The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis
Giuseppe Mossetti1,
Domenico Rendina1,
Roberto Viceconti1,
Giuseppe Manno2,
Vincenzo Guadagno2,
Pasquale Strazzullo1 and
Vincenzo Nunziata1
1 Department of Clinical and Experimental Medicine and 2 Department of Gynecology, Urology, Obstetrics and Human Reproduction, Federico II University Medical School, Naples, Italy
Correspondence and offprint requests to: Professor Vincenzo Nunziata, Dipartimento di Medicina Clinica e Sperimentale, Università Federico II, via S. Pansini, 5 80131 Naples, Italy. Email: nunziata{at}unina.it
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Abstract
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Background. Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship.
Methods. The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (APCaOx) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants.
Results. Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91±0.89 vs 3.46±1.39 mmol/24 h, P = 0.004) and higher APCaOx (2.02±0.51 vs 1.53±0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and APCaOx between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7±12.1 vs 38.1±12.7 years, P = 0.008) and higher values of FHS (2.45±1.9 vs 0.83±0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative.
Conclusions. Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.
Keywords: hypercalciuria; family history score; nephrolithiasis; renal citrate handling; VDR alleles
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Introduction
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Nephrolithiasis is a multi-factorial disease influenced by environmental as well as hormonal and genetic factors. Calcium oxalate is the most common crystalline component of stones. In a majority of stone formers, the initial step of stone formation is crystallisation of calcium oxalate in urine supersaturated with it. According to Hess and Tiselius [1], calcium oxalate supersaturation is directly related to the urinary concentrations of calcium and oxalate, and inversely related to those of magnesium and citrate. Higher urinary uric acid excretion may be another factor predisposing to the formation of calcium oxalate stones.
Hypercalciuria is the biochemical alteration most commonly associated with calcium nephrolithiasis. Idiopathic hypercalciuria (IHc) favours calcium stone formation by increasing urinary saturation of calcium salts and deactivating charged inhibitors of calcium oxalate crystallization. Frequently, IHc is associated with other metabolic risk factors for kidney stone formation, such as hyperuricosuria, hyperoxaluria and hypocitraturia. At least one-third of recurrent stone-forming patients have both hypercalciuria and hypocitraturia [2,3]. Previous studies have demonstrated that idiopathic hypocitraturia in stone-forming patients results from excessive net tubular re-absorption of a normal filtered load of citrate [2]. In a previous report, Rudman et al. [3] suggested the presence of a common underlying disorder that directly or indirectly influences the renal handling of citrate, calcium and phosphate in stone-forming patients with idiopathic hypocitraturia. The vitamin D receptor (VDR), which is involved in the control of genomic and non-genomic effects of 1,25(OH)2D3, regulates the cellular expression of the molecules involved in the tubular handling of calcium and phosphate through vitamin D-responsive elements located in the promoter region of their genes [4,5]. We have recently demonstrated a different distribution of 3' VDR gene polymorphisms and haplotypes between stone-forming patients with or without idiopathic hypocitraturia and healthy controls [6].
In this study, we investigated the relationship of VDR polymorphisms, defined by BsmI, TaqI and FokI restriction endonucleases, and VDR haplotypes to the urinary supersaturation of calcium oxalate salts in recurrent stone-forming patients with idiopathic hypercalciuria. We also analysed the association of VDR haplotypes with the age at onset and the familial incidence of nephrolithiasis.
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Subjects and methods
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We studied 110 unrelated Caucasian recurrent stone-forming patients with idiopathic hypercalciuria (M:F ratio 66:44; mean age 41.38±13.56 years; BMI 27.41±4.01 kg/m2). In addition, 127 unrelated control subjects (M:F ratio 73:54; mean age 41.06±13.97 years; BMI 27.28±3.93 kg/m2) without known personal or family histories of nephrolithiasis were recruited among members of the Postgraduate School of Internal Medicine, family reference panel (one per family) and among patients spouses. All subjects were maintained on a metabolicaly constant diet: a daily calcium content of 1000 mg, 100 mEq sodium, 900 mg phosphorus, 300 mg carbohydrate and 70 g protein (total 2200 calories) for 7 days.
On day 8, at 09:00 h, a urine sample was collected for pH determination after an overnight fast, 3 h after the first void. Also collected were 24 h urine samples, which were analysed for calcium, phosphate, potassium, sodium, chloride, cystine, oxalate, urate and creatinine. Fasting blood samples were drawn to measure serum total calcium, ionised calcium, total alkaline phosphatase, sodium, potassium, chloride, magnesium, phosphate, creatinine, intact parathormone, 25(OH)D3, 1,25(OH)2D3, urate and thyroid-stimulating hormone.
