Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, 19901999
Bénédicte Stengel1,
Solenne Billon1,
Paul C.W. van Dijk2,
Kitty J. Jager2,
Friedo W. Dekker3,
Keith Simpson4 and
J. Douglas Briggs, on behalf of the ERAEDTA Registry Committee2
1 Institut National de la Santé et de la Recherche Médicale, INSERM Unité 258, Villejuif, France, 2 ERAEDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, 3 Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands and 4 Scottish Renal Registry, Glasgow Royal Infirmary, Glasgow, UK
Correspondence and offprint requests to: Dr Bénédicte Stengel, INSERM Unité 258, 16 avenue P. Vaillant Couturier, 94807 Villejuif cedex, France. Email: stengel{at}vjf.inserm.fr
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Abstract
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Background. The epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) varies considerably worldwide, but we have lacked reliable quantitative estimates of trends in the incidence by age, sex and cause in Europe over the last decade.
Methods. We analysed data from nine countries participating in the ERAEDTA registry: Austria, Belgium, Denmark, Finland, Greece, The Netherlands, Norway, Spain and UK (Scotland). Adjusted incidence rates for age and sex were studied for 2 year periods between 1990 and 1999. Average annual changes (%) were estimated by Poisson regression.
Results. The adjusted incidence rate of RRT increased from 79.4 per million population (pmp) (range: 58.4101.0) in 19901991 to 117.1 pmp (91.6144.8) in 19981999, i.e. 4.8% (3.16.4%) each year. This increase did not flatten out at the end of the decade, except in The Netherlands, and was greater in men than women, 5.2 vs 4.0%/year. In most countries, the incidence rate remained stable for those younger than 45 years; it rose by 2.2%/year on average in the 4564 year age group and by 7.0% among those 6574 years; it tripled over the decade in those 75 years or older, and by 19981999 it ranged from 140.9 to 540.4 pmp between countries. The incidence of ESRD due to diabetes, hypertension and renal vascular disease nearly doubled over 10 years; in 19981999, it varied between countries from 10.2 to 39.3 pmp for diabetes, from 5.8 to 21.0 for hypertension, and from 1.0 to 15.5 for renal vascular disease.
Conclusion. RRT incidence continues to rise but at various rates in the European countries studied, tending to widen the gap between them. This mainly results from enlarging differences in incidence in the elderly and, to a lesser extent, in that due to diabetes, hypertension and renal vascular disease.
Keywords: age; diabetic nephropathy; end-stage renal disease; incidence; renal replacement therapy; renal vascular disease
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Introduction
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The incidence of renal replacement therapy (RRT) for end-stage renal disease (ESRD) continues to increase throughout the world, but at rates that vary considerably between countries. Over the last decade, RRT registries have reported average annual increases of 11% in Japan [1], 9% in Australia and 6.5% in New Zealand [2] and 6.1% in Canada [3]. In the US, the annual growth has fallen from 5.4% at the beginning of the 1990s to 2.3% at the end of the decade [4,5]. In the same period, data from national and regional registries and from repeated cross-sectional surveys in Western Europe have shown increases in rates ranging from 3 to 4.3% per year in Germany [6], Spain [7], the UK [8] and France [9]. In the early 1990s, there was a wide variation in RRT incidence among European countries [10], but reliable and comparable estimates of subsequent trends were not readily accessible before the new European Renal AssociationEuropean Dialysis and Transplant Association (ERAEDTA) registry began in 2000 [11,12].
Similarly, the pattern of trends by age and primary renal disease differs quite substantially from one country to another, in particular for the elderly and for diabetes- and hypertension-related ESRD [13,5,13], but we have lacked recent reliable quantitative data for Europe.
We have therefore studied the RRT incidence in nine European countries from 1990 through to 1999 with the aim of quantifying trends and analysing geographic variations by age, sex and ESRD cause.
