NDT Advance Access originally published online on September 2, 2005
Nephrology Dialysis Transplantation 2006 21(1):113-119; doi:10.1093/ndt/gfi083
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
Relationship between renal artery stenosis and intrarenal damage in autopsy subjects with stroke
1 Division of Hypertension and Nephrology, Department of Medicine and 2 Department of Pathology, National Cardiovascular Center, Suita, Osaka, Japan
Correspondence and offprint requests to: Satoko Nakamura, MD PhD, Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. Email: snakamur{at}hsp.ncvc.go.jp
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Abstract |
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Background. In patients with cardiovascular disease (CVD), renal dysfunction is a risk factor for the prognosis, but substantial evidence is still lacking about the relationship between clinical characteristics and renal histology. The aim of our study was to evaluate the relationship between the extent of renal parenchymal damage, renal artery stenosis (RAS) and clinical characteristics in autopsy subjects with stroke.
Methods. During the 17-year period 1980–1997, 2167 subjects were autopsied at the National Cardiovascular Center. We studied retrospectively all the autopsy cases aged 40 years and older who had a history of stroke. Thus, 346 subjects remained and they were classified into two groups. Thirty-six subjects had RAS (group A). Three hundred and ten subjects had no RAS, and we randomly chose 102 subjects among them (group B). We evaluated renal parenchymal damage using a semi-quantitative chronic damage score.
Results. The average overall chronic damage score was significantly higher in the stenosed kidneys of group A than in the non-stenosed kidneys of group B (9.0±2.6 vs 7.0±2.7). The contralateral kidneys of group A had a tendency to have milder renal damage than stenosed kidneys. Furthermore, the total score was higher in the subjects with hypertension, diabetes mellitus, proteinuria, renal insufficiency and CVD than in the subjects without such complications. The total score had a significant association with RAS, proteinuria, renal insufficiency, CVD and weight of the kidney.
Conclusions. In autopsy subjects with stroke, we demonstrated that co-existing renal parenchymal damage was more severe in the subjects with RAS, hypertension, diabetes mellitus, proteinuria and renal insufficiency than those without such complications. The presence of RAS, impaired renal function and proteinuria was closely correlated with the severity of renal parenchymal damage.
Keywords: atherosclerosis; autopsy; chronic damage score; renal artery stenosis; stroke
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Introduction |
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In Japan, as well as in the USA and Europe, the number of patients with end-stage renal disease (ESRD) requesting renal replacement therapy is increasing annually [1,2]. Major causes of this increase are thought to be associated with hypertension and diabetes. In addition, atherosclerotic renal artery stenosis (RAS) has also been recognized to be commonly associated with ESRD. The prevalence of atherosclerotic RAS increases with age, particularly in patients with diabetes, cardiovascular disease (CVD) or hypertension [3]. It has been estimated that ischaemic renal disease due to atherosclerotic renovascular disease including RAS may account for 5–22% of patients with ESRD who are older than 50 years [4,5]. RAS frequently complicates patients with CVD, including myocardial infarction, stroke and progression of heart failure. RAS exists in 10–20% of patients with CVD such as myocardial infarction or stroke, as we previously reported [6,7]. Several angiographic studies reported that the prevalence of RAS ranges from 11 to 42% in patients with generalized arterial disease [3–5].
Primary diseases of the renal arteries often involve the large renal arteries. However, most of the patients with atherosclerotic disease had impaired renal function despite having no significant large RAS. Such a secondary disease is frequently characterized by small vessel and intrarenal vascular disease. Evidence now suggests that in the majority of patients with atherosclerotic RAS, the cause of chronic renal disease is unlikely to be simply the ischaemic effect of a proximal RAS. It is now recognized that intrarenal damage, with or without small vessel disease, is a major contributor to renal impairment [8]. Such renal parenchymal injury has been termed ‘ischaemic nephropathy’ [9], and histological changes include a constellation of interstitial fibrosis, tubular atrophy, glomerulosclerosis (including focal segmental glomerulosclerosis), periglomerular fibrosis and a variety of arteriolar abnormalities. Ischaemic nephropathy is defined as an obstruction of renal blood flow that leads to ischaemia and excretory dysfunction. The relationships among renal excretory dysfunction, RAS and clinical characteristics are complex. In contrast, renal dysfunction is less common with fibromuscular dysplasia than atherosclerotic RAS, suggesting that atherogenic factors serve to increase renal injury.
