Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis

Janette C. Cansick1, Rachel Lennon2, Carole L. Cummins3, Alexander J. Howie4, Mary E. McGraw2, Moin A. Saleem2, E. Jane Tizard2, Sally-Anne Hulton1, David V. Milford1 and C. Mark Taylor1

1 Department of Paediatric Nephrology, Birmingham Children's Hospital, 2 Department of Paediatric Nephrology, Bristol Hospital for Sick Children, 3 Institute of Child Health, University of Birmingham and 4 Department of Pathology, University of Birmingham, UK

Correspondence and offprint requests to: Dr Janette Christine Cansick, Department of Nephrology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. Email: jcansick{at}doctors.org.uk



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Prognostic factors and outcome are incompletely known in childhood mesangiocapillary glomerulonephritis (MCGN). This study aimed to correlate renal outcome with clinical and histopathological variables.

Methods. We conducted a two-centre retrospective analysis of children with MCGN.

Results. Fifty-three children presented at a mean age of 8.8 years (range: 13 months–15 years). They were followed for a median of 3.5 years (range: 0–17 years). Histological classification identified 31 type 1, 14 type 2, two type 3 and six undetermined type. Mean renal survival [time to end-stage renal failure (ESRF)] was projected to be 12.2 years [confidence interval (CI): 9.7–14.6 years]. Five and 10 year renal survival was 92% (CI: 88–100%) and 83% (CI: 74–92%), respectively. Those with nephrotic syndrome at presentation had mean renal survival of 8.9 years (CI: 7.1–10.7 years) vs 13.6 years for those without (CI: 10.8–16.5 years) (P = 0.047). The mean estimated glomerular filtration rate (eGFR) at 1 year in those who progressed to ESRF was 52 vs 98 ml/min/1.73 m2 in those who did not (P < 0.001). Chronic damage scored on the first biopsy in 31 children (one centre) was positively associated with adverse renal outcome at 5 years: <20% was associated with 100% and ≥20% with 71% 5-year renal survival (P = 0.006). In 29 children treated with steroid there was a higher proportion (76%) with reduced eGFR at presentation and a significantly higher incidence of nephrotic syndrome (P = 0.002) and hypertension (P = 0.037). There were no significant differences in outcome eGFR, hypertension or proteinuria.

Conclusions. Nephrotic syndrome at presentation and subnormal eGFR at 1 year were adverse features. The finding that structural disease at onset predicted poor renal outcome at 5 years has implications for the design of therapeutic trials. Treatment of MCGN was variable and not evidence-based.

Keywords: childhood; chronic renal damage; mesangiocapillary glomerulonephritis; prognostic factors; renal survival; treatment



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The group of disorders collectively called mesangiocapillary glomerulonephritis (MCGN) or membranoproliferative glomerulonephritis is rare in children. These disorders more commonly present in adolescents and affect both sexes equally. The incidence of MCGN is unknown and varies between countries.

MCGN may appear as a primary disorder or secondary to other chronic disease, including infections such as hepatitis B or C, systemic lupus erythematosus, liver disease and malignancy. Complement activation is often seen. Usually, there is a reduction in circulating complement C3 and evidence of alternate pathway activation. Immunohistochemistry usually reveals complement deposition in glomeruli [1]. In some children there is a genetic basis, for example through autoimmune phenomena or inherited defects of the complement pathways [1]. A few cases have been described in which no immunological abnormality has been found, for example a family with X-linked inheritance [2].

Traditionally, MCGN is considered to have two main pathological types, type 1 and type 2; these are likely to be different disorders with different aetiology and pathogenesis. Type 1 MCGN, also called subendothelial MCGN, is characterized by heavy deposition of immune complexes on the endothelial side of the glomerular basement membranes with widespread formation of a new basement membrane inside the old. Type 2 MCGN is also known as dense-deposit disease and has electron-dense material in the glomerular basement membrane on electron microscopy. A third type (type 3) has also been described, in which subepithelial immune deposits are also seen. This may be a variant of type 1. There are also other types in which there is no deposition of complement or immunoglobulin in the kidney.

