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NDT Advance Access published online on October 15, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn572
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Changes in the glomerular density and size in serial renal biopsies during the progression of IgA nephropathy

Nobuo Tsuboi, Tetsuya Kawamura, Takeo Ishii, Yasunori Utsunomiya and Tatsuo Hosoya

Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

Correspondence and offprint requests to: Nobuo Tsuboi, Division of Kidney and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-Ku, Tokyo 105-8461, Japan. Tel: +81-3-3433-1111; Fax: +81-3-3433-4297; E-mail: nobuotsuboi{at}aol.com



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Supplementary data
 Conflict of interest statement
 References
 
Background. Although there have been many reports on clinicopathological studies of IgAN, information is limited regarding the long-term evolution of a renal histology by analysing samples obtained not only during normal renal function but also after the establishment of an impaired renal function in individual patients.

Methods. We analysed 18 pairs of serial biopsy specimens from 18 patients with IgA nephropathy (IgAN) in whom the first renal biopsies were performed while normal renal function was still present and the second biopsies were performed after impaired renal function was established. The glomerular density (GD, number of non-sclerotic glomeruli per renal cortical area) and mean glomerular area (MGA) were compared between the specimens.

Results. The GD at the first biopsy of each patient showed a striking variation (1.3–5.2/mm2). As a whole, the GD decreased (2.7 ± 1.2 versus 1.4 ± 0.7/mm2) and the MGA increased (19.7 ± 4.2 x 103 versus 23.5 ± 4.5 x 103 mm2) between the biopsies, respectively. The degrees of change in the GD and the MGA between the biopsies differed remarkably among the individuals. The patients with a high GD in the first biopsy progressed slowly, but showed a large decrease in the GD and a large increase in the MGA between the biopsies, respectively. The patients with a low GD, who already had enlarged glomeruli in the first biopsy, tended to progress rapidly.

Conclusions. Our results suggest that both the nephron number and glomerular enlargement play a crucial role as compensatory mechanisms against renal functional deterioration in progressive IgAN. The GD during normal renal function may determine these compensatory changes and thereby make it possible to predict the renal prognosis in IgAN.

Keywords: glomerular density; glomerular hypertrophy; IgA nephropathy; nephron number; renal biopsy



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Supplementary data
 Conflict of interest statement
 References
 
Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis (GN) and a major cause of end-stage renal failure worldwide. In recent studies, it has been shown that 30–40% of patients progress to end-stage renal failure within 10–25 years [1,2]. Clinically, an advanced age, hypertension, heavy proteinuria and impaired renal function at presentation are known to be poor prognostic indicators [3–5]. The histology of IgAN ranges from a minimal lesion to a diffuse proliferative and crescentic GN. There have been several studies examining the potential correlation of the histological features of IgAN in the renal biopsy with the clinical outcome [6–8]. Most of these studies consistently found that advanced glomerulosclerosis and interstitial fibrosis with tubular atrophy are adverse prognostic indicators in IgAN. Such a correlation between those structural injuries and the poor prognosis of renal function is not limited to IgAN, but is common to many forms of chronic glomerular diseases [9].

Like other biologic variables, it seems that there is a substantial variation in glomerular (nephron) number among ‘normal’ people. A recent study examining a series of 37 autopsies reported that the average glomerular number was 617 000 per kidney with a range of 331 000–1 424 000, i.e. more than a fourfold variation [10]. Another study analysed 78 autopsy kidneys and demonstrated a mean of 810 646 glomeruli per kidney with a range of 228 441–1 825 380, i.e. approximately a ninefold variation [11]. Notably, both of these studies found that the glomerular volume varied inversely with the glomerular number. Many studies have so far demonstrated that renal injury, consisting of a reduced nephron number with enlarged glomeruli, may lead to an accelerated loss of the renal function in both experimental and human renal diseases [12–14]. In populations at high risk of renal failure, such as Blacks, Pima Indians and Aboriginal Australians, large glomeruli are a common finding at the early stages of renal disease [15–17]. These observations have led to the hypothesis that kidneys with reduced nephron number, presumably having less functional reserve, may cause a glomerular enlargement and may thus be more susceptible to subsequent renal injury and functional decline.