It is likely that many cases of atherosclerotic RAS are never detected because refractory hypertension or renal failure does not develop, and the mechanism and the pathological feature remain unclear. There are few reports which have investigated the relationship among the pathological findings, atherosclerotic RAS and clinical characteristics. The aim of our study was to assess the correlation among severity of intrarenal damage, RAS and clinical characteristics in autopsy subjects with stroke.
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Methods |
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Study subjects
During the 17-year period 1980–1997, 2167 subjects were autopsied at the National Cardiovascular Center in Suita City, Osaka, Japan. We studied retrospectively all the autopsy cases of subjects aged 40 years and older who had a stroke any time in their past medical history. Subjects with nephrectomy (n = 8), horseshoe kidney (n = 2), renal cell carcinoma (n = 5) or dissecting aneurysm of the aorta involving the renal artery (n = 2) were excluded from this study. We also excluded subjects without precise information on the renal artery (n = 14) and appropriate renal specimens for analysis (n = 17). Thus, 346 subjects remained and they were classified into two groups. Thirty-six subjects had RAS (group A); 26 subjects had unilateral and 10 subjects had bilateral renal artery disease. Three hundred and ten subjects had no RAS, and we randomly chose 102 subjects among them (group B). We studied these two groups.
Hypertension was defined as a patient's use of antihypertensive medication and/or having a well-established history of elevated casual blood pressure 
140/90 mmHg. Diabetes mellitus was defined as a patient's use of oral hypoglycaemic agents or insulin, and/or having a fasting glucose level >126 mg/dl or random non-fasting blood glucose level >200 mg/dl. Hypercholesterolaemia was defined as a patient's taking lipid-lowering agents and/or having a serum cholesterol level >220 mg/dl. Proteinuria was diagnosed as a urinary protein level >0.5 g/day, and renal insufficiency as a serum creatinine level >1.5 mg/dl. To exclude patients with glomerulonephritis from our study population, we excluded those patients with macroscopic haematuria using the urine paper strip test. We estimated the creatinine clearance (ml/min) according to Cockcroft and Gault with the following formula: [140 – age (years)] x body weight (kg)/[72 x serum creatinine (mg/dl)]. A correction factor of 0.85 was used for females. Laboratory data, including serum creatinine, cholesterol, glucose and urinalysis, were collected within 1 year before the fatal event that led to death (i.e. septicaemia and multiple organ failure). The types of aortic aneurysm were diagnosed from the autopsy findings that showed dilation of the aorta. Peripheral vascular disease was diagnosed by subjective and objective complaints and findings arising from leg ischaemia or an ankle/brachial artery index <0.9. Coronary artery disease was diagnosed from the autopsy findings that showed the luminal area narrowing by >75%.
Autopsy study
According to the regulations of our pathology department, the autopsy examination was performed as soon as possible after the patient's death, and the mean duration was 2.7±2.3 h (range 0.5–5 h). The renal arteries and kidneys were removed on block. The bilateral renal arteries were dissected to examine the presence of stenosis. Macroscopically apparent stenosis of the renal artery with >75% narrowing in the luminal area was considered significant. Of these 346 patients, 36 patients had atherosclerotic RAS. Finally, 138 subjects (36 subjects with RAS and 102 subjects without RAS) were subjected to histological analysis. The renal outer cortex was examined, and 100–150 glomeruli were studied.
