Time trends in initiation and dose of dialysis in end-stage renal disease patients in The Netherlands

Nephrol Dial Transplant (2003) 18: 552 558 Original Article Time trends in initiation and dose of dialysis in end-stage renal disease patients in The Netherlands Fabian Termorshuizen 1, Johanna C. Korevaar 1, Friedo W. Dekker 2, Kitty J. Jager 3, Jeannette G. van Manen 1 and Elisabeth W. Boeschoten 4,5 and Raymond T. Krediet 4 for The NECOSAD Study Group 6 1 Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, Amsterdam, 2 Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, 3 Department of Medical Informatics, Academic Medical Centre, University of Amsterdam, Amsterdam, 4 Department of Nephrology, Academic Medical Centre, University of Amsterdam, Amsterdam and 5 Dianet Dialysis Centres, Amsterdam and Utrecht, The Netherlands 6 Apperloo A. J., Barendregt J. N. M., Birnie R. J., Boekhout M., Boer W. H., Bommel E. F. H. van, Büller H. R., Charro F. Th. de, Doorenbos C. J., Dorp W. T. van, Es A. van, Fagel W. J., Feith G. W., Franssen C. F. M., Frenken L. A. M., Geelen J. A. C. A. van, Geerlings W., Gerlag P. G. G., Gorgels J. P. M. C., Grave W., Huisman R. M., Jansen M. A. M., Jie K., Koning-Mulder W. A. H., Koolen M. I., Kremer Hovinga T. K., Lavrijssen A. T. J., Mulder A. W., Parlevliet K. J., Rosman J. B., Saase J. L. C. M. van, Schonk M. J. M., Schuurmans M. M. J., Stevens P., Tijssen J. G. P., Valentijn R. M., Vastenburg G., Verburg C. A., Verhagen C. E., Verstappen V. M. C., Vincent H. H. and Vos P. Abstract Background. The guidelines published by the NKF- Dialysis Outcomes Quality Initiative (DOQI) in 1997 advocate an earlier start of dialysis in ESRD patients and a higher dialysis dose than usual. We studied the possible influence of the increasing emphasis on adequate dialysis on the management of ESRD patients in The Netherlands in 1993 2000. Methods. The NECOSAD study on the adequacy of dialysis started in 1993. This prospective multi-centre study included ESRD patients older than 18 years who started HD or PD as the first RRT. We analysed the distribution of age, gender, primary renal disease and co-morbidity, the mean residual renal function and the mean dialysis-ktuv urea at 3 months in 1569 consecutive patients by calendar year of initiation dialysis. Results. Age, gender, primary renal disease and number of co-morbid conditions at the start of dialysis remained stable over time between 1993 and 2000. The mean renal KtuV urea at 3 months increased from 0.5 in 1993 to 0.8 per week in 2000 (P-0.01). An upward trend remained after adjustment for patient characteristics and dialysis centre. The total KtuV urea at 3 months increased from 3.3 in 1993 to 3.7 per week in 2000 in HD (P-0.01) and from 2.0 in 1993 to 2.3 Correspondence and offprint requests to: F. Termorshuizen, Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Email: f.termorshuizen@amc.uva.nl per week in 1999 in PD patients (P-0.01). An upward trend in the dialysis-ktuv urea was found after adjustment for renal KtuV urea (HD: q0.3 per week, Ps0.06; PD, q0.2 per week, P-0.05). Conclusions. These results indicate a tendency towards earlier introduction of RRT and higher doses of dialysis in The Netherlands. Possible effects of this development on mortality, morbidity, quality of life and the balance between costs and benefits need further investigation. Keywords: adequacy; co-morbidity; DOQI guidelines; patient characteristics; renal replacement therapy; time trends Introduction The results of the National Cooperative Dialysis Study (NCDS) in the USA have led to the development of KtuV urea to quantify the dialysis dose in end-stage renal disease (ESRD) patients treated with haemodialysis (HD) [1]. KtuV urea is also used to assess the dose of peritoneal dialysis (PD) [2]. Guidelines on good clinical practice for dialysis treatment were first published in 1997 by the National Kidney Foundation Dialysis Outcomes Quality Initiative (NFK-DOQI) [3]. Amongst others, guidelines based on KtuV urea were formulated for the start of dialysis and the minimum dose for # 2003 European Renal Association European Dialysis and Transplant Association

