Incidence of anaemia, and use of epoetin therapy in pre-dialysis patients: a prospective study in 403 patients

Pierre-Yves Jungers1, Christophe Robino1, Gabriel Choukroun1, Thao Nguyen-Khoa2,3, Ziad A. Massy3 and Paul Jungers1,

1 Departments of Nephrology and 2 Biochemistry A and 3 INSERM U507, Necker Hospital, Paris, France



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Background. Recent American and European guidelines recommend that epoetin therapy should be considered whenever the blood haemoglobin (Hb) level is <10–11 g/dl in dialysis patients and in pre-dialysis patients. Thus, data on the current prevalence of anaemia with respect to the degree of chronic renal insufficiency are needed in order to determine the potential indications of epoetin therapy in the pre-dialysis period.

Methods. We prospectively studied 403 consecutive ambulatory pre-dialysis patients whose serum creatinine (Scr) was 200 µmol/l or more at their first passage at our out-patient clinic between January 1 and June 30, 1999. Hb and Scr values were determined at each visit until June 30, 2000, or until the start of maintenance dialysis. Patients had a clinical and laboratory evaluation every 2–3 months, and monthly when treated with epoetin.

Results. The mean (±SD) age of patients was 60.9±17.2 years at presentation. The Hb level was <11 g/dl in 62% of patients with Scr >=400 µmol/l, and in 58% of patients with an estimated creatinine clearance (Ccr) <20 ml/min/1.73 m2. The proportion of anaemic patients was higher for any given Ccr value in females than in males. A total of 136 patients were treated with epoetin during the observation period. At the start of epoetin, their mean Hb value was 9.5±0.6 g/dl and Ccr level 13.9±4.9 ml/min/1.73 m2. Among the 123 patients who began maintenance dialysis therapy during the observation period, 85 (or 69%) received epoetin therapy before the start of dialysis. Their mean Hb value at the start of dialysis was 10.8±1 g/dl compared with 10.5±1.1 g/dl in the 41 dialysed patients who did not require epoetin therapy during the pre-dialysis period.

Conclusions. Based on the data gained in a large cohort of patients receiving regular pre-dialysis nephrological care, the proportion of subjects with a Hb level <11 g/dl may be estimated at ~60% when the Ccr is <20 ml/min/1.73 m2. If the Hb level is to be maintained at no less than 11 g/dl, at least two-thirds of patients at this advanced stage of chronic renal failure should require pre-dialysis epoetin therapy.

Keywords: anaemia; chronic renal insufficiency; epoetin therapy; haemoglobin



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Anaemia is a major complication of chronic uraemia, both during maintenance dialysis and in the pre-dialysis period. Anaemia develops from the moderate stage of chronic renal insufficiency (CRI), worsens in parallel with the progression of renal failure and is not, or incompletely, improved by maintenance dialysis. A direct relationship has been shown between the degree of anaemia as reflected by blood haemoglobin (Hb) or haematocrit (Hct) level, and the degree of renal failure in pre-dialysis patients [1,2]. However, contemporary epidemiological data on the incidence of anaemia and its level relative to the degree of renal failure in pre-dialysis patients are few [3]. Such data should be relevant for evaluating the current potential indications of recombinant erythropoietin (rHuEPO or epoetin) therapy in pre-dialysis patients.

Guidelines for the use of epoetin therapy in pre-dialysis and dialysis patients recently appeared. In the USA, the recent NKF-DOQI [4] recommend that epoetin therapy should be started when the Hct level is <30% (or Hb level <10 g/dl), with a target Hct level of 33–36% (roughly corresponding to a Hb level of 11–12 g/dl). In Europe, the recent European Best Practice Guidelines [5] recommend that epoetin therapy should be considered in pre-dialysis patients if the Hb level is consistently <11 g/dl.