For light microscopic study, paraffin-embedded renal tissues obtained by standard autopsy methods were cut at 2 µm thickness and stained with haematoxylin–eosin (HE), periodic acid–Schiff (PAS) and Masson trichrome. Two independent pathologists who were blinded to the clinical information analysed the histopathological findings in the renal block. A semi-quantitative chronic damage score according to the method of Wright et al. [10], which was a modified version of the Banff classification of renal allograft pathology (Table 1) [11], was used to evaluate the extent of glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolar hyalinosis. These were scored from 0 to 3 (normal to severe). The total score for each renal block was also calculated (‘chronic damage score’, maximum = 12). At least 100 glomeruli were observed to evaluate the pathological damage score and, where assessments were clearly discordant, the slides were reviewed and a consensus score identified. In subjects with unilateral RAS, we evaluated each kidney.
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Statistical analysis
All analyses were performed with the program Stat-View 5.0 system (Abacus Concepts, Berkeley, CA). The results were expressed as the mean±SD. The significance of the differences between the two groups was analysed by the Student t-test,
2 analysis. A P-value of <0.05 was considered to be of statistical significance. Linear regression analysis was performed to identify the relationship between histological score and clinical variables. Multiple linear regression analysis was used to assess predictive variables of severity of renal parenchymal damage. Independent variables were age, gender, hypertension, diabetes mellitus, proteinuria, renal insufficiency, the presence of CVD, weight of the kidney and RAS. |
Results |
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Clinical features
Among 2167 autopsy cases between 1980 and 1997, a total of 138 subjects (group A, n = 36; group B, n = 102) older than 40 years who had a clinical history of stroke were included in the present analysis.
The clinical characteristics of the subjects in this study before their death are summarized in Table 2. The mean age and gender were similar in the two groups, but the percentage of subjects with hypertension (P<0.05) was significantly higher in group A than in group B. In addition, the subjects in group A had worse renal function (creatinine clearance 33.8±21.9 ml/min in group A vs 57.0±30.3 ml/min in group B, P<0.001). Proteinuria was noted in 42% of group A and 53% of group B. Renal insufficiency was noted in 61% of group A and 23% of group B (P<0.001).
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In group A, 26 subjects had unilateral disease (16 stenosis and 10 occlusion), while 10 had bilateral disease (two bilateral occlusion, four occlusion and stenosis, and four bilateral stenosis). The degree of narrowing of the renal artery luminal area was 75% in 12 patients, 90% in eight patients and 99% in 16 patients. Only eight of the 36 cases had the established diagnosis of RAS before their death. In 26 patients with unilateral RAS, the degree of narrowing of the luminal area of the contralateral renal artery was 50% in seven patients and 60% in one patient. The mean percentage narrowing of the renal artery was 89.1±10.5% in the stenosed kidney (n = 36) and 15.8±24.2% in the contralateral kidney (n = 26) (P<0.0001).
Histopathological features
The renal weight and renal histological scores of all the subjects are given in Table 3. The renal weight was different between stenosed kidneys and non-stenosed kidneys. The average overall chronic damage score in the stenosed kidney of group A was significantly higher than in the non-stenosed kidney in group B (stenosed kidney 9.0±2.6 vs non-stenosed kidney 7.0±2.7). Significant differences between the groups were found for the total score (P<0.0005), interstitial fibrosis (P<0.0005), tubular atrophy (P<0.0001) and glomerulosclerosis (P<0.001) when scored semi-quantitatively. There were no significant differences between the two groups in scores for arteriolar hyalinosis. In this study, we defined stenosis as >75% narrowing of the renal artery luminal area, and this is an 
50% diameter stenosis seen in angiography. Definition as >90% narrowing of the luminal area (i.e. 70% diameter stenosis) may be considered more familiar. The histological findings between kidneys with >90% and <90% narrowing also showed a significant difference (8.7±2.6 vs 7.3±2.8, P<0.05). However, the histological findings were similar in patients with >90% narrowing and in patients with 75% narrowing (8.7±2.6 vs 9.4±2.7, P = 0.67).
