1 Servicio Nefrología, Hospital Gregorio Marañon, Madrid, Spain, 2 Klinische Abteilung für Nephrologie und Dialyse, Universitätsklinik für Innere Medizin III, Wien, Austria, 3 Department of Renal Medicine, King's College Hospital, London, UK, 4 Service de Néphrologie, Hôpital Tenon, Paris, France, 5 Klinika Chorob Nerek AM, Gdansk, Poland and 6 Division of Nephrology, University Hospital CHUV, Lausanne, Switzerland
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Abstract |
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Methods. For this epidemiological study, a retrospective chart review was conducted for patients who started haemodialysis or peritoneal dialysis between 1 August, 1999 and 6 April, 2000. All adult patients who entered one of the 779 participating centres in 21 European countries, Israel or South Africa were included, except for patients who underwent dialysis only during an acute episode. In addition to demographic characteristics, the study examined the prevalence of anaemia, anaemia management including the use of iron supplementation and epoetin, source of referral to the dialysis centre, comorbidities and major clinical events.
Results. A total of 4333 new dialysis patients were included in the survey. At the first visit to the dialysis centre, 68% of the patients had a haemoglobin (Hb) concentration 11.0 g/dl; Hb concentration was positively correlated with creatinine clearance rate (r=0.43, P<0.01). Patients who received epoetin had a mean Hb concentration of 8.8 g/dl at the start of epoetin treatment, and 96% of these patients had an Hb concentration
11.0 g/dl. Only 26.5% of the patients received epoetin before dialysis. The length of time under the care of a nephrologist was associated with meeting the European Best Practice Guidelines (EBPG) target Hb concentration, as well as receiving epoetin.
Conclusions. Few pre-dialysis patients met the EBPG target for Hb concentration, despite regular nephrology care.
Keywords: anaemia management; best practice guidelines; epidemiology; epoetin; pre-dialysis
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Introduction |
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In 1999, the European Dialysis and Transplantation Association (EDTA) published the European Best Practice Guidelines (EBPG) for the treatment of renal patients with anaemia [5]. These guidelines reviewed 200 additional publications and, based on three levels of evidence in accordance with the criteria of the US Agency for Health Care Policy and Research, updated the recommendations for the diagnosis and treatment of patients with anaemia from a European point of view. The EBPG aim to achieve haemoglobin (Hb) concentrations >11.0 g/dl in 85% of renal patients.
The European Survey on Anaemia Management (ESAM) [6] was published in 2000. This survey compiled prospective epidemiological data relating to the treatment of anaemia in a selected group of patients (n=14 527) on haemodialysis or peritoneal dialysis from 14 European countries. The results of this survey emphasized the small percentage of patients who began epoetin treatment pre-dialysis (only 11% of the patients on haemodialysis), and the low Hb concentration in patients at the start (mean <9.0 g/dl) and at the end of treatment.
The PRE-dialysis Survey on Anaemia Management (PRESAM) has been designed with the aim of evaluating the nephrological and anaemia management of pre-dialysis patients during the 12 months before dialysis. In this survey, the participating centres were asked to include all patients who started dialysis between 1 August, 1999 and 6 April, 2000. Retrospective data on the patients, and the diagnosis and treatment of anaemia were requested for the 12 months pre-dialysis. This survey fulfilled two objectives: to reveal the diagnostic and therapeutic patterns of anaemia in these patients and to document the pattern of referral of patients with chronic renal disease to a nephrologist before the start of dialysis in Europe, Israel and South Africa. A detailed analysis of the patient referral pattern will be presented elsewhere [7].
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Subjects and methods |
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Data collection and management
Collected data included: start date of dialysis, date of the first visit to a nephrologist, aetiology of chronic renal failure, source of referral to dialysis centre, date of the first consultation in the dialysis centre where the patient is currently dialysed, clinical data on the first visit to dialysis centre (including body weight, blood pressure, Hb and serum creatinine concentrations), and data related to comorbidity (such as diabetes type 1 or 2, hypertension, haemoglobinopathy, coronary heart disease, neoplasia, chronic hepatitis, cardiac failure, bronchopneumopathy, infectious disease, arrhythmia and inflammatory disease). Data were also collected on drug treatments, iron supplementation, major clinical events in the year as well as the month before dialysis (including angina pectoris, cardiac failure, myocardial infarction, infectious disease, inflammatory disease, bleeding, transfusion, surgery other than dialysis access and renal transplantation), and the type of vascular access (native fistula, synthetic fistula or catheter) when starting haemodialysis. Finally, the use of epoetin (including the physician who started epoetin treatment, epoetin dose, route and frequency of administration, and reasons for starting epoetin treatment), iron supplementation, Hb concentration, serum ferritin and serum creatinine concentrations, and transferrin saturation at the start of epoetin treatment were documented. Reasons for starting epoetin treatment could be low Hb concentration, cardiac failure, coronary heart disease, symptoms of anaemia (i.e. tiredness and dyspnoea), patient complaint or other. In addition, the target Hb concentration (the concentration aimed for in the individual patient, which was decided at the start of epoetin treatment and at the start of dialysis) was recorded [8].