Although there have been many reports on clinicopathological studies of IgAN, information is limited regarding the long-term evolution of a renal histology by analysing samples obtained not only during normal renal function but also after the establishment of an impaired renal function in individual patients. Most of the studies using serial biopsies have been performed without changes in the renal function or simply to evaluate the effectiveness of immunosuppressive therapy [18–21]. The present study aimed at exploring the clinicopathological features of patients with progressive IgAN by investigating the relationship between the changes in the histological findings from serial renal biopsies and the renal outcome. All the patients recruited in this study showed a progressive deterioration of the renal function, and renal biopsies were performed both before and after the establishment of an impaired renal function. We focused mainly on the glomerular density (GD) and glomerular size in these biopsies with the hypothesis that these histological backgrounds impose a high susceptibility to progressive renal injury through non-immunological mechanisms in patients with IgAN.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Supplementary data
 Conflict of interest statement
 References
 
Patient selection
Patients with IgAN for whom serial renal biopsies were performed at Jikei Hospital and Jikei Daisan Hospital in Tokyo from 1977 to 2006 were recruited in this study. The inclusion criteria were as follows: (1) patients who received the first biopsy when their creatinine clearance (Ccr) was 80 ml/min or more, and (2) the second biopsy was performed after impaired renal function was established. An impaired renal function was defined as a deterioration of the Ccr, i.e. 70 ml/min or less with >20% decrease from its baseline. Since the duration between the serial biopsies varied for patients in this study, we used the percent change in Ccr from the baseline per year (Formula Ccr) to evaluate the degree of renal functional change. Formula Ccr was calculated by the following formula: [(Ccr at the first biopsy) – (Ccr at the second biopsy)] x 100/(Ccr at the first biopsy) x (the time between the two biopsies in years). Those with repeated renal biopsies simply to judge the effectiveness of corticosteroid or other immunosuppressive therapies were excluded from this study. Renal tissue specimens that contained <10 glomeruli (including globally sclerotic glomeruli) on light microscopy were excluded from the analysis.

Pathological analysis
All kidney tissue specimens were obtained by a percutaneous needle biopsy. The tissues were embedded in paraffin, cut into 3- to 4-µm sections and stained with haematoxylin–eosin, periodic acid-Schiff, Masson's trichrome and periodic acid-methenamine. The percentages of glomeruli affected by global/segmental sclerosis, crescents and adhesion to Bowman's capsule were assessed. The severity of mesangial and intracapillary proliferation was evaluated and scored for the individual glomeruli. The mesangial proliferation was scored as grade 0, 25% or less; grade 1, 26–50%; grade 2, 51–75% or grade 3, 76% or more of the mesangial areas containing more than three mesangial cells. The intracapillary proliferation was scored as grade 0, 3 or fewer; grade 1, 4–9; grade 2, 10–19 or grade 3, 20 or more intracapillary infiltrating cells per glomerulus. The severity was defined by averaging the score of the individual glomeruli. For the interstitium, we semiquantitatively analysed the total area showing chronic fibrotic changes and the results were expressed as the percentage of affected interstitial area over the total cortical area.

The mean glomerular area (MGA) and the glomerular density (GD) were determined using a computed imaging analyser (Scion Image). The glomerular area was defined as the area described by the outer capillary loops of the tuft. The MGA was calculated by averaging the areas of all the glomeruli except for those with <40% of the maximum glomerular area within each specimen to avoid measuring a cross-section far from the maximal planar area. This is based on the fact that the planar cross-section of trichotomy of a sphere is equivalent to 40% of the maximal cross-sectional area. The maximal glomerular area was determined by measuring three serial sections in each sample. The GD was determined by calculating the number of glomeruli that were not globally sclerotic per total renal cortical area, excluding interstitial fibrosis that was measured using a computed imaging analyser. The measurement of GD is strongly influenced by the degree of global sclerosis and interstitial fibrosis, especially in cases with an impaired renal function. As for the GD, we excluded global sclerosis and interstitial fibrosis as non-functional areas, and similar results were obtained using the GD with other definitions that do not exclude global sclerosis and/or interstitial fibrosis (data not shown). The rate of change in the GD or MGA between the first and the second biopsy (Formula GD or Formula MGA) was calculated by the following formula: Formula GD or Formula MGA = [(GD or MGA at the second biopsy) – (GD or MGA at the first biopsy)] x 100/(GD or MGA at the first biopsy) x (the time between the two biopsies in years).

