Assessment of vascular calcification in ESRD patients using spiral CT

Sharon M. Moe1,2,, Kalisha D. O'Neill1, Naomi Fineberg1, Scott Persohn3, Sadiq Ahmed1, Patrick Garrett1 and Cristopher A. Meyer3

1 Department of Medicine and 3 Department of Radiology, Indiana University School of Medicine and 2 Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Dialysis patients have increased vascular calcification of the coronary arteries and aorta by electron beam CT scan. The purpose of the present study was to utilize an alternative machine, spiral CT, to assess calcification in end-stage renal disease (ESRD) patients.

Methods. Two groups of patients with ESRD were evaluated: group 1, those receiving a renal transplant (n=38); and group 2, those remaining on dialysis (n=33). All patients underwent quad-slice spiral CT with retrospective gating to evaluate coronary artery and aorta calcification scores. Both area (Agatston method) and volume calculations were utilized, with retrospective gating in all but 16 subjects. Laboratory tests, medications and clinical characteristics were analysed.

Results. Using spiral CT, the intra-reader variability for coronary artery calcification (after correction for very low scores) was 0.9% mean / 0% median using the area (Agatston method) and 2.9% mean / 0% median using volume calculations. Group 1 patients were younger, more likely to be Caucasian and on peritoneal dialysis, had lower serum calcium and higher C-reactive protein levels than group 2. In patients without vs those with coronary artery calcification, only longer duration of dialysis (34±64 vs 55±50 months, P=0.004; r=0.39, P=0.005) and increasing age (39±13 vs 54±10 years, P<0.001; r=0.29, P=0.039) were associated, whereas only increasing age was associated with aorta calcification.

Conclusion. In ESRD patients, the factors correlating with coronary calcification were duration of dialysis and advancing age, whereas only age correlated with aorta calcification. Spiral CT offers an alternative technique for the assessment of these changes.

Keywords: coronary artery disease; dialysis; spiral CT; transplant; vascular calcification



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Atherosclerotic disease remains a major cause of morbidity and mortality in the general population. The assessment of coronary arteries by new non-invasive imaging techniques such as electron beam CT scan (EBCT) and intravascular ultrasound has heightened the awareness that >70% of atherosclerotic plaques observed in the ageing population are calcified [1]. Furthermore, in non-dialysis patients, the magnitude of calcification by EBCT correlates with the severity of obstructive coronary artery disease by angiography [1], and with clinical cardiac events [2]. Cardiovascular disease and stroke are also the leading causes of death in patients with end-stage renal disease (ESRD) that require dialysis, at a risk that is 10- to 20-fold that of the age- and sex-matched general population [3]. Studies evaluating coronary calcification by EBCT in patients with ESRD have demonstrated 2- to 5-fold more coronary artery calcification (CAC) than age- and sex-matched individuals with angiographically proven coronary artery disease. Furthermore, in a follow-up of these 57 haemodialysis patients, every patient had an increase in calcification score when followed-up just 1–2 years later [4]. Goodman et al. [5] demonstrated that this process also affects young adults on dialysis, with a sharp increase in the magnitude of CAC by EBCT after age 20.

