Relationship of renal dysfunction to proximal arterial disease severity in atherosclerotic renovascular disease

Mathavakkannan Suresh1, Paul Laboi1, Hari Mamtora2 and Philip A. Kalra1,

1 Departments of Renal Medicine and 2 Radiology, Hope Hospital, Salford, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Renal impairment is common in patients with atherosclerotic renovascular disease (ARVD), but its pathogenesis is uncertain. This study investigated whether any relationship existed between renal function and the severity of proximal renal arterial lesions in patients with ARVD.

Methods. A cohort of 71 patients had creatinine clearance measured at the time of digital subtraction angiography; eight patients were diabetics and were excluded from further analysis. The severity of proximal renovascular lesions was estimated by standard methodology, and patients were sub-grouped according to residual patency of the proximal renal arteries (e.g. normal=2.0; unilateral occlusion )RAO(=1.0). Renal bipolar lengths at ultrasound were also assessed.

Results. Sixty-three non-diabetic patients (mean±SD age 67.7±5.8 years; 34 males) were suitable for study. No differences in renal function (mean±SD creatinine clearance (ml/min)) were seen between patients with unilateral (32.1±18.9, n=36) or bilateral (31.7±20.9, n=27) disease, or between sub-groups with RAS <60% (28.3±13.9, n=15), unilateral RAS >60% (38.9±24.6, n=12), bilateral RAS >60% (36.3±20.4, n=6) or unilateral RAO (30.3±17.7, n=28), and mean average renal size similarly did not differ between the sub-groups. No correlation existed between residual patency and creatinine clearance (r=0.015); mean±SD renal function was almost identical in the four patency sub-groups, and average renal size mirrored this pattern. Mean 24-h urinary protein excretion was similar for the four groups, but patients with minimal ARVD had significantly less comorbid vascular disease.

Conclusions. These findings suggest that the severity of proximal renal artery lesions is often unrelated to the severity of renal dysfunction in patients with ARVD. Associated renal parenchymal damage is the more probable arbiter of renal dysfunction, and this should be considered when revascularization procedures are contemplated.

Keywords: atherosclerotic renovascular disease; bipolar renal length; creatinine clearance; proximal lumen patency; renal function; renal parenchymal damage; ultrasound



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Atherosclerotic renovascular disease (ARVD) is common, frequently associated with other vascular pathologies, and is particularly prevalent in ageing populations. It is commonly associated with chronic renal failure [1] and it probably accounts for over 15% of all patients with end-stage renal failure (ESRF) and more than 25% of the elderly dialysis patients in some centres [2]. However, despite the high prevalence of these patients, the pathogenesis of the renal dysfunction that occurs in association with ARVD is still not fully understood.

The natural history of proximal arterial lesions in ARVD has previously been defined by non-invasive [3] and invasive [4] studies that have demonstrated a rapid rate of progression of high-grade renal artery stenoses (RAS) to renal arterial occlusion (RAO) with consequent loss of functioning renal mass. This has underpinned the rationale of maintaining renal arterial patency by angioplasty, with or without endovascular stent placement, in order to preserve renal function in patients with severe RAS. However, more recent studies, performed in an era when aspirin and lipid-lowering therapy are widely used in patients with ARVD, show a lower rate of RAS progression [5] and that other factors, such as hypertension, may be more important than RAO in determining progression to renal atrophy.