Data were collected using a three-page pre-printed data collection tool (DCT). Each participating centre received DCTs and detailed instructions for their completion. The DCTs were scanned electronically using TELEform® scanning software. The scanned DCTs were reviewed and validated, and added to an SPSS® database. Data were then edited against a previously established series of domain and consistency edits. These established criteria-specified mandatory fields including the year of birth, start date of dialysis and serum creatinine concentration at the first visit to the dialysis centre. Of the 4729 original DCTs, 396 (8%) lacked data in one or more of these outlined areas and were therefore excluded from the database. The resulting analytical database therefore consisted of 4333 valid cases for which the mandatory data were available. Some of the non-mandatory data, however, were not available for all 4333 cases because of values outside the predefined boundaries, logical inconsistencies with other data, or questionable or missing units.
Data transformations included the calculation of creatinine clearance using the CockcroftGault formula as follows:
for men: ([140 age]xweight in kg)/(72xserum creatinine in mg/dl);
for women: {0.85x([140 age]xweight in kg)}/(72xserum creatinine in mg/dl) [9].
Iron status was also calculated using the following criteria: adequate iron status=serum ferritin 100 µg/l+transferrin saturation
20%; functional iron deficiency=serum ferritin 100 µg/l+transferrin saturation <20%; absolute iron deficiency=serum ferritin <100 µg/l.
Statistical analysis
Standard descriptive statistics were calculated for all study variables. Bivariate and multivariate distributions were examined by plotting distributions and stratification. Difference testing between groups was performed using the two-tailed t-test, analysis of variance, 2 or their non-parametric equivalent where appropriate. Significance for main effects was tested at the
=0.05 level.
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Results |
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Four of the five most prevalent comorbidities at a patient's first visit to a dialysis centre were cardiac-related: hypertension (78%), coronary heart disease (23%), cardiac failure (15%) and arrhythmia (8%). Eighty-four percent of patients had at least one cardiovascular comorbidity, including hypertension (total n=4333). Excluding hypertension, 34% of the patients had at least one of the following conditions: coronary heart disease, cardiac failure or arrhythmia. Diabetic patients comprised 30.8% (1336/4333) of the total survey sample and they had a significantly higher rate of hypertension compared with non-diabetic patients (n=2997) (84 versus 76%, P<0.01). Similarly, 36% of the diabetic patients had coronary heart disease and 22% had cardiac failure compared with 18 and 12%, respectively, of non-diabetic patients (P<0.01).
At their first visit to the dialysis centre, 57.3% of the patients (total n=3918) had been under the care of a nephrologist for >1 year, 31.4% had been under the care of a nephrologist for <6 months and 14.1% for <1 month (Table 2). Haemodialysis was started for 87.3% of the patients, whereas peritoneal dialysis was started for 12.7% (total n=4190). For more than half of the sample, dialysis was started because of fluid overload. Other reasons included severe acidosis and malnutrition. At the start of dialysis, 42.4% of the patients received iron supplementation (total n=4187).
Haemoglobin values
At the patients' first visit to the dialysis centre, the mean Hb concentration was 10.0±2.1 g/dl (total n=4020) (Table 2), and 68% of the patients had an Hb concentration
11.0 g/dl. The mean Hb concentration at the start of dialysis was 9.5±1.7 g/dl, and 80% of the patients had an Hb concentration
11.0 g/dl (total n=3629). There was a significant difference in the mean Hb concentration between patients from western Europe (9.8±1.6 g/dl) and those from central or eastern Europe (8.7±1.8 g/dl) (P<0.01) (Table 3
). For patients who received epoetin, the mean Hb concentration at the start of epoetin was 8.8 g/dl, and 96% of these patients had Hb concentrations
11.0 g/dl (n=2910) (Table 4
). The mean Hb concentration was 9.0±1.2 g/dl for patients from western Europe and 8.2±1.3 g/dl for patients from central or eastern Europe (P<0.01) (Table 3
).
