered from possible selection bias [7], or used indirect methods to diagnose renal artery stenosis [8].

We studied the prevalence of ARAS in patients 45 years of age or older who were soon starting renal replacement therapy. We used spiral CT angiography (SCTA), which has emerged as a highly accurate non-invasive method to visualize the renal arteries and to identify renal artery stenoses [12,13].



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
From July 1997 until January 1999, 80 consecutive patients of 45 years of age or older (51 males and 29 females) who were visiting the pre-dialysis outpatient ward of the University Medical Center Utrecht and who were scheduled for starting dialysis were asked to participate. The protocol was approved by the Institutional Ethical Committee for studies in Humans. Fifty-three patients gave written informed consent. Two patients died in the interval between selection and the diagnostic procedure. All other patients entered the dialysis programme. Forty-one patients underwent SCTA. To avoid contrast-induced nephropathy and need for dialysis SCTA was performed in the first weeks after initiation dialysis. In two patients the SCTA failed. In ten others no SCTA was performed because magnetic resonance angiography (MRA) or intra-arterial angiography had been performed in the 3 months preceding dialysis (n=4 and n=6, respectively) for clinical suspicion of renovascular disease. In total 49 patients could be evaluated for the presence of a renal artery stenosis.

Methods
For each included patient we examined all clinical data. Hypercholesterolaemia was defined as serum cholesterol levels of >6.5 mmol/l or the use of lipid-lowering drugs.

SCTA was performed with a commercially available scanner (Tomoscan SR 7000; Philips Medical Systems, Best, The Netherlands), according to our protocol as described before [13]. SCTA-, MRA- and intra-arterial angiography images were evaluated independently by two radiologists. A renal artery diameter reduction of 50% or more in the two-dimensional plane assessed by two radiologists was considered as a significant renal artery stenosis. A 50% reduction in the two dimensional plane corresponds with a 75% reduction of the arterial lumen, which has shown to be haemodynamically significant [14]. In case of disagreement about the presence of a significant stenosis a third radiologist evaluated these scans.

Statistical analysis
All values are expressed as mean±standard deviation. For the comparison of statistical significance between two groups, the Student's t-test was used. Differences between frequency distributions were tested by {chi}2 test or Fisher's exact test for small samples. A difference was considered significant if P<0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Of the 49 patients enrolled, 20 (41%) had a renal artery stenosis, of which 12 had unilateral disease, six bilateral disease and two a stenosis to a single kidney (Figure 1Go). All stenoses were judged to be caused by atherosclerosis. Women were more likely to have ARAS than men, 75 (9/12) vs 30% (11/37, P<0.01) (Figure 1Go, Table 1Go). The prevalence of bilateral ARAS or a stenosis in a single kidney was not significantly different between women and men (25%, 3/12 vs 14%, 5/37, NS). Relatively more women than men refused participation in this study, which could have introduced a bias. Except for this sex distribution, the clinical characteristics of the non-participants and participants were not different (Table 1Go). Nonetheless, even assuming that findings in all these patients would have been negative, the prevalence of ARAS would still be 31% (9/29) in women and 22% (11/51) in men (NS) and for bilateral ARAS 10% in both sexes (3/29 and 5/51, respectively).



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Fig. 1.  Patient selection, ESRF, end stage renal failure, ARAS, atherosclerotic renal artery stenosis.

 

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Table 1.  Baseline characteristics

 
In five of the patients with bilateral stenosis this diagnosis was not new: they previously (range 3 months to 2 years earlier) underwent treatment with arterial stenting or angioplasty, but nonetheless progressed to ESRF. Reinvestigation showed restenosis in three of them. In two re-angioplasty was tried without success; in the other patient no second attempt was made because of complicating cholesterol embolism. In the other three patients with bilateral stenosis, and all 12 patients with unilateral stenosis, this finding was new. In many of them, i.e. all subjects with bilateral and four with unilateral stenosis, the cause of the renal failure was unknown. Assuming that in these patients, and in the patients diagnosed with end-stage renal disease due to hypertension or renovascular disease, ARAS was the cause of renal failure, a total of 13 patients (13/49, 27%) entered the dialysis programme because of this problem. In the 31 patients who could not be studied six (19%) were diagnosed as such (unknown two, hypertension three and renal artery stenosis one).