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Subjects and methods
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Population
The ERAEDTA registry began operating in Amsterdam in June 2000 [11,12]. The registry office, located in the Academic Medical Center, collects data exclusively through national or large regional registries for two purposes: (i) to provide standardized epidemiological data on RRT in Europe and (ii) to answer specific questions with more focused studies of patient samples. The technical aspects and methods used for combining the data from different countries have been published elsewhere [12]. The data for this study come from national or regional registries in nine countries currently contributing to the new ERAEDTA database and covering a population of 82 million people: Austria (8.1 million population in 1999), Belgium (10.2 million), Denmark (5.3 million), Finland (5.2 million), Greece (10.6 million), Norway (4.5 million), Scotland (5.1 million), The Netherlands (15.8 million) and Spain (17.3 million), including three autonomous communities: Andalusia (7.2 million), Catalonia (6.1 million) and Valencia (4.0 million). These registries were asked to participate because they had high-quality data available for the past 10 years. We defined incident cases as patients who either started chronic dialysis or underwent pre-emptive transplantation between 1990 and 1999. We excluded patients with a diagnosis of acute renal failure, those not residing in the area of a contributing registry, and those with a missing start date. Despite differences in the management and financial support between registries, modalities of patients enrolment are very standard: all are registered prospectively from the first day of RRT treatment; with the exception of the Catalonia registry, data are collected on a voluntary basis, but the contributing registries have developed validation processes to assess the completeness and accuracy of registration. Over the study period, all registries have reported centre participation rates of 100% and patient registration rates above 98% [1416]. Altogether, the registries reported 76,921 new patients who started RRT between 1990 and 1999.
Mid-year census population estimates by age and sex were downloaded from the Census Worldwide web site for each country and for each year between 1990 and 1999 (www.census.gov/ipc/www/idbnew.html). 1990 population estimates were not available for Austria, and we used the average population of 1989 and 1991 as an estimate. Similarly, because there were no figures for 1989 and 1990 for Greece, we used the 1991 population for both 1990 and 1991. We would point out that the data from Spain comes only from three regional registries and may not therefore be representative of the entire population of Spain.
Data collection
National and regional registries send anonymous data to the ERAEDTA, including date of birth, sex, primary renal disease, date of start of the first RRT, history of treatment modalities and, when applicable, date and cause of death. Most of the registries use the ERAEDTA classification for coding renal diseases. The data from those using another coding system (for example, the Finnish registry uses the 10th Revision of the International Classification of Diseases) are recoded by these registries into the ERAEDTA system. In our analysis, we classified primary renal diseases into nine groups (Appendix 1).
Statistical analysis
Incidence rates were studied in 2-year periods to make estimates more accurate, particularly in the analysis by subgroup of renal diseases. For each 2-year period, we used the sum of the two mid-year populations as the denominator. Adjustment of the incidence rates for age and sex used the mid-1995 European population as the reference (Appendix 2) [17].
Because ESRD is an uncommon disease, we estimated average annual changes (%) in adjusted incidence rates by Poisson regression, with the GENMOD procedure in SAS software. In this model, we calculated expected incidence counts by pooling data from the registries as a whole in each group of age, sex and primary renal disease in 19901991. Poisson regression thus estimated ß of the average change over 2 years. The per cent change over 2 years was given by exp (ß)1, and the per cent annual change obtained by calculating exp (ß/2)1. When trends were not linear, e.g. for The Netherlands, we estimated different trends for different periods.
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Results
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Trends in the overall incidence of RRT, 19901999
The mean adjusted RRT incidence rate increased from 79.4 per million population (pmp) in 19901991 to 117.1 pmp in 19981999, i.e. an average of 4.8% each year (Figure 1). Except in The Netherlands, this increase was almost linear and did not flatten out near the end of the decade. It ranged from 3.1% in Austria to 6.4% in Denmark and the gap between countries tended to increase for the most recent period. Table 1 lists the countries in decreasing order of overall RRT incidence in 1999. We see that in the early 1990s, the difference between the countries with the lowest (Finland) and highest (Austria) incidence rates were 42.6 pmp, whereas it is now 53.2 pmp between Finland and Belgium. Large regional variations were also observed in Spain: Andalusia (adjusted incidence rate in 19981999: 115.5 pmp; mean annual change: 5.6%, 95% confidence interval [4.76.6]); Catalonia (136.5pmp; 4.2% [3.45.1]); Valencia (154.4; 4.6% [3.65.6]).