Despite such concordant recommendations, there is evidence from large recent inquiries both in the USA [69] and in Europe [10] that epoetin therapy is far from being prescribed to all patients who potentially require it, and that the mean level of blood Hct at initiation of epoetin therapy is strikingly lower than what is recommended. Taking advantage of the large number of CRI patients regularly followed at our institution, we sought to determine the relationship between the level of blood Hb and the degree of renal failure assessed by serum creatinine (Scr) and creatinine clearance (Ccr) in the whole cohort of ambulatory CRI pre-dialysis patients followed at our out-patient renal clinic during a recent period. In particular, we evaluated the proportion of male and female patients with a Hb level of <11 g/dl, who are potential candidates for epoetin therapy, and the actual number of patients who were started on epoetin therapy during the observation period. We analysed the influence of age, gender, type of nephropathy, treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II (AII) receptor antagonists (ARAs), or presence of diabetes on the relationship between the Hb level and renal function, an indication for epoetin therapy.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
The study was cross-sectional with a prospective follow-up. All 403 consecutive ambulatory pre-dialysis patients followed as out-patients at the Nephrology Department of Necker Hospital, whose Scr was >=200 µmol/l at any time between January 1 and June 30, 1999 (a 6-month inclusion period) were included. Excluded from the study were 30 patients referred in emergency conditions at the advanced stage of renal failure and who, therefore, had not benefited from previous regular nephrological care. The course of Hb and Scr was followed until June 30, 2000, or until the start of dialysis (or death). All of these patients were regularly followed at our institution and benefited from a homogeneous therapeutic policy aimed at slowing the progression of renal failure and limiting clinical complications of uraemia [11]. Particular attention was given to blood pressure control, with target systolic and diastolic blood pressure values in agreement with the recommendations gained from the MDRD study [12]. ACEIs (or ARAs) were given to all patients with proteinuria in excess of 1 g/day, unless there was a contraindication. Iron status (determination of serum ferritin concentration and siderophilin saturation coefficient) was regularly checked and oral iron supplementation given if the serum ferritin was <200 µg/l and/or the saturation coefficient <0.20 [13]. Our policy for anaemia therapy was to initiate epoetin whenever the Hb level was <10 g/dl, and optionally according to clinical tolerance in patients with Hb ranging from 10 to 11 g/dl.

In all patients, the following data were recorded: date of birth, gender, body height and weight, and type of primary nephropathy. Baseline Scr level was chosen as the Scr value recorded at first passage at the out-patient clinic between January and June, 1999. In the follow-up study, we recorded Scr, Ccr, and Hb levels at the start of epoetin therapy in rHuEPO-treated patients, and the same parameters at the start of maintenance dialysis in patients who started dialysis during the observation period. In addition, we recorded the presence of diabetes mellitus (either cause of renal failure or associated with another renal disease), and treatment with AII inhibitors (ACEIs or ARAs). Ccr was estimated using the Cockcroft and Gault formula [14].

Statistical analysis used the SAS® software package. Data are presented as mean±SD. The Student's t test, ANOVA or the Mann–Whitney test, when required, were used to compare means between independent groups. The Pearson {chi}2 test was used to compare qualitative variables. Values of P<0.05 were assumed to be significant. Univariate and multivariate regression analyses were performed to evaluate the relationship between Hb level (taken as the dependent variable) and age, gender, Scr level, presence of polycystic kidney disease (PKD) or diabetes, and use of AII inhibitors as covariables. Only variables which reached statistical significance at the P<0.05 level by univariate analysis were included in the multivariate model.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Demographic characteristics of the studied population
The studied cohort includes 403 adult pre-dialysis patients (265 males, 138 females, 95% Caucasian) aged 18 years or more, whose Scr was >=200 µmol/l. As a whole, 123 of these patients had to start maintenance dialysis between January 1999 and June 2000, and 136 were treated with epoetin during this period.

The demographic characteristics of patients, categorized according to gender, are given in Table 1Go. The male-to-female sex ratio was 1.92. The mean age of patients at their first passage in the out-patient facility during the first semester of 1999 was 60.9±17.2 years, not significantly differing between males and females. The high proportion of PKD (16%) reflects the interest of our department for hereditary kidney diseases. Patients with hypertensive nephroangiosclerosis were 21.8% (including 11/88 with demonstrated renal artery stenosis). Patients with diabetic nephropathy were 13.1% (including 92% type 2 diabetes), the total proportion of diabetic patients being 14.4%. Males were predominant among patients with glomerular, vascular, or diabetic nephropathies. As a whole, 65.8% of patients were treated with AII inhibitors, and this proportion did not differ between males and females.