The ion activity product of calcium oxalate salts in urine (APCaOx) was estimated, according to Hess and Tiselius [1] as follows:
where A is a factor determined by the length of the urine collection period (1.9 for a 24 h collection period).
The net urinary charge was estimated according to the formula proposed by Smulders and co-workers [9]. Serum total calcium, urinary calcium, serum and urinary magnesium were determined by atomic absorption spectrophotometry. Ionised calcium was determined using an ion-selective electrode. Intact serum parathormone levels were measured using an immunometric assay (Immulite Intact PTH, Diagnostic Products Corporation, Los Angeles, CA, USA). Serum levels of 25(OH)D3 were determined by a modified competitive protein-binding assay (Vitamin D3 Screen, Buhlmann laboratories AG; Allschwill, Switzerland); serum levels of 1,25(OH)2D3 were estimated using a radioimmunoassay test (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). Urinary cystine levels were estimated using high-performance liquid chromatography. Urinary oxalate levels were measured using ion chromatography. Urinary sodium and potassium were estimated using flame photometry. Serum TSH levels were measured by an immunoradiometric assay (IRMA-mat TSH, Byk-Sangtec Diagnostica, Dietzenbach, Germany). Other blood and urinary parameters were obtained using an automatic analyser. All parameters were measured according to the manufacturers instructions.
Exclusion criteria
Exclusion criteria for both patients and controls were: gouty diathesis (defined as the idiopathic formation of pure or mixed uric acid stones, in the presence or absence of gouty arthritis [1]), cystinuria >70 µmol/24 h, renal tubular acidosis (defined as urinary pH >6 or positive urinary net charge [7]), or both, creatinine clearance <0.75 ml/s/m2 for men and <0.85 ml/s/m2 for women, debilitating physical illnesses, hyperthyroidism (serum TSH <0.1 mIU/l), primary hyperparathyroidism, Paget's bone disease, urinary infections, incomplete family histories, and the use of medications such as corticosteroids, diuretics, bisphosphonates, non-steroidal anti-inflammatory drugs, vitamin D or lithium. To evaluate the influence of VDR polymorphisms on tubular calcium and citrate handling in healthy subjects, additional criteria for excluding potential control subjects from enrolment were the presence of one or both of idiopathic hypercalciuria and hypocitraturia, defined as urinary citrate excretion lower than 1.7 mmol/24 h [1,6]. Postmenopausal or pregnant women were not enrolled in the study.
All patients reported two or more calcium oxalate stones excreted or removed over the preceding 4 years. Images, obtained by X-ray or ultrasound examinations, and physico-chemical analyses of kidney stones were available for each patient. Patients and controls were born and resided in Campania, a Southern Italian region. The study was approved by the Medical School Ethical Committee of the University Federico II of Naples. Written informed consent was obtained from all subjects.
Classification of patients according to calciuria
Hypercalciuria was defined as a urinary calcium excretion greater than 7.5 mmol/day in men, 6.25 mmol/day in women, or 0.1 mmol/kg/day on a 1000 mg/day calcium diet [1,6]. Idiopathic hypercalciuria was defined as hypercalciuria in the absence of elevated PTH, vitamin D or TSH levels.
Family history of nephrolithiasis
Data about nephrolithiasis in the parents and siblings of each patient were collected through a specific questionnaire according to the criteria proposed by Yang et al. [8]. The questionnaire included the following information: (i) age of parents and, if deceased, their age at death; (ii) number, age and sex of siblings, and, if deceased, their age at death; (iii) whether or not a diagnosis of nephrolithiasis had been made in first-degree relatives of the patient, the type of renal stones excreted or removed and the age at which the diagnosis was made.
Family history score
The family history score is a continuous variable based on the comparison of the number of observed or reported nephrolithiasis events with the number expected. According to Yang et al. [8], the family history score for the ith family was calculated as follows:
where Ti is the family history score for family i, Oij is the observed nephrolithiasis status for the jth member of the family i (0 or 1) and Eij is the expected risk for nephrolithiasis for the jth member of the family i. This risk was estimated as
where k is the age group, ID is the incidence density in the kth age group and
t is the age interval. Epidemiological data was obtained from a study by Serio and Fraioli [9].