Time trends in dialysis treatment in The Netherlands HD and PD. Although developed for the USA and not always based on conclusive evidence, these guidelines have been promoted worldwide. The KtuV urea targets set by the DOQI guidelines were generally higher than those employed in the majority of patients. This relates both to the renal KtuV urea at the start of dialysis treatment and the KtuV urea by dialysis thereafter [2,4 6]. If adopted, the DOQI guidelines are therefore likely to lead to changes in dialysis practice. Various recent studies in the US and Canada indicated upward trends in both the residual renal function at the initiation of renal replacement therapy (RRT) [5,6] and the dose of dialysis thereafter [7 9]. The aim of the present study was to examine whether a time trend was present in the initiation and the dose of dialysis in ESRD patients in recent years in The Netherlands. We also examined whether the distribution of patients in terms of age, gender, co-morbidity and primary kidney disease changed in the same years and whether differences in patient characteristics by calendar year of starting dialysis might explain time trends in dialysis practice. Subjects and methods Patients The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) is a multi-centre prospective cohort study in which ESRD patients are followed from the time of initiation of dialysis until transplantation or death. All patients older than 18 years and starting chronic dialysis as the first RRT were eligible for the NECOSAD study. A first cohort of 250 ESRD patients from 13 dialysis centres was recruited in 1993 and 1994 (NECOSAD-1). In 1997 2000, a second cohort was recruited from 38 centres (NECOSAD-2) (ns1391). Patients who survived the first 3 months of dialysis and who were still in follow-up 3 months after the start were included in the present analysis. This was done because in 1993 and 1994 no data at the time of initiation of RRT were collected and for the years 1997 2000 full data from the 0-month visit were available for a limited part of the participants. Furthermore, by restricting the analysis to patients at the 3-month visit patients with acute renal failure were excluded. These patients were not of interest for the present analysis, which aimed to evaluate trends in chronic dialysis treatment. The data of 1319 NECOSAD-2 participants were included in the present analysis. Thirty-seven patients died within 3 months after the start. In 23 patients the participation was finished before the 3-month visit (mainly because of refusal). In 12 patients no data from the 3-month visit were available. Data collection procedures Data on demography, primary kidney disease and comorbidity were collected at the time of entry in the study. Data on residual renal function, nutritional status, biochemistry and dialysis characteristics (current modality, KtuV urea, ultrafiltration) were collected 3 months after the start of RRT ( baseline visit ). For a subgroup of NECOSAD-2 patients detailed information on residual renal function and nutritional status just prior to or at the time of initiation of RRT was available ( 0-month visit ). Primary kidney disease was classified according to the codes of the European Renal Association-Dialysis and Transplantation Association (ERA- EDTA) [10]. Based on the number of co-morbid conditions a patient was classified according to the Davies co-morbidity index as having no, intermediate, or severe co-morbidity [11]. To monitor renal function both urea and creatinine were measured in simultaneously obtained plasma and urine samples. Residual renal function was expressed as residual GFR (rgfr), calculated as the mean of renal creatinine and urea clearance, adjusted for body surface area (mluminu 1.73 m 2 ), and as weekly renal KtuV urea, in which V was calculated according to Watson et