Characteristics and risk factors of intrarenal arterial lesions in patients with IgA nephropathy

Jie Wu, Xiangmei Chen, Yuansheng Xie, Nobuaki Yamanaka, Suozhu Shi, Di Wu, Shuwen Liu and Guangyan Cai

Kidney Center of PLA, Department of Nephrology, Chinese General Hospital of PLA, Beijing, China

Correspondence and offprint requests to: Prof. Xiangmei Chen, Kidney Center of PLA, Department of Nephrology, Chinese General Hospital of PLA, Fuxing Road 28, Beijing 100853, China. Email: xmchen{at}public.bta.net.cn



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Although the clinical importance of immunoglobulin-A nephropathy (IgAN) is widely recognized, the characteristics of intrarenal arterial lesions in this disease and the main factors associated with them have not been studied extensively, and a large-scale analysis of intrarenal arterial lesions in IgAN has not been performed.

Methods. To clarify these issues, we investigated the prevalence, underlying factors and significance of intrarenal arterial lesions in 1005 patients with IgAN. We distinguished different degrees of severity of small artery and arteriolar lesions (mild, moderate and severe), using a semi-quantitative scoring system. We compared the arterial lesions of IgAN patients with those of 627 non-IgAN patients, who had mesangial proliferating glomerulonephritis without IgA deposits, and of 221 patients with membranous nephropathy (MN).

Results. The IgAN patients with arterial lesions were significantly younger than the non-IgAN and MN patients (mean ages 34.6 vs 40.4 and 47.7 years, respectively). The prevalence of intrarenal small artery and arteriolar lesions was 54.6% in IgAN patients, compared with 26.6 and 47.1% in non-IgAN and MN patients, respectively; the percentages of moderate/severe arterial lesions were 37.0 vs 21.6 and 23.1%, respectively; and the percentages of hyaline changes were 43.7 vs 16.8 and 21.2%, respectively. The differences in the prevalence of lesions between IgAN patients and the two other groups were statistically significant for all three parameters. Our search for possible relationships between arterial–arteriolar lesions and various indirect outcome markers disclosed significant associations with hypertension, higher serum creatinine and uric acid, high urinary protein excretion, glomerulosclerosis, tubular atrophy and interstitial fibrosis. Furthermore, these parameters were changed more markedly in IgAN patients with moderate/severe arterial lesions and hyaline changes than in IgAN patients who had mild arterial lesions and wall thickening alone.

Conclusions. The prevalence of small intrarenal arterial–arteriolar lesions was higher in IgAN patients than in non-IgAN and MN patients; moreover, the lesions in IgAN patients were associated with younger age, were more severe and exhibited a higher degree of hyaline changes. Finally, the severity of small arterial– arteriolar lesions was linked to several markers of adverse outcome.

Keywords: arterial hyaline changes; immunoglobulin-A nephropathy; intrarenal arterial lesions



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Immunoglobulin-A nephropathy (IgAN) is a common and progressive glomerulonephritis [1]. Generally, it has been considered that impaired renal function, severe proteinuria, hypertension, glomerulosclerosis and interstitial fibrosis are the strongest and most reliable predictors of an unfavourable outcome in IgAN [2]. Unfortunately, the importance of arterial lesions in IgAN patients has not been studied well.

A large-scale analysis focused on intrarenal arterial lesions has not been performed, although the clinical relevance of vascular lesions in IgAN has been studied, including intrarenal vascular sclerosis in 43 patients with IgAN reported by Feiner et al. [3], clinicopathological correlations in a series of 143 patients with IgA glomerulonephritis reported by Mustonen et al. [4] and comparison of pathological lesions on repeated renal biopsies in 73 patients with primary IgA glomerulonephritis by Alamartine et al. [5]. Because the clinical and pathological characteristics of IgAN patients vary greatly, the conclusions based on data on a limited number of patients are weak, especially in retrospective studies. In addition, the characteristics of factors underlying intrarenal arterial lesions in IgAN are not well known.