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Table 1.  Demographic characteristics and distribution of renal disease in male and female pre-dialysis patients

 

Relationships between Hb, Scr, and Ccr at baseline
The mean Hb values corresponding to increasing Scr values are shown in Figure 1AGo. The mean Hb concentration declined from 12.5±1.6 g/dl in patients with Scr 200–299 µmol/l to 10.3±0.9 g/dl in patients with Scr >=600 µmol/l. The proportion of male and female patients with Hb levels <10, 10–10.9, 11–11.9, and >=12 g/dl with respect to the Scr value is given in Table 2Go. The overall proportion of patients with Hb levels <11 g/dl gradually increased with the Scr level, from 18% (Scr 200–299 µmol/l) to 37% (Scr 300–399 µmol/l), 59% (Scr 400–499 µmol/l), 67% (Scr 500–599 µmol/l), and up to 76% for Scr >=600 µmol/l. The proportion of patients with Hb levels <11 g/dl was consistently higher in females than in males at any given Scr level, this difference being especially apparent for Scr values ranging from 200 to 500 µmol/l.



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Fig. 1.  Mean haemoglobin (Hb) levels corresponding to increasing Scr values (A) and to decreasing Ccr values (B).

 

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Table 2.  Correlation between the degree of anaemia (blood HB concentration, g/dl) and the level of Scr in male (M) and female (F) pre-dialysis patients

 
The mean Hb values corresponding to decreasing Ccr values are shown in Figure 1BGo. The mean Hb concentration decreased from 12.9±1.6 g/dl in patients with Ccr levels >=25 ml/min/1.73 m2 to 11.2±1.4 g/dl in those with Ccr levels of 15–20 ml/min/1.73 m2. The proportion of male and female patients with Hb levels <10, 10–10.9, 11–11.9, and >=12 g/dl with respect to Ccr value is given in Table 3Go. The overall proportion of patients with Hb <11 g/dl gradually rose with decreasing Ccr values, from <15% in patients with Ccr levels >=20 ml/min/1.73 m2, to 44% for Ccr levels 15–19.9 ml/min/1.73 m2 and to 61% for Ccr levels <15 ml/min/1.73 m2. Again, the proportion of patients with Hb levels <11 g/dl was higher among females than males at any Ccr level, the difference being especially apparent for Ccr values <20 ml/min/1.73 m2.


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Table 3.  Correlation between the degree of anaemia (blood Hb concentration, g/dl) and the level of Ccr in male (M) and female (F) pre-dialysis patients

 
The relationship between individual Ccr and Hb values in male and female patients is shown in Figure 2Go. The relationships were Hb=0.104 Ccr+9.83, r=0.54 in males and Hb=0.076 Ccr +9.73, r=0.38 in females. The association was highly significant (P<0.0001), but weak by indicative of large inter-individual variations in the Hb level for any given level of renal function.



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Fig. 2.  Relationship between Hb and Ccr levels in male (A) and female (B) pre-dialysis patients. Regression lines are given with the 95% confidence interval.

 

Characteristics of patients at the start of epoetin therapy
Overall, 136 patients (33.7%) received epoetin therapy during the observation period (79 males, 57 females). Epoetin therapy had been initiated before January 1, 1999 in 18 patients, whereas it was started thereafter in the other 118 patients. Characteristics of these 136 patients at the start of epoetin therapy are given in Table 4Go. Their mean age was 61.5 years, not differing between males and females. The proportion of patients treated with epoetin therapy was higher in females (57/138 or 41.3%) than in males (79/265 or 29.8%, P<0.05), but the degree of renal dysfunction and the degree of anaemia at the start of epoetin therapy was similar in both genders. The mean Ccr value was close to 14 ml/min/1.73 m2 and mean Hb level close to 9.5±0.6 g/dl in both males and females. The mean siderophilin saturation was 23%, with similar values in males and females (respectively, 22.6±8.7 and 24.4±10.2%). The mean serum ferritin level was slightly but not significantly higher in males (259±186 µg/l) than in females (201±207 µg/l).


