1Department of Nephrology and Dialysis, A Manzoni Hospital, Lecco, Italy, 2University Renal Research and Education Association, Ann Arbor, MI, USA, 3Nephrology and Hemodialysis Service, Hôpital St-André, Bordeaux, France, 4Nephrology Section, University of Heidelberg, Heidelberg, Germany, 5Department of Nephrology, Universita Federico II, Naples, Italy, 6Nephrology Service, Hospital General Vall dHebron, Barcelona, Spain, 7Department of Renal Medicine, Lister Hospital, Stevenage, UK and 8Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Correspondence and offprint requests to: Dr Friedrich K. Port, MD, MS, University Renal Research and Education Association, 315 W. Huron St., Suite 260, Ann Arbor, MI 48103, USA. Email: fport{at}urrea.org
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Abstract |
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Methods. Baseline data on demographics, co-morbidities and anaemia management in 4591 haemodialysis patients from 101 nephrology facilities were collected in 19982000. Using multivariate Cox survival analyses to adjust for patient characteristics, relationships between haemoglobin concentration at study entry and rates of mortality and hospitalization were evaluated.
Results. For a year 2000 sample of prevalent patients on haemodialysis >180 days, mean haemoglobin concentration was 11.0 g/dl; 53% had a haemoglobin concentration 11 g/dl [19981999 = 44% (P < 0.05)]. In 2000, 84% of prevalent patients were prescribed recombinant human erythropoietin (rHuEpo). Higher haemoglobin concentrations were associated with decreased relative risk (RR) for mortality (RR = 0.95 for every 1 g/dl higher haemoglobin, P = 0.03) and hospitalization (RR = 0.96, P = 0.02). Patients with haemoglobin <10 g/dl were 29% more likely to be hospitalized than patients with haemoglobin 1112 g/dl (P < 0.001).
Conclusion. Even after adjustment, lower haemoglobin concentrations were associated with higher morbidity and mortality in European haemodialysis patients. A trend to increased haemoglobin concentrations was observed following publication of the European Best Practice Guidelines (EBPG) on anaemia management for chronic kidney disease patients, but efforts must continue to achieve EBPG goals.
Keywords: anaemia; chronic kidney disease; morbidity; mortality; haemodialysis; rHuEpo
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Introduction |
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In recent decades, several important advances have been made in the treatment of end-stage renal disease (ESRD) [2], not least the management of anaemia associated with chronic kidney disease (CKD). The burden of anaemia in these patients is substantial, causing considerable morbidity and dramatically reducing their quality of life [36]. Until 15 years ago, the mainstay of treatment was blood transfusion, with all its associated risks. However, the management of renal anaemia has been transformed over the past decade by the introduction of recombinant human erythropoietin (rHuEpo). Over this period, rHuEpo has become accepted as an effective and well-tolerated treatment, and its clinical benefits in patients with CKD are well documented [716]. As a result of the introduction of rHuEpo into routine nephrology practice, guidelines have been developed for the treatment of anaemia for CKD patients. Contributions have included the European Renal Association's Best Practice Guidelines (EBPG) [17] and the Dialysis Outcomes Quality Initiative of the US National Kidney Foundation (NKF-DOQI) [18].
The present study investigated the level of anaemia in a representative cross-section of maintenance haemodialysis patients and correlations of anaemia with morbidity and mortality in five European countries. In addition, anaemia management treatment practices also are reported.
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Subjects and methods |
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The facility selection protocol included the following key aspects. Facilities participating in the Euro-DOPPS were randomly selected from a list of all dialysis units within each country. Only facilities having more than 24 haemodialysis patients were eligible for study participation. These facilities typically serve 95% of all facility-based haemodialysis patients in each country. Selection was stratified such that facility samples provide proportional representation of the types of haemodialysis units and geographic regions within each country. Among randomly selected facilities, >90% agreed to participate. Data were collected from Euro-DOPPS dialysis units from May 1998 through to November 2000, with 98% of all participating dialysis units entering the DOPPS between May 1998 and February 1999. Additional details of the DOPPS data collection protocol and study design have been described previously [1].
Data source: patient samples used for analysis
Limited data were collected from all haemodialysis patients (n = 11 422, census patients) >17 years of age, receiving chronic maintenance haemodialysis, haemodiafiltration or haemofiltration at each participating Euro-DOPPS dialysis unit during study participation from 1998 to 2000. From the list of census patients, a sample of patients was selected randomly at each DOPPS facility at the beginning of the study to achieve an average of 30 randomly selected patients per facility (range 2040 patients, dependent on facility size; average facility size = 60 haemodialysis patients). For these random sample patients (n = 4591), detailed longitudinal data were collected, including patient demographics, over 65 indications of baseline co-morbidity, measures of socioeconomic status, baseline and longitudinal laboratory data, vascular access use and procedures, hospitalization and outpatient events, characteristics of haemodialysis treatment, prescribed and delivered haemodialysis dose, medications, measures of anaemia and mineral metabolism management, residual renal function, patient quality of life assessments, primary causes of ESRD, modality history during ESRD and pre-ESRD care.