These results imply that the use of EBCT may also have prognostic implications for dialysis patients. Unfortunately, EBCT machines are not readily available due to relatively high initial and maintenance costs and limited uses other than the quantification of CAC. A more widely available technology is that of spiral (or helical) CT scan. Recent new software adaptations and increased speed of gantry rotation have allowed the use of spiral CT scans also to quantify CAC. The purpose of the present study was to determine the utility of retrospectively gated spiral CT for the assessment of coronary artery and aorta vascular calcification and to identify potential risk factors for calcification in ESRD patients on haemodialysis and patients undergoing renal allograft surgery utilizing this new technique. In addition, the present study evaluated the variability and effect of gating on calcification scores.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Two patient groups were examined: group 1, patients with ESRD undergoing a renal transplantation at Indiana University, referred from the entire state of Indiana; and group 2, patients with ESRD undergoing chronic haemodialysis at Indiana University. The purpose of separating the patient groups were: (i) these represent baseline data from a longitudinal comparison study that is in progress; (ii) patients accepted for renal transplantation are generally ‘healthier’ than those who are not considered transplant candidates; and (iii) there are some methodological differences for data collection between the two groups. However, all subjects had ESRD. All patients age 18 and over and without metallic objects in their chest (stents, clips) or significant arrhythmia that would preclude gating during the spiral CT were eligible. The study was approved by the Institutional Review Board, and all patients gave written informed consent. Group 1 recipients had serum collected immediately prior to the transplantation for all of the laboratory tests, and underwent the spiral CT scan within 3 days after the transplantation, and thus the results are representative of ESRD, not transplantation. Thus, for group 1, all laboratory tests are from a single serum sample. Patients in group 2 (chronic dialysis) underwent the spiral CT at their convenience, and laboratory values were averaged from the previous 12 months for pre-dialysis chemistries, parathyroid hormone (PTH), alkaline phosphatase and cholesterol. A serum sample was obtained pre-dialysis at the time of consent for analysis of homocysteine, bone alkaline phosphatase and C-reactive protein (CRP) in both groups. For group 2 patients, a second serum sample was collected 3–4 months later for an additional CRP measurement because of the possibility of intermittent increases in this level. The two values for CRP were averaged to obtain the final value.

Medical charts were reviewed for clinical history and medications, and supplemented with information obtained directly from the patient. Patients were considered to have a history of coronary artery disease if there was an abnormal angiogram or stress test, myocardial infarction or history of angina. Diabetes was defined as present if it was the cause of ESRD and/or there was current need for insulin or oral anti-hyperglycaemic agents. Hypertension was defined as taking a blood pressure-lowering medication. Peripheral vascular disease was defined by history, abnormal arterial Dopplers or arteriogram. The dialysis modality was that modality the patient was receiving at the time of the study. Tobacco use was defined as ever using a tobacco product. The medications (other than phosphate binders) were those prescribed at the time of the spiral CT scan. Elemental calcium intake from phosphate binders was determined by taking the number of pills per day multiplied by the elemental calcium content as described in the Physician's Desk Reference. For group 1 patients, this was the binder type and dose prescribed at the time of the transplantation. For group 2 patients, this was the cumulative dose of calcium in the year preceding the spiral CT scan divided by the number of days to achieve an average g/day.

Serum assays
Serum was analysed for calcium, phosphorus and total alkaline phosphatase by colorimetric methods using a Roche Autoanalzyer (Boehringer Manheim, Indianapolis, IN); intact PTH by immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA); bone-specific alkaline phosphatase by enzyme-linked immunosorbent assay (ELISA; Metra Biosystems, Mountain View, CA); homocysteine by ELISA (Biorad); and CRP by ELISA (Alpha Diagnostics, San Antonio, TX). Values for total cholesterol, if available, were obtained from the patients' medical record from the previous 6 months.

Spiral CT scan
CT scans were performed with the quad-slice technique on the model MX 8000 scanner (Philips Medical Systems, Cleveland, OH). The data acquisition parameters were: 120 kVp, 400 mAs, nominal slice width 2.5 mm (effective width 3.2 mm), gantry rotation time 0.5 s, table feed 7.5 mm/s [pitch 0.375 (x4 slices/rotation)]. Data were reconstructed with a 180° linear interpolation algorithm providing a temporal resolution of 270 ms, retrospective ECG gating during diastole, 1.3 mm longitudinal increment, 512x512 matrix, field of view 25 cm2, medium body (C) filter, and no edge enhancement. Data were transferred to a workstation and analysed with HeartBeat-CS software (MX View, Marconi Medical Systems, Cleveland, OH). On the basis of the ECG tracing, the software program automatically selected a reduced set of diastolic images from each cardiac cycle. The proximal coronary arteries were scored, beginning with the first image in which a coronary artery was seen (usually the left anterior descending) and continuing for 6 cm along the long axis of the patient [6]. All pixels with density >=130 Hounsfield units (HU) were highlighted automatically in colour on the images. The observer placed an electronic region of interest (ROI) around each highlighted CAC and assigned one of four locations to each calcified plaque: left main, left anterior descending (LAD), circumflex or right coronary artery. Branches of the LAD, circumflex and right coronary arteries were considered parts of those arteries. The descending aorta was evaluated over the 6 cm in the z-axis direction. A minimum plaque area of 0.5 mm2 was used to reduce errors due to noise. Calcium scoring was performed using two scoring systems and identical ROIs by the same viewer (CM).