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Table 4.  Characteristics of patients at start of epoetin therapy

 

Follow-up study
Of the 403 patients, 123 (30.5%) started maintenance dialysis between January 1999 and June 2000. Of them, 85 (69%) were treated with rHuEPO. Epoetin therapy was initiated concomitant with start of dialysis in three cases and <1 month before first dialysis in 10 cases. The other 72 patients (58% of dialysed patients) received epoetin therapy for at least 1 month before starting dialysis, the duration of epoetin therapy being between 1 and 2.9 months before start of dialysis in 25 patients, between 3 and 5.9 months in 17 patients and >=6 months in 30 patients. The characteristics of patients at the start of dialysis, with respect to the presence or absence of epoetin therapy for at least 1 month before the start of dialysis, are given in Table 5Go. Ccr and Hb levels were similar in both groups. In particular, the mean Hb concentration was 10.5±1.1 g/dl in patients who did not receive rHuEPO therapy before the start of dialysis, and 10.8±1.0 g/dl in epoetin-treated patients.


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Table 5.  Characteristics of patients at start of dialysis (D) whether or not they had received epoetin therapy for at least 1 month in the pre-dialysis period

 

Influence of age, anti-AII drugs, and type of nephropathy
Age had a limited influence on the level of anaemia in pre-dialysis patients. Among patients who started dialysis therapy during the observation period, those who required pre-dialysis epoetin therapy were slightly, but not significantly, older than those who did not require it (59.8±17.5 vs 55.7±16 years, NS). In the whole series, the proportion of subjects treated with anti-AII drugs was the same among patients receiving epoetin therapy or not. Similarly, the proportion of patients with PKD or with diabetes mellitus was similar among patients treated or not with epoetin (data not shown).

Univariate regression analysis did not disclose any significant relationship between age, use of anti-AII drugs, diabetes or PKD, and Hb level, whereas both the Ccr level and gender had a significant association with the Hb level (P<0.001 for both). By multivariate analysis, only gender and Ccr emerged as independent significant variables.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
The problem of anaemia in uraemic patients has been dramatically transformed since the widespread use of rHuEPO in the early 1990s, both in dialysis and in pre-dialysis patients [15]. Initially, indications of epoetin therapy in CRI pre-dialysis patients were limited to patients with marked, symptomatic anaemia. However, in view of the obvious benefits of the treatment in terms of quality of life and prevention of left ventricular hypertrophy, indications of epoetin therapy were progressively extended.

Recent NKF-DOQI guidelines [4] recommend that rHuEPO therapy should be considered in pre-dialysis patients with Hb levels <11 g/dl, with a target Hct value of 33–36% (corresponding to a Hb value of 11–12 g/dl). The recent European Best Practice Guidelines [5] recommend that epoetin treatment should be considered whenever the Hb concentration is consistently <11 g/dl (Hct <33%) on repeated testing, these recommendations applying equally to patients already on dialysis and to those not yet receiving dialysis; the recommended target level is a Hb concentration >11 g/dl, with no upper limit mentioned, except for patients with cardiovascular disease, for whom a Hb concentration limited to 11–12 g/dl is suggested.

Data on the level of Hct (or Hb) in relationship with the degree of renal insufficiency allow one to estimate the proportion of CRI patients who are potential candidates for epoetin therapy. Recently, Hsu et al. [3] reported the results of a cross-sectional study in a hospital-based population of 12055 adult ambulatory patients, of whom ~5% had an estimated Ccr of 40 ml/min/1.73 m2 or less. They expressed their data as the per cent decrease in Hct level in various ranges of Ccr values, the Hct level observed in the group with Ccr >80 ml/min/1.73 m2 being taken as the reference, but they did not provide the mean values of Hct with respect to the various degrees of renal dysfunction. However, they mention that the proportion of patients with Hct <33% was 63% in males and 56% in females with Ccr <=20 ml/min, which is in general agreement with our findings.