al. [12].Thecontribution of renal function to fluid balance was estimated from a 24-h urine collection in PD patients and from an inter-dialytic urine collection in HD patients. Urea clearance by dialysis was expressed as weekly dialysis KtuV urea. Peritoneal KtuV urea was calculated from a 24-h dialysate collection and the dialysate and plasma urea concentrations. HD KtuV urea was estimated according to the second-generation Daugirdas formula based on one plasma urea measurement before and one after the dialysis session, the ultrafiltration and the duration of the session [13]. The daily protein intake shortly preceding or at the time of the 0-month visit was calculated from the urea excretion in the urine [normalized protein equivalent of nitrogen appearance (npna)], according to Bergström et al. [14] and normalized to actual body weight. Statistical analysis We examined the differences in patient and treatment characteristics at the 3-month visit by calendar year of initiation of dialysis and assessed whether the possible differences might fit into a time trend. In the univariate analyses, means and percentages were calculated by year of initiation of RRT and tested by means of the F-test (ANOVA) and the x 2 -test when appropriate. The Mantel Haenszel x 2 -test for trends was used to test whether yearly differences in percentage might fit into a time trend. In a multivariate regression analysis the possible associations between the year of initiation of RRT on the one hand, and rgfr, renal KtuV urea, urine production, and dialysis-ktuv urea at 3 months on the other, were adjusted for age, gender, primary kidney disease and number of co-morbid conditions, as these factors might confound the time trends of interest. The renal KtuV urea and the body mass index (BMI) were also included in the multivariate model for the time trend in the dialysis-ktuv urea. The renal KtuV urea was included because a higher residual renal function will often lead to a lower prescribed KtuV urea delivered by dialysis. Consequently, a time trend towards a higher residual renal function at baseline may lead to a non-independent decline in the dialysis dose or a spurious absence of a time trend in the dialysis dose. Furthermore, a possible time trend in the BMI may influence the time trend in dialysis dose, as urea clearance by dialysis is normalized to the urea distribution volume. Calendar time of initiation of RRT was categorized into 6 calendar years (1993 1994, 1997 2000) to enable the consideration of time trends other than strictly linear ones. The number of recruiting dialysis centres and the number of recruited patients within a dialysis centre varied in the course of the NECOSAD study and this might confound the time trends of interest because of possible differences in patient care among dialysis facilities. Therefore the possible effect of dialysis centre on dialysis practice was taken into account by including the centre as a categorized variable in the statistical models. The model for the dialysis-ktuv urea was designed for HD and PD patients separately. The overall effect of the 553

554 F. Termorshuizen et al. inclusion of calendar year of initiation of RRT in the multivariate models was tested by means of the partial F-statistic. We examined whether the percentage of timely starters, as defined on the basis of the DOQI guidelines, increased in recent years. This was done in a subgroup of NECOSAD-2 patients in whom sufficient data on renal function and nutritional status at the 0-month visit (i.e. the start of dialysis) were available. Patients were classified as timely starters when the renal KtuV urea was above 2.0 per week or the npna was above 0.8 gukg and the BMI was at least 20 kgum 2 at the time of initiating RRT [15]. Differences in the number of timely starters by year of initiating RRT were tested by means of the x 2 -test. Finally, the mortality rates (number of deaths per year of follow-up) in the first year following the 3-month visit were calculated by year of