One scoring system which simulates the Agatston method [6] determines the density of the highest density pixel in each plaque and applies a weighting factor to each plaque, dependent upon the peak density in the plaque:Density (HU) of 130–199=weight of 1; density of 200–299=weight of 2; density of 300–399=weight of 3; density of 400+=weight of 4.

The score for each plaque equals the plaque areaxweighting factorxincrement/slice width. The score for the entire specimen equals the sum of the scores for each plaque. This score is then normalized to the original Agatston score by multiplying the total score by 3.2/3.0 (=1.07) to correct for the increase in slice thickness. (The original Agatston method used a slice thickness of 3 mm, whereas this method used an effective slice thickness of 3.2 mm.) It is of note that the slices were reconstructed at 1.3 mm overlap to avoid over-scoring. This technique is called ‘calcification score by area’.

The second scoring method, called average-continuous, uses a weighting factor (F)=(A/100)–0.5, where A is the average density of each plaque on each image. The score for each plaque is calculated by multiplying the area of each plaque in mm2 (to generate a volume determination) by the weighting factor. The score for the entire specimen equals the sum of the scores for each plaque. As above, this score is then multiplied by 1.07. This technique is called ‘calcification score by volume’.

Statistical methods
Demographic and descriptive data from the two study groups were compared using t-tests for continuous variables, Fisher's exact test for discrete variables and the Mann–Whitney U-test for ordinal variables (number of medications and calcium binder content). For patients who had only non-gated calcification scores (13/71), the linear regressions described below were used to convert them to gated scores. Calcification scores were skewed to the right and were log transformed before conversion from non-gated to gated scores. They were then back-transformed to the original unit. The log transformation reduced the skewness to levels acceptable for linear regression.

Two analyses were performed to examine the relationships between calcification scores and other variables. The first looked at factors related to development of calcification. Patients with no calcification were compared with those with calcification using the Mann–Whitney U-test for continuous variables and Fisher's exact test for discrete variables. The second analysis looked at factors related to the amount of calcification present in those who had some calcification in the coronary arteries or aorta. The levels of calcification were correlated with continuous variables using the Spearman rank correlation coefficient and compared in categories of discrete variables using the Mann–Whitney U-test.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Variability and reliability of spiral CT scan
To determine the intra-reader variability, randomly selected gated scans were re-read by the same observer at different time points from 3 days to 3 weeks apart. The two readings of both the CAC and aorta calcification (AoC) scores by either method (area or volume) were highly correlated (r=0.99, P<0.001). Intra-reader variability (defined as absolute difference between two readings/average of the two readings [7]) with a small randomly selected subset of patients (n=15) was 27% by area and 24% by volume for CAC, and 6% for both area and volume for AoC scores. The median variability for CAC was 3.2% by area and 2.6% by volume. This variability is artificially inflated by very low scores. If we recalculate the variability assuming that for scores <10, a difference of <10 is not meaningful (n=3/15), then the variability changes to 0.9% mean/0% median for CAC score by area and 2.9% mean/0% median for CAC score by volume. However, even without this adjustment, the intra-scan variability is better than previous studies calculating variability in the same manner for EBCT where mean variability was 15–37%, and median intra-scan variability was 5–8% (reviewed in [7]).