Nearly all patients were hypertensive or treated for hypertension, irrespective of the presence of renal artery stenosis. The number of antihypertensive drugs and the duration of hypertension were not different between patients with and without ARAS. Prevalence of a history of diabetes, hypercholesterolaemia, smoking and presence of clinically manifest extrarenal atherosclerotic disease was also not different (Table 1Go). Mean pole-to-pole kidney size was significantly less in kidneys with a stenosis as compared with kidneys of patients without a stenosis (9.1±1.4 vs 10.0±2.6 cm, P<0.05). The survival rate 30 months after starting renal replacement therapy was not significantly different for patients with and without ARAS (65%, 13/20 vs 79%, 23/29).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study, we demonstrate that in patients >45 years starting renal replacement therapy the prevalence of ARAS is high. Forty-one per cent of the patients had at least an unilateral stenosis and 16% had bilateral stenosis or a stenosis in a single kidney. We were unable to scan 31 of the 80 elegible patients. Although their clinical characteristics with respect to age, renal diseases, risk factors for atherosclerosis and the presence of cardiovascular disease were not different from the investigated patients, this may have introduced a bias. But even if we assume that these patients had no renal artery stenosis the overall prevalence of ARAS was still 25%, and for bilateral ARAS 10%.

This is the first study in which all patients entering dialysis were investigated for the anatomical presence of a renal artery stenosis irrespective their renal diagnosis. We used SCTA as a minimal invasive method to visualize the renal arteries. It is a robust and highly sensitive and specific method to diagnose ARAS and it may be even superior to standard angiography [13].

The high prevalence of ARAS in patients starting with dialysis confirms the observations that renovascular disease might be an important cause of renal failure in the elderly. Reported estimations vary between 11.2 and 38.7% [510]. This wide range probably reflects the lack of uniformity in definition and mode of diagnosis in these studies (Table 2Go). In two registry reports using EDTA diagnostic code system [5,9] patients were classified as suffering from renovascular disease (without further precision) based on the physicians opinion of the most likely diagnosis. In Mailloux et al. [6] study the classification was based on either angiography, or a suggestive renography in the absence of significant proteinuria or abnormalities in the urine sediment. The estimated prevalence is these three studies was 11.2 [5], 18 [10] and 16.6% [6]. Scoble et al. [7] concluded from their angiographic study that atherosclerotic renal disease accounted for 14% of elderly patients starting dialysis. However, renal angiography was performed only if no other diagnosis was made or renovascular disease was suspected on clinical grounds. As in neither of these studies [57,10] the diagnosis of renovascular disease was considered or explored in case of another available diagnosis, the diagnosis of renovascular disease was probably underestimated.


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Table 2.  Prevalence of renal stenosis in patients starting dialysis; overview of published studies

 
Appel et al. [8] performed renal artery duplex studies in elderly patients starting dialysis irrespective of the diagnosis. The outcome, 22% for unilateral and 11% for bilateral stenosis was less than found in our study. Remarkably, no case of renal artery stenosis was found in Afro-Americans, who accounted for half of their patients. Consequently, the prevalence in Caucasians was about twice as large as the overall outcome, i.e. much like the figures presented by us. The higher figures found in the study by Appel et al. [8] and the present one indeed take into account that renal artery stenosis can also occur in patients in whom another diagnosis for their renal dysfunction has already been made. The only registry study showing a similar high figure of renovascular disease as found with systematic study concerns the regional Italian survey reported by Piccoli et al. [9]. Perhaps this reflects the relatively high age (>65 years) in that study.