In order to clarify these issues, we investigated the prevalence, underlying factors and significance of intrarenal arterial lesions in 1005 patients with IgAN. We distinguished different degrees of severity of small artery and arteriolar lesions (mild, moderate and severe), using a semi-quantitative scoring system. We compared the arterial lesions of IgAN patients with those of 627 non-IgAN patients, who had mesangial proliferating glomerulonephritis without IgA deposits, and of 221 patients with membranous nephropathy (MN). Our data demonstrated that the intrarenal arterial lesions of IgAN were important pathologically and should be duly considered clinically.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Among 3530 patients who underwent renal biopsy and immunofluorescence examination from 1987 to 2002 in our Kidney Center, we identified 1164 patients with IgAN. The selection of this group was based on a diagnosis limited to primary glomerulonephritis and with a predominant deposition of IgA in the mesangium. No patients had clinical or histological evidence of systemic diseases, such as systemic lupus erythematosus, Henoch–Schönlein purpura, chronic liver disease, ANCA-related glomerulonephritis or necrotizing vasculitis. The exclusion criterion for the present study was a renal biopsy specimen for light microscopic examination that contained less than five glomeruli and five arteries including small arteries or arterioles. As a result, 1005 of the 1164 patients with IgAN remained for inclusion in this study (658 males and 347 females).

We also studied 627 non-IgAN patients, who had mesangial proliferating glomerulonephritis without IgA deposits, and 221 patients with idiopathic MN as disease controls.

Judgment criteria of intrarenal arterial lesions and their degree of severity
Renal biopsy specimens were examined by light, immunofluorescence (IF) and electron microscopy. The stains applied to renal biopsy specimens used for light microscopy included haemotoxylin and eosin, periodic acid–Schiff (PAS), PAM and Masson stains. Each renal biopsy specimen was examined and scored independently by two pathologists experienced in renal biopsy interpretation, who had no knowledge of the patients' clinical data. The intrarenal arterial lesions were defined as arterial–arteriolar wall thickening alone or arterial–arteriolar wall thickening with hyaline changes. The arterial wall thickening included one or both of intimal thickening and medial thickening, consisting of an accumulation of extracellular matrix, proliferation of spindle-shaped cells (smooth muscle cells) or both. The arterial–arteriolar hyaline change, or hyalinosis, was defined as any change that resulted in the glassy, pink or red homogenous appearance of the arterial or arteriolar wall without cellular proliferation in paraffin-embedded and PAS-stained renal biopsy specimens. Following Katafuchi et al.'s criteria [6], arterial wall thickening was semi-quantitatively estimated based on the cross-sectional ratio of luminal diameter to outer diameter. Arterial–arteriolar wall thickening was defined if that ratio was less than about 0.5. The degree of severity of wall thickening and hyaline change in small arteries or arterioles was semi-quantitatively defined as follows: 0, no intrarenal arterial lesions in any arterial cross-section throughout the specimen; 1, arterial lesions involving <10% of the arterial cross-sections; 2, arterial lesions involving between 10% and 25% of the arterial cross-sections; 3, arterial lesions involving >25% of the arterial cross-sections throughout the specimen. When arterial wall thickening (proliferation of intima, media or both) and arterial hyaline changes were observed simultaneously, the scores were calculated for each change and the arterial lesion score was the score of arterial wall thickening plus the score of arterial hyaline change. We divided the patients into four groups according to their scores of arterial lesions as follows: 0, no arterial lesions; 1–2, mild arterial lesions; 3–4, moderate arterial lesions; 5–6, severe arterial lesions.

Clinical data
Though the study is retrospective, for each patient clinical data had been collected at the time of renal biopsy, including age, sex, blood pressure, serum creatinine, serum uric acid, serum triglycerides, serum cholesterol, serum albumin and the amount of 24 h urinary protein excretion.