Further, outcomes in ARVD seem to vary; some patients with severe proximal artery lesions maintain well-preserved renal function, yet others with lesser lesions can still progress to ESRF. This has been highlighted by isotopic techniques that estimate single kidney glomerular filtration rate (SK-GFR) [6]. The effects of revascularization with renal angioplasty [7,8], stenting [9], or renovascular surgery [10,11] upon renal functional outcome are similarly unpredictable. Thus, although individual patients with ARVD have been rescued from dialysis treatment by surgery [12] or angioplasty, the majority of patients manifest no improvement in renal function, or indeed, some show progressive renal functional decline, after revascularization. There is now an increasing recognition that, in many patients with ARVD, the extent of renal parenchymal injury rather than the severity of proximal vascular lesions is the chief determinant of renal functional outcome. This study sought to investigate the relationship of renal dysfunction to the extent of proximal arterial lesions in a cohort of patients with ARVD.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A cohort of 71 patients with varying degrees of ARVD entered the local renovascular disease database between 1995–1997. They had all been referred with either hypertension or chronic renal failure. Renal arterial anatomy was investigated by digital subtraction angiography, the studies being interpreted by a single vascular radiologist who was blinded to the renal functional data. The percentage stenosis of any given RAS was estimated by standard methodology; the reference diameter was the renal artery luminal diameter immediately distal to the stenosis (excepting cases with post-stenotic dilatation, in which case the diameter immediately distal to the dilated segment was used):

(00A)

The renal angiographic findings were categorized as unilateral or bilateral disease, taking account of whether the renal arterial anatomy demonstrated insignificant disease (normal vessel up to <25% narrowing), mild-moderate RAS (>25 to <60% stenosis), severe RAS (>60% RAS) or occlusion (RAO) in either or both arteries. As the purpose of the study was to examine the relationship between renal arterial anatomy and renal function at the time of angiography, a simple scoring system for proximal renovascular disease severity was developed which also denoted the residual lumen patency of the proximal renal arteries (patency index).

Examples of patency index calculation:

Bilateral normal arteries=2.0

Unilateral RAO (contralateral normal) or bilateral 50% RAS=1.0

Unilateral RAO with contralateral 60% RAS, or bilateral 80% RAS=0.4

Bilateral RAO=0.

Where a kidney was supplied by more than one renal artery, the residual patency was estimated from the proportionate narrowing of the total arterial supply of that kidney (e.g. if a kidney was supplied by two arteries, one having 80% RAS and the other being normal, the patency score for that kidney would be 0.6). Renal function was assessed by creatinine clearance just prior to the angiographic procedure. Bipolar renal length of all kidneys was determined by renal ultrasound and 24-h urinary protein excretion was also measured. Other demographic data including age at presentation, sex, blood pressure, and presence of other vascular disease (angina, myocardial infarction, or cerebrovascular or peripheral vascular disease) were also recorded. The renal function of patients with RAO was also further classified with respect to accompanying contralateral disease, as this provided an important insight into pathogenetic mechanisms.

Statistical analyses
Patients were stratified into sub-groups based upon their residual patency index; their clinical and investigational characteristics were compared in the context of these sub-groups. The angiographic findings were also represented in standard groupings (unilateral/bilateral, RAS <60%, RAS >60% or RAO), and renal function as well as renal size were also analysed between these groups. Means, standard deviations (SD), and median values are displayed where appropriate. Mean renal size for each sub-group was derived from the average ultrasound bipolar renal length (i.e. (right+left)/2) for each patient. Variables were analysed by two-way analysis of variance (ANOVA). When the ANOVA indicated significant differences among patient groups, differences in categorical data were analysed with {chi}2 tests. For continuous data, means were compared by t tests. A P value of less than 0.05 was considered a significant difference. A correlation study was used to test the relationship between renal function and residual lumen patency.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Diabetes was present in eight patients, and as the co-existence of diabetic nephropathy would have confounded the renal functional data, they were excluded from the study. Mean (±SD) age of the remaining 63 patients was 67.7±5.8 years and male (n=34) to female ratio was 1.2 : 1; 12 patients had been investigated for secondary hypertension (plasma creatinine <120 µmol/l) and 51 patients primarily for chronic renal failure.

The relationship between standard angiographic findings, renal function and ultrasonographic renal size is depicted in Table 1Go. The 36 patients with unilateral disease (i.e. insignificant RAS, significant RAS or RAO affecting one kidney, the contralateral vessel being normal) had similar renal function (creatinine clearance 32.1±18.9, range 3–66 ml/min) to the 27 patients who had bilateral disease (clearance 31.7±20.9, range 6–71 ml/min). Renal function was also remarkably similar when sub-group analysis compared patients with mild-moderate or severe RAS (in both unilateral or bilateral categories), and also those patients with unilateral RAO. There were no significant differences in renal length between patients with unilateral or bilateral RAS, but kidneys with RAO were significantly smaller (e.g. in the 28 patients with unilateral RAO, the RAO kidney was 7.68±1.3 cm compared to 10.02±1.15 cm for the contralateral kidney; P<0.001). These findings suggest that, with the exception of kidneys shrunken by RAO, chronic renal parenchymal damage is the chief determinant of renal dysfunction in patients with ARVD.


