A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients

Hans Furuland1,, Torbjörn Linde1, Jarl Ahlmén2, Anders Christensson3, Ulf Strömbom4 and Bo G. Danielson1

1 Department of Medical Sciences, University Hospital, Uppsala, 2 Department of Renal Medicine, Skaraborgs Hospital, Skövde, 3 Department of Nephrology and Transplantation, University Hospital, Malmö and 4 Department of Nephrology, Varberg Hospital, Varberg, Sweden



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Partial correction of renal anaemia with erythropoietin improves quality of life (QoL). We aimed to examine if normalization of haemoglobin with epoetin alfa in pre-dialysis and dialysis patients further improves QoL and is safe.

Methods. 416 Scandinavian patients with renal anaemia [pre-dialysis, haemodialysis (HD) and peritoneal dialysis patients] were randomized to reach a normal haemoglobin of 135–160 g/l (n=216) or a subnormal haemoglobin of 90–120 g/l (n=200) with or without epoetin alfa. Study duration was 48–76 weeks. QoL was measured using Kidney Disease Questionnaires in 253 Swedish dialysis patients. Safety was examined in all patients.

Results. QoL improved, measured as a decrease in physical symptoms (P=0.02), fatigue (P=0.05), depression (P=0.01) and frustration (P=0.05) in the Swedish dialysis patients when haemoglobin was normalized. In pre-dialysis patients, diastolic blood pressure was higher in the normal compared with the subnormal haemoglobin group after 48 weeks. However, the progression rate of chronic renal failure was comparable. In the normal haemoglobin group (N-Hb), 51% had at least one serious adverse event compared with 49% in the subnormal haemoglobin group (S-Hb) (P=0.32). The incidence of thrombovascular events and vascular access thrombosis in HD patients did not differ. The mortality rate was 13.4% in the N-Hb group and 13.5% in the S-Hb group (P=0.98). Mortality decreased with increasing mean haemoglobin in both groups.

Conclusions. Normalization of haemoglobin improved QoL in the subgroup of dialysis patients, appears to be safe and can be considered in many patients with end-stage renal disease.

Keywords: anaemia; end-stage renal failure; erythropoietin; haemoglobin; mortality; quality of life



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients with end-stage renal disease (ESRD) often suffer from anaemia due to erythropoietin deficiency. Partial correction of anaemia with erythropoetin treatment has been shown to improve quality of life (QoL) [1], physical exercise capacity [2] and ameliorate left ventricular hypertrophy [3], an established risk factor for cardiovascular morbidity and mortality in ESRD [4]. Uncontrolled studies suggest that complete correction of anaemia further improves QoL [5], neuro-cognitive function [6], physical exercise capacity [7] and decreases left ventricular mass [8,9].

Conflicting evidence has been reported from a large randomized study in haemodialysis (HD) patients with cardiac disease. This study was prematurely terminated due to a trend towards higher mortality and an increased frequency of vascular access thrombosis (VAT) in the normal-haematocrit group compared with the low-haematocrit group [10]. A confusing aspect of this study was that the mortality rate in both treatment groups decreased as a function of higher haematocrit values and that the lowest mortality rate was found in the patients with a haematocrit >39%. However, since it was a post-hoc analysis there is a possibility that survival bias may have had an influence on the results.

Normalization of haemoglobin in HD patients with asymptomatic cardiomyopathy was investigated in a randomized study from Canada [11]. No regression of established cardiomyopathy was observed, but the study data suggested that normalization of haemoglobin might prevent left ventricular dilatation. No increase in mortality was associated with normalization of haemoglobin levels but QoL improved.

The optimal target haemoglobin level for epoetin treatment is a matter of debate. For instance, the European Best Practice Guidelines issued by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) [12] recommend a target haemoglobin level of >110 g/l with no upper limit, except for patients with cardiovascular disease and/or diabetes.