Histopathological data
The pathological diagnoses by light microscopy of all patients with IgAN in our Kidney Center fell within the grades I–V of pathological damage, according to the grading system of Lee et al. [7]. The main levels of Lee's grading are: grade I, mostly normal glomeruli; grade II, less than half of the glomeruli show localized mesangial proliferation and sclerosis; grade III, diffuse mesangial proliferation and thickening with focal and segmental variation with focal interstitial oedema and infiltrate occasionally present; grade IV, marked diffuse mesangial proliferation and sclerosis with tubular atrophy and interstitial inflammation; grade V, similar to grade IV, but more severe.

The pathological features of the patients in the present study were scored by light microscopy according to the scoring system of Katafuchi et al. [6]. Glomerular lesions (total score: 0–12) included glomerular hypercellularity, glomerular segmental lesions (crescents, adhesions and segmental sclerosis) and global glomerular sclerosis. The glomerular lesion score of each type was determined as follows: 0, no lesion; 1, lesion in <10% of glomeruli; 2, lesion in >10% but <25% of glomeruli; 3, lesion in >25% and <50% of glomeruli; 4, lesion in >50% of glomeruli. The severity of interstitial cell infiltration, interstitial fibrosis and tubular atrophy in each patient was scored (total score: 0–9) semi-quantitatively from 0 to 3, according to the percentage of the tissue injured: 0, no lesion; 1, <25%; 2, ≥25% and <50%; 3, ≥50%.

Statistical analysis
The chi-square test was used to analyse the frequency of categorical variables. Differences in the continuous variables between the groups were compared using the unpaired t-test (Student's t-test). Results were expressed as means±SD. The variables used in univariate and multivariable analyses were expressed using a binary scale, such as absent/present, and coded as 0/1. After the single-variable analysis, significant single variables were used for multivariate regression analysis. The results of multivariate analysis were expressed by a hazards ratio and 95% confidence interval (CI). In the Cox analysis, exp (ß) was the hazard ratio for a case with the characteristic, as compared with a case without the characteristic. For all analyses, P < 0.05 was considered statistically significant. We used the SPSS 10.0 statistical software (SPSS Inc., Chicago, IL, USA) for statistical analysis.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Comparison of age of the patients
The mean age of the patients with IgAN was 30.8±12.0 years and the mean age of IgAN patients with intrarenal arterial lesions was 34.6±11.5 years. The mean age in the non-IgAN patients was 31.0±14.5 years and the mean age in the non-IgAN patients with intrarenal arterial lesions was 40.4±15.0 years. The mean age of patients with MN was 43.8±13.9 years and the mean age of MN patients with intrarenal arterial lesions was 47.7±12.8 years. The IgAN patients with intrarenal arterial lesions were significantly younger than the non-IgAN and MN patients with intrarenal arterial lesions, respectively (P<0.001).

Prevalence of intrarenal arterial lesions
Of the 1005 IgAN patients, 456 (45.4%) did not have arterial lesions and 549 (54.6%) did. Among patients with arterial lesions, 346 (34.4%) had mild, 152 (15.1%) moderate and 51 (5.1%) severe lesions.

Of the 627 non-IgAN patients, 460 (73.4%) did not have arterial lesions and 167 (26.6%) did, including 131 (20.9%) mild, 32 (5.1%) moderate and four (0.6%) severe cases. The prevalence of arterial lesions in non-IgAN patients was less than in IgAN patients (P<0.01).

Of the 221 MN patients, 117 (52.9%) did not have arterial lesions and 104 (47.1%) did, including 80 (36.2%) patients with mild arterial lesions, 15 (6.8%) with moderate lesions and nine (4.1%) with severe lesions. The prevalence of arterial lesions in MN patients was less than in IgAN patients (P<0.05) (Table 1).


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Table 1. Comparison of intrarenal arterial lesions in patients with IgAN, non-IgAN and MN

 
Comparison of severity and pathological type in patients with arterial lesion
The arterial lesions were more severe (percentage of moderate/severe lesions was higher) and the percentage of arterial hyaline change was higher in IgAN patients with intrarenal arterial lesions at the time of renal biopsy compared with non-IgAN or MN patients with arterial lesions (Table 2).