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Table 1. Angiographic classification of ARVD and renal function

 
The patency index enabled patients in different renovascular anatomical categories to be grouped together such that comparisons could be made according to overall renovascular disease severity. Table 2Go displays the clinical characteristics and basic investigations of the patients, as separated into four sub-groups by patency index. Hypertension (BP >160/90, or receiving treatment) was documented in 90% of patients; 44 (70%) patients had comorbid vascular disease. Patients with residual patency >1.5 had very mild ARVD (e.g. <50% narrowing of only one renal artery) whereas those in patency groups 0.5–0.9 and <0.5 had severe proximal ARVD. As was shown with respect to standard angiographic findings, renal function was completely independent of the severity of proximal ARVD (Figure 1Go), and the lack of correlation of creatinine clearance with residual lumen patency (r=0.015) is highlighted in Figure 2Go. This was further exemplified by the fact that four patients with lumen patency >1.5 had creatinine clearances of <20 ml/min and yet three patients with lumen patency <0.5 had clearances of >50 ml/min. Similarly, both the mean level of proteinuria and renal ultrasound size within each sub-group were not predictive of the severity of proximal ARVD. However, patients with the least severe ARVD had significantly less comorbid vascular disease than the other patient groups.


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Table 2. Residual proximal renal artery lumen patency and clinical characteristics of patients

 


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Fig. 1. Relationship of renal artery lumen patency to renal function in patients with ARVD. Patients are separated into sub-groups according to residual patency. Renal functional comparisons between the patency sub-groups were all non-significant.

 


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Fig. 2. Correlation study assessing the relationship of renal artery patency to renal function (creatinine clearance) in patients with ARVD. There was no significant correlation (r=0.015).

 
As it might have been anticipated that those patients with RAO would have more advanced renal dysfunction, these were also analysed separately. There were 28 patients with unilateral RAO, and their overall renal function (creatinine clearance 30.3±17.7; range 3–66 ml/min) was not different from any of the above patency groups. Seventeen of these patients had normal contralateral vessels, seven mild-moderate RAS, and four severe contralateral RAS; even allowing for small patient numbers, it was still surprising that renal function was very similar in these different sub-groups. In Table 3Go the RAO patients are separated according to the severity of contralateral renovascular disease. It can be seen that 14 patients with RAO had severe renal dysfunction (creatinine clearance of <25 ml/min) despite having normal or only mild-moderate RAS in the contralateral vessel, whereas three of the four patients with contralateral severe RAS had much better renal function than this, again stressing the importance of co-existing renal parenchymal injury in the pathogenesis of renal dysfunction in ARVD. There was a notable trend of mean contralateral (non-RAO) renal size becoming progressively smaller with worsening renal function; this supports the relationship of overall renal function with total renal mass, and is in accordance with the observation that renal atrophy may occur independently of RAS in ARVD [5].


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Table 3. Contralateral disease severity and renal function in patients with renal artery occlusion (RAO)