The aim of the present study was to investigate the effects of elevating haemoglobin concentrations with epoetin alfa from subnormal to normal values in both pre-dialysis and dialysis patients, with special emphasis on QoL and safety.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study subjects
This was a multicentre, randomized, open-label trial in patients with renal anaemia. Sixty-two hospital centres in Sweden (48), Norway (eight), Finland (five) and Iceland (one) participated in the trial. The study was conducted in accordance with the Helsinki declaration and its amendments and was approved by the Medical Products Agency and the Ethics Committee at each centre. All patients gave written informed consent. Enrollment took place between 1995 and 1996.

Patients were stratified into three groups: pre-dialysis, HD and peritoneal dialysis (PD) patients. The pre-dialysis patients (serum creatinine >300 mmol/l or creatinine clearance <30 ml/min) were not expected to become dialysis-dependent within 1 year. All patients had haemoglobin values in the subnormal range (90–120 g/l) for at least 3 months with or without epoetin therapy prior to entering the study. Exclusion criteria were anaemia from causes other than chronic renal failure; diastolic blood pressure repeatedly >=100 mmHg; uncontrolled diabetes (HbA1c >10%); clinically relevant abnormal liver function; severe secondary hyperparathyroidism (cystic bone disease, parathyroid hormone >300 ng/l); clinical signs of aluminum intoxication (serum aluminum >100 mg/l) or treatment with desferrioxamine; uncontrolled overhydration in HD patients (requiring repeatedly ultrafiltration of >=4 l); active infection, inflammation or malignancy.

As a result of the premature termination of the American normal haematocrit trial [10], the present study was halted in 1996 for an interim safety analysis. An amendment added new exclusion criteria: angina pectoris and/or congestive heart failure corresponding to New York Heart Association classes III and IV; history of a coronary-artery by-pass grafting and/or percutaneous transluminal coronary angioplasty <2 years ago; history of transmural myocardial infarction <3 years ago; permanent atrial fibrillation or uncontrolled arterial hypertension. A total of 33 patients in the study were excluded for this reason.

Study protocol
Patients in all three stratified groups (pre-dialysis, HD, PD) were randomized to either the normal haemoglobin group (N-Hb) or the subnormal haemoglobin group (S-Hb). In the N-Hb group, patients received epoetin alfa (Eprex®, Janssen-Cilag AB, Sollentuna, Sweden) to achieve target haemoglobin levels of 135–150 g/l in females and 145–160 g/l in males. In the S-Hb group, the target haemoglobin level was 90–120 g/l with or without epoetin alfa treatment.

The study duration was extended from 48 weeks to 76 weeks in Sweden (48 study centres) due to a slower increase in haemoglobin values than anticipated. Since the withdrawal rate was high, results at week 48 are presented for many variables.

Epoetin alfa was administered subcutaneously and the dose adjusted according to response in haemoglobin values and reticulocyte count. Patients randomized to N-Hb not already receiving epoetin, initially received 50 U/kg of epoetin alfa three times weekly. For patients already receiving epoetin, the initial dose increment was 50%. The dose was increased by 25% if reticulocytes had not increased by >=75% after 2 weeks of treatment. Epoetin alfa was increased by a further 25%, if the increase in haemoglobin level was <10 g/l after 4 weeks. The dose was then adjusted every 2 weeks, aiming at a monthly increase in haemoglobin of 10–15 g/l, to reach the target haemoglobin level within 3 months. Patients received iron supplementation with oral ferrosulphate or i.v. iron sucrose (Venofer®, Vifor, Switzerland) to keep transferrin saturation >20% and serum ferritin levels between 400 and 800 mg/l during the correction phase and >250 mg/l during the maintenance phase.

Evaluations and safety
Data were collected of vital signs, biochemical variables and concomitant drug therapy.

QoL in the 253 Swedish dialysis patients was assessed at baseline and after 1 year using a Kidney Disease Questionnaire (KDQ parts 1 and 2) [13]. In KDQ part 1 the patients selected the six most troublesome physical symptoms at baseline from a predefined list of 30 and made a new grading of these symptoms after 48 weeks. In KDQ part 2, scales graded 1–7 (where 1 means a severe problem and 7 no problem) were used to assess fatigue, depression, frustration and relationships with others. A more extensive evaluation of QoL data for both dialysis and pre-dialysis patients will be presented separately.