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Fig. 1. Incidence rates of RRT for ESRD and mean annual change (%) by country, 19901999. Per million population, adjusted for age and sex. *Data from three autonomous communities: Andalusia, Catalonia and Valencia.
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Table 1. Incidence rates of RRT by age group, sex, time period and country, 19901999 (pmp, ranked by overall incidence rate in 19981999)
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Trends in RRT incidence by age and sex, 19901999
In most but not all countries, the overall RRT incidence increased faster among men than women, namely, 5.1% [4.75.4] vs 4.3% [3.94.7] per year. The exception was Denmark (6.3 vs 6.5%) where the trends were very similar for both sexes.
Over this decade, the overall incidence rate decreased, although not significantly, in both men and women younger than 19 years (Figure 2). It remained stable or decreased among women aged 2044, except in Belgium, Denmark and Norway (Table 1), while among men it continued to increase in all the countries studied, although only slightly. In the 4564 year age group, the overall rate rose by an average of 2.2% [1.82.7] annually increasing more than twice as fast in men (2.8%) than women (1.3%). For those 6574 years old, the incidence rate rose by an average of 6.5% [6.07.0] a year, ranging from 3.4% [2.24.6] in The Netherlands to 10.9% [8.313.6] in Finland. In those aged 75 years or more, the overall RRT rate more than tripled over the decade for both sexes, but with large differences between countries: it increased by a factor of 2.1 in The Netherlands, 2.5 in Austria, 3.1 in Belgium, 3.2 in Greece, 3.6 in Norway, 3.8 in Spain, 6.6 in Scotland, 9.3 in Denmark and 30.6 in Finland. In 19981999, the incidence rate for those 75 years or older was nearly four times higher in Belgium than in Finland.
Trends in RRT incidence by cause of ESRD, 19901999
Overall, the incidence of ESRD due to glomerular, tubulointerstitial and toxic nephropathies remained stable over the decade, while there was a large rise in that related to diabetes, hypertension and renal vascular diseases which nearly doubled over the decade (Table 2). The growth for the latter three causes involved mainly those older than 65 (Figure 3), but was also statistically significant in the 4564 year age group, and was particularly high for diabetes. Glomerulonephritis, which was the largest single cause of ESRD in Europe in 19901991, now ranks second after diabetes. Unknown or missing causes also doubled over the period.
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Table 2. Incidence rates of treated ESRD by primary renal disease, time period and country, 19901999 (pmp, adjusted for age and grouped by sex)
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Fig. 3. Incidence rates of RRT for ESRD due to diabetes mellitus (DM), hypertension (HT) and renal vascular disease (RVD) (average % annual change), among patients aged 4564 and 65+, 19901999. Per million population, adjusted for age and sex.
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Although these overall trends applied to most countries, there were some noticeable differences. The incidence of ESRD due to toxic nephropathy decreased in Austria (-3.8%/year [-6.8; -0.6]) and The Netherlands (-3.9%/year [-7.8; 0.2]), whereas it remained unchanged in the other countries, particularly in Belgium, which remains the country with the highest incidence rate. ESRD due to hypertension nearly doubled in all countries except The Netherlands, where the rise was not statistically significant. The annual increase in the incidence due to diabetes was lower in Norway (3.8% [0.17.6]) and The Netherlands (4.3% [2.66.0]) than Belgium (10.6% [9.012.3]) or Greece (11.1% [9.213.0]). The RRT incidence in the 4564 year age group is thought to reflect the true incidence of ESRD more closely, as it is less subject to access and referral variation than in patients of 65 years or older. In this 4564 year age group, the largest range in RRT incidence between countries was that for diabetes, varying from 15.1 pmp in Norway to 65.6 in Austria (Figure 4). The ESRD incidence of unknown or missing cause at least doubled over the 10-year period in all countries except Spain and Austria, ranging in 19981999 from 5.9 to 34.2 pmp.