 
Renal biopsies were only available on four patients who had been suspected of having other co-existing renal disease (two had proteinuria >2 g/day, and the other patients no evident arterial bruits). Histopathological analysis revealed focal segmental glomerulosclerosis (one patient), glomerulosclerosis and tubular atrophy, compatible with ‘ischaemic nephropathy’ (two patients), and cholesterol atheroemboli (one patient).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study further emphasizes that factors other than the severity of proximal renal vascular lesions are likely to contribute to the pathogenesis of renal dysfunction in patients with ARVD, and the findings are therefore consistent with the variability of renal functional outcomes that follow revascularization procedures in these patients [13]. Restoration of renal artery patency in patients with high-grade RAS has been possible with surgical and angioplasty techniques for many years, and although an overall improvement in renal function may be seen after revascularization, sub-group analysis usually depicts a disparity in functional outcomes with the majority of patients showing no change after revascularization, whereas the remaining patients are equally divided into those manifesting progressive deterioration or definite improvement of renal function [7–10]. Patency is not always preserved after angioplasty alone as there is a strong likelihood of re-stenosis, especially in ostial lesions, but its use in combination with endovascular stenting yields high patency rates [14,15] and yet a similar stratification of renal functional outcomes [9,15]. Further, studies with SK-GFR have confirmed that angioplasty of a tight stenosis usually does not increase individual kidney function in patients with ARVD [6]. However, younger patients with fibromuscular dysplasia of the renal artery do show an improved SK-GFR after angioplasty, which could be explained by the presence of healthy renal parenchyma distal to the stenosis.

It is likely that the pathogenesis of renal dysfunction in patients with ARVD is multi-factorial. This has been inferred by Caps et al. [5] who used serial duplex ultrasound to examine factors that determine progression to renal atrophy in a cohort of patients with ARVD. The cumulative risk of renal atrophy was greatest in patients with poorly controlled hypertension; although kidneys with RAS >60% had a high rate of atrophy, the vast majority had not progressed to RAO. These data suggest that hypertension and ischaemia are likely to provoke renal parenchymal damage by different mechanisms. A limitation of the study was that although renal atrophy appeared to correlate with renal dysfunction, the possible contribution of injury (e.g. hypertensive damage) in the contralateral (non-atrophied) kidney was not excluded. Indeed, isotopic studies have shown that the SK-GFR may be similar in the paired kidneys from patients with high-grade unilateral RAS and normal contralateral vessel [6]. Further, SK-GFR may not correlate with bipolar renal length as determined by ultrasound [16].

In the current study, the severity of ARVD was described by both standard renal angiographic anatomy and by residual luminal patency. Although the study was only cross-sectional and the division of patients into sub-groups of differing patency was arbitrary, there was absolutely no relationship between proximal renovascular narrowing and overall renal dysfunction. Renal impairment was equally marked in patients with mild proximal ARVD as in those with severe bilateral disease, or in those patients who had unilateral RAO. Kidneys affected by RAO were significantly smaller than those with RAS, but just as for renal function, average renal size was not predictive of the sub-grouping of ARVD severity. Renal histology was only obtained in a minority of patients, but it was representative of the spectrum of changes described as ‘ischaemic nephropathy’ [17]. Perhaps the renal parenchymal damage might be more appropriately termed ‘atherosclerotic nephropathy’ [18] in some patients, as intra-renal atheroma, hypertensive damage, and cholesterol emboli may develop independently of the ischaemia that would be consequent upon a high-grade stenosis. Such a hypothesis would explain the findings of this and other [5,8,9,15] studies, as well as the previously described inconsistencies in renal functional outcome seen after revascularization in ARVD. Proteinuria has recently been shown to be a non-specific marker of this parenchymal damage in patients with ARVD [19].

Our findings suggest that underlying renal parenchymal damage is a major determinant of renal dysfunction in ARVD, and, with the exception of kidneys affected by RAO, it should be considered independently of the proximal renal arterial disease in these patients. Studies that help distinguish the varying contributions of renal ischaemia, hypertensive damage, and intra-renal atherosclerosis to the pathogenesis of renal dysfunction in these patients are now required. Only such clinicopathological clarity will enable appropriate selection of patients, and indeed, those particular kidneys, most likely to benefit from revascularization, thereby facilitating the chances of optimal long-term renal functional outcome after surgery, angioplasty, or endovascular stenting in the future.



   Notes
 
Correspondence and offprint requests to: Dr P. A. Kalra, Consultant Nephrologist, Department of Renal Medicine, Hope Hospital, Stott Lane, Salford M6 8HD, UK. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 30. 6.99
Revision received 3.12.99.