To compare the effect of gating on spiral CT scores, the relationship of non-gated to gated scores was examined for ESRD patients participating in a reliability substudy who had scores >0 (presence of calcification) for each of the four spiral CT assessments. The scores were log transformed because of skewed data for this analysis as described in the statistical methods section. The results demonstrate that there was a very close correlation between the two techniques for each of the determinations: calcification score by area for CAC [R2=0.90; P<0.001; log (CAC score by area gated)=0.712+0.843xlog (CAC score by area non-gated), n=16]; calcification score by area for AoC [R2=0.99, P<0.001; log (AoC score by area gated)=0.089+0.972xlog (AoC score by area non-gated), n =12]; calcification score by volume for CAC [R2=0.88, P<0.001, log (CAC score by volume gated)=0.908+0.767xlog (CAC score by volume non-gated), n =16]; calcification score by volume for AoC [R2=0.99, P<0.001; log (AoC score by volume gated)=0.193+0.935xlog (AoC score by volume non-gated), n =12].

Patient characteristics and calcification scores
The demographic, medication use and laboratory values of the ESRD patients are shown in Table 1Go, and differences between groups 1 and 2 noted. The patients in group 1 (undergoing renal transplantation) were younger, had been on dialysis for a shorter time, were more likely to be on peritoneal dialysis as a modality, were more likely to be Caucasian, and smoked less than group 2 (dialysis patients that were not transplanted). Three patients in group 1 had never been dialysed. There was no difference in the prescribed medications between the two groups except that the patients receiving dialysis had a lower intake of calcium-containing phosphate binders for unclear reasons, although it should be emphasized that the collection methods for calcium intake for these two groups differed (see Subjects and methods). Laboratory tests revealed that the dialysis patients had a lower serum calcium and albumin level, and a higher CRP level.


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Table 1.  Population description

 
There was a strong correlation between the CAC score by the area and volume methods (r=0.99, P<0.001) and between the AoC score by the area and volume methods (r=0.99, P<0.001). This was true for the entire group, group 1 alone, and group 2 alone. In the group 1 subjects, the CAC score and AoC score did not correlate by either method (r=0.11, P=0.603 by area method). However, for the group 2 subjects, there was a significant relationship between CAC and the AoC (r=0.42, P=0.032).

The CAC score by area method was 567±1291 (median 49), and slightly greater by the volume method (Table 2Go). The low median scores are a result of several patients without calcification. Fifty patients had evidence of CAC (26 group 1, 24 group 2) and 21 patients did not have CAC (seven group 1, 14 group 2). If patients with and without calcification are compared, the only identifiable risk factors (Table 3Go) are age (r=0.29, P=0.039) and duration of dialysis (r=0.39, P=0.005). The relationships among age, duration of dialysis and CAC score are depicted in Figure 1Go.


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Table 2.  Calcification scores

 

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Table 3.  Comparison of individuals with and without coronary artery calcificationa

 


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Fig. 1.  Effect of age and duration of dialysis on total coronary artery calcification score. Filled circles, patients with ESRD who underwent a renal transplant and spiral CT scan (group 1); open circles, patients with ESRD on dialysis (group 2). Both increasing age and increasing duration of dialysis were associated with increased coronary artery calcification scores.

 
The AoC score by area was 1164±3790 (median 1) and slightly greater by volume methods (Table 2Go). Similarly to CAC, the low median score is indicative of several patients without AoC. Forty-one patients had AoC (17 group 1, 20 group 2) and 30 patients had no AoC (21 group 1, 13 group 2). Age was the only predictor of subjects with and without AoC (41±12 years in those without AoC vs 57±9 years in those with AoC, P<0.001; Figure 2Go). However, in those patients with calcification, age was not significantly correlated. Duration of dialysis did not relate to AoC. Interestingly, when the two groups were combined, the elemental calcium content was higher in those without calcification (2161±1859 g/day) compared with those <1?twb=.2w>with calcification (1159±1422 g/day, P=0.008). However, it was not different when each group (transplant and dialysis) was evaluated separately. Given the methodological differences between this calculation in group 1 and group 2, this is not likely to be clinically relevant, particularly when prospective data are now available [8].



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Fig. 2.  Effect of age on aorta calcification score. Filled circles, patients with ESRD who underwent a renal transplant and spiral CT scan (group 1); open circles, patients with ESRD on dialysis (group 2). Only increasing age was associated with increasing calcification of the aorta.