Given the apparent abundance of atherosclerotic renal artery disease in elderly patients starting dialysis, two questions are important: was it the (main) cause of renal failure, and could angioplasty have prevented or postponed the need for dialysis. In 13 patients with ARAS the registered diagnosis of ESRF was either hypertension, renovascular disease or unknown. Assuming that in these patients ARAS was indeed the cause of renal failure, a total of 13/49 (27%) patients entered the dialysis programme because of this problem. In the 31 subjects who could not be studied, at least six (19%) fulfilled these criteria. Therefore, it is unlikely that the high frequency of ARAS in the patients who underwent SCTA was due to selection bias.

All 12 cases of unilateral stenosis were newly identified. In four of these no other cause of renal failure was known. Of course, this single abnormality cannot cause renal failure. On the other hand, it is well known that atherosclerotic renovascular disease is complex: it also involves renal parenchymal changes in ipsilateral as well as contralateral kidneys, due to, respectively, ischaemia or high perfusion pressure, in addition to metabolic factors and smoking [15]. The relevance of a unilateral stenosis for overall renal function thus depends upon the severity of parenchymal disease in the contralateral kidney. Indeed, we observed that many patients with unilateral ARAS and no apparent other renal disease display a decrease in renal function upon starting ACE-inhibition [16], or show a halt in progression of renal dysfunction upon stenting [3]. Conceivably, treatment of a single renal artery stenosis can also be beneficial to slow down progression of renal failure in patients who also have some other primary form of parenchymal disease, but that is difficult to prove and to our knowledge their are no examples reported in the literature.

Eight patients had bilateral ARAS and in seven it was the only recognized cause of renal failure. Five had been treated for ARAS in an earlier stage. Two of these had patent renal arteries at the time of starting dialysis and in another three re-stenosis was found but re-intervention was not successful or contra-indicated. In the remaining three patients with bilateral disease (38%) this was newly diagnosed. Our study was not designed to study the effect of rescue revascularization in these patients with terminal renal failure. In fact, our experience in that context is limited, and only few data are available in the literature. Altogether, the efficiency of rescue therapy, whether surgical or radiological, is limited and seems to be of benefit only in carefully selected patients with sufficient viable kidney mass [7,17]. One larger series in 20 patients presenting with ARAS and ESRF showed that surgical intervention could improve renal function, and 14 patients were still off dialysis one year later [18]. Based on this scarce information, it seems defendable to search for this diagnosis in cases of quickly progressing unexplained renal failure [18], in order to try rescue revascularization. That renal artery stenting at an earlier stage of renal dysfunction can stabilize or slow down progression has so far been shown only in uncontrolled studies [3,4,19]. Controlled studies are needed to answer the question whether early treatment is indeed helpful. An answer is much needed, as the efficiency of late rescue therapy is limited and mortality of patients with ARAS entering dialysis is relatively high [4,20].

A trend for a high mortality in patients with ARAS entering dialysis was also seen in present study: after 30 months 65% of the patients with renal artery stenosis were alive compared with 79% of the patients with other causes of renal failure. This survival rate was better than survival rate of 45% reported in the same category of dialysis patients 10 years ago in the US [20]. Most patients die from cardiovascular diseases. Possibly the more widespread use of statins, ACE-inhibitors and improvements in intervention cardiology is having a beneficial effect on survival.

In conclusion, ARAS may be an important cause of ESRF, and can also occur in patients with known causes of renal parenchymal disease.



   Acknowledgments
 
This study was supported by a grant from the Dutch Kidney Foundation (C99.1810).

Conflict of interest statement. None declared.



   Notes
 
Correspondence and offprint requests to: Dr Jaap J. Beutler, Department of Nephrology and Hypertension, University Medical Center Utrecht, Room F03.226, PO Box 85500, 3508 GA Utrecht, The Netherlands. Email: j.j.beutler{at}azu.nl Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 22. 7.02
Accepted in revised form: 27. 1.03