initiation of RRT (1993 2000). In a multivariate Poisson regression model differences in mortality rates by calendar year were adjusted for the effects of age, gender, co-morbidity, primary kidney disease and blood concentration of albumin at baseline. The contribution of year of initiation of RRT to the regression model was tested by means of the likelihood ratio-statistic (type 3). All analyses were performed with SAS statistical software, version 6.12. A P value of O0.05 was regarded as statistically significant. A P value from 0.05 to 0.15 was regarded as borderline significant. Results Patient characteristics The mean age at initiation of RRT increased from 55.0 years in 1993 to 58.0 years in 2000, but the differences by calendar year did not reach the level of statistical significance (Table 1). The percentage of patients aged 65 years or older differed by year of initiation of RRT (P-0.01). However, no consistent time trend in this percentage was established (Ps0.72). Table 1. Patient characteristics at 3 months by year of starting renal replacement therapy (RRT) Differences in the number of co-morbid conditions in the course of years were noticed (P-0.15), but a time trend was not found (P)0.15). Differences in mean haemoglobin concentration at the 3-month visit by year of initiation of RRT were found (P-0.01) and these differences indicated a consistent increase from 10.6 in 1993 to 11.3 gudl in 2000. Alongside this trend in haemoglobin, a trend towards a higher percentage of patients who were treated with Epo was found (P- 0.01). Furthermore, an increase in the mean BMI from 24.2 in 1993 to 25.0 kgum 2 in 2000 (P-0.05) was noted. Residual renal function by year of initiation of dialysis Univariate. The rgfr, renal KtuV urea and urine production at the 3-month visit increased in the period 1993 2000 among both HD and PD patients (Table 2). The mean renal KtuV urea at 3 months increased from 0.51 in 1993 to 0.80uweek in 2000 when the data of HD and PD patients were put together (P-0.01). Multivariate. For the multivariate regression analysis on residual renal function the data of the HD and PD patients were put together. This was done because no significant difference in the residual renal function at 3 months and no significant difference could be established in the trend in the course of the calendar years between HD and PD patients. Changes over time in the rgfr, renal KtuV urea, and urine production adjusted for age, gender, primary renal disease, co-morbidity and dialysis centre are shown in Table 3. An independent and statistically significant effect of calendar year of initiation of dialysis on the residual renal function was found. The adjusted differences by year of start of RRT indicated a time trend towards a higher GFR, renal KtuV urea and urine production at 3 months. 1993 1994 1997 1998 1999 2000 Patients (n) 54 196 329 485 331 174 Haemodialysis at 3 months, n (%) 28 (51.9) 104 (53.1) 217 (66.0) 299 (61.7) 203 (61.3) 117 (67.2) b Mean age, years (SD) 55.0 (15.5) 57.5 (15.3) 59.1 (15.9) 59.1 (15.6) 58.1 (14.7) 58.0 (16.2) P65 years, % 33.3 36.7 47.1 43.5 34.4 41.4 b Male, % 50.0 60.7 60.2 62.5 59.2 61.5 Primary renal disease Diabetes, % 16.7 14.3 15.8 14.8 15.4 14.9 Glomerulonephritis, % 11.1 12.8 12.8 16.3 13.9 12.6 Renal vascular disease, % 20.4 24.0 17.9 19.4 18.7 16.1 Other, % 51.9 49.0 53.5 49.5 52.0 56.3 Co-morbidity Davies risk I (none), % 40.7 51.5 43.5 49.9 43.5 50.0 II (low), % 48.1 42.9 45.9 40.6 49.5 36.8 a III (high), % 11.1 5.6 10.6 9.5 6.9 13.2 a Co-morbidity Diabetes mellitus, % 24.1 16.3 20.4 19.4 22.4 21.4 Cardiovascular, % 33.3 26.0 35.3 30.5 28.1 32.8 Haemoglobin (gudl) (SD) 10.6 (1.6) 10.8 (1.6) 10.9 (1.5) 11.1 (1.6) 11.2 (1.7) 11.3 (1.5) c Use of Epo, % 79.6 72.9 82.8 83.2 81.9 87.9 c Body mass index, kgum 2 (SD) 24.2 (4.0) 23.8 (4.1) 24.2 (4.0) 24.4 (3.8) 25.0 (4.6) 25.0 (4.0) b P-values refer to the differences in mean or percentage between calendar years of initiation RRT (ns1569). a 0.05-PO0.15; b 0.01-PO0.05; c PO0.01.