Renal function was estimated by local routine methods, either endogenous creatinine clearance (24 h urine collection), iohexol clearance or Cr-EDTA clearance at weeks 0 and 48 in pre-dialysis patients.

Adverse events and serious adverse events (SAE), number of days of hospitalization and sick leave, were regularly monitored. Thrombovascular events (TVE) and VAT were recorded and categorized centrally by one coordinator based on a WHO classification. The dose of heparin and low molecular weight heparin at HD were recorded. Blood pressure readings were taken and blood specimens drawn from HD patients before midweek HD sessions. Blood pressure was measured after >10 min rest in the supine position, using a sphygmomanometer. Antihypertensive medication was modified as necessary. The amount of antihypertensive medication was estimated using a daily defined dose of an antihypertensive drug, according to the dosing guidelines issued by the Medical Products Agency of Sweden.

The causes of death were registered based on clinical diagnosis and/or autopsy (in 24 cases). Cardiovascular causes included myocardial infarction, atherosclerotic disease of the coronary arteries, aorta and peripheral arteries, congestive heart failure, sudden death and cerebrovascular disease. Non-cardiovascular causes included sepsis/infection, uraemia NUD and malignancy.

Statistical analysis
It was calculated that 60 patients in each treatment group were needed to detect a 30% improvement in exercise test capacity with a power of 90% at a significance level of 5%, assuming that SD was ±30% and that 25% would become withdrawals. It soon became apparent that many patients were unable to perform an exercise test making the evaluation of this variable impossible in a controlled trial. Therefore, an additional 180 patients were included to form a database for safety evaluation of 300 patients. Because of a high withdrawal rate, slower increase in haemoglobin values than anticipated, and to compensate for withdrawals caused by the new exclusion criteria in the amendment, an additional 116 patients were recruited. In the QoL analyses, the Wilcoxon rank sum test adjusted for baseline values was used to compare changes from baseline to week 48 between treatment groups. Comparison of mortality, TVE and SAE between treatment groups was performed using a respective logistic regression analysis model including the following variables: dialysis or pre-dialysis patient, age, gender, congestive heart failure, ischaemic heart disease, peripheral vascular disease, atrial fibrillation, valvular disease, diabetes, cancer, hypertension, increased blood pressure, albumin and platelets. All variables with a P-value <0.2 in the univariate analyses were tested for inclusion in the final model in a stepwise forward manner. The final model included variables or interactions terms with P-values of 0.05 or less. Treatment group was included in the model regardless of P-value. Odds ratios with 95% confidence intervals were calculated. The estimated cumulative hazard (probability of death) is presented in Kaplan–Meier curves. All other efficacy and safety variables were tested by Student's t-test, Wilcoxon rank sum test or Fisher's exact test as appropriate. The level of statistical significance was 5%. All analyses were conducted on an intent-to-treat basis. In addition, an analysis was made with the ‘last observation carried forward’, i.e. the last observed value of the withdrawals was used as the final value, thereby including all participating patients in the calculations. Another analysis evaluated efficacy vs effectiveness (per protocol) by creating subsets of patients that had reached target haemoglobin level in the respective group. In all statistical analyses the software SAS® System version 6.12 for Windows was used.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics and baseline values
Of the 416 patients enrolled, 216 were randomized to the N-Hb group and 200 to the S-Hb group. Patient characteristics were comparable between the N-Hb group and S-Hb groups and within the three stratified patient categories (pre-dialysis, HD, PD) (Table 1Go). Study participation ranged from 9 to 546 days and 210 patients completed the study (Table 2Go). The most common reasons for discontinuation were transplantation and death. All reasons for discontinuation, except for death, tended to be more frequent in the N-Hb group. Patient characteristics and baseline values for the discontinued patients were comparable in the N-Hb and S-Hb groups.