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Epoetin treatment
Only 26.5% (1085/4095) of the patients started epoetin treatment before dialysis (Table 4). Dialysis was started before epoetin treatment in 12.8% (523/4095) of the patients, epoetin and dialysis were started simultaneously in 32.5% (1332/4095) of the patients, and 28.2% (1155/4095) did not receive epoetin at any time. The mean Hb concentration at the start of dialysis in patients who had received epoetin before starting dialysis was 10.3 g/dl compared with 9.2 g/dl in those who started epoetin after dialysis, 8.9 g/dl in those who started epoetin and dialysis simultaneously, and 9.4 g/dl in those who received no epoetin (Table 4
). The percentage of patients meeting the EBPG target Hb concentration of >11.0 g/dl at the start of dialysis was 31% of those who started epoetin first, 14% of those who started dialysis first, 8% of those who started dialysis and epoetin simultaneously, and 17% of those who were not treated with epoetin.
The percentage of patients who received epoetin before dialysis increased with the length of time under the care of a nephrologist (Figure 4A and B). There was also an increase in the mean Hb concentration at the start of epoetin treatment for patients who received epoetin before dialysis, from 8.5 g/dl in patients who were under the care of a nephrologist for <1 month (n=18) to 9.1 g/dl in patients under the care of a nephrologist for >1 year (n=711). When patients from western Europe were analysed separately, the mean Hb concentration increased from 8.6 g/dl in patients who were under the care of a nephrologist for <1 month (n=17) to 9.1 g/dl for those who were under the care of a nephrologist for >12 months (n=606) (Figure 4B
). In the entire sample, patients who started epoetin pre-dialysis had a mean Hb concentration of 9.0 g/dl at the start of epoetin treatment (n=994). Those who started dialysis first had a mean Hb concentration of 8.7 g/dl at the start of epoetin treatment (n=444) and those who started epoetin and dialysis simultaneously had a mean Hb concentration of 8.6 g/dl (n=1112) (Figure 4A
). For patients from western Europe, mean Hb concentrations at the start of epoetin were 9.2 g/dl (n=212) for those who started dialysis first and 8.8 g/dl (n=773) for those who started epoetin and dialysis simultaneously (Figure 4B
). For patients from central and eastern Europe, these Hb concentrations were 8.3 g/dl (n=228) and 8.1 g/dl (n=329), respectively (Figure 4B
).
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The mean dose at the start of epoetin treatment was 6302±3944 IU/week. For patients who received epoetin pre-dialysis (n=1031), the mean dose was 5832±3429 IU/week. This was similar to the mean dose for patients who received epoetin after the start of dialysis (5660±3542 IU/week) (n=488). These mean doses were significantly lower than those for patients in whom dialysis and epoetin were started simultaneously (6852±4208 IU/week; F=28.9, P<0.01) (n=1244). The association between Hb concentration and epoetin dose was weak for all patients regardless of when epoetin was started in relation to dialysis.
Iron supplementation
At the start of dialysis, 40% had adequate iron status and 60% had iron deficiency (39% had absolute deficiency and 22% functional deficiency) (total n=1997). Two-thirds of the patients who received epoetin pre-dialysis also received iron supplementation (total n=1060) (Table 4). Of the patients who started epoetin and dialysis simultaneously (n=1276), only 40% received iron supplementation, although 59% were iron deficient. In the patients who started epoetin treatment after dialysis (n=506), 32% received iron supplementation, although 62% were iron-deficient. In the patients treated with epoetin, there were no significant differences in iron status (i.e. adequate, functional deficiency, or absolute deficiency) between those who started epoetin before, after or simultaneously with dialysis. Of the patients who were not treated with epoetin, 56% were iron-deficient (37% absolutely and 19% functionally).
No iron supplementation was given to 74.6% of the patients who did not receive epoetin, whereas only 51.0% of the patients who were treated with epoetin were not supplemented. Additionally, of the patients who were treated with epoetin pre-dialysis, only 33% did not receive iron supplementation. Of the patients who received epoetin pre-dialysis and also iron supplementation, the majority (67%) were treated with oral iron only, 16% were treated with intravenous (i.v.) iron only and 10% were given both i.v. and oral therapy.