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In the stenosed kidneys, the histological damage was not correlated with the degree of luminal narrowing. There was no difference in histological score among patients with different degrees of stenosis.
Renal weight was different between stenosed kidneys and contralateral kidneys. There was a trend to more severe renal damage in the stenosed than in the contralateral kidneys. Total score, interstitial fibrosis and tubular atrophy had a tendency to be more severe in stenosed kidneys. The glomerular sclerosis was significantly more severe in stenosed than in the contralateral kidneys.
Renal weight was not different between non-stenosed kidneys of group B and contralateral kidneys of group A. Tubular atrophy had a tendency to be more severe in the contralateral than in the non-stenosed kidneys.
The renal histological scores of the subjects with and without clinically diagnosed complications are given in Table 4. The total score was higher in the subjects with hypertension, diabetes, proteinuria, renal insufficiency or other CVD (CVD other than hypertension and stroke) than in the subjects without these complications.
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Linear regression analysis between renal histological score and clinical characteristics is summarized in Table 5. It was seen that RAS, hypertension, diabetes, proteinuria, renal insufficiency, other CVD and weight of the kidney were significantly correlated with the total score. RAS was significantly correlated with glomerular sclerosis, interstitial fibrosis, tubular atrophy and total score. Age and gender did not show any tendency of association with any histological observations. Multiple linear regression analysis was performed to assess predictive variables of the severity of renal parenchymal damage (Table 6). RAS, proteinuria, renal insufficiency and other CVD were significantly associated with total score. RAS was significantly associated with interstitial fibrosis, tubular atrophy and total score.
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Discussion |
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The results of this study demonstrated that moderate to severe renal parenchymal damage was found in autopsy subjects with stroke, and the histological change was more severe in the subjects with RAS, hypertension, diabetes mellitus, proteinuria, renal insufficiency and/or any types of CVD. This parenchymal damage had a trend to be more evident in the stenosed kidney than in the contralateral kidneys without significant stenosis. Multivariate linear regression analysis demonstrated that RAS, proteinuria, renal insufficiency and CVD were correlated independently with the renal histological score.
Impaired renal function is a known risk factor for the prognosis of the general population and patients with CVD [12–14]. In our previous study [6,7], impaired renal function had a relationship to the presence of RAS. We therefore considered that RAS was one of the independent predictors of renal function in the subjects with stroke or myocardial infarction [6,7]. RAS and the ensuing parenchymal ischaemia may be involved in the causal mechanism of the renal parenchymal damage. Indeed, successful surgery or angioplasty of RAS is known to stabilize renal function, control blood pressure and attenuate the aggravation of atherosclerosis [15–17]. RAS is thus an important predictor of renal function; however, it is also true that renal dysfunction is not totally attributable to the presence of RAS. To understand the pathogenesis of renal dysfunction in patients with cardiovascular complications, the kidney itself should be examined in relation to the clinically observable findings of a variety of atherosclerotic vascular diseases.
Our present study provided useful information to understand the relationship between clinical characteristics of the subjects with stroke and precisely defined renal histology available only after their death. A modified Banff classification of renal allograft pathology [11] used in our study has been used recently as a routine method to clarify biopsy-proven atherosclerotic nephropathy, on the basis of understanding that the severity of histological damage is an important determinant and predictor of renal function outcome [10]. In our study, this method was again useful, and it clearly demonstrated the statistically significant correlation between the severity of disease and renal parenchymal damage.
If RAS really causes impaired renal function and renal parenchymal damage, this should be more evident in the stenosed kidney than in the contralateral kidney without stenosis. In our study, we found a trend to more severe renal damage in the stenosed than in the contralateral kidney. Tubular atrophy had a trend to be more evident in contralateral kidneys than in the non-stenosed kidneys, although the degree of RAS was <60% in the contralateral kidneys. Kidneys with RAS are considered to be exposed to high angiotensin II levels and ischaemia, but protected from high systemic pressure. In contrast, contralateral kidneys are exposed to high angiotensin II levels and high systemic blood pressure. Our histological findings between stenosed and contralateral kidneys suggested that renal ischaemia had an impact to cause the glomerular and tubulointerstitial changes. From the findings between non-stenosed and contralateral kidneys, the renal ischaemia is considered to start from the tubular changes at an early phase, because even luminal narrowing <60% already induced the tubular changes.