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Table 1.  Patient characteristics and baseline values

 

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Table 2.  Summary of discontinuations

 

Anaemia management
Target haemoglobin levels were reached after ~5 months in the N-Hb group (Figure 1Go). Mean weekly doses of epoetin alfa differed significantly between the N-Hb and S-Hb groups in pre-dialysis and HD patients (Table 3Go), but did not reach statistical significance in the smaller group of PD patients (n=51). More patients were treated with i.v. iron sucrose and received higher doses in the N-Hb group than in the S-Hb group, with the difference reaching statistical significance in HD and PD patients (Table 3Go). No substantial differences in transferrin saturation or serum ferritin between the N-Hb and S-Hb groups were observed during the study. At week 48, transferrin saturation was 32±16 and 31±15% and serum ferritin was 559±421 and 487±339 µg/l in the N-Hb and S-Hb groups, respectively. Haemoglobin level, epoetin dose and i.v. iron dose was significantly higher in the N-Hb compared with the S-Hb group in an analysis with the ‘last observation carried forward’ (data not shown).



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Fig. 1.  Mean haemoglobin concentration (±SEM) for pre-dialysis, HD and PD patients in the N-Hb and S-Hb groups during the study.

 

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Table 3.  Summary of haemoglobin levels and dosages of epoetin alfa and iron sucrose

 

Quality of Life
KDQ evaluation of QoL in the Swedish dialysis patients showed amelioration of the main physical symptoms in the N-Hb compared with the S-Hb group. Of the 253 dialysis patients in the KDQ analysis, 9% had missing observations at baseline, and 117 (46%) were evaluated at week 48 (Table 4Go). Change in KDQ score for the main physical symptoms, fatigue, depression and frustration favoured the N-Hb group compared with the S-Hb group. In general, patients in the S-Hb group worsened, while patients in N-Hb stayed the same or improved over time. At week 48, each of the KDQ scores were positively correlated with the haemoglobin levels in the N-Hb group (r=0.32–0.37; P<0.02). The differences in fatigue and depression persisted in a ‘last observation carried forward’ analysis. In a per protocol analysis all KDQ parameters were significantly better (between 0.39 and 0.91 U) for those in the N-Hb group that reached target Hb compared with the ones that did not.


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Table 4.  QoL in dialysis patients

 

Renal function in pre-dialysis patients
Glomerular filtration rate was estimated in 46 pre-dialysis patients at baseline, and was 16±9 ml/min/1.73 m2 (n=24) and 17±6 ml/min/1.73 m2 (n=22) in the N-Hb and S-Hb groups, respectively. At week 48, glomerular filtration rate was 13±10 ml/min/1.73 m2 (n=19) in the N-Hb group and 16±7 ml/min/1.73 m2 (n=21) in the S-Hb group (P=0.43). Two pre-dialysis patients in the N-Hb group were transferred to dialysis before week 48. Other reasons for discontinuation were patient request (one), adverse event (one) and investigators decision (one) in the N-Hb group, and patient request (one) in the S-Hb group. A per protocol analysis of the patients that reached target Hb did not show any difference between treatment groups.

Serious adverse events, sick leave and hospitalization
In a multivariate logistic regression analysis of SAE the number of patients with at least one SAE was 110 and 97 (odds ratio 1.23 and 1.0) in the N-Hb and S-Hb groups, respectively (P=0.32). Independent risk factors for SAE were baseline serum albumin <36 g/l, atrial fibrillation or diabetes at baseline and increasing age (up to 76 years). Five patients in the N-Hb group and seven in the S-Hb group had sepsis. The number of days of hospitalization in percentage of total days in study were 4.8±9.4 and 3.8±8.8 (P=ns) and of sick leave 6.5±21 and 5.4±20 (P=ns) in the N-Hb and S-Hb groups, respectively.