Statistical analysis
The results are expressed as the mean ± SD and compared using a paired or unpaired t-test as required. A simple linear regression analysis was applied to study the relationship between continuous variables. The nephron number in individuals with a normal renal function, as reflected by GD in the present study, is considered to be normally distributed [10,11]. We therefore did not modify this value when performing the statistical analyses. Clinically relevant parameters or variables, which were significantly associated based on a univariate analysis, were included in the multivariate regression analysis. Because the distribution of urinary protein excretion, global sclerosis and the cellular/fibrocellular crescent was skewed, the log-transformed values were used in the regression analysis, and similar results in terms of the significance of these parameters were obtained with non-transformed data (data not shown). Values of P < 0.05 were considered to be statistically significant. All statistical analyses were performed using the Statview software program.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Supplementary data
 Conflict of interest statement
 References
 
Patients
Between 1977 and 2006, we performed repeat renal biopsies on 61 patients who were diagnosed to have primary IgAN at the first renal biopsy in order to evaluate the histological changes during the progression of their clinical course. The specific indications for the repeat biopsies include a decline in renal function and/or an increase in proteinuria. Twenty-seven of these 61 patients were excluded because they did not fulfil the inclusion criteria in terms of the renal functional decline between the serial biopsies. The reason for the exclusion of these 27 patients was the uncertainty of their renal prognosis. In the majority of these 27 patients, the second biopsies were performed within a few years after the first biopsies. Therefore, a possibility remained that they maintained a stable renal function because of their shorter intervals between the serial biopsies, and this factor made it difficult to use them as controls in the ‘non-progressive’ group. Twelve of the remaining 34 patients who had already shown renal dysfunction (Ccr < 80 ml/min) at the first biopsy were also excluded. Moreover, 4 of these 22 pairs of renal biopsy samples that contained <10 glomeruli on light microscopy were excluded from the analysis. Finally, 18 pairs of the serial biopsy samples from 18 patients were eligible for this study. As illustrated in Figure 1, all the patients recruited in this study received repeated renal biopsies. The first renal biopsies were performed while normal renal function was still present and the second biopsies were performed after impaired renal function was established. Among these patients, 4 patients received corticosteroid therapy and 12 received either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin type I receptor blocker (ARB) or both between the first and the second biopsy. In this study, individuals undergoing repeated renal biopsies simply to judge the effectiveness of corticosteroids or other immunosuppressive therapies were excluded at the initial step of the recruitment. However, four patients who received corticosteroids between the serial biopsies were included, because the second biopsies were performed for these patients due to increased proteinuria, at least several years after completing the corticosteroid therapeutic protocol. None of these patients received any medication for the treatment of IgAN before the first biopsy.


Figure 1
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  		Fig. 1 An illustration of the time course of the patients recruited for this study. The patients received the first biopsy when their creatinine clearance (Ccr) was 80 ml/min or more, and the second biopsies were performed after impaired renal function was established. Impaired renal function was defined as a deterioration of Ccr, i.e. 70 ml/min or less with a >20% decrease from its baseline.

 
Clinical and laboratory findings
The clinical and laboratory findings at the time of the biopsies are summarized in Table 1. The 18 patients included nine males and nine females. The mean age was 30.6 ± 9.8 years (range 18–51 years) at the first biopsy and 39.7 ± 10.7 years (range 23–57 years) at the second. The median duration between the biopsies was 9.2 ± 5.3 years (range 2.5–25 years). The blood pressures were similar in the first and the second biopsy. In comparison to the first biopsy, the urinary protein excretion significantly increased while haematuria significantly decreased at the second biopsy. The creatinine clearance decreased from 99 ± 15 ml/min (range 80–130 ml/min) at the first biopsy to 56 ± 14 ml/min (range 24–70 ml/min) at the second biopsy. The average Formula Ccr was –5.9%/year (range –12.0–1.8%/year). At the second biopsy, the serum albumin and immunoglobulin A concentrations significantly decreased while the serum total cholesterol and uric acid levels significantly increased in comparison to the first biopsy.