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Table 2. Comparison of the severity and type of arterial lesions in patients with different types of renal disease

 
Comparison of clinical characteristics of patients with arterial lesions of different degrees of severity
Age, blood pressure, serum creatinine, serum uric acid, serum triglycerides and 24 h urinary protein at the time of the renal biopsy were significantly higher in IgAN patients with arterial lesions than in the IgAN patients without arterial lesions. Furthermore, the changes in these parameters were more distinct in the patients with severe arterial lesions than in those with mild arterial lesions. Serum albumin level was significantly lower in the patients with arterial lesions than in the patients without arterial lesions (Table 3).


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Table 3. Comparison of clinical characteristics in intrarenal arterial lesions with different degrees of severity

 
Comparison of pathological findings in patients with arterial lesions of different severities
The pathological findings of all IgAN patients were scored by light microscopy, according to the scoring system of Katafuchi et al. [6]. The scores of glomerular hypercellularity, segmental glomerular lesions, global glomerular sclerosis, tubular atrophy, interstitial cell infiltration and interstitial fibrosis were higher in the patients with arterial lesions than in the patients without arterial lesions. Furthermore, global glomerular sclerosis, tubular atrophy, interstitial cell infiltration and interstitial fibrosis in the patients with moderate/severe arterial lesions were more distinct than those in the patients with mild lesions (Table 4).


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Table 4. Comparison of pathological findings in intrarenal arterial lesions with different degrees of severity

 
We also analysed the status of intrarenal arterial lesions in patients with different Lee's pathological grades. The results showed that arterial lesions were present mainly in the IgAN patients with Lee's pathological grades III, IV and V, especially IV, whereas intrarenal arterial lesions were rare in the IgAN patients with Lee's pathological grades I and II (Figure 1).



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Fig. 1. The status of intrarenal arterial lesions according to different Lee's pathological grades.

 
Comparison of intrarenal arterial lesions of different pathological types
Age, blood pressure, serum creatinine, serum uric acid at the time of renal biopsy and global glomerular sclerosis, tubular atrophy, interstitial cell infiltration, interstitial fibrosis were significantly higher in the IgAN patients with arterial hyaline change than in the IgAN patients who had only arterial wall thickening but not arterial hyaline change (Table 5).


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Table 5. Comparison of intrarenal arterial lesions with different types of pathology

 
Underlying factors for intrarenal arterial lesions
Univariate analysis showed that age >35 years, high blood pressure, high blood uric acid, high serum triglyceride, high serum cholesterin, serum creatinine ≥133 µmol/l, 24 h urinary protein ≥3.5 g, proportion of glomerular hypercellularity ≥25%, glomerular segmental lesions ≥25%, glomerular sclerosis ≥25%, tubular atrophy ≥25%, interstitial cell infiltration ≥25% and interstitial fibrosis ≥25% were correlated closely with intrarenal arterial lesions (Table 6).


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Table 6. Univariate analysis of risk factors for intrarenal arterial lesions

 
Multivariate logistic regression analysis showed that the significant independent factors associated with intrarenal arterial lesions included high blood pressure, high blood uric acid, serum creatinine ≥133 µmol/l, 24 h urinary protein ≥3.5 g, proportion of global glomerular sclerosis ≥25%, tubular atrophy ≥25% and interstitial fibrosis ≥25% (Table 7).


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Table 7. Multivariate regression analysis of risk factors for intrarenal arterial lesions

 
Effects of hypertension and age on the severity and type of intrarenal arterial lesions
In order to clarify the clinical significance by different pathological types of intrarenal arterial lesions in IgAN patients, we analysed the effects of hypertension and age on the severity and type of intrarenal arterial lesions (Tables 8 and 9). In Table 8, we show that the percentage of moderate/severe arterial lesions and the percentage of arterial wall thickening with hyaline change were higher in the IgAN patients with hypertension than in the patients without hypertension. Table 9 shows that the effects of hypertension on the pathological type of intrarenal arterial lesions occurred mainly in IgAN patients <35 years old. The effects of hypertension on the pathological types of intrarenal arterial lesions were not statistically different in the patients >35 years old.