Thromboembolic complications
In a multivariate logistic regression analysis the number of TVE were 56 and 47 (odds ratio 1.24 and 1.0) in the N-Hb and S-Hb groups, respectively (P=0.37). Increasing age (up to 76 years), presence of hypertension prior to or during the study, ischaemic heart disease at baseline and dialysis were found to be independent risk factors for TVE. Few VAT events occurred. Among the 293 HD patients, seven (5%) in N-Hb group and three (2%) in S-Hb group had a thrombotic complication in their fistula, graft or dialysis catheter anytime during the study (P=0.34). In the per protocol analysis there was no difference in the frequency of VAT and TVE for those who reached target Hb. At week 48, the mean dose of heparin for HD was 7373±3178 and 6666±2791 IU (P=0.30), and the dose of low molecular weight heparin was 5119±2848 and 4440±2639 IU (P=0.37) in the N-Hb and S-Hb groups, respectively.

Blood pressure and antihypertensive medication
Blood pressure values and the amount of antihypertensive medication were evaluated at baseline and weeks 12, 24, 48 and 76. Blood pressure in pre-dialysis patients was 147±21/90±6 and 148±24/83±11 mmHg at week 48 in N-Hb and S-Hb patients, respectively (P=0.02 for diastolic blood pressure). Also, in the ‘last observation carried forward’ and per protocol analysis, pre-dialysis patients had a significantly higher diastolic blood pressure in the N-Hb group. In PD patients, blood pressure was 143±23/88±12 and 144±28/80±10 mmHg at week 12 (P=0.04 for diastolic blood pressure) in the N-Hb and S-Hb groups, respectively. Otherwise, there were no significant differences in blood pressure between N-Hb and S-Hb in either pre-dialysis, HD or PD patients. The amount of antihypertensive medication and the proportion of patients treated with antihypertensives, were comparable between treatment groups.

Mortality
The overall mortality rate for all three patient groups was comparable between the N-Hb (13.4%) and S-Hb (13.5%) groups (Table 5Go). There was no significant difference in mortality between the treatment groups when causes of death were divided between cardiovascular and non-cardiovascular causes. The causes of death for pre-dialysis, HD and PD patients are also shown in Table 5Go.


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Table 5.  Cardiovascular and non-cardiovascular causes of death (n)

 
Survival was analysed only for the larger HD group. The probability of death did not differ between the randomized groups (P=0.50) (Figure 2Go). The survival curve ends after 48 weeks because the remaining number of patients was markedly reduced due to completion of the study or withdrawals, which makes interpretation difficult. Analysis of mortality rate vs mean haemoglobin level (for 4 weeks) showed a correlation between higher haemoglobin levels and lower mortality rate in both the N-Hb and S-Hb groups (P<0.05 by log rank test for both groups) (Figure 3Go). The cumulative probability of death in the N-Hb group was higher for those that did not reach Hb-target (<135 g/l) compared with the patients that reached the Hb-target (P=0.032 by log rank test).



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Fig. 2.  Probability of death for HD patients until week 48 in the N-Hb and S-Hb groups by log rank test (P=0.50).

 


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Fig. 3.  Probability of death by log rank test at different mean haemoglobin intervals in the N-Hb group (P<0.05) and the S-Hb group (P<0.05).

 
Multivariate logistic regression analysis of mortality showed that treatment group was not a risk factor. The odds ratio for mortality in the N-Hb group compared with the S-Hb group was 1.16 (95% confidence interval 0.63–2.11, P=0.63). However, increasing age, serum albumin <36 g/l and presence of valvular disease at baseline were independent risk factors for mortality. There was no difference in the i.v. iron sucrose dose between survivors and non-survivors in the N-Hb and S-Hb groups.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present investigation different effects of renal anaemia treatment aimed at reaching a normal or subnormal Hb value was compared. The study showed beneficial effects of haemoglobin normalization on QoL in HD patients and provided no evidence that this treatment accelerates the progression of renal disease, increases TVE, SAE or mortality. The need for hospitalization and sick leave was not affected. Recent studies have also suggested additional benefits in QoL and safety with complete haemoglobin correction in both pre-dialysis [8] and dialysis patients [5,6,9,11]. Notable is the even greater difference in QoL when evaluating the effectiveness in reaching target Hb rather than the efficacy. To obtain these results the dose of epoetin alfa was ~60% higher in the N-Hb compared with the S-Hb group.