Our prospective observational study provides comprehensive information as to the level of Hb with respect to graded values of Scr and Ccr in a large cohort of adult pre-dialysis CRI patients, followed in a recent period. In the whole series, we observed that a Hb value <11 g/dl (corresponding to a Hct level <33%), was present overall in 61% of patients with a Ccr <15 ml/min/1.73 m2 and in 45% of those with a Ccr ranging from 15 to 20 ml/min/1.73 m2.

With respect to the influence of gender, our observations are in agreement with data from the USRDS registry report, with a higher proportion of anaemia in female patients [6], but at variance with those of Hsu et al. [3], who report that at any given level of renal function men had a larger decrease in Hct than women.

Opinions as to the effects of AII inhibitory drugs on the degree of anaemia in uraemic patients and their response to epoetin therapy are conflicting [16]. We did not observe a discernible influence of AII inhibitory drugs on the degree of anaemia or the response to epoetin therapy in our pre-dialysis CRI patients.

Patients with PKD have been reported as having higher Hb levels than other patients at a comparable degree of renal dysfunction or while on maintenance dialysis. However, Delaney et al. [17] found similar Hct levels in PKD patients and other CRI patients at comparable degrees of renal insufficiency. In our cohort, the mean Hb level of PKD patients did not differ from that of other CRI patients at comparable Ccr values, nor did the prevalence of epoetin therapy. This may be accounted for by the fact that some polycystic patients had indeed high Hb values, while other had low Hb values due to intra-renal bleeding, so that the resulting average Hb value was similar in PDK and non-PKD patients. A lower Hct level in CRI patients with type 2 diabetes mellitus compared with patients with non-diabetic renal disease was reported by Ishimura et al. [18]. We observed no discernible difference in the degree of anaemia or prevalence of epoetin therapy between diabetic and non-diabetic pre-dialysis CRI patients in our series.

Our data provide relevant information as to the proportion of pre-dialysis patients who are potential candidates for epoetin therapy. On the basis of current recommandations, i.e. epoetin therapy indicated in CRI patients with a Hct level <33% (or Hb <11 g/dl), at least 60% of our pre-dialysis patients with Ccr <20 ml/min/1.73 m2 were potential candidates for epoetin therapy, and nearly all of them actually received rHuEPO therapy. In contrast, a number of recent reports indicate that such recommendations are far from being followed in all pre-dialysis patients, and that epoetin treatment is often under-prescribed. In the 1999 USRDS report [6], the proportion of anaemic end-stage renal disease (ESRD) patients already treated prior to the start of renal replacement therapy was only 24%. Obrador et al. [7] reported that only 23% of a sample of 155051 dialysis patients in the USA received epoetin therapy prior to initiation of maintenance dialysis despite 51% of them had an Hct <=28%. In a retrospective observational cohort study, Fink et al. [9] report that among 4866 incident patients who started maintenance dialysis between April 1995 and December 1996, only 22.7% were given epoetin therapy prior to initiation of dialysis [9].

In Europe, a multinational cooperative study (the ESAM study) involved 14527 patients who were on maintenance dialysis at the end of 1998 [10]. Among the 13121 prevalent patients treated with haemodialysis, only 11.2% had received epoetin therapy before starting dialysis, whereas epoetin therapy was initiated only at the time when dialysis was started in 36% of cases or after start of haemodialysis in 52.8% of cases. The mean Hb value at start of epoetin therapy was 8.9±1.2 g/dl in patients treated prior to start of dialysis, i.e. very low in relation to the European Best Practice Guidelines recommendations. According to this report, the proportion of French dialysis patients who received rHuEPO therapy prior to the start of dialysis was only 7.8%, and the mean Hb level of French patients at start of dialysis was 8.3±1.1 g/dl. However, both early- and late-referred patients were included in this study, and late-referred patients are likely to have contributed to the low mean Hb level and low prevalence of epoetin-treated patients. Indeed, epoetin therapy is a component of optimal pre-dialysis care, as pointed out by several authors [711].