A negative family history score indicates that a family contains fewer members with nephrolithiasis than would be expected, whereas a positive value indicates that it contains more. In the present study, we set the family history score of families with a negative score value equal to zero.
Genotyping
DNA extraction and genotypic analysis of VDR gene polymorphisms were performed as previously described [6]. The forward primer for the BsmI and TaqI polymorphisms was 5'-CAACCAAGACTACAAGTACCGCGTCAGTGA-3' [6]. The reverse primers were 5'-AACCAGCGGGAAGAGGTCAAGGG-3' and 5'-CACTTCGAGCACAAGGGGCGTTAGC-3' for the BsmI and TaqI polymorphisms, respectively [6]. The forward and reverse primers for the FokI polymorphism were 5'-AGCTGGCCCTGGCACTGACTCTGCTCT-3' and 5'-ATGGAAACACCTTGCTTCTTCTCCCTC-3', respectively [10]. DNA was digested with TaqI, BsmI and FokI under standard conditions; the products were analysed by electrophoresis on an agarose gel containing ethidium bromide. The PCR product for the BsmI polymorphism was 825 bp long, and the restriction fragments were 650 and 175 bp long. The PCR product for the TaqI polymorphism was 2000 bp long; the lengths of the fragments after digestion with TaqI were 1800 and 200 bp. The PCR product for the FokI polymorphism was 265 bp long; the lengths of the fragments after digestion with FokI were 69 and 196 bp. The PCR products were verified by sequence analysis. Genotypes were defined as B, T and F (in the absence of restriction sites) or b, t and f (in the presence of restriction sites). All patients and control subjects were genotyped. TaqI (exon 9) and BsmI (intron 8) polymorphisms are located, in linkage disequilibrium, in the 3' region of the VDR gene. FokI polymorphism (exon 2) is located in the 5' region of the VDR gene. This site is not genetically linked to the above Taq/Bsm cluster. Patients and control subjects were classified considering both the 3' and 5'-VDR gene polymorphisms simultaneously, according to criteria recently proposed by Whitfield et al. [11].
Statistical analysis
All data are given as mean±SD. Statistical analyses were performed with SPSS statistics package version 9.0. Contingency table chi square tests were used to compare VDR genotype frequencies and other qualitative data. Analysis of variance with Bonferroni correction for multiple comparisons was used to compare quantitative data. To estimate haplotype frequencies we used the computer program Estimated Haplotype (EH) (Linkage Program, version 5.1) [12]. All statistical tests were two-sided. A P-value <0.01 was considered statistically significant.
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Results
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The prevalence of BsmI, TaqI and FokI VDR genotypes in hypercalciuric stone-forming patients (IHc) and healthy controls (C) is shown in Table 1. VDR genotype frequencies were in Hardy-Weinberg equilibrium in both IHc and C. The observed VDR allelic frequencies as well as the linkage disequilibrium between BsmI and TaqI VDR sites are comparable with published data in unrelated Caucasian subjects [13].
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Table 1. The prevalence of ApaI, BsmI and FokI VDR polymorphisms in hypercalciuric calcium oxalate recurrent stone-forming patients and healthy controls
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No differences were detected between IHc and C in the distribution of BsmI, TaqI and FokI VDR alleles and in estimated haplotype frequencies (P>0.01). Among the recurrent stone-forming patients with IHc, there were 18 bbTT homozygote subjects (16.4%), 30 BBtt homozygotes (27.3%) and 62 heterozygotes (56.4%). Among the controls, there were 17 bbTT homozygotes (13.4%), 34 BBtt homozygotes (26.8%) and 76 heterozygotes (59.9%).
Clinical and biochemical parameters of the study participants, classified according to 3' VDR haplotypes, are shown in Tables 2 and 3. None of the stone-forming patients or controls had serum potassium levels higher than 4.9 mmol/l. In bbTT IHc patients the urinary supersaturation of calcium oxalate salts, estimated by APCaOx values, was significantly higher than in BBtt IHc patients (P = 0.006). The 24 h urinary citrate excretion in IHc patients was also significantly different between the two groups (P = 0.004). Heterozygous IHc patients had intermediate values of estimated urinary supersaturation of calcium oxalate salts and of 24 h citraturia. Among healthy control subjects, a similar trend for lower values of 24 h urinary citrate excretion in bbTT subjects, compared with BBtt, and intermediate levels for heterozygous participants were observed (P = 0.094).