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Fig. 4. Incidence rates of RRT for ESRD due to diabetes among 4564 years old and mean annual change (%) by country, 19901999. Per million population, adjusted for age and sex. *Data from three autonomous communities: Andalusia, Catalonia and Valencia.
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Trends were similar among men and women for the increases in ESRD due to diabetes (8.0 vs 7.8%/year), hypertension (6.8 vs 8.3%/year) and renal vascular disease (9.6 vs 9.9%/year), but patterns for ESRD due to tubulointerstitial nephritis and toxic nephropathies were quite different. Both of these increased significantly in men over the period (+1.4% [0.22.5] and +5.9% [2.89.0]/year, respectively) and decreased in women (-2.2% [-3.3; -1.1] and -2.7% [-4.5; -0.9]/year, respectively). The rise in incidence due to tubulointerstitial nephritis in men was caused mainly by acquired obstructive uropathy: this almost doubled in men aged 6574 years old, from 11.5 pmp in 19901991 to 20.7 in 19981999, and almost tripled in those 75 years or older, from 9.0 to 25.4 pmp.
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Discussion
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The incidence of RRT has continued to rise rapidly in the European countries we studied over the last decade. The incidence among those older than 75 years has tripled and that due to diabetes, hypertension and renal vascular disease almost doubled. Although the trends have often been similar between countries, there have been some striking differences. The overall incidence rose almost linearly in all countries except The Netherlands where it flattened out near the end of the decade. The trends by age group were very similar among those younger than 65 years, but differed substantially for the elderly. The incidence of ESRD due to diabetes more than doubled in Belgium and Greece but increased at a much slower rate in The Netherlands and Norway. These differences have tended to widen the gap in the overall RRT incidence between countries. We would point out that the main aim of the ERAEDTA registry is to analyse data at a national level rather than reflect the regional variations that may occur, particularly in large countries, such as Spain where large differences in RRT incidence have been reported between autonomous communities [7]. Because this study only deals with nine countries, it has not been possible in this analysis to extrapolate from the data to the situation prevailing in the whole of Europe. Incidence rates of some other countries or large regions in 1999 are nevertheless shown in Table 3 to put our data into a wider European perspective.
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Table 3. Crude incidence rates of RRT in some other European countries or regions (data from national or regional registry reports or large regional surveys)
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Variations in the incidence of RRT and the trends between countries and between regions may result from a combination of (i) true differences in incidence and causes of ESRD, (ii) differential improvement in survival from cardiovascular- and diabetes-related diseases, which can be considered as competing risks, thus increasing the occurrence of ESRD, (iii) differences in the rate at which patients are referred and accepted for (and agree to) RRT, particularly among the elderly and (iv) reporting or registration errors within registries. Despite expected differences in the methods of data acquisition between the registries from different countries, the good quality of the participating registries makes it unlikely that notification rates play a major role in the variations observed between countries. For example, the striking difference in overall incidence rate between the two neighbouring countries, Belgium and The Netherlands, cannot be attributed to variations in registration alone. Improvements in the methods of data collection over the period cannot nonetheless be totally excluded as an explanation for some of the increase in incidence rates. Differences in inclusion criteria could however have an impact on RRT incidence. Tsakiris et al. [18] observed that the percentage of patients who die within the first 90 days after beginning dialysis varied from 2 to 11% between countries which may reflect different strategies for registering incident patients who die soon after starting RRT. Nonetheless, these percentages were not systematically higher in countries with the highest incidence, e.g. it was low in Belgium and high in Norway, which suggests that this factor would tend to reduce rather than increase the variations observed. Finally, the geographic variations and the trends observed in RRT incidence cannot be explained by differences in the age distribution between countries or by a change in these distributions over the study period, since rates were adjusted for age.