Time trends in dialysis treatment in The Netherlands Table 2. Mean GFR, urine production and KtuV urea (SD) at 3 months, by year of initiation of RRT and modality (HD vs PD) 555 1993 1994 1997 1998 1999 2000 Haemodialysis (ns789) Patients (n) 22 92 184 249 156 86 Residual GFR (mluminu1.73 m 2 ) 2.44 (1.39) 3.07 (2.65) 3.09 (2.70) 3.41 (4.22) 3.33 (2.68) 4.12 (3.18) a Urine production (mlu24 h.) 516.2 (328.4) 601.7 (457.4) 658.1 (575.3) 745.0 (625.0) 800.8 (725.4) 892.7 (697.7) b Renal KtuV urea (uweek) 0.53 (0.33) 0.61 (0.53) 0.60 (0.50) 0.67 (0.57) 0.69 (0.54) 0.84 (0.66) b Dialysis KtuV urea (uweek) 2.80 (1.03) 2.68 (0.83) 2.62 (0.83) 2.74 (0.82) 2.71 (0.72) 2.86 (0.81) Total KtuV urea (uweek) 3.32 (0.90) 3.28 (0.88) 3.22 (0.85) 3.41 (0.93) 3.40 (0.73) 3.70 (0.91) c % P3.6uweek (DOQI) 31.8% 38.0% 26.6% 37.0% 40.4% 59.3% c Treatment time (huweek) 9.8 (1.9) 9.1 (2.0) 9.3 (2.3) 9.4 (2.0) 9.5 (2.1) 9.5 (1.7) Frequency 3 vs 2 timesuweek (%) 45.5% 40.2% 51.1% 50.6% 64.7% 70.9% c Peritoneal dialysis (ns528) Patients (n) ns21 ns83 ns93 ns161 ns120 ns50 Residual GFR (mluminu1.73 m 2 ) 2.80 (2.34) 3.06 (2.20) 4.01 (2.79) 4.03 (2.68) 3.83 (2.66) 4.29 (2.46) b Urine production (mlu24 h.) 641.2 (631.1) 773.3 (677.6) 1164.4 (927.3) 1094.1 (806.4) 952.8 (692.2) 1020.6 (634.0) c Renal KtuV urea (uweek) 0.48 (0.39) 0.59 (0.46) 0.80 (0.56) 0.81 (0.57) 0.76 (0.56) 0.75 (0.50) b Dialysis KtuV urea (uweek) 1.50 (0.40) 1.48 (0.32) 1.47 (0.46) 1.54 (0.38) 1.58 (0.41) 1.38 (0.33) b Total KtuV urea (uweek) 1.99 (0.51) 2.08 (0.47) 2.27 (0.51) 2.34 (0.62) 2.34 (0.61) 2.12 (0.55) c % P2.0uweek (DOQI) 38.1% 54.2% 67.7% 67.7% 66.7% 50% b Dwell volume (ml) 1857 (231.5) 1877 (248.5) 1924 (230.1) 1943 (248.8) 1982 (337.5) 1952 (292.6) a Changesu24 h P5 vs O4 0% 3.61% 9.89% 13.21% 19.17% 6.12% c P-values refer to the differences in mean (ANOVA) or percentage (x 2 ) between calendar years of RRT initiation. a 0.05-PO0.15; b 0.01-PO0.05; c PO0.01. Table 3. Multivariate regression analysis on residual renal function at 3 months by year of RRT start Year of dialysis start rgfr (mluminu1.73 m 2 ) b parameter Dose of dialysis by year of initiation dialysis Univariate. No differences in the mean dialysis KtuV urea by year of initiation of RRT were observed in HD patients (Table 2). The differences in the mean dialysis- KtuV urea by year of initiation of RRT reached the level of statistical significance in PD patients (P-0.05). However, this finding was due to the decline in the mean dialysis-ktuv urea between 1999 and 2000. When the data of PD patients in 2000 were excluded from the statistical inference, no differences by year of initiation could be established (Ps0.2116; data not shown). Differences in total KtuV urea (renalqdialysis) at 3 months by year of initiation of RRT were found among both HD and PD patients (P-0.01) (Table 2). These differences indicated higher values of total KtuV urea in recent years. The percentage of HD patients with a total KtuV urea up to the DOQI standard (P3.6uweek) increased from 32% in 1993 to 59% in 2000 (Ps0.007). Such a trend towards a higher percentage Renal KtuV urea (uweek) b parameter 1993 0 0 0 1994 q0.303 q0.117 q109.13 1997 q0.735 q0.173 q255.3 1998 q0.884 q0.219 q302.7 1999 q0.850 q0.231 q314.9 2000 q1.253 q0.287 q340.8 Overall test for year of dialysis start Ps0.07 Ps0.014 Ps0.003 R 2 (complete model) 17.3% 16.2% 18.4% Urine production (mlu24 h.) b parameter The b parameters indicate the change over time since 1993 (sreference year), adjusted for age, gender, Davies co-morbidity score, primary renal disease and dialysis centre. of patients who were treated up to the DOQI standard (total KtuV urea P2.0uweek) was also suggested in PD patients (Ps0.065). However, the percentage of PD patients with a total KtuV urea up to the DOQI standard decreased from 66.7% in 1999 to 50.0% in 2000. A trend towards higher values became more apparent when the data of PD patients in 2000 were excluded from the analysis (Ps0.0033). Multivariate. Changes over time in the dialysis KtuV urea adjusted for patient characteristics (including renal KtuV urea and BMI) and dialysis centre are presented in Table 4. An upward trend was suggested in both HD and PD patients. However, in PD patients the dialysis KtuV urea decreased in 2000. When the data of PD patients in 2000 were excluded from the analysis, the change over time still reached the level of statistical significance (Ps0.026, data not shown). No effect of year of initiation of RRT could be established when the residual renal KtuV urea was excluded from the

556 F. Termorshuizen et al. Table 4. Multivariate regression analysis on dialysis KtuV urea at 3 months by year of RRT start Year of dialysis start Haemodialysis at 3 months Dialysis KtuV urea (uweek) b parameter Peritoneal dialysis at 3 months Dialysis KtuV urea (uweek) b parameter 1993 0 0 1994 q0.029 q0.037 1997 q0.078 q0.134 1998 q0.147 q0.158 1999 q0.146 q0.160 2000 q0.333 q0.051 Overall test for year of dialysis start Ps0.056 Ps0.012 R 2 (complete model) 38.7% 43.2% The b parameters indicate the change over time since 1993 (sreference year), adjusted for patient characteristics (including renal KtuV urea ) and dialysis centre. multivariate regression models (HD, Ps0.279; PD, Ps0.246, data not shown). Percentage of patients who start dialysis in time according to the DOQI guidelines. In a subgroup of the included NECOSAD-2 patients with sufficient data at the time of initiation of dialysis and who received predialysis care, the percentage of timely starters was 62.2% in the years 1997 2000 (ns392). The percentage of patients starting in time increased from 51.0% in 1997 to 66.1% in the 3 years thereafter (Ps0.058). This trend was not modified when patients who died or were lost to follow-up in the first 3 months after the start were also included (ns411). Mortality rates by year of initiation dialysis. The crude mortality rate in the first year following the 3-month visit in 1993u1994 (NECOSAD-1) was 0.134uperson year. A small increase to 0.163uperson year in 2000 was noted, but differences by year of start dialysis were not statistically significant (Ps0.9326). Adjusting the yearly differences for the effects of age, gender, comorbidity, primary kidney disease, serum albumin and body mass index did not modify this result (Ps0.6192) (Figure 1). Discussion The results of the present analysis show a trend towards an earlier start of dialysis in the course of the years 1993 2000. A tendency towards a higher KtuV urea delivered by dialysis was found, especially in HD patients. No time trend in the distribution of patients by age, gender, primary renal disease and number of co-morbid conditions could be established, and the haemoglobin concentration and the body mass index tended to increase. Hence, the time trend in residual renal function was probably not due to a worse clinical condition or differences in case mix but indicates an independent tendency towards a start at an earlier stage of the renal disease. Patient characteristics, residual renal function and dialysis facility may all have their influences on the dialysis treatment in ESRD and have to be taken into account to enable the establishment of independent time trends in the timing and the intensity of dialysis Fig. 1. Crude mortality rates (number of eventsuperson year) in the first year after the 3-month visit by calendar year of initiation of dialysis.