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Table 8. Comparison of the severity and type of arterial lesions in patients with and without hypertension

 

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Table 9. Comparison of pathological type of arterial lesions at different ages in patients with or without hypertension

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Although the clinical relevance of intrarenal arterial lesions in IgAN has been studied [8], a large-scale analysis has not been published. The present study focused on intrarenal arterial lesions: their prevalence and age, the clinical significance of intrarenal arterial lesions with different degrees of severity (mild, moderate or severe) and different lesion types (arterial wall thickening alone or arterial wall thickening with hyaline change) and factors underlying intrarenal arterial lesions. We analysed the data of 1005 patients with idiopathic IgAN and compared them with 627 patients with non-IgAN and 221 patients with MN.

An earlier study by Feiner et al. [3] indicated that intrarenal vascular sclerosis was present in one-third of 43 biopsy patients with IgAN. Our data showed that the incidence of intrarenal arterial lesions was 54.6, 26.6 and 46.1% in IgAN, non-IgAN and MN patients, respectively, suggesting that intrarenal arterial lesions in IgAN were very common and that the prevalence of intrarenal arterial lesions in IgAN was higher than in non-IgAN (P<0.01) and MN patients (P<0.05), although the patients with MN were older than the patients with IgAN (Table 1). The average age of IgAN patients with intrarenal arterial lesions was less than that of non-IgAN or MN patients with arterial lesions (Table 2). The reason that arterial lesions are more common in IgAN than in non-IgAN patients is unclear. A potential explanation could be that primary IgAN is an immune complex-mediated glomerulonephritis [1] and that intrarenal arterial lesions might be related to immune abnormality, including C3 deposition. The studies showed that the number and intensity of vascular C3 deposits were significantly greater on the repeated renal biopsy alone, with an increase of tubulointerstitial and vascular lesions [5].

In order to identify factors underlying intrarenal arterial lesions in patients with IgAN, we explored the correlation between intrarenal arterial lesions with different degrees of severity and clinical or pathological characteristics at the time of renal biopsy. Our data show that age, blood pressure, serum creatinine, serum uric acid, serum triglyceride, 24 h urinary protein, glomerulosclerosis, tubular atrophy, interstitial cell infiltration and interstitial fibrosis were significantly higher in the IgAN patients with intrarenal arterial lesions than in the patients without arterial lesions. Furthermore, the changes of these components were more distinct in the IgAN patients with severe arterial lesions than in those with mild arterial lesions. The results of multivariate regression analyses show that high blood pressure, hyperuricaemia, increases of serum creatinine, heavy proteinuria, distinct glomerulosclerosis, tubular atrophy and interstitial fibrosis were independently associated with intrarenal arterial lesions in the patients with IgAN. Moreover, the severity of these factors and the severity of intrarenal arterial lesions were consistent. These factors might be not only causes of intrarenal arterial lesions, but also results of arterial lesions in IgAN. Some or all of these factors have been recognized as markers of adverse outcome in IgAN [2,9]; our results indirectly suggest that intrarenal arterial lesions might be important indicators of the severity of disease.

Regarding the relationship between hypertension and intrarenal arterial lesions, it was believed that hypertension caused arteriolar nephrosclerosis and ischaemic renal injury superimposed on primary renal parenchymal disease, contributing to progressive renal insufficiency [10]. On the other hand, vascular lesions are not only strongly correlated with but may even precede the development of hypertension, as confirmed by longitudinal observations [11]. Our previous studies have shown that a renal arteriolar lesion is the independent factor for hypertension in patients with IgAN [12]. In addition, some patients without hypertension have arterial lesions, suggesting that other factors may produce arterial lesions. It has been reported that age is the main clinical determinant of large artery stiffness and central arteries stiffen progressively with age, whereas peripheral arteries change little with age [13]. In order to clarify the significance of intrarenal arterial lesions of different pathological types, we compared clinical and pathological characteristics between patients with arterial wall thickening alone and patients with arterial hyaline change and analysed the effects of hypertension and age on arterial wall thickening alone and arterial wall thickening with arterial hyaline change. Our data have shown that the percentage of moderate/severe arterial lesions and the percentage of arterial hyaline change were higher in the IgAN patients with hypertension than in the IgAN patients without hypertension (Table 8). The effects of hypertension on the pathological type of intrarenal arterial lesions were mainly in seen in the IgAN patients <35 years old. The pathological type of intrarenal arterial lesion was not statistically different between the patients with and without hypertension >35 years old (Table 9).