As expected, the principal determinant of the geographic variations of overall RRT incidence was age. The overall incidence was highest when the incidence for the 6574 and 75 and older age groups was highest. On the other hand, contrary to what might have been expected, the overall RRT incidence did not necessarily increase at the fastest rates in those countries where it was lowest at the beginning of the decade. For example, Finland, with the lowest rate in Europe, witnessed a considerable increase in the RRT incidence among those older than 65 years, but the rates for those under 45 tended to decrease, resulting in an overall growth rate around the European mean. Also, The Netherlands, despite an initial low incidence rate, was the only one of the nine countries studied where the incidence was stable at the end of the 1990s. Observations should be continued over a longer period to confirm these trends.
Moulton et al. [19] argued that incidence rates in the 4064 year age group reflect underlying geographic variations in true ESRD incidence more accurately than rates among the elderly. If that is correct, our observation of much greater ranges in RRT incidence rates among the 6574 age group (from 290.9 to 490.1 pmp) and the over-75 age group (from 140.9 to 540.4 pmp) than in those aged 4064 years (from 135.3 to 203.1 pmp) would indicate that the geographic variations in the incidence among older patients on RRT may be due to other causes. These may include a combination of inadequate diagnosis, failure of referral to nephrologists, limited access to dialysis facilities, and patients reluctance to accept RRT.
While age is the most important factor determining the variations between countries in the incidence and trends of RRT, the causes of ESRD also have an influence. The primary renal disease for which the RRT incidence varies most is diabetes mellitus, with a range in 1999 from 10.2 pmp in Norway to 39.3 pmp in Austria while the gap between countries for the other known causes was less. Germany, with the highest overall RRT incidence rate in Europe, i.e. 148 pmp in 1999, also had the highest crude RRT incidence rate for diabetes at 51 pmp (Table 3). While the increase in this cause of renal failure was particularly large among those older than 65 years, it was also observed in the 4564 year age group in all countries except Norway. Nonetheless, despite these increases, the incidence of RRT in diabetic patients in Europe is only a quarter that of the US white population, which was 94.8 pmp in 1999 [5]. The cause of these geographic variations is probably multifactorial including variations in the prevalence of diabetes [20] and/or in the management of patients (secondary prevention), differences in mortality for example from cardiovascular disease prior to reaching ESRD, and also the persistence in some countries of limited access to RRT for these patients.
The incidence of RRT for ESRD attributed to hypertension or to renal vascular disease has also increased substantially during these 10 years. Unlike diabetes, this increase has involved mainly the age group older than 65 years, as has also been reported by the Australian registry ANZDATA [21]. While there is a wide range in the incidence of RRT for ESRD attributed to hypertension, from 5.8 pmp in Finland to 21 pmp in Norway, all European countries studied reported a much lower incidence than has been reported for the white population of the US (41.8 pmp) [5]. In contrast the pattern of RRT for ESRD due to renal vascular disease in North America [3,4] and Europe seem very similar with respect to the mean incidence and the rate at which it is increasing. Maisonneuve et al. [22] nevertheless pointed out that if the three registries (ANZDATA, USRDS, ERAEDTA) have similar codes for renal disease due to hypertension, the use of the category renal vascular disease unspecified (Appendix 1) by the ERAEDTA makes difficult the comparison of this cause of ESRD within European registries or with other registries. Thus, we cannot rule out that variations in coding these diseases between registries partly explain differences in incidence rates between countries although not to the extent of obscuring major trends.
Overall, the incidence of RRT associated with glomerular nephropathies has remained stable during the 1990s. The slight variations observed between countries may be in part explained by different practices in coding as suggested by the fact that incidence is highest when the proportion of diagnoses confirmed histologically is lowest [10]. Detailed analysis of the trends according to histologic type is limited by the low percentage (40%) of histologically confirmed diagnoses.