Time trends in dialysis treatment in The Netherlands [5,16]. The increasing haemoglobin concentration at baseline may be due both to the higher mean residual renal function at baseline and the increasing percentage of patients using Epo [9]. In each calendar year the distribution of age, gender and primary renal disease in the NECOSAD population was similar to that of all new dialysis patients in 1993 2000 in The Netherlands (data from the national registry on renal replacement therapy in The Netherlands, RENINE, not shown) [10]. Hence, this agreement strongly suggests that the NECOSAD study population was a representative sample of all new dialysis patients in The Netherlands. Our results are in accordance with reports from the USA and Canada, in which time trends towards an earlier start of dialysis and a higher dialysis dose were demonstrated [5 9]. For instance, in the US Renal Data System (USRDS) an increase of the estimated GFR at the initiation of RRT from 7.1 in 1995 to 8.3 mlumin in 2000 was found (http:uuwww.usrds.org). In a special USRDS study, it was shown that the delivered KtuV urea increased from 0.91uHD session in 1987 to 1.18uHD session in 1997, suggesting that the increasing emphasis on adequate dialysis had started to exert its influence even before the publication of the DOQI guidelines [7]. In the Peritoneal Dialysis-Core Indicators Study (PD-CIS) the weekly KtuV urea increased from 1.9 to 2.3 and the frequency of achievement of minimal DOQI adequacy criteria increased from 23 to 63% in a random sample of the 1995 2000 US PD population [9]. It can be questioned whether the DOQI guidelines on the start and the dose of dialysis should be implemented in other countries without any modification. Guidelines may require adaptation because of differences in patient characteristics between countries. For example, ESRD patients in The Netherlands start dialysis at a more favourable nutritional status than ESRD patients in the USA. Our data indicate that no favourable and significant trend in mortality alongside the differences in dialysis practice was present. However, other in-depth analyses are required to establish definitely the relationship between an early startuhigher dose of dialysis and patient outcome. Some studies have suggested that a profit in terms of reduced morbidity or better survival may be achieved by an earlier start and higher doses of dialysis. An early start of RRT has been advocated in recent years to prevent malnutrition and hence a poor clinical outcome [4,16,17]. For example, a difference in survival at a difference in the mean renal KtuV urea at the time of initiation dialysis of 0.4uweek has been reported by Tattersall et al. [4]. This figure suggests that the observed time trend in residual renal function may be of clinical importance, as it is in the same order of magnitude. However, other studies did not confirm the more favourable outcome in patients with a high residual renal function at the start of dialysis. For instance, in a first analysis of data of NECOSAD-2 patients (ns253) an earlier start of dialysis was not associated with a more favourable survival and higher health-related quality of life [15,18]. Also, in a study by Davies et al. [19], it was strongly suggested that the decrease in residual renal function is an important predictor of mortality, but no difference in residual renal function shortly after the start of dialysis between survivors and non-survivors was found, although the mean initial value for the renal KtuV urea was only 0.8uweek. However, a recently published registry study from Scotland also reported no beneficial effect of renal function at the start of dialysis (median creatinine clearance 8.3 mlumin) on survival [20]. Various studies have indicated that a high dose of dialysis is associated with a reduction of mortality and morbidity rates [1,2,21]. However, recent studies among PD patients have made it likely that the effect of dialysis dose for the survival was of secondary importance in comparison with the influence of residual renal function, when taken into account properly [22]. It is speculative whether this might be the explanation for the observed decline in PD dose in 2000. However, data from 2001 and 2002 are needed to examine whether the decrease in 2000 is temporary and perhaps due to a sampling error or statistical fluctuation, or is a real ongoing downward trend. In the United States a decrease in mortality in recent years in both HD and PD patients, together with a shift towards the adequacy standards of DOQI, has been reported. It has been debated whether the trend in mortality was solely due to changes in dialysis dose, as the improvements in mortality pre-dated improvements in adequacy. The lower mortality might as well have been caused by better anaemia control, and the introduction of biocompatible dialysis membranes [23]. We conclude that there has been a tendency towards an earlier start of RRT and a higher dialysis dose in The Netherlands in recent years. The effects of this development on mortality, morbidity, quality of life and the balance between costs and benefits need further investigation. Acknowledgements. We thank Martin Nieuwenhuizen for supplying information from the national registry on renal replacement therapy in The Netherlands (RENINE). 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