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the present study, we utilized quad detector helical CT scan for the assessment of coronary artery calcification and calcification of the descending aorta in two groups of patients with ESRD: those receiving a renal transplant and those continuing on dialysis. Recent studies have utilized EBCT to assess CAC in the ESRD population, and demonstrated markedly increased values [4,5]. The use of EBCT has allowed more precise quantification of vascular calcification than plain X-rays because of its excellent temporal resolution, which allows imaging only during diastole. However, EBCT has limited application except in the assessment of coronary calcification and is not readily available in many hospitals. In contrast, almost every hospital has a multipurpose spiral CT and, with software adjustments to allow gated imaging, the newer, faster spiral CTs can assess CAC. The advancements in both technologies have improved the variability in both EBCT [7] and spiral CT [9].

EBCT uses a gun of electrons to generate a beam focused on a tungsten ring target. The beam then sweeps from side to side along the tungsten ring generating a fan of X-rays. This allows for excellent temporal resolution (100 ms per image). Generally the faster the scanning is, the less the radiation dose delivered, and the more image noise. Multidetector spiral CT (MDCT) such as quad-slice with retrospective ECG gating, uses an X-ray tube and an array of detectors attached to a gantry that rotates around the patient. For state-of-the-art CT scanners, gantry rotation time is <=0.5 s. Since data are then segmented to reconstruct images with every 180° plus fan angle of gantry revolution, an effective temporal resolution of ~270 ms is achieved. Newer methods may offer improved resolution [9]. The advantage of MDCT over EBCT is improved signal to noise ratio and improved spatial resolution (9 lp/cm for MDCT vs 6 lp/cm for EBCT). Because this is a volumetric data set, there is also improved z-axis (longitudinal) resolution.

Using a protocol of overlapping increments of 1.5 mm similar to the one utilized in the present study, a recent comparison in 50 patients demonstrated that multislice spiral CT with ECG gating with volume scoring had a variability of 8% compared with EBCT with Agatston methodology (22%) or volume methodology (15%) [10]. The sensitivity of spiral CT with gating software is significantly better with a 130 HU threshold for scoring compared with 90 HU with non-gated spiral scans [11]. The intra-reader variability was comparable in the present study. Thus, the use of spiral CT with new methodologies offers at least comparable, if not improved, variability over EBCT, and greater availability of machines, although the methodologies for spiral CT are still evolving [9]. The disadvantages of spiral CT compared with EBCT are that of increased radiation exposure, with a 3- to 4-fold radiation exposure for spiral CT compared with EBCT, and decreased temporal resolution, which may lead to increased motion artefact at rapid heart rates. However, a recent study in beating phantoms demonstrated low variability with MDCT compared with EBCT, and no change at different heart rates [9], but this needs confirmation in humans.

We found minimal and expected differences in the group 1 (transplant) and group 2 (dialysis) patient populations: younger age, shorter duration of dialysis and more use of peritoneal dialysis in those in group 1. The latter is probably an artifact of ease of recruiting with haemodialysis patients compared with peritoneal dialysis patients. In both groups of patients, age and duration of dialysis correlated with CAC, whereas only age correlated with AoC. These risk factors have prevailed across multiple studies evaluating various techniques for the quantification of vascular calcification in ESRD, including EBCT [4,5], B-mode ultrasound [12] and now spiral CT in the present study. However, unlike other studies [5], we did not find a significant difference in parameters of mineral metabolism. Unfortunately, we were unable to assess cumulative laboratory data or phosphate binder use in the group 1 patient population, and thus the results are not comparable with other studies and should be interpreted cautiously. However, despite a diverse patient population and a relatively small sample size, the major findings of this study are similar to previous studies: calcification of the coronary arteries was a prominent finding, and of much greater quantity than found in previous studies in non-ESRD patients. Of concern was the prevalence and magnitude of calcification in patients undergoing renal transplant. A study comparing longitudinal changes in calcification in these two patient populations is currently ongoing.