Concerning a relationship between renal function and arterial lesions, it has been reported that increased serum creatinine is associated with poor outcome in IgAN [2,9]. The study by Bos et al. [14] showed that loss of renal function is accompanied by the intimal proliferation of renal arterioles, even in the absence of hypertension. Our data confirm that the severity of intrarenal arterial lesions and the degree of impairment of renal function are consistent in IgAN patients (Table 3). The renal insufficiency is independently associated with arterial lesions.

Glomerulosclerosis, the common terminal event in chronic glomerular diseases such as IgAN, leads to end-stage renal disease [15]. Multivariate analysis has shown that global and segmental glomerulosclerosis independently adversely affect renal outcome [16]. Hotta et al. [17] reported that in their study, seven out of 15 IgAN patients with global sclerosis had hyaline arteriolosclerosis (46.7%). Our current data also show that the severity of arterial lesions is closely related to the degree of glomerulosclerosis.

Our previous studies have shown that tubulointerstitial lesions are one of the key factors for the prognosis of IgAN and are closely related to the severity of glomerular and vascular lesions, which may further lead to the development of tubulointerstitial lesions [18]. Our data confirm that vascular lesions and glomerular and tubulointerstitial changes are related to each other. The initial mechanism for vascular lesions may be the glomerular inflammatory changes of IgAN. Subsequently, glomerular inflammation may induce interstitial cellular infiltration by mediators released from the glomerular resident or infiltrating cells, and the inflammatory cells in the interstitium may release some mediators, which lead to the phenotypic change of interstitial and tubular epithelial cells into myofibroblastic cells and, thence, to interstitial fibrosis, tubular atrophy and vascular lesions. At the same time, the vascular lesions influence the blood supply to the glomeruli, tubules and interstitium, and they cause more damage to the glomerular and tubulointerstitial tissues. Finally, the vascular lesions participate in the vicious cycle that these tissues undergo [19].

A limitation of this study could be the combined analysis of small interlobular arteries and arterioles and our failure to characterize the deposition of various serum proteins in the subendothelial space. Although this was a retrospective study, we believe that with its precise clinical and histological data in IgAN patients it will have referential value for clinicians.

In conclusion, in patients with IgAN, the prevalence of arterial lesions was higher, patients with arterial lesions were younger, arterial lesions were more severe and the percentage of arterial hyaline changes was higher, compared with non-IgAN and MN patients. Intrarenal arterial lesions, especially with arterial hyaline change, and their severity in IgAN were closely related to the markers of adverse renal outcome, such as hypertension, hyperuricaemia, increasing serum creatinine, heavy proteinuria, distinct glomerulosclerosis, tubular atrophy and interstitial fibrosis. These factors were independent risk factors for intrarenal arterial lesions in patients with IgAN, by multivariate regression analysis, and might not be the causes of intrarenal arterial lesions, but also the result of arterial lesions in IgAN. As intrarenal arterial lesions are important indicators of the severity of disease, the importance of intrarenal arterial lesions in IgAN should be duly considered clinically.



   Acknowledgments
 
The authors thank all colleagues who recorded medical information, collected the clinical data, performed renal biopsies and made histopathological diagnoses. This study was supported, in part, by a grant from the Creative Research Group Fund of the National Natural Science Foundation of China (30121005), a grant from the Key Technologies Research and Development Programme of the Tenth Five-year Plan of the People's Republic of China (2001BA701A14a) and a grant from the National Basic Research Program of China (973 Program, G 2000057000).

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 11.11.03
Accepted in revised form: 13.10.04





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