In this regard, our data highlight the beneficial results of a well-defined policy for the active treatment of anaemia in pre-dialysis CRI patients, according to the recommendations of the NKF-DOQI guidelines [4] and of the European Best Practice Guidelines [5]. In our department, since 1998, epoetin therapy is assumed to be indicated in all CRI patients whose Hb level is <10 g/dl, and optional in patients with a Hb between 10 and 11 g/dl, according to the clinical tolerance of anaemia. As a result, 58% of ESRD patients received epoetin therapy for at least 1 month prior to start of dialysis. Their mean Hb level at the start of rHuEPO therapy was 9.5 g/dl, and their mean Hb level at start of dialysis was 10.8±0.9 g/dl. Interestingly, the mean Hb level at the start of dialysis of patients who did not require epoetin therapy was similar (10.5 g/dl) thus indicating that the recommendations were homogeneously followed. Of note, such results apply only to early-referred patients, who were regularly followed at our renal clinic. During the same observation period, 30 patients were referred to us in emergency conditions, without previous nephrological care. None of them had received epoetin therapy and their mean Hb level at start of dialysis was 8.6±1.2 g/dl. We observed previously that late-referred patients had a significantly lower Hb level at ESRD than patients who received nephrological care for at least 6 months [19].

The great majority of our CRI patients received only oral iron supplementation, which was usually initiated long before the start of epoetin therapy, and only three pre-dialysis patients received i.v. iron supplementation. Nevertheless, our results favourably compare with those reported by Silverberg et al. [20] who used systematic i.v. iron supplementation alone or in combination with low-dose epoetin in pre-dialysis patients [20].

Our data provide a basis for economic estimations of the cost of epoetin therapy, based on the predictable number of potential candidates and the average duration of therapy in the pre-dialysis period. On the basis of current recommendations, at least 50% of pre-dialysis patients with a Ccr <=20 ml/min/1.73 m2 should receive epoetin therapy for a predictable average duration of 12–18 months. Of note, when starting at this level, the weekly dose of rHuEPO needed to raise the Hb level to 11–12 g/dl is rather low (<=50 IU/kg/week), and the cost of epoetin therapy is thus largely compensated by its clinical benefits. Indeed, besides the obvious improvement in general condition and quality of life of patients, partial correction of anaemia has been shown to result in a protective effect against left ventricular hypertrophy [21] and, according to recent studies it may improve survival on dialysis [22]. Last but not least, epoetin therapy has also been shown to slow the progression of CRI [23], thus delaying by several months the need for starting dialysis, at least in part of patients. This results in substantial savings, as the cost of dialysis is considerably higher than the cost of conservative treatment including rHuEPO.



   Conclusions
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
In conclusion, our study based on a large cohort of pre-dialysis CRI patients followed at a single nephrology clinic, provides contemporary data on the degree of anaemia with respect to the degree of renal insufficiency, in patients who benefit from regular nephrological management. A blood Hb concentration of <11 g/dl is observed in nearly 50% of patients with an estimated Ccr level of <20 ml/min/1.73 m2, more frequently in women than in men. Such data allow that the prediction of epoetin therapy, according to current recommendations, will be indicated in at least 50% of pre-dialysis patients. This proportion may be even higher if a higher Hct or Hb threshold value is adopted to decide the indication of epoetin therapy. One important finding of this report is to confirm the positive results of a proactive policy of treatment of anaemia in CRF patients, as part of an integrated pre-dialysis management programme. In view of the benefits of anaemia correction in terms of improved quality of life and cardiac condition, and possible retardation of dialysis, larger utilization of epoetin therapy in pre-dialysis patients should be encouraged. The optimal time and Hb value to initiate epoetin therapy and the optimal Hb target to achieve remain to be determined.



   Notes
 
Correspondence and offprint requests to: Emer. Prof. Paul Jungers, MD, Department of Nephrology, Necker Hospital, 149, rue de Sèvres, F-75743 Paris Cedex 15, France. Email: jungers{at}necker.fr Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 

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Received for publication: 7. 9.01
Accepted in revised form: 6. 3.02