The observation of a higher incidence of RRT in men than in women is confirmed and the difference has even increased over the past decade. Although ESRD related to diabetes, hypertension and renal vascular disease have increased at a similar rate in both sexes, the initially higher incidence for these three causes in men explains most of the difference observed. Also, it is interesting to note the trends for tubulointerstitial and toxic nephropathies, which have always had a higher incidence in women, but have changed in different directions over the decade. The former has tended to diminish in women but increase in men, this increase being due to the presence of more older men on RRT, in whom obstructive uropathy related ESRD is common. A similar trend with an increased incidence in men and decrease in women has occurred with toxic nephropathies, especially in Belgium, and here also the incidence of analgesic-related ESRD remains one of the highest in Europe, despite a substantial decline between 1970 and 1990 [23].
In conclusion, this analysis provides accurate information on RRT incidence for the past decade in a number of European countries. In particular it shows the trends between countries and for the various age groups and primary renal diseases. The most obvious trends are the rapid increase in RRT incidence in the older patient and in those with diabetes mellitus. These changes are due in large part to an increase in these population groups in the community. However, improved access to RRT will also have contributed to the increases in incidence observed and we cannot know the extent of this contribution. The main value of this analysis is to point out the areas, which require further investigation and to provide the background information on which further research can be based. Probably the most important question that needs to be answered is to what extent the wide differences in RRT incidence between countries is due to under-provision of dialysis in the countries with lower incidence rates rather than differences in the prevalence of the various primary renal diseases. A second important question is when the year on year increase in incidence of RRT is going to slow and then level off. So far, there is no sign in this analysis of a slowing with the possible exception of The Netherlands. In this regard, careful validation of The Netherlands data has confirmed the completeness of recording of RRT incidence in that country. Assessment of future trends in RRT incidence is obviously important for health care planning. Among other questions is to what extent the wide variation in incidence of RRT in diabetic patients is due to a variation in prevalence of type 2 diabetes in the community rather than to differences in the natural history of the disease or to differing selection criteria for RRT. The ERAEDTA Registry aims to provide answers to some of these questions by means of future analyses, particularly regarding this latter point.
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Appendix 1
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Appendix 2
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Acknowledgments
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We would like to thank the patients and the staff of dialysis and transplant units for contributing the data via their national and regional renal registries. We also would like to thank the following registries for the contribution of these data: Austrian Dialysis and Transplant Registry (OEDTR), General Hospital of Wels, Wels, Austria (Dr R. Kramar and Dr H. K. Stumvoll); Danish National Registry (Dr H. Løkkegaard); Dutch End-Stage Renal Disease Registry (RENINE), Erasmus University Hospital, Rotterdam, The Netherlands (Dr F. Th. de Charro); Finnish Kidney Disease Registry and Department of Medicine, Helsinki University Hospital, Helsinki, Finland (Dr C. Grönhagen-Riska and Dr P. Finne); Dutch speaking Belgian Registry (Dr J. Donck, Dr H. Augustijn); French-Belgian Nephrologists Registry, Centre Hospitalier Etterbeek-Ixelles, Brussels, Belgium (Dr F. Collart); Greek national registry (Dr D. Tsakiris); Norwegian Renal Registry, Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway (Dr T. Leivestad); Scottish Renal Registry, Glasgow Royal Infirmary, Glasgow, Scotland, UK (Dr K. Simpson); Spanish Nephrology Association registry (Dr F. Garcia-Lopez) and the regional registries of Andalusia (Dr M. Calero), Catalonia (RMRC) (Dr M. Clèries and Mr E. Vela), and Valencia (Dr MJ. Garcia-Blasco) and the other ERAEDTA registry committee members for their advice in the analysis and the drafting of this paper: Dr G. Colasanti, Dr C. Grönhagen-Riska, Dr T. Feest, Dr A.J. van der Heijden, Dr H.J. Schober-Halstenberg, Dr D. Tsakiris, Dr K. Verrier-Jones. Research funding: The ERAEDTA Registry is funded by the European Renal Association (ERA). The following companies have committed funds in the form of unrestricted educational grants to assist the ERA in the financial support of the Registry: Amgen, Baxter, Fresenius, Gambro, Hoffmann-La Roche and Hospal.
Conflict of interest statement. None declared.
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Received for publication: 12. 9.02
Accepted in revised form: 12. 3.03