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Table 2. Clinical and laboratory parameters in hypercalciuric calcium oxalate recurrent stone-forming patients and healthy controls
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Table 3. Urinary parameters in hypercalciuric recurrent calcium oxalate stone-forming patients and healthy controls
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As shown in Figure 1, mean age at onset of nephrolithiasis was significantly lower in bbTT than in BBtt IHc patients (29.7±12.1 vs 38.1±12.7 years, P = 0.008). Conversely, the mean value of the family history score was significantly higher in this same group compared with BBtt patients (2.45±1.9 vs 0.83±0.7, P = 0.006) (Figure 2). The heterozygous patients had intermediate values for both mean age at onset of nephrolithiasis and family history scores.

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Fig. 1. Age at onset of nephrolithiasis in recurrent calcium oxalate stone-forming patients with idiopathic hypercalciuria, classified according to 3' vitamin D receptor haplotypes. Additional analysis of FokI alleles was not informative. Values are expressed as mean±SD. P-values refer to differences between homozygous subjects analysed by multiple comparison test (Bonferroni).
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Fig. 2. Family history score values in recurrent calcium oxalate stone-forming patients with idiopathic hypercalciuria, classified according to 3' vitamin D receptor haplotypes. Additional analysis of FokI alleles was not informative. Values are expressed as mean±SD. P-values refer to differences between homozygous subjects analysed by multiple comparison test (Bonferroni).
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According to the data presented, the APCaOx values, 24 h urinary citrate excretion, mean age at onset of nephrolithiasis as well as family history scores were significantly different in hypercalciuric stone formers with the bb and TT VDR genotypes compared with patients with the BB and tt VDR genotypes (data not shown).
Cross-genotyping in the VDR start codon and the 3'-end loci showed a similar prevalence of FokI polymorphism across the Bsm/Taq cluster. Thus, there was no evidence of a linkage disequilibrium between the two loci (Table 4). These results are in accordance with published data. Further analysis of FokI alleles did not provide more information. No statistical association was observed between the FokI allelic variants and any of the clinical and biochemical parameters investigated. In particular, no statistically significant interaction was found between FokI genotypes and urinary supersaturation of calcium oxalate salts, age at onset of nephrolithiasis or family history scores in any of Bsm/Taq cluster groups (data not shown).
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Table 4. VDR gene start codon (FokI) and 3'-BsmI/TaqI haplotype cross-genotypes in hypercalciuric recurrent calcium oxalate stone-forming patients and healthy controls
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Discussion
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Genetic factors are important determinants of kidney stone formation. A positive family history has been reported in 16 to 37% of patients who have formed a kidney stone, and the relative risk for stone formation in men with a positive family history of nephrolithiasis vs those without was found to be 2.57 [14]. This increased relative risk for stone disease persisted after adjustment for known environmental factors that influence the prevalence of disease. Thus, it is felt that up to 60% of the increased risk of stone formation among relatives of patients with idiopathic nephrolithiasis may be related to genetic factors. Therefore, a positive family history is the single most important risk factor for nephrolithiasis after controlling for known dietary factors [14].
The VDR is a candidate-gene for calcium kidney stone disease. An increase in VDR activity is involved in stone formation in genetic hypercalciuric rats, an animal model of calcium nephrolithiasis. These animals show enhanced intestinal calcium absorption and a defect in renal calcium resorption. These changes have been associated with 2-fold increases of VDR in the duodenum and kidney cortex [15]. Unfortunately, to our knowledge, no data are available about urinary citrate excretion in genetic hypercalciuric rats on normal diets when compared with normal rats. However, these animals physiologically adapt their urinary citrate excretion to reduced dietary phosphate and an increased dietary intake in acid precursors [15]. A recent study in humans has also demonstrated an association between idiopathic calcium stone formation and the micro-satellite marker D12S339, which is close to the VDR locus [16].
Experimental evidence suggests the possible role of VDR in the regulation of tubular citrate handling. In humans, VDR is involved in the control of both genomic and non-genomic effects of 1,25(OH)2D3, which in renal tubular cells directly modulates the intracellular citrate metabolism and the expression of enzymes involved in the transmembrane transport of calcium, phosphate and dicarboxylates [4,6]. Moreover, VDR is directly involved in the regulation of the protein kinase pathway, which modulates the function of the sodium/citrate membrane co-transporter [17]. Finally, VDR and COUP-TF (the chicken ovalbumin upstream promoter-transcription factor, a member of the steroid receptor family) regulate the transcriptional activity of phosphoenolpyruvate carboxykinase gene, an enzyme that controls intracellular metabolism and urinary excretion of citrate [18].