Kubo et al. demonstrated that age, systolic blood pressure, renal function and proteinuria were common risk factors for glomerular and renal vascular changes in the general population by an autopsy-based survey [18]. There is a strong body of evidence that renal tubulointerstitial change is one of the causes of renal functional decline in animal models or patients with various diseases [19,20]. However, Kubo et al. could not examine the tubulointerstitial pathological change, since many subjects in their study underwent autopsy examination >24 h after death, and post-mortem interstitial changes were severe. In contrast, in our study, all autopsy examinations were performed immediately after death, and renal tubulointerstitial changes could be examined without post-mortem oedema. This would be one reason why we successfully found the significant changes in tubular atrophy and interstitial fibrosis in the patients with stroke.
In the population without apparent CVD, renal parenchymal damage was dependent on age, blood pressure, renal function and proteinuria [18]. However, in our present study, diagnosed CVD such as stroke and renal parenchymal damage was not dependent on age. Therefore, in patients with stroke, complication of any CVD and/or renal dysfunction is considered to be closely associated with renal parenchymal damage, regardless of the age of patients. Both age and the systemic atherosclerosis caused the renal damage in the patients with CVD such as stroke; therefore, there was no strong relationship between age only and renal damage. The age-independent renal damage in patients with stroke is thus in contrast to the evidence obtained in the general population in the Hisayama study [18].
There are several limitations in this study that require mention. Firstly, there is the possibility that our study population might include subjects with chronic glomerulonephritis. However, we looked at clinical records and blood examination, excluded macrohaematuria using the urine strip test, and we were unable to detect chronic glomerulonephritis. Secondly, we did not evaluate histological findings in subjects without CVD. However, it is very difficult to perform renal biopsy for all the subjects despite normal renal function in the clinical situation. The reason why we evaluated the subjects with stroke was because it has been reported that cerebrovascular lesions reflect the systemic atherosclerosis and that patients with both stroke and renal dysfunction had a higher mortality risk [14]. Kubo et al. have reported intrarenal histological changes in the general population, although they had evaluated only glomerular sclerosis and arteriolar hyalinosis in their study [18]. We referred to their report and evaluated glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriolar hyalinosis in our study, because we did not have a suitable control group of similar age and with hypertension, but without RAS. In their study, the group aged 60–79 (a similar age to our study population) had 3.8–24.1% glomerular sclerosis and 3.8–17.2% arteriolar sclerosis. These histological findings were given a score of 1 using our semi-quantitative histological scoring. Therefore, the scores of glomerular sclerosis and arteriolar hyalinosis in the general population were lower compared with our study population. The histological findings of Kubo et al. showed that glomerular sclerosis and arteriolar hyalinosis increased linearly with age, but our study showed that the degree of renal damage had no association with advancing age.
In conclusion, in the subjects with CVD such as stroke, co-existing renal parenchymal damage was more severe in the subjects with RAS, hypertension, diabetes mellitus, proteinuria and renal insufficiency than those without such complications. In the subjects with stroke, impaired renal function and proteinuria were closely correlated with the severity of renal parenchymal damage. Thus, the presence of RAS and/or other CVD can be important predictors of renal parenchymal damage as a prognosis. Potentially existing renal parenchymal damage should therefore be taken into account in treating patients with atherosclerotic vascular lesions, referring to functional characteristics observable in clinical practice. These patients need aggressive treatment for the kidney and cardiovascular system to ensure the protection of these organs.
Conflict of interest statement. None declared.
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Accepted in revised form: 25. 7.05
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