The mean CAC score by area was 567±1291 (range 0–8772, median 49, inter-quartile range 0–575). These values obtained are of the same level as non-dialysis patients with angiographically proven two vessel disease (341±796; mean±SD) [13].While the mean scores in the present study are similar to the coronary artery calcium scores in a recent study assessed with EBCT, the median is less [14]. The differences may reflect a lower mean age of our patient population (49 vs 57 years), and shorter duration of dialysis (25 vs 37 months). In addition, a greater percentage of patients had no evidence of CAC in the present study (32%) vs only 17% in the study by Raggi et al. [14], contributing to the greater median score in the latter.

In non-dialysis patients, the magnitude of CAC correlates with angiographically proven obstructive (atheromatous) coronary artery disease by both EBCT [1] and spiral CT [11,15]. In addition, CAC correlates with cardiac events in non-ESRD patients [2]. At this time, there are no published data comparing EBCT or spiral CT with angiographic findings or prospective cardiac events in the ESRD patient population. However, Blacher et al. recently found that the extent of calcification by ultrasound was predictive of both all-cause and cardiovascular mortality [12], and Raggi et al. found a significant relationship of coronary artery calcification by EBCT to a history of various cardiovascular events [14]. Given the difference in the magnitude of calcification in the coronary arteries of dialysis patients compared with non-ESRD patients, and the substantial risk for cardiovascular disease in ESRD patients compared with the general population, it is possible that this excess calcification may be an additional cardiovascular ‘risk’ factor unique to the ESRD population. Clearly, longitudinal studies are required to evaluate fully its predictive value in assessing cardiovascular risk.

Although we were unable to identify mineral metabolism as a significant risk factor for vascular calcification in the present study, other studies in dialysis patients using alternative techniques (EBCT, ultrasound) demonstrated an elevated serum phosphorus, an elevated serum calciumxphosphorus product or increased calcium load as risk factors [5,8,16]. However, the mechanism by which the elevated concentration of these ions leads to calcification in dialysis patients is unknown. Jono et al. [17] found in cultured human vascular smooth muscle cells that a concentration of 2 mM phosphorus in the medium induced Cbfa1, a bone differentiation factor. Recently, we have found evidence of osteopontin, bone sialoprotein, alkaline phosphatase and type I collagen expression at the site of calcification in small arterioles in the skin of patients with calcific uraemic arteriolopathy [16] and in the inferior epigastric artery of dialysis patients [18]. We also demonstrated the expression of Cbfa1 in calcified areas in both the intima and media of inferior epigastric arteries [19]. This would imply that the deposition of mineral into vascular tissue in dialysis patients is not simply metastatic, but rather an active process. The duration of dialysis as a major risk factor for vascular calcification in nearly all studies implies accumulation of some as yet unidentified uraemic toxin(s). Recent studies from our laboratory demonstrated that pooled uraemic serum of dialysis patients could induce osteopontin expression in cultured bovine vascular smooth muscle cells, even with a low final phosphorus concentration in the medium of 0.6 mM. The addition of an exogenous phosphorus source to the uraemic serum, such that final phosphorus concentrations were 10–12 mM, failed to augment the effect of uraemic serum alone [20]. Thus, while phosphorus levels and calcium load are critical, additional uraemic factors are likely to be involved.

In conclusion, the use of new generation spiral CT scans with gating is a viable and widely available technique for the assessment of coronary artery and aortic vascular calcification in ESRD patients. Longitudinal studies assessing the predictive value of this technique in determining cardiac events are needed, as is further understanding of the pathogenesis of this process.



   Acknowledgments
 
The authors wish to thank Ms Anni Hine for her excellent secretarial assistance. Supported by funding from the National Kidney Foundation of Indiana and the National Institutes of Health (S.M.M.).



   Notes
 
Correspondence and offprint requests to: Sharon M. Moe, MD, Associate Professor of Medicine, Assistant Dean for Research Support, Indiana University School of Medicine, 1001 West 10th Street, OPW 526, Indianapolis, IN 46202, USA. Email: smoe{at}iupui.edu Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 25. 7.02
Accepted in revised form: 17. 1.03