Patients without iron supplementation received the highest mean epoetin dose of 6591 IU/week (n=4187). Patients with both i.v. and oral iron supplementation received a mean epoetin dose of 5940 IU/week, those with only oral iron received a mean dose of 5861 IU/week, and those given i.v. iron alone were treated with the lowest epoetin dose with a mean of 5278 IU/week.
Attainment of EBPG targets
The EBPG for the management of anaemia in renal patients recommends an individual target Hb concentration of >11.0 g/dl, and aims for an Hb concentration of >11.0 g/dl in 85% of all patients. The mean individual target Hb concentration in the overall PRESAM sample at the start of dialysis was 11.6±0.7 g/dl (total n=2943) (Table 4). Nevertheless, only 18% of the patients had an actual Hb concentration >11.0 g/dl at the start of dialysis (Figure 5A
). This percentage was 22% for patients from western Europe, and 10% for patients from eastern or central Europe (Figure 5B
). Overall, the lowest incidence of patients who met the EBPG target Hb concentration of >11.0 g/dl was in the cohort who had been under the care of a nephrologist for <1 month (n=455) (Figure 5A
). This was also observed when patients from western Europe or from eastern and central Europe were analysed separately (Figure 5B
). In the cohort who had been under the care of a nephrologist for >12 months, both EBPG targets for Hb and ferritin concentrations were met by 26% of all patients in the sample who received both epoetin and iron, compared with only 18% of the patients who received epoetin only, 11% who received iron only, or 11% who received neither treatment. A comparison of patients from western Europe and from central and eastern Europe showed that a greater proportion of patients from western Europe were iron-deficient (P<0.01) (Figure 5C
).
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Comorbidity
Patients treated with epoetin pre-dialysis had significantly lower rates of cardiac failure in the year before dialysis than patients not treated with epoetin pre-dialysis (20 vs 24%, P<0.05). They also had significantly lower incidences of ischaemic heart disease (either angina or myocardial infarction) (17 vs 21%, P<0.05) and lower rates of blood transfusion (17 vs 21%, P<0.05). Furthermore, 11% required blood transfusions in the month before dialysis, compared with 19% of those who did not receive epoetin pre-dialysis (P<0.001). Similarly, patients treated with epoetin pre-dialysis also had lower rates of clinical events in the month before dialysis compared with those who did not receive epoetin pre-dialysis (cardiac failure 20 vs 23%, P<0.05; ischaemic heart disease 12 vs 16%, P<0.001).
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Discussion |
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The finding that 57% of the patients who were referred to a dialysis centre had been under the care of a nephrologist for >1 year and only 14% for <1 month is promising. The latter are patients who, according to several authors [11,12], would have to be considered as being so-called late referrals'. However, the mean creatinine clearance rate at the first visit to a nephrologist was only 18.2 ml/min, with over 35% of the patients having rates below 10 ml/min. Therefore, despite more than half of the patients being under the care of a nephrologist for >1 year, most arrived at the dialysis centre with an extremely advanced degree of renal insufficiency.
It is of particular significance that in this survey 68% of the patients had an Hb concentration 11.0 g/dl (mean Hb concentration, 10.0 g/dl) when they arrived at the dialysis centre for the first time, and should therefore, according to the EBPG, be considered for treatment with epoetin. Even when only patients from western Europe were considered, 78% had an Hb concentration
11.0 g/dl (median Hb concentration, 9.8 g/dl). The mean Hb concentration at the start of the treatment with epoetin was only 8.8 g/dl. These values are very similar to those observed in the ESAM survey, despite the fact that the ESAM patients were on dialysis and had started treatment several years before. The patients who had been under the care of a nephrologist for >1 year had higher Hb concentrations than those who had been referred later. Nevertheless, these patients started haemodialysis with a mean Hb concentration of 9.6 g/dl, which is still much lower than the recommended concentration. Even when only patients from western Europe were considered, this latter group of patients started dialysis with a mean Hb concentration of 9.8 g/dl. In other words, as in the ESAM survey, the inadequate treatment of patients with anaemia cannot be attributed exclusively to the late referral of the patients. It may also be attributed to the fact that some nephrologists do not follow the recommendations in the EBPG. Comparisons between patients from western and from eastern/central Europe show that patients from eastern/central Europe are less likely to receive epoetin treatment before starting dialysis, and have lower Hb concentrations at the start of epoetin treatment as well as at the start of dialysis. This probably reflects differences in funding available to the health care systems in the respective regions.