The prognostic factors and outcome in children are incompletely known. This is partly due to small numbers of patients with short follow-up periods. Some studies have combined children with adults, the latter being more likely to show a more rapid decline in renal function. In studies exclusively of children, 10 year renal survival has been between 61% and 84% [3–5]. Nephrotic syndrome has been documented as an adverse presenting feature [6,7], as have hypertension [6,8] and dense-deposit disease [9]. Japanese studies report a more favourable outcome [10,11], but this is probably due to early detection since there is routine urinary screening of school age children.

The evidence base for treatment is weak. A recent review of clinical trials in adults and children [12] recommended high-dose alternate-day steroids for children presenting with nephrotic syndrome and/or renal impairment. Although there are studies of other immunosuppressant agents and anti-platelet drugs, there is insufficient evidence to support the use of these in children.

In order to further determine prognostic factors for outcome, identify renal survival and review current treatment practice, we performed a review of all patients with MCGN as their primary histological diagnosis in two tertiary referral centres for paediatric nephrology in the United Kingdom. We analysed clinical data and histology findings and applied an index of chronic damage; this has not previously been considered in this disease.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
A retrospective analysis of children with a histological diagnosis of MCGN was undertaken in two tertiary referral centres for paediatric nephrology, serving a total population of 10 million. The children were identified from biopsy records over a 20 year period (January 1980–December 1999) in Birmingham Children's Hospital and from a database over a 15 year period (January 1986–December 2000) in Southmead Hospital, Bristol.

Definitions
Proteinuria was defined on an early morning urine sample (urine sample obtained immediately after rising in the morning) as either ≥1+ protein on strip reagent, e.g. Albustix (Bayer Diagnostics, Newbury, England) or protein/creatinine ratio ≥20 mg/mmol. Minimal proteinuria was defined as 20–200 mg/mmol and nephrotic range proteinuria as >200 mg/mmol or ≥3+ on dipstix.

Nephrotic syndrome was defined as oedema with hypoalbuminaemia <25 g/l and nephrotic range proteinuria.

Haematuria was defined as macroscopic if visible to the naked eye and microscopic if ≥1+ blood on urine dipstix.

Hypertension was taken as a blood pressure documented as >95th percentile for height [13] or administration of antihypertensive agents, with the exception of angiotensin-converting enzyme (ACE) inhibition used solely to manage the nephrotic state in the absence of hypertension.

Estimated glomerular filtration rate (eGFR) was calculated from the Schwartz formula [14] as height x 40 / creatinine (ml/min/1.73 m2). Serum creatinine was measured by Kodak analyser in one centre and Jaffe method (Bayer Dax, Bayer Diagnostics, Newbury, England or Ortho Vitros, Ortho Clinical Diagnostics, Rochester, USA) in the other.

Chronic renal failure (CRF) was defined as eGFR <80 ml/min/1.73 m2, with mild being 60–79, moderate 30–59 and severe <30 ml/min/1.73 m2. End-stage renal failure (ESRF) was taken as commencement of renal replacement therapy or pre-emptive transplantation.

End-points for renal outcome
These were ESRF and eGFR.

Histological subtypes
MCGN is characterized on light microscopy by diffuse and global mesangial hypercellularity, often giving the glomeruli a lobular appearance. Type 1 MCGN is characterized by subendothelial immune deposits with doubled glomerular basement membranes and type 2 by electron-dense material in the glomerular basement membrane on electron microscopy. In type 3 MCGN, subepithelial immune deposits are also seen.

Index of chronic damage
The index of chronic damage was measured using image analysis on renal biopsy specimens stained by periodic acid–methenamine silver (PA–silver) and was the proportion of cortical cross-sectional area with chronic damage, defined as globally sclerosed glomeruli, atrophic tubules and interstitial fibrosis [15]. Cortex was outlined and the cross-sectional area measured. Parts of the cortex with chronic damage were then outlined and measured. This image was then converted to binary for measurement of the amount of chronic damage and subsequent computation of the index of chronic damage. Measurements were made by one observer (J.C.C.) after tests on preliminary specimens showed satisfactory agreement with the author who developed the method (A.J.H.). This was undertaken on the presentation biopsy on 31 of 34 cases from Birmingham only. Three specimens were unavailable for analysis.