Informed patient consent was obtained, and consent rates approached or exceeded 90% in each country. To maintain an approximately constant random sample patient cohort over time, additional patients entering the unit since the time of the previous random selection were routinely randomly selected to replace sample patients who left the study for any reason (e.g. death, transfer to different facility, change in modality, transplant). The total number of random sample patients for whom data were collected in each country were France (n = 981), Germany (n = 908), Italy (n = 869), Spain (n = 936) and the UK (n = 897).
Analyses presented in this paper were based on either all patients in the random sample patient group or three sub-samples of the random sample patient group. (i) A point-prevalent (cross-sectional at one point in time) patient sample pertaining to random sample patients dialysing in Euro-DOPPS units on June 1, 2000 (n = 2590); this sample served to provide a recent estimate of anaemia management practices after publication of the EBPG on Anaemia Management in September 1999 [17]. (ii) A point-prevalent sample (n = 2595) of haemodialysis patients entering the Euro-DOPPS at the time of facility entry into the study (i.e. between May 1998 and April 1999). This 19981999 sample was used to indicate baseline characteristics of the patient population at the time of study entry and also to indicate anaemia management practices prior to publication of the EBPG for anaemia. (iii) An incident patient subgroup (n = 1023), consisting of random sample patients who received their first dialysis treatment as chronic ESRD patients within 10 days before study entry. The purpose of the incident patient subgroup was to study anaemia levels and rHuEpo therapy at the time patients first started dialysis and whether rHuEpo treatment was provided during the pre-ESRD period.
Measures of anaemia management
The measures of anaemia management studied were based upon longitudinal collection of patient haemoglobin concentrations, type and amount of i.v. iron preparation administered, type, dose and route of rHuEpo administration, and whether rHuEpo was prescribed prior to starting dialysis. In addition, medical directors at 97 of the 101 Euro-DOPPS facilities provided information on dialysis unit policies regarding whether a patient's haematocrit or haemoglobin level was required to fall below a predetermined threshold before rHuEpo therapy could be initiated at the unit.
Statistical analysis
All statistical analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC, USA). Many of the statistical models that used patient haemoglobin concentrations were restricted to patients on haemodialysis for >180 days to allow a sufficient time for patient haemoglobin values to reflect haemodialysis treatment practices. For a similar reason, models examining rHuEpo use were restricted to patients on haemodialysis for >90 days. The time period of 180 days for haemoglobin analyses and 90 days for rHuEpo-use analyses were based on the time-trend results found for incident haemodialysis patients shown in Figure 4. In the case of mortality and hospitalization analyses, the main models used the patient haemoglobin value at study entry (i.e. baseline) without a restriction for the amount of time on dialysis. However, sensitivity analyses, limited to patients on haemodialysis for >180 days, also were performed for mortality and hospitalization, as indicated.
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Adjusted analyses
Logistic regression, mixed linear regression and Cox survival models were developed to examine the relationship between anaemia management and outcomes for haemodialysis patients, as well as factors associated with the level of achieved haemoglobin. All of these models were adjusted for age and gender, 14 classes of co-morbidity, country and facility clustering effects. Additional adjustments, if any, are indicated in the tables and figures. The 14 classes of co-morbidity included: coronary artery/cardiac disease, congestive heart failure, other cardiac disease, peripheral vascular disease, hypertension, cerebrovascular disease, diabetes mellitus, lung disease, dyspnoea, history of ever having cancer (active or inactive, excluding skin cancer), gastrointestinal bleeding in the 12 months prior to study entry, neurologic disease, psychiatric disease and recurrent skin disease (including gangrene).
Predictors of i.v. iron use, rHuEpo use and level of anaemia
Logistic regression was used to examine the following outcomes: (i) odds of whether i.v. iron was prescribed (yes vs no) for prevalent haemodialysis patients; (ii) odds of rHuEpo being prescribed (yes vs no) for prevalent haemodialysis patients and during the pre-ESRD period for patients new to haemodialysis; and (iii) the likelihood of a patient having a low haemoglobin (10 g/dl) vs higher haemoglobin (
11 g/dl) concentration in a prevalent haemodialysis patient sample; and (iv) the likelihood of a patient having a haemoglobin >11 g/dl (yes vs no) as a function of a dialysis unit initiating rHuEpo therapy at a higher (>10 g/dl) vs lower (<10 g/dl) haemoglobin threshold value.
Logistic regression analyses employed the GENMOD procedure (generalized linear model) of SAS with a binomial error distribution and logit link function. Facility clustering effects were modelled using an exchangeable correlation matrix.
Effect of patient characteristics and rHuEpo treatment practices on study population mean haemoglobin value
Mixed linear regression models were used to analyse the effect of patient demographic characteristics, facility characteristics (e.g. i.v. iron use), route of rHuEpo administration and 14 classes of co-morbidity upon the observed mean haemoglobin value for the study population. Mixed linear regression models used the mixed linear regression procedure of SAS, with facility treated as a random effect to account for facility clustering.