The high proportion of withdrawals may be a source of bias in the present study. However, the analysis with the ‘last observation carried forward’ did not significantly alter the results. There tended to be more withdrawals in the N-Hb group principally due to adverse events or investigators decision. This may not necessarily be caused by effects of Hb normalization. The possibility that AE is more frequently reported and that investigators action is more common in the treatment group of an open study has to be taken into consideration. Another point of uncertainty is that the rather small sample size results in insufficient statistical power comparing the frequency of cardiovascular causes of death between the treatment groups.

The impact of epoetin treatment on residual renal function has been questioned, but now animal as well as human studies have reported unchanged or even improved renal function after partial correction of anaemia with epoetin, when blood pressure has been corrected for [14,15]. In the present study, renal function remained unchanged in both randomized groups, suggesting that normalizing haemoglobin does not have a deleterious effect on renal function. However, the patient group was small and three different clearance methods were used, of which endogenous creatinine clearance has a greater variance, making the results less precise.

In the American normal haematocrit trial [10], thrombosis of the vascular access site was more frequent in the normal-haematocrit group, whereas higher haematocrit values were not associated with an increased general thrombosis rate. No increases in TVE or VAT related to haemoglobin normalization were observed in the present study, which is in concordance with findings reported by Foley et al. [11]. As a result of the present study blood haemostasis [16] and renal transplantation outcome [17] have been investigated without showing negative effects when haemoglobin was normalized.

Several mechanisms by which erythropoietin could promote hypertension are possible, for example changes in vasopressor activity and vascular remodelling [18]. In current practice, though, hypertension is generally a minor clinical problem when treatment strategies most commonly aim at subnormal haemoglobin levels [19]. Our study indicates that normalization of haemoglobin in pre-dialysis patients may increase the need for antihypertensive medication in order to avoid the negative effects on progression of renala disease and the cardiovascular system. However, the amount of antihypertensive medication was not increased in this study.

In the present investigation the mortality rate was lower compared with the American normal haematocrit trial, a study in which clinical signs of severe heart disease were an inclusion criteria. Our study had no such criteria; in fact patients with severe heart disease were excluded. Furthermore, the incidence of diabetes, hypertension and peripheral vascular disease was more common in the American trial, which might explain their higher mortality. Our study also found a correlation between decreasing mortality rate and increasing haemoglobin levels in both treatment groups. However, this observation does not prove any causal relationship between a high Hb and a low mortality. The association may be due to other factors such as different concomitant diseases, which may alter the response to epoetin therapy.

It has been implied that high levels of i.v. iron could increase susceptibility to serious infections [10]. In the present study, the incidence of sepsis was not higher in the N-Hb group than the S-Hb group, even though N-Hb patients received significantly more i.v. iron than S-Hb patients. Furthermore, dosages of i.v. iron sucrose were the same for survivors and non-survivors in both groups. These observations are in agreement with a recent systematic review, which was unable to find a relationship between i.v. iron and increased frequency of infections [20].

To summarize, effects of renal anaemia treatment aimed at reaching a normal Hb level was examined. QoL was improved in the subgroup of dialysis patients. In safety analysis there were no deterioration of residual renal function in pre-dialysis patients, no increase in VAT for HD patients and no increase in TVE, SAE, morbidity and mortality for all patients. The probability of death in HD patients did not differ between the two groups. Blood pressure in pre-dialysis patients increased slightly, which needs attention. On the basis of this study, it appears that normalization of haemoglobin can be considered in many patients with renal anaemia.



   Acknowledgments
 
We are indebted to Kerstin Wiklund, PhD, at Clinical Data Care for statistical support. We also wish to thank all doctors and study nurses at the participating centres. Funding by Janssen-Cilag AB, Sollentuna, Sweden.



   Notes
 
Correspondence and offprint requests to: Hans Furuland, MD, Department of Internal Medicine, University Hospital, Entrance 40, S-751 85 Uppsala, Sweden. Email: hans.furuland{at}medsci.uu.se Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 31. 7.01
Accepted in revised form: 3.10.02