Statistical analysis
The Kaplan–Meier product limit method was used to study renal survival. The equality of survivor function across groups was tested by the log-rank test. The t-test for equality of means was used to compare the difference in eGFR at 1 year between those who subsequently progressed to end-stage renal failure and those who did not. Pearson's chi-squared test was used to identify differences in the steroid-treated and non-steroid-treated groups.

For analysis by histological subtype, type 3 was grouped with type 1.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Fifty-three patients were identified, 21 female and 32 male, 34 in Birmingham and 19 in Bristol. Their age at presentation ranged from 13 months to 15 years (median: 9 years). Their features are presented in Table 1.


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Table 1. Details of all patients, including demographic features, presentation features, treatment received and outcome

 
Twenty patients had their first renal biopsy within a month of presentation and a further 19 within 6 months. Thirty-one had type 1 MCGN, 14 type 2 and two type 3. In six cases a clear allocation to a subgroup could not be made. Two of these presented with ESRF, one had sclerosed glomeruli, one had no glomerulus available for electron microscopy, one showed immune deposits of mixed pattern (types 1 and 2) and the last was non-immunological (X-linked inheritance).

There were collections of cells within Bowman's space, or crescents, in four biopsies.

Patients were followed until either ESRF or to their last clinic appointment. This was for a median of 3.5 years (range: 0–17 years). There were 24 patients in follow-up at 5 years and seven patients at 10 years.

Presentation features
Table 2 shows features at presentation and comparison with other published studies. Of those with nephrotic syndrome, all had additional features. Twelve were hypertensive and 19 had renal impairment. Of the two with normal renal function, one was hypertensive and the other had hypocomplementaemia. Ninety-two per cent of the total had proteinuria and 81% had hypoalbuminaemia; 87% had haematuria (70% microscopic, 17% macroscopic). Of the 40 children with hypocomplementaemia, 27 had isolated low serum concentration of C3, 11 low C3 and C4 and two isolated low C4.


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Table 2. Features at presentation and comparison with other published studies

 
Associated findings
Five of 14 children with type 2 MCGN had partial lipodystrophy.

Five children were found to have invasive pneumococcal disease at onset; the focus of infection was pneumonia in two children and peritonitis in one child. Four children had other streptococcal infections. Viral infections at presentation included one parvovirus, one Epstein–Barr virus and one varicella zoster virus. Of the 19 children tested for hepatitis B, all had negative serology.

One case has previously been described with a non-immunological disorder (normal plasma complement C3 and no complement deposition in the renal biopsy), apparently with X-linked recessive inheritance [2]. There were two further cases that gave a history of family members with glomerulonephritis.

Renal outcome
At final follow-up, 35 children (66%) had normal eGFR, two (4%) mild CRF, six (11%) moderate CRF, two (4%) severe CRF and eight (15%) ESRF.

Using the Kaplan–Meier method, the mean overall renal survival was 12.2 years [confidence interval (CI): 9.7–14.6 years]. Five year renal survival was 92% (CI: 88–100%) and 10 year renal survival was 83% (CI: 74–92%) (Figure 1). This is compared with other published studies of children in Table 3.



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Fig. 1. Kaplan–Meier curve for overall renal survival showing 92% renal survival at 5 years.

 

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Table 3. Renal outcome compared with other published studies in children

 
Age and sex
There were no statistical differences in renal survival when analysed by age or sex.

Histology
The mean renal survival for types 1 and 3 combined was 10.9 years (CI: 10.2–11.7 years) and was not significantly different from type 1 alone (data not shown) or type 2 (9.9 years; CI: 7.3–12.5 years; P = 0.156); (Figure 2). Of the four with crescents, two had normal renal function at follow-up, one moderate renal failure and one ESRF.