Mortality and hospitalization analyses
Cox regression analysis was used to model time to death (for mortality analyses) or time to first overnight hospital admission (for hospitalization analyses). Mortality and hospitalization models used either baseline haemoglobin as a continuous variable or categories of baseline haemoglobin (<10 g/dl, 10.010.99 g/dl, 11.011.99 g/dl, 12 g/dl). Models were adjusted for patient characteristics and other covariates, as indicated, and included all study patients participating in the Euro-DOPPS from 1998 to 2000. Observation time was censored either when a patient departed from the facility or at the last date of known follow-up, whichever was earliest.
Cox regression analyses employed the PHREG procedure (proportion hazards regression) of SAS, providing adjustments for standard error estimates based on the sandwich estimator [20] to account for facility clustering effects.
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Results |
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Guideline 7 of the EBPG on anaemia management recommends that the percentage of hypochromic red cells (or TSAT) and serum ferritin should be determined at least once every 36 months for patients attaining the target haemoglobin concentration of >11 g/dl. To evaluate the frequency of monitoring iron stores in haemodialysis patients, the DOPPS determined the percentage of haemodialysis patients participating in the study for at least 8 months for whom serum iron, serum ferritin or total iron binding capacity (TIBC) were measured (Table 3). Ferritin was the most commonly performed measure of iron status, as reported for 90% of haemodialysis patients in France, Italy, Spain and the UK but for only 63% of patients in Germany. Patients with either a ferritin or a TIBC measurement during the first 8 months of study participation accounted for 67% of German haemodialysis patients. Serum iron was not routinely measured in the UK (32% of patients), and TIBC was not routinely measured in Germany or the UK (reported for 1922% of patients).
rHuEpo therapy
The distribution of rHuEpo dose in prevalent haemodialysis patients who had been on dialysis >90 days is shown in Figure 2. The mean dose of rHuEpo was 109 IU/kg/week, with nearly 75% of patients having an rHuEpo dose in the range from 18 to 144 IU/kg/week. The mean rHuEpo dose varied substantially across countries from 86 IU/kg/week in Germany to 132 IU/kg/week in Italy (Table 4). After adjusting for country, haemoglobin concentration, 14 classes of co-morbidity and years of ESRD treatment, the mean weekly rHuEpo dose was found to be significantly higher if rHuEpo was administered intravenously [22.5 U higher compared with subcutaneous (s.c.) administration (P < 0.001)], or if patients were female (17.6 U higher compared with males, P < 0.001), or older than 74 years (11.9 U higher compared with age 4564 years, P = 0.03).
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Several factors were associated with higher odds of whether a haemodialysis patient was prescribed rHuEpo during the pre-ESRD period. These included referral to a nephrologist at least 1 month prior to ESRD (AOR = 10.7, P = 0.001), female gender (AOR = 1.5, P < 0.001) and absence of coronary artery disease (AOR = 1.5, P = 0.09).
A time-trend analysis was performed to determine how rHuEpo administration and mean haemoglobin concentrations changed during the first year of haemodialysis therapy. The results shown in Figure 4 indicate that 42% of new ESRD patients in the Euro-DOPPS were prescribed rHuEpo when first starting haemodialysis. For this incident patient cohort, rHuEpo treatment increased markedly during the first 3 months of haemodialysis and attained a steady state of >80% rHuEpo administration within 35 months after initiating haemodialysis. Mean haemoglobin concentrations also dramatically increased during the first year of haemodialysis, from an initial mean concentration of 9.4 g/dl to a steady-state value of 10.8 g/dl. The increase in mean haemoglobin concentration occurred 1.53 months after the increase in rHuEpo use. This is consistent with the established relationship that increased rHuEpo administration results in a subsequent increase in patient haemoglobin concentration.
Patient characteristics associated with lower haemoglobin concentrations
Several characteristics were associated with lower mean concentrations in prevalent haemodialysis patients in the Euro-DOPPS (data not shown) who were prescribed rHuEpo. These characteristics included female gender (-0.16 g/dl, P = 0.01), peripheral vascular disease (-0.22 g/dl, P = 0.02), gastrointestinal bleeding in the 12 months prior to study entry (-0.30 g/dl, P = 0.03), history of cancer (-0.34, P = 0.001) and if the patient had not received i.v. iron during the 4 months prior to the haemoglobin reporting date (-0.20 g/dl, P = 0.02). This analysis was adjusted for patient age, gender, 14 classes of co-morbidity, country of residence and facility clustering effects. The lower mean haemoglobin values for females, patients having had gastrointestinal bleeding within the prior 12 months, or patients with a history of cancer are not surprising, based on similar observations in non-ESRD patients.
An analysis adjusted for patient demographics and 14 classes of co-morbidity also was performed to determine which patient characteristics were associated with a lower haemoglobin level of 10 g/dl compared with a higher haemoglobin level (
11 g/dl). Prevalent patients with low haemoglobin were more likely to have had cancer, gastrointestinal bleeding within the 12 months prior to study entry, or diabetes (P < 0.05). However, the following characteristics were not significantly related (P > 0.05) to whether a patient had a low vs high haemoglobin: age, coronary artery disease, congestive heart failure, other cardiac disease, hypertension, cerebrovascular disease, peripheral vascular disease, dyspnoea, neurologic disease, psychiatric disease or recurrent