For patients who were not treated with epoetin and who had not received blood transfusions in previous months, there was a clear correlation between the degree of renal insufficiency (creatinine clearance rate) and the degree of anaemia (Hb concentration). However, there was great variability, and patients with creatinine clearance rates as low as 20 ml/min had a range of Hb concentrations from severe anaemia to normal (from 4.8 to 14.2 g/dl). In patients with creatinine clearance rates >50 ml/min, the mean Hb concentration was only 12.0 g/dl, indicating that there was a large proportion of anaemic patients in this group. Another notable finding is that no significant differences were observed in the relationship between Hb concentration and creatinine clearance rate in diabetic patients compared with non-diabetic patients. This is in contrast to other studies, which showed that diabetic patients are more affected by anaemia with declining renal function [13].
In this survey we observed that 26.5% of all patients in the sample received treatment with epoetin before starting dialysis (36% of the patients from western Europe and 10% of the patients from central or eastern Europe). In a review of more than 150 000 patients on dialysis in the USA, Obrador et al. [14] found that only 23% of the sample had received treatment with epoetin before starting dialysis. It is also of interest to emphasize that in our survey patients who start dialysis when they already receive epoetin have a higher Hb concentration than those not being treated (10.3 versus 9.2 g/dl), though the concentration is still much lower than that recommended in the EBPG. In addition, the mean Hb concentration was 9.2 g/dl in patients who started treatment with epoetin after dialysis. This study showed that the patients who had been under the care of a nephrologist for >1 year have received treatment with epoetin more often. When the reasons for starting treatment with epoetin were analysed, Hb concentration alone was only responsible for 25% of the cases. It appears that doctors postponed treatment with epoetin until patients showed symptoms of anaemia. The mean initial dose was slightly >6000 IU/week (but this varied greatly), and the mean dose was lower in patients who were treated with epoetin before dialysis.
A total of 60% of the patients were iron-deficient (39% absolutely and 22% functionally), and two-thirds of the patients treated with epoetin pre-dialysis also received iron supplementation. The iron status of the patients did not improve with length of time under the care of a nephrologist. Iron supplementation continued to be insufficient, perhaps because only 26% of the patients received i.v. iron supplementation, and some nephrologists probably do not follow the recommendations in the EBPG. As observed in the ESAM, in patients who did not receive iron supplementation, doses of epoetin were the highest.
The EBPG recommend an individual target Hb concentration of >11.0 g/dl with the aim of achieving this in 85% of the patients in the unit. For the patients studied in the PRESAM, however, the mean individual target was 11.6 g/dl (median value: 12.0 g/dl for patients in western Europe and 11.0 g/dl for patients in central or eastern Europe), but only 18% of the patients (22% of the patients from western Europe and 10% of the patients from central or eastern Europe) had an Hb concentration >11.0 g/dl when starting dialysis. The percentage of patients whose Hb concentration reached 11.0 g/dl was correlated with the length of time under the care of a nephrologist. One significant observation was that a lower incidence of heart failure and ischaemic heart disease is observed in the patients undergoing treatment with epoetin before dialysis than in patients who were not treated with epoetin before the start of dialysis. The cohort treated with epoetin before dialysis also had significantly lower rates of blood transfusions than those not treated with epoetin.
In summary, this pre-dialysis survey serves to draw attention to the following points. More than 30% of the patients had been followed by a nephrologist for <6 months when they started dialysis, which probably invalidated or reduced the effectiveness of measures taken to delay the progression of chronic renal insufficiency and control comorbidity. Cardiovascular comorbidities are extremely common, particularly in diabetic patients and, in this survey, diabetes was the most common cause of chronic renal insufficiency. Although being under the care of a nephrologist for >1 year is associated with less frequent (predominantly heart-related) complications, only a small proportion of patients receive treatment with epoetin before starting dialysis. Patients start dialysis with severe anaemia, and treatment with epoetin is started at Hb concentrations far below those recommended by the EBPG.
It is to be hoped that the data reported in this survey may draw attention to the risks of late treatment of anaemia and help to improve the management of anaemia during the initial stages of chronic renal insufficiency. Such improvements in practice may positively impact quality of life and cardiac status, and may even delay the progression of chronic renal insufficiency [15].
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Acknowledgments |
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Notes |
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References |
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