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Fig. 2. Kaplan–Meier curve for renal survival by histological type.

 
Nephrotic syndrome
The mean renal survival for the patients who presented with nephrotic syndrome was 8.9 years (CI: 7.1–10.7 years) compared with 13.6 years (CI: 10.8–16.5 years) in the remainder of patients (P = 0.047) (Figure 3).



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Fig. 3. Kaplan–Meier curve showing mean renal survival of 8.9 years for those presenting with nephrotic syndrome vs 13.6 years in the other patients (P = 0.047).

 
Proteinuria
There was no significant difference in renal survival in those who presented with heavy proteinuria (so-called nephrotic range proteinuria) compared with those with no or minimal proteinuria. Fifteen patients had no or minimal proteinuria at presentation. They were followed for a mean period of 5.7 years (range: 2–11.5 years). Of these, 14 children had not progressed to ESRF after 10 years. Thirty-eight children had heavy proteinuria and were followed for a mean of 4.5 years (range: 0–17 years). Some 89% (95% CI: 73–100%) had not reached ESRF after 5 years and 78% (95% CI: 42–100%) had not reached ESRF after 10 years.

The degree of proteinuria at 1 year also had no significant association with renal survival. Of 32 patients with data available for proteinuria at 1 year, of the eight patients who had no proteinuria, none progressed to ESRF at 5 years. Of the 24 children who had minimal or nephrotic range proteinuria 1 year from presentation, 96% (95% CI: 84–100%) had not reached ESRF at 5 years.

Hypertension
Hypertension observed at presentation or at 1 year also did not correlate with renal survival. Twenty-seven patients were not hypertensive at diagnosis and none progressed to ESRF after 5 years; at 10 years 67% (95% CI: 21–100%) had not progressed to ESRF. Of the 26 children who were hypertensive at diagnosis, 84% (95% CI: 61–100%) had not reached ESRF after 5 years and 84% (95% CI: 33–100%) had not reached ESRF after 10 years.

Of 33 patients with data available for hypertension at 1 year, 25 were not hypertensive and 96% (95% CI: 82–100%) of these survived free of ESRF at 5 years (one child reached ESRF). Of the eight children who were hypertensive 1 year after presentation, none had progressed to ESRF by the end of follow-up.

Hypocomplementaemia
There was no significant difference in renal survival between those with normal serum complement concentration at presentation compared with those with low complement concentration (data not shown).

Renal impairment
There was no significant difference in renal survival between those with renal impairment at presentation and those with normal renal function. In those with renal impairment at 1 year, however, the 5 year renal survival was 87% (CI: 70–100%) compared with 100% in those with normal eGFR at 1 year (P = 0.037). Mean renal survival was 11.3 years (CI: 8–14.7 years) in those with low eGFR at 1 year compared with 13 years if normal (P = 0.065).

In both types 1 and 2 MCGN the mean difference in eGFR at 1 year was significantly lower in those who progressed to ESRF than in those who did not (P = 0.001 for both types). There was no significant difference in the mean presentation eGFR in those who did or did not progress to ESRF in both types (Figure 4).



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Fig. 4. Box plot showing the mean, 25th and 75th centiles and range of eGFR at presentation, 1 year and 5 years. This shows a significantly lower mean difference in eGFR at 1 year in those who progressed to ESRF compared with those who did not in both types 1 and 2.

 
Index of chronic damage
The renal outcome (ESRF, low eGFR or normal eGFR) at last follow-up related to the index of chronic damage on the initial biopsy is shown in Figure 5. The mean time of survival with normal eGFR in the patients with an index of chronic damage ≥20% was 7.0 years (CI: 3.6–10.5 years) compared with 12.3 years (CI: 9.1–15.4 years) in those with an index of chronic damage <20% (P = 0.02). Five year survival with normal eGFR in those with an index of chronic damage ≥20% was 71% compared with 100% in those with index of chronic damage <20% (P = 0.006) (Figure 6). There was no correlation between the eGFR at the time of biopsy and the index of chronic damage.



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Fig. 5. Scatter plot showing the renal outcome depending on index of chronic damage on the initial renal biopsy specimen (Birmingham patients). This shows that, in general, those with a low index of chronic damage have a good short-term prognosis and those with a very high index of chronic damage proceed to ESRF early.

 


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Fig. 6. Kaplan–Meier curve for renal survival for index of chronic damage showing 71% 5 year renal survival in those with index of chronic damage ≥20% and 100% in those <20%.

 
Treatment
Types of treatment
Twenty-four children (45%) received no disease-modifying treatment. The other 29 children were all treated with prednisolone; 15 of these also received methylprednisolone. Azathioprine was used as a steroid-sparing agent in 12 patients. Six children received cyclophosphamide and four received plasma exchange. Other medications used were dipyridamole and/or aspirin in 23 children and an ACE inhibitor in 27 children.

Presentation and treatment
Children with nephrotic syndrome at presentation were significantly more likely to receive disease-modifying treatment (P = 0.002). Similarly, a higher proportion of those with hypertension at presentation were treated (P = 0.037). Although a higher percentage of those with impaired renal function at presentation received treatment, this was not statistically significant (P = 0.33). There were no significant differences between the treatment and non-treatment groups when analysed for demographic features, type of MCGN and presence of haematuria or hypocomplementaemia at presentation.

Treatment and outcome
There were no differences in outcome measured by eGFR, hypertension and proteinuria at final follow-up between the treated and non-treated groups.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Mesangiocapillary glomerulonephritis describes a heterogeneous group of disorders that share similar histopathological appearances. These include lobulated glomeruli with mesangial cellular proliferation and capillary wall thickening due to endocapillary cellular proliferation with interposition of cells and deposits between the basement membrane and the endothelium. The diagnosis is rare. In this paper we report the clinical experience over >15 years from two paediatric nephrology centres that serve an estimated total population of 10 million. We confirm the clinical course in childhood, previously described by others. However, we also identify novel prognostic features that have implications both for understanding the pathogenesis and for the design of clinical trials in these patients.

The case presentation and renal survival was similar both between the two centres that contributed to the study and to some published series [3–5]. However, there are notable differences between this experience and that of other parts of the world. For example, Japanese studies report a higher incidence of patients presenting with isolated microscopic haematuria [10,11]. Some of these patients are identified earlier in the course of the disease than is the case for British children by routine urinalysis screening of school children. In other countries, a higher proportion of cases are associated with chronic infection, particularly viral hepatitis, and a lower proportion exhibit persistent hypocomplementaemia [16].

In our study, three features predicted adverse outcome: nephrotic syndrome at presentation, low eGFR at 1 year and a higher index of chronic damage on the original biopsy; neither the severity of proteinuria per se nor the histological subtype of MCGN was significantly associated with prognosis.

We confirm that nephrotic syndrome at presentation is associated with an adverse prognosis, an observation previously made by Somers et al. [6] and Schwertz et al. [7]. However, the degree of proteinuria at onset in those patients without nephrotic syndrome did not predict outcome; neither did the degree of proteinuria at 1 year. This is, perhaps, surprising given the assumption that proteinuria is a clinical indicator of disease activity.

It is interesting that overall our patients had a reduced eGFR at presentation with no difference between good and poor outcome groups. At 1 year there was an improvement in function in those who had the better outcome, compared with a further decline in those with poor outcome. While the further decline in function in the adverse group is perhaps expected, and to some extent axiomatic, the cause of the reversible reduction in eGFR in the others is not clear. There was no correlation between eGFR at the time of biopsy and the index of chronic renal parenchymal damage. This implies that impaired eGFR at onset may or may not indicate structural disease and cannot be used as a prognostic indicator.