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  		Table 1 Clinical and laboratory findings at biopsies

 
Pathological findings
The pathological findings at the time of the biopsies are summarized in Table 2. The average total glomerular number identified in the biopsy specimens was 21.0 ± 10.1 (range 10–42) at the first biopsy and 16.7 ± 4.3 (range 10–26) at the second biopsy. In the first series of biopsies, the chronic pathological changes were comparatively mild. The rate of global sclerosis was 12.4 ± 10.4% and the degree of interstitial fibrosis was 15.6 ± 7.3%, respectively. In the second series of biopsies, these chronic pathological changes were markedly increased. The rate of global sclerosis was 47.3 ± 16.1% and the degree of interstitial fibrosis was 47.5 ± 18.5%, respectively. In comparison to the first biopsy, the other chronic pathological changes including glomerular capsular adhesion and segmental glomerular sclerosis significantly increased at the second biopsy. On the other hand, the degree of acute lesions such as cellular or fibrocellular crescent formation, mesangial proliferation and intracapillary proliferation was comparable in both the first and the second biopsy.


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  		Table 2 Pathological findings at biopsies

 
Quantitative analysis of glomerular density and size
The renal cortical area measured in the specimens was 7.1 ± 3.0 mm2 (range 1.7–14.9 mm2) at the first biopsy and 8.1 ± 3.2 mm2 (range 3.6–14.2 mm2) at the second biopsy. The renal cortical area, excluding the interstitial fibrosis, was 5.9 ± 2.2 mm2 (range 1.6–10.5 mm2) at the first biopsy and 4.1 ± 1.8 mm2 (range 2.0–8.7 mm2) at the second biopsy. In comparison to the first biopsies, the mean GD decreased (2.7 ± 1.2/mm2 versus 1.4 ± 0.7/mm2, P = 0.0025) and the MGA increased (19.7 ± 4.2 x 103 mm2 versus 23.5 ± 4.5 x 103 mm2, P = 0.0002) at the second biopsies, respectively (Table 2). As illustrated in Figure 2A and B, the degrees of changes in the GD and MGA between the first and the second biopsy differed remarkably among the individuals. Notably, the GD and MGA of each patient showed a striking variation at the first biopsies, performed when renal function was within the normal range. The maximum value for the variation in the GD at the first biopsy reached fourfold (range 1.3–5.2/mm2). Likewise, the maximum value for the variation in the MGA at the first biopsy was nearly twofold (range 15.1–28.5 x 103 mm2) (Figure 2B). Figure 3A and B illustrates the relationship between the GD and MGA at the first and the second biopsy, respectively. In the first series of biopsies when the renal function was normally maintained, a significant inverse correlation was observed between the GD and MGA (r = –0.539, P = 0.021). However, in the second series of biopsies when impaired renal function was established, such a correlation was not observed. Figures 4A and B show the relationships between the GD in the first biopsies and the rates of changes in the GD (Formula GD) and MGA (Formula MGA) between the first and the second biopsies, respectively. Interestingly, the GD in the first biopsy closely and inversely correlated with Formula GD (r = –0.660, P = 0.003), while also correlating with the Formula MGA (r = 0.513, P = 0.029). On the other hand, neither Formula GD nor Formula MGA correlated with the MGA at the first biopsy (data not shown).


Figure 2
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  		Fig. 2 Changes in GD (A) and MGA (B) between biopsies. The median value is shown for each group.

 

Figure 3
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  		Fig. 3 Relationship between GD and MGA at the first (A) and the second biopsy (B).

 

Figure 4
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  		Fig. 4 Correlation of GD in the first biopsy and the rate of change in GD between the first and the second biopsy (Figure 4GD, A) and the rate of change in MGA between the first and the second biopsy (Figure 4MGA, B).

 
Structural and functional correlations
The GD and MGA at the first biopsy were next analysed for their correlations with the renal outcome. The GD at the first biopsy significantly correlated with Formula Ccr, an indicator of the rate of decline in renal function (r = 0.597, P = 0.009) (Figure 5A). These results show that the renal function deteriorated more slowly in the patients with a higher GD than it did in those with a lower GD at the first biopsy. On the other hand, the MGA at the first biopsy did not show significant correlations with the Formula Ccr (Figure 5B).


Figure 5
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  		Fig. 5 Correlation of the rate of change in Ccr (Figure 5Ccr) and GD in the first biopsy (A) and MGA in the first biopsy (B).

 
Relationship between GD and other clinicopathological factors
Based on the previous observation that essential hypertension is associated with low nephron number and glomerular hypertrophy [22,23], the GD and MGA were analysed for their correlation with blood pressure at the first biopsy. As shown in Figure 6A, the GD in the first biopsy showed a significant inverse correlation with the mean arterial pressure (r = –0.679, P = 0.002). The GD also correlated significantly and inversely with the systolic blood pressure and the diastolic blood pressure (data not shown). On the other hand, the MGA did not show significant correlations with the blood pressure (data not shown). The relationship between the GD and urinary protein excretion at the first biopsy was analysed since the latter has been considered to be another risk factor for the progression of IgAN [1–4]. As shown in Figure 6B, we did not find any correlations between the GD and the urinary protein excretion. Figure 7 shows the relationship between the GD and the chronic pathological changes in the biopsies. The GD at the first biopsy did not show a significant correlation with the percent of globally sclerotic glomeruli on that biopsy (Figure 7A). Furthermore, the distribution of GD in patients with interstitial fibrosis occupying <20% of the renal cortex in the biopsy specimen was not statistically different from that in patients with lesions occupying 20% or more of the renal cortex (Figure 7B).


Figure 6
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  		Fig. 6 Relationship between GD and mean arterial pressure (A), GD and urinary protein excretion (B) at the first biopsy.

 

Figure 7
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  		Fig. 7 Relationship between GD and rate of global sclerosis (A), GD and degree of interstitial fibrosis (B).

 
Multivariate analysis
To examine whether GD in the first biopsy is an independent predictor that influences a decline in the renal function, we performed a multivariate regression analysis using Formula Ccr as a purpose variable. Table 3 summarizes the results of the simple and the multivariate regression analysis. The clinicopathological parameters used for this analysis include age, Ccr, the mean arterial pressure, 24-h urinary protein excretion, GD, MGA, global sclerosis, mesangial cell proliferation and cellular/fibrocellular crescent. In the simple regression analysis, the mean arterial pressure and GD were found to be significant factors that were associated with the Formula Ccr. In a multivariate regression analysis, the GD and cellular/fibrocellular crescent were found to be significant factors that were independently associated with the Formula Ccr.


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  		Table 3 Factors at first biopsy influencing decline in renal function (Table 3Ccr) by simple and multivariate regression analysis

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Supplementary data
 Conflict of interest statement
 References
 
In this retrospective study, we compared 18 pairs of serial biopsy specimens from 18 patients with IgAN who showed a progressive deterioration in their renal function. We analysed the glomerular density and size in these biopsies and found a striking variation in these histological parameters among the individuals even at the first biopsy, which was performed when the renal function had been normally maintained. The large variation observed in the GD at the first biopsy is not likely to be the result of renal scarring, since the chronic pathological changes such as the rate of global sclerosis and the degree of interstitial fibrosis were very mild at the first biopsy. In addition, neither the rate of global sclerosis nor the degree of interstitial fibrosis was associated with the GD at that biopsy. These results suggest that the large variation observed in GD at the first biopsy may be due in part to a substantial difference in the glomerular (nephron) number among the individuals, and they are consistent with recent studies on autopsy kidneys showing a large variation in the glomerular (nephron) number among people without renal diseases [10,11]. Furthermore, marked differences in the degrees of changes in the GD and MGA between the serial biopsies were noted. Notably, GD at the first biopsy was closely associated with both Formula GD and Formula MGA and it also showed a good correlation with Formula Ccr. These results closely correlate with the notion that the glomerular (nephron) number as well as glomerular enlargement play significant roles as compensatory mechanisms against renal functional deterioration [12].

In the present study, the GD at the first biopsy correlated with the Formula Ccr and inversely with the mean arterial pressure. These results suggest the diagnostic significance of the GD during the normal renal function for predicting the renal prognosis in IgAN, and they are also consistent with the prevailing notion that hypertension is a risk factor predicting the progression of IgAN to renal failure [3–5]. Notably, during normal renal function, the GD correlated with the mean arterial pressure, which was mostly distributed in the normal range at the first biopsy, thus suggesting the possibility that low GD-related abnormalities in glomerular haemodynamics may accelerate the progression of IgAN. On the other hand, we did not find a significant correlation between the GD at the first biopsy and the amount of urinary protein excretion, another established risk factor for the progression of IgAN [1–5]. The result might be due to the fact that the GD affects the renal prognosis independently from the amount of urinary protein excretion. The results of a multivariate regression analysis of the present study may also support this possibility. Another possible explanation is our exclusion of the patients without a renal functional decline between biopsies. Using a larger population of patients with IgAN that also includes patients without a renal functional decline during the observation periods (>5 years), we are currently investigating the relationship between the GD at the time of a normal renal function and the long-term renal prognosis. The results obtained from those studies may therefore help to resolve these issues.

An issue in the evaluation of the GD in renal biopsy specimens concerns the limitation of morphological measurement using tissue specimens obtained by a needle biopsy. In order to examine the effect of ageing on the renal histology, we previously performed a morphometric study on normal human kidneys from 84 patients who underwent an autopsy because of sudden death. The study showed that the average GD calculated from ~200–500 glomeruli ranges from 1.7 to 5.2/mm2 (Hamaguchi et al., unpublished data). This distribution was quite similar to our present results ranging from 1.3 to 5.2/mm2, and thus supporting the validity of the method of evaluating GD using samples obtained by needle biopsy. At present, it is not certain whether the GD in the renal biopsy specimen simply represents the nephron number of the whole kidney, since data on the total cortical volume of the kidney in these patients were not available. However, our observation that the GD inversely correlated with the MGA at the first biopsy probably reflects the functional adaptation of the glomeruli in patients with low GD or a small number of functioning nephrons. In addition, the significant inverse correlation between the GD and the blood pressure at the first biopsy indicated the pathophysiological role of low GD in blood pressure control similar to that of a small number of nephrons [22,23].

A low nephron number is related to a low birth weight (LBW), which has also been implicated in hypertension and the progression of various chronic renal diseases including IgAN [24–28]. The association between a LBW and the progression of chronic renal diseases may be related to the impediment of nephrogenesis caused by the intrauterine environment, as shown in various studies [29,30]. A LBW, in association with a low nephron number, is therefore a risk factor for the progressive loss of renal function, especially when exposed to an extrinsic renal injury such as IgAN, which eventually causes progressive glomerular scarring and loss of functional nephrons, later in life. Inversely, the patients with a relatively high nephron number may have the potential to preserve renal function in these situations. The results of this study showing that the patients with a high GD were associated with a slow progression in spite of a large decrease in their GD may therefore support this possibility. On the other hand, the magnitude and/or duration of immunologic activation presumably have a great influence on the course of this disease. In support of this, the extent of acute lesions such as cellular or fibrocellular crescent formation, mesangial proliferation and intracapillary proliferation was comparable at both the first and the second biopsy in our patients who showed a progressive decline in renal function to variable degrees. Consistent with the hypothesis that non-immunologic mechanisms mediate the compensatory glomerular hypertrophy against the functional loss of nephron mass [31,32], we could not find any correlation between GD, Formula GD, MGA or Formula MGA and the degree of these acute lesions (data not shown).



   Supplementary data
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Supplementary data
Conflict of interest statement
 References
 
Supplementary data are available online at http://ndt.oxfordjournals.org.



   Conflict of interest statement
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Supplementary data
 Conflict of interest statement
References
 
None declared.



   Acknowledgments
 
We thank Ms Tomoko Hayakawa for her valuable technical assistance. This study was supported by the Jikei University Research Fund.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Supplementary data
 Conflict of interest statement
 References
 

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Received for publication: 6. 5.08
Accepted in revised form: 18. 9.08


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