The VDR gene is highly polymorphic, and a few in vitro studies were performed to investigate possible differences in receptor function as related to its allelic variants. Whitfield et al. [11] have recently detected functional alterations in VDR by simultaneous analysis of 3' and 5' VDR sites, and have shown that the b and F alleles appear to be more active than the B or f alleles, without significant differences in the intracellular abundance of VDR. In view of their potential influence on hormonal signals, VDR gene polymorphisms have been studied recently in relation to disorders of calcium metabolism and in calcium kidney stone disease. Most of these studies analysed the relationships of various physiological parameters of interest to single VDR polymorphisms of the Bsm/Taq/Apa cluster group. As far as we can tell, none of these studies demonstrate a significant relationship between these VDR allelic variants and urinary calcium excretion in stone-forming patients when dietary calcium intake is higher than 1 g/24 h [6,10,19,20]. Moreover, a relationship has been suggested between the aggressiveness of calcium nephrolithiasis and the 3' VDR genotypes [19,20]. None of the genetic association studies performed so far in stone-forming patients have analysed the relationship of physiological parameters relevant to calcium stone formation (i.e. urinary supersaturation of calcium oxalate salts) to 3' and 5' VDR polymorphisms considered together. The present study provides original evidence of a statistically significant and clinically relevant association between the bT VDR haplotype, earlier age at onset and higher familial incidence of nephrolithiasis among patients with IHc and recurrent calcium oxalate nephrolithiasis. These associations are strengthened by the finding of reduced urinary citrate excretion in those individuals, which may provide a plausible explanation for the association observed with the increase in the urinary supersaturation of calcium oxalate salts. None of the numerous other serum and urinary biochemical parameters evaluated in patients and controls differed significantly by Bsm/Taq genotype, including urinary excretion of uric acid and oxalatetwo frequent and important predisposing factors to the formation of calcium oxalate stones. It is remarkable that even among healthy controls, homozygous bT subjects showed a trend to lower urinary citrate excretion compared with Bt subjects, despite the exclusion of subjects with obvious hypocitraturia from the control group. Renal tubular acidosis (RTA) may be a cause of hypercalciuria, hypocitraturia and nephrolithiasis. In particular, classic type I and distal type IV RTA are associated with calcium phosphate and calcium oxalate nephrolithiasis, respectively [7]. Based on the criteria proposed by Lash et al. [7], the biochemical parameters used in this study to exclude the diagnosis of renal tubular acidosis include urinary pH (of a spot urine sample after an overnight fast) and urinary net charge. None of the stone-forming patients or healthy subjects showed abnormal serum potassium levels. Citrate directly inhibits spontaneous nucleation of calcium oxalate. It is also a potent inhibitor of calcium oxalate and calcium phosphate crystal growth, agglomeration and aggregation [13]. Owing to the inhibitory action of citrate, patients with hypocitraturia have a markedly increased risk of forming calcium-containing renal stones.
The early age at onset of nephrolithiasis at the population level has significant financial and social implications. Renal stones tend to recur, and the rate of recurrence increases progressively with time, from 15% at 1 year up to 75% at 20 years. The earlier patients start to form stones the longer will be the period of their lives in which they are exposed to the risk of stone recurrence, and the more stones they are likely to form during the course of their lives if they are not managed prophylactically. Epidemiological data indicate that the severity of nephrolithiasis has an impact on its potential progression to end-stage renal failurein Italy, the prevalence of chronic renal failure related to idiopathic nephrolithiasis is
16% [9]. The higher prevalence in the Caucasian population of the VDR polymorphic variants examined in this study adds to the clinical importance of our findings, in terms of genetic susceptibility to nephrolithiasis [13].
In conclusion, our results indicate that the 3' VDR haplotypes significantly influence the age at onset and the familial prevalence of nephrolithiasis as well as the urinary supersaturation of calcium oxalate salts in stone-forming patients with IHc. The association observed might also reflect a linkage disequilibrium of BsmI and TaqI VDR polymorphism with another unknown functional variant of the VDR gene or with genetic variation at a different locus close to the VDR gene. Studies in varied populations are warranted to confirm our results.
Conflict of interest statement. None declared.
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Received for publication: 24. 9.03
Accepted in revised form: 25. 2.04