Our study shows that chronic renal parenchymal damage, quantified histologically in the initial biopsy, is a useful indicator of outcome. This relationship holds over 5 years of follow-up. Because we have too few children followed for longer periods, we are not in a position to know if the prediction serves over a longer period. The implication of this is that much structural damage may already have taken place in the poor outcome group by the time they reach medical attention. Conversely, those that have not developed structural damage at the time of diagnosis are unlikely to show renal impairment in 5 years. This has potential implication for the design of treatment trials, as discussed below.

In our patients there was a trend for cases with dense-deposit disease to have a less-favourable course than MCGN types 1 and 3, but this did not achieve statistical significance, probably due to the small numbers followed beyond 5 years. The observation is, however, compatible with the finding of Habib et al. [9] that dense-deposit disease carries a worse prognosis.

Treatment of this cohort of children broadly reflected current practice in the United Kingdom, as determined by a questionnaire survey of all the other 11 tertiary paediatric nephrology units in the United Kingdom (This questionnaire can be viewed online as supplementary data). The survey showed that more children with nephrotic syndrome or hypertension at presentation were likely to be treated with steroids. In our study there was a significantly higher proportion of nephrotic cases in the steroid-treated group. There was no significant difference in outcome eGFR between the steroid-treated and -untreated groups. This is compatible with steroids having therapeutic benefit.

Evidence-based recommendations for the treatment of idiopathic MCGN [12] attributed grade A evidence (based on overview of randomized controlled trials with no heterogeneity) [17] to the use of high-dose alternate-day steroids for children presenting with nephrotic range proteinuria (>3 g/day) or impaired renal function. The evidence for this recommendation is predominantly based on the International Study of Kidney Disease in Children (ISKDC) [5] as well as other smaller studies that have corroborated the use of steroids [9,18–20]. The ISKDC study [5] is the largest randomized controlled trial and recruited 80 children with MCGN, a creatinine clearance >70 ml/min/1.73 m2 and proteinuria ≥40 mg/h/m2. Renal survival at 130 months was 61% in the steroid-treated group and 12% in the placebo group. However, this was not statistically significant (P = 0.07) and the authors comment that in order to reach significance, twice the actual number of recruits would have been necessary. Also, there was a significantly longer duration of disease prior to entry into the trial in the placebo group (18.1 vs 8.9 months) that might contribute to the poorer outcome in the placebo group.

Levin [12] advocated the use of steroids for heavy proteinuria and renal impairment. Our limited data do not support this. We suggest that nephrotic syndrome at presentation, not heavy proteinuria alone, should influence treatment strategy. More importantly, renal impairment at presentation is itself not an adverse prognostic factor, as it may be reversible, even though the cause of impairment may not be clinically apparent.

Beyond the general agreement over the need to actively treat nephrotic MCGN, there is currently little evidence on which to treat children. Conventionally, clinicians have looked to adequately powered randomized controlled trials to address the problem. The rarity of the disorder (or disorders) implies the need for these to be multicentre or even multinational and to allow for follow-up into adult life.

Our experience suggests that in some patients extensive, irreversible renal damage occurs prior to presentation and has a powerful knock-on effect on outcome. An index of chronic damage, such as we have used here, needs to be taken into consideration in randomizing or stratifying cases in a trial. We propose that disease activity and disease staging need to be considered separately, both in day-to-day clinical practice as well as in trial design. For example, immunosuppressive therapy aimed at disease activity may not be able to show benefit in cases with extensive chronic damage or may be clinically inappropriate. Instead, it would be reasonable to consider a different approach for patients with established structural damage to moderate the progression of scarring where the population of surviving nephrons is already reduced. On the other hand, in those patients with minimal structural damage at onset, any benefit from treatments aimed at suppressing disease activity may not become apparent for a very long time. Permanent changes in GFR are late features and proteinuria may not be a reliable surrogate of disease activity. In our opinion, a histological end-point of quantified structural damage on follow-up biopsies is likely to be helpful as an interim measure.



   Acknowledgments
 
We would like to thank Dr Rosemary Greenwood, statistician at Bristol Children's Hospital, for her advice.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29.12.03
Accepted in revised form: 28. 7.04





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