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NDT Advance Access published online on July 4, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn371
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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


Malignant hypertension in IgA nephropathy was not associated with background pathological phenotypes of glomerular lesions

Lei Jiang*, Jun-jun Zhang*, Ji-cheng Lv, Gang Liu, Wan-zhong Zou, Ming-hui Zhao and Hong Zhang

Renal Division of Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China

Correspondence and offprint requests to: Hong Zhang, Renal Division of Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, No. 8 Xi-Shi-Ku Street, Beijing 100034, People's Republic of China. Tel: +86-10-66551122 Ext: 2388; Fax: +86-10-66551055; E-mail: hongzh{at}bjmu.edu.cn



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. It was reported that IgA nephropathy (IgAN) was the major cause of secondary malignant hypertension (MHT). However, the pathogenesis of MHT secondary to IgAN (IgAN-MHT) is unknown and its association with glomerular pathological phenotypes remains inconclusive. The present study aimed to investigate whether glomerular pathological phenotypes and anti-endothelial cell antibodies (AECA) were associated with the occurrence of IgAN-MHT.

Methods. The glomerular pathological phenotypes of 45 patients with IgAN-MHT were analysed using Haas’ histologic grading system of IgAN. Sera were collected from 34 of the 45 patients with IgAN-MHT, 19 patients with primary MHT, 41 patients with non-MHT IgAN and 10 healthy volunteers. AECA of both IgG and IgA isotypes were detected by western blot analysis using human umbilical vein endothelial cell lysate as antigen.

Results. In the 45 patients with IgAN-MHT, 7 (15.56%), 5 (11.11%), 13 (28.89%), 9 (20%) and 11 (24.44%) patients were graded as Hass I, II, III, IV and V, respectively. Although the severity of non-ischaemic sclerosis, crescents and mesangial proliferation were significantly different between patients with different grades, the levels of blood pressure, SCr and proteinuria at presentation were comparable. Eleven and four protein bands of endothelial proteins could be blotted by AECA-IgG and AECA-IgA in sera from patients with IgAN-MHT. The prevalences of anti-121 kD AECA-IgG (15/34) and anti-92 kD AECA-IgA (10/34) in IgAN-MHT were significantly higher than that of primary MHT, non-MHT IgAN and normal controls, respectively. Patients with anti-92 kD AECA-IgA had more severe glomerular ischaemic sclerosis (6.25–92.86%, median 39.61%) than those without (0–91.67%, median 18.18%, P = 0.035). There was no significant difference in the prevalence of AECA between IgAN-MHT patients with different background glomerular lesions. Only one IgAN patient with MHT was found with both anti-121 kD AECA-IgG and anti-92 kD AECA-IgA. No particular manifestations were found.

Conclusions. The occurrence of IgAN-MHT was not associated with the background glomerular pathological phenotypes of IgAN. AECA might play a role in the pathogenesis of IgAN-MHT.

Keywords: anti-endothelial cell antibodies; IgA nephropathy; malignant hypertension; pathology



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Idiopathic IgA nephropathy (IgAN) is one of the major causes of secondary malignant hypertension (MHT) [1–4], accounting for one-third of all secondary causes and 40% of glomerular causes. Although MHT secondary to IgAN (IgAN-MHT) has been reported for >30 years [5], the pathogenesis remains unknown.

It was suggested that, in patients with IgAN, the occurrence of MHT was on the basis of advanced IgAN. This was supported by the observation that most patients with IgAN-MHT presented with wide spread glomerular sclerosis, mesangial expansion or crescents [1–3]. However, it is not always the case; we and others have noticed that some IgAN patients, with a few or even no non-ischaemic sclerotic glomeruli or crescents, could present with MHT [2]. Clinical observations showed that their renal functions could improve markedly after effective anti-hypertensive therapy within a few months, resembling that of patients with primary MHT, while the renal outcome of patients with advanced renal pathology was much poorer [3]. However, the clinico-pathological differences of IgAN-MHT patients with different background glomerular lesions have not been investigated in detail.

As a category of MHT, IgAN-MHT was also characterized by endothelial injury and severe vascular lesions. Some researchers have found serum anti-endothelial cell antibodies (AECAs), a heterogeneous group of antibodies, in the mediation of IgAN [6–9], as well as in vascular disorders [10,11]. Their findings suggested that AECAs might play a role in immunological vascular lesions in IgAN. Hence, we postulated that AECAs might be involved in the pathogenesis of IgAN-MHT.

In the present study, we investigated the renal pathological phenotypes of patients with IgAN-MHT and their association with clinical characteristics. Serum AECAs were also detected as a possible contributing factor to the development of IgAN-MHT.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients
Forty-five patients with renal biopsy-proven IgAN-MHT, diagnosed from 1992 to 2007 in our hospital, were enrolled in the present study.

The diagnosis criteria of MHT were as follows: (1) marked elevation of blood pressure (BP), especially when diastolic blood pressure exceedes 130 mmHg; (2) hypertensive retinopathy of grade III or IV using Keith-Wagener–Barker's classification (i.e. bilateral linear or flame-shaped haemorrhages or ‘cotton-wool’ exudates with or without papilloedema on funduscopic examination) [12,13]. Idiopathic IgAN was diagnosed based on the presence of predominant mesangial IgA deposits by immunofluorescence, and systemic diseases were excluded. The diagnosis of IgAN-MHT was made when a patient was clinically diagnosed with malignant hypertension and clinico-pathologically diagnosed with idiopathic IgA nephropathy.

Clinical and laboratory data of patients at the time of renal biopsy were collected as baseline data, including serum creatinine (SCr), daily urinary protein excretion (UP), serum IgA level, etc. Systolic blood pressure and diastolic blood pressure of patients at the time of admission were recorded, and mean arterial pressure (MAP) was calculated.

To detect AECAs, sera from 34 of the above 45 IgAN-MHT patients were obtained on the morning of the day of renal biopsy. Disease controls included the following: (1) Forty-one patients with non-MHT idiopathic IgAN. According to pathological classification of Haas, 8 (19.5%) were classified in Haas’ grade I, 4 (9.8%) were in grade II, 14 (34.1%) in grade III, 9 (22.0%) were in grade IV and 6 (14.6%) were in grade V. (2) Nineteen patients with primary MHT and with renal biopsy data. The diagnosis of primary MHT was made when secondary hypertension such as renal parenchymal diseases, renal artery stenosis, scleroderma or endocrinological hypertension were excluded according to clinical and pathological examinations. Sera from 10 healthy volunteers were used as normal controls.

Renal histopathology
Percutaneous renal biopsy specimens were processed routinely by the standard protocol. For light microscopy, paraffin sections were stained with haematoxylin–eosin, Masson's trichrome and methenamine silver. Two pathologists who were blinded to patients’ data examined the biopsy slides separately. Glomerular lesions, except for glomerular ischaemic sclerosis which could be identified from non-ischaemic sclerosis characterized by the collapsed capillary tuft without apparent mesangial matrix expansion, were taken as ‘background lesions’ and were analysed and graded using Haas’ grading system for IgAN [14]. Renal lesions were also analysed according to pathological schema described previously [15,16].

(1)  The percentages of glomeruli with cellular crescents, fibrocellular crescents, ischaemic sclerosis, non-ischaemic global sclerosis, segmental sclerosis and fibrous crescents to total glomeruli number.
(2)  Mesangial proliferation index (MsI): no or focal mild proliferation, 1+; diffuse mild or focal prominent proliferation, 2+ and diffuse prominent proliferation, 3+.
(3)  Endothelial proliferation index (EPI): <50% of glomeruli proliferated, 1+; >50% of glomeruli proliferated but most were segmental, 2+ and >50% of glomeruli globally proliferated, 3+.
(4)  Tubulointerstitial index (TI): according to the ratio of involved area to total tubulointerstitial area in the slide (0%, 0; <10%, 1+; 10–25%, 2+; 25–50%, 3+; 50–75%, 4+; ≥75%, 5+).
(5)  Renal arteriole lesions including ‘onion skinning’, fibrinoid necrosis and hyaline change.

The clinical and pathological characteristics were compared between patients with IgAN-MHT and patients with primary MHT and between IgAN-MHT patients with different background pathological lesions.

Preparation of primary human umbilical vein endothelial cells (HUVEC)
In accordance with our previous publication [17], endothelial cells were harvested from human umbilical veins by collagenase (0.1%, Gibco, Invitrogen Corporation, NY, USA) digestion and plated in culture flasks in the M199 medium (Gibco) supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, 20% foetal calf serum (Gibco), 50 µg/ml heparin, 2.38 mg/ml HEPES and 20 µg/ml endothelium cell growth factor (ECGF, Roche, Mannheim, Germany). Cultures were maintained in a humidified atmosphere of 5% CO2 at 37°C, and the culture medium was changed three times a week. After 5– 7 days, the monolayer was treated with 0.05% trypsin and 0.02% EDTA in a Ca+–Mg++-free Hanks's balanced salt solution and cells were resuspended in a complete medium. Subcultures were performed approximately every 4–5 days at the ratio of 1:2–3. Cells were identified by typical endothelial cell morphology with phase contrast microscopy; the endothelial markers von Willebrand factor and Weibel–Palade bodies were detected by indirect immunofluorescence and immunohistochemistry with rabbit anti-human vWF antibody (ZYMED) and electron microscopy, respectively. Cells were used for antigen extraction between the fourth and fifth passages.

Preparation of soluble proteins from HUVEC
Primary HUVEC were trypsinized from the flasks and washed three times with ice-cold phosphate buffered saline, counted and lysed (108 cells/ml) by 1% Triton X-100 (Sigma) with 1.0 mmol/l phenylmethylsulphonyl fluoride on ice for 30 min with gentle agitation. After centrifugation at 4°C at 15 000 g/min for 15 min, the supernatant was collected as soluble proteins [17].

Western blot analysis to detect AECA
Soluble proteins from HUVEC were electrophoresed under reducing conditions on sodium dodecylsulphate gradient of polyacrylamide gel (20 mA, 100 min). The proteins were then transferred to a nitrocellulose (NC) membrane (Schleicher & Schuell, NH, USA) by the electrophoretic semi-dry blotting system (Amersham Pharmacia, NJ, USA) at 0.8 mA/cm2 for 70 min. The NC membrane was cut into strips which were blocked at room temperature for 60 min with 4% skimmed milk in a 10 mmol/l Tris/HCl buffer with 0.1% Tween-20 (TBST). Serum samples were diluted at 1:50 in TBST/4% skimmed milk and incubated overnight at 4°C in gentle agitation, followed by three washes with TBST for 10 min each time. The strips were then incubated with phosphatase-labelled affinity-purified goat anti-human IgG or goat anti-human IgA (Sigma, St. Louis, MO, USA) diluted at 1:6000 with TBST/4% skimmed milk for 1 h at room temperature with gentle agitation. After three washes with TBST (10 min each time), the reaction was revealed by addition of appropriate substrates: nitroblue tetrazoleum (NBT) and 5-bromo-4-chloro-3-indolylphosphate (BCIP) (Sigma). The reaction was stopped after 5–10 min with distilled water [17].

Statistical analysis
The quantitative data were expressed as mean ± SD or mean (minimun–maximum). Differences of quantitative parameters between groups were assessed using the t test or Mann–Whitney U-test. Differences of qualitative results were compared using the {chi}2 test. P <0.05 was considered significant. Analysis was performed using the SPSS statistical software package (version 12.0; Chicago, IL, USA).



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Clinical and pathological characteristics of patients with IgAN-MHT
MHT was the first clinical manifestation of the disease in 28 patients with IgAN-MHT (62.2%). Four patients (8.9%) showed macroscopic haematuria episodes in the past. Eleven patients (24.4%) had a history of hypertension. Eight patients (17.8%) had a history of oedema or proteinuria or microhaematuria with a course of 10 months-7 years (median 15 months), and one of them had taken a renal biopsy and been diagnosed with mildly mesangial proliferative IgAN 7 years before he presented MHT. More clinical and pathological characteristics of patients with IgAN–MHT were displayed in Table 1.


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  		Table 1 Comparison of the clinical and pathological features between patients with IgAN-MHT, primary MHT and non-MHT IgAN

 
Compared with primary MHT, patients with IgAN-MHT had significantly lower diastolic blood pressure (140.25 ± 19.54 versus 151.43 ± 20.32, P = 0.041) and MAP (162.40 ± 20.42 versus 174.44 ± 19.65, P = 0.031), but higher prevalence of microscopic haematuria (75.6% versus 33.3%, P = 0.001), higher serum IgA level (2.57 ± 0.81 versus 1.87 ± 0.68, P = 0.013) and more proteinuria (2.97 ± 1.88 versus 1.75 ± 1.13, P = 0.007). SCr was not significantly different between the two groups (89–2060, median 414.34 versus 111–1568, median 560.60).

Pathological analysis showed that in comparison with primary MHT, the prevalence of non-ischaemic global sclerosis (17.2% versus 0.4%, P < 0.001) and crescent formation (10.8% versus 1.6%, P < 0.001) was significantly higher in the IgAN-MHT group. The mesangial proliferation (1.8 versus 0.1, P < 0.001) in IgA–MHT was significantly more severe than that in primary MHT. No significant difference was found in the severity of ischaemic sclerosis, segmental sclerosis, tublointerstitial lesions and ‘onion skinning’ and hyaline changes of arteries and arterioles.

Comparing with non-MHT IgAN patients, patients with IgAN-MHT had more ischaemic sclerosis (28.0% versus 1.86%, P < 0.001) and more severe tubulointerstitial lesions (3.6 versus 2.1, P < 0.001), but the other glomerular lesions and arterial lesions were similar. The level of proteinuria was also comparable (Table 1).

The glomerular background lesions were graded using Haas’ grading system. It was shown that the background pathological phenotypes of patients with IgAN-MHT were heterogeneous. Seven patients (15.6%) were in grade I, 5 (11.1%) in grade II, 13 (28.9%) in grade III, 9 (20%) in grade IV and 11 (24.4%) in grade V.

Comparison of clinical and pathological characteristics of patients with IgAN-MHT with different background glomerular lesions
Patients with IgAN-MHT were further divided into two subgroups according to the background glomerular lesions: a relatively mild group including Haas I, II and III (Haas I–III, n = 25) and a relatively severe group including Haas IV and V (Haas IV and V, n = 20).

Patients in grades I–III had significant lower prevalence of microscopic haematuria (60.0% versus 95.0%, P = 0.012). The levels of blood pressure, SCr and proteinuria were comparable between the two subgroups (Table 2).


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  		Table 2 Comparison of the clinical and pathological features between subgroups of patients with IgAN-MHT

 
Although non-ischaemic global sclerosis, crescents and mesangial proliferation, which were included in Haas’ classification criterion for glomerular lesions, were more severe in grades IV–V than grades I–III, the indices of ischaemic sclerosis and tubulointerstitial lesions were comparable between the two subgroups. For vascular lesions, the prevalence of ‘onion skinning’ was comparable between the two subgroups, while the hyaline change was more frequently found in grades IV–V (Table 2).

Outcome of patients with MHT
Five patients with pMHT and 17 patients with IgAN-MHT were followed up for >1 year. The prevalence of patients free of persistent dialysis or kidney transplantation at 1 year was 3/5 (60%) in patients with pMHT, 7/8 (87.5%) in patients with IgAN-MHT in Haas grades I–III and 4/9 (44.4%) in patients with IgAN-MHT in grade IV–V. It suggested that patients in grades I–III had a better renal outcome than those in grades IV–V (P = 0.131). However, the blood pressure, SCr and urinary protein excretion at presentation were comparable between these grades I–III and grades IV–V patients (P > 0.05).

Detection of AECA-IgG and AECA-IgA
For AECA-IgG, 11 protein bands of endothelial antigens at 209, 163, 121, 94, 87, 77, 61, 54, 42, 34 and 26 kD could be blotted in western blot analysis by sera from patients with IgAN-MHT and two disease control groups (Figure 1). The prevalence of anti-121 kD AECA-IgG was significantly higher in patients with IgAN-MHT than those with non-MHT IgAN (44.12% versus 12.20%, P = 0.002) or those with primary MHT (44.12% versus 15.79%, P = 0.037).


Figure 1
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  		Fig. 1 Western blot analysis of AECA-IgG using human umbilical vein endothelial cells (HUVEC) as antigens. The chromatograms are only representative of some cases. Lane 1: blank control, lanes 2–4: sera from patients with non-MHT IgAN, lanes 5–8: sera from patients with IgAN-MHT and lanes 9–12: sera from patients with pMHT.

 
For AECA-IgA, four protein bands of endothelial antigens at 193, 141, 115 and 92 kD could be blotted in western blot analysis by sera from patients of IgAN-MHT and non-MHT IgAN groups (Figure 2). The anti-141 kD and 92 kD bands could not be found in the primary MHT group. The prevalence of anti-92 kd AECA-IgA was significantly higher in patients with IgAN-MHT than those with primary MHT (29.41% versus 0%, P = 0.024) although it was also higher than those with non-MHT IgAN (29.41% versus 12.20%, P = 0.064); the difference was not significant (Table 3).


Figure 2
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  		Fig. 2 Western blot analysis of AECA-IgA using human umbilical vein endothelial cells (HUVEC) as antigens. The chromatograms are only representative of some cases. Lane 1: blank control, lanes 2–4: sera from patients with non-MHT IgAN, lanes 5–8: sera from patients with IgAN-MHT and lanes 9–12: sera from patients with pMHT.

 

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  		Table 3 Prevalences of AECAs in patients with IgAN-MHT and with primary MHT

 
Between IgAN-MHT patients with relatively mild and severe background pathological lesions, there was no significant difference in the prevalences of anti-121 kD AECA-IgG (42.9% versus 46.2%, P = 0.851) and anti-92 kD AECA-IgA (33.3% versus 20.0%, P = 0.379).

In normal controls, no AECA-IgA or AECA-IgG was detected except the anti-94 kD AECA-IgG in one individual.

Association between AECA and clinical pathological parameters in patients with IgAN-MHT
In the IgAN-MHT group, there was no significant difference in age, gender, BP, SCr, Alb, UP, history or family history of hypertension between patients with and without anti-121 kD AECA-IgG. Glomerular and arterial pathological parameters were also comparable between patients with and without anti-121 kD AECA-IgG. In patients with anti-92 kD AECA-IgA, the percentage of glomerular ischaemic sclerosis was significantly higher (6.25–92.86%, median 39.61%) than those without (0–91.67%, median 18.18%, P = 0.035).

Only one IgAN patient with MHT was found with both anti-121 kD AECA-IgG and anti-92 kD AECA-IgA. No particular manifestations were found. The prevalence of other bands was very low and failed to correlate with any parameter.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In patients with malignant hypertension secondary to IgA nephropathy (IgAN-MHT), it was suggested that the occurrence of malignant hypertension was usually associated with severe background glomerular lesions [1,3]. In the present study, however, more than half of the patients with IgAN-MHT were identified with relatively mild background glomerular lesions (Haas I, II and III), rather than uniformly severe. The major different approach of the present study was that we carefully analysed the background glomerular lesions of IgAN and ischaemic sclerosis, respectively. The latter lesion more possibly resulted from the hypertensive injury. Moreover, it revealed that ischaemic clinical and pathological features were more severe in patients with IgAN-MHT than those of IgAN patients without MHT, while other manifestations were comparable (Table 1). Therefore, the pathological background severity of IgAN might not be associated with the occurrence of malignant hypertension in patients with IgAN.

As reported previously [1–3], some of the clinical and pathological characteristics of patients with IgAN-MHT were different from those of primary MHT. The current study confirmed that, compared with patients with primary MHT, patients with IgAN-MHT tended to have more proteinuria, higher prevalence of haematuria and higher serum IgA level, which are valuable biomarkers to differentiate IgAN-MHT from primary MHT. Interestingly, the current study found that the blood pressure, especially diastolic blood pressure and mean arterial pressure, was significantly lower in patients with IgAN-MHT, which might indicate that patients with underlying glomerular diseases might be more susceptible to malignant hypertension.

On comparison between IgAN-MHT patients with different background glomerular phenotypes (Haas grades I–III and IV–V), we found that although the non-ischaemic global sclerosis, crescents and mesangial proliferation were significantly different, the blood pressure, SCr and proteinuria were comparable in the two subgroups. Discriminating different roles of ischaemic and non-ischaemic lesions to current renal function impairment might imply the different response to therapy, as well as different possibility or degree of renal function improvement.

The major limitation of the current study was short of sequential follow-up data. From the literature, the renal outcomes of IgAN-MHT were controversial [1–3,18]. One of the reasons could be that, the pathological severity of IgAN-MHT was variable in different studies. With the limited data that we obtained in the present study, there seemed to be a trend that IgAN-MHT patients in grades I–III had better outcomes than those in grades IV–V although their clinical manifestations such as SCr were similar at presentation. It suggested the importance of looking into the background pathological phenotype of patients with IgAN-MHT.

Our study indicated that the occurrence of IgAN-MHT was not associated with the background glomerular lesions of IgAN; therefore, other mechanisms might be involved in the onset and progression of the malignant course. Previous studies had found AECA of both IgG and IgA isotypes in IgAN [6–9] and suggested that AECA might play an important role in vascular injury of IgAN. In the present study, we detected AECA by western blot analysis, which could identify the binding specific to the extracted endothelial cell antigen, including the surface antigens and exposure of the subintimal antigens of damaged endothelial cell. Moreover, the molecular weight of antigens recognized by AECA could also be evaluated. It was found that both AECA-IgG and AECA-IgA were detectable in IgAN-MHT patients, while they were negative in normal controls, which confirmed that both AECA-IgG and AECA-IgA might contribute to the pathogenesis of some patients with IgAN-MHT. Importantly, patients with IgAN-MHT had the highest prevalence of anti-121 kD AECA-IgG and anti-92 kD AECA-IgA, which suggested that the above-identified AECAs might play particular roles in IgAN-MHT. However, their roles seemed independent since they coexisted only in one patient. Furthermore, other bands of AECAs detected in western blot in the present study failed to correlate with any phenotype, but their roles still could not be ruled out.

The target antigens of AECA are a heterogeneous group of proteins on the membrane or within the cytoplasm of endothelial cells. Although a few antigens such as heat-shock protein 60 in SLE have been recognized [19] most of them for AECA remain unknown. Till now, we have not identified the exact antigens of anti-121 kD AECA-IgG and anti-92 kD AECA-IgA. Since they had less prevalence in pMHT, we speculated that these antigens were associated with the particular immunological situation of IgAN-MHT rather than merely unraveled by shear stresses. Once AECAs were generated, they could exert their pathological effects by the activation of endothelial cells with increased expression of adhesion molecules [20], increased secretion of proinflammatory cytokines [20,21] and the release of vasoconstrictive agents to promote hypertension and vascular lesions in IgAN-MHT. Nevertheless, their antigens and their actual significance still need further investigation.

In the present study, antigens were provided by HUVEC, for renal endothelial cells were not available. So the differences of various types of endothelial cells could not be excluded. Other well-documented mechanisms of primary MHT such as the activation of renin–angiotensin system and sodium depletion were not referred to in the present study, but their roles in IgAN-MHT could not be excluded.

We concluded that the occurrence of IgAN-MHT was not associated with background glomerular phenotypes of IgAN. The ischaemic lesions and the background lesions might both contribute to the impairment of renal function at presentation, but might be associated with a different prognosis, which deserves further investigation. AECA might play a role in the pathogenesis of IgAN-MHT but might not be associated with the background lesions.



   Acknowledgments
 
This work was supported by the Grant of National Nature Science Foundation of China (30670981) and the Foundation of Ministry of Education, People's Republic of China (985-2-007–113) to H.Z.

Conflict of interest statement. None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.



   Notes
 
* Both authors made equal contribution to this work. Back



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 3.08
Accepted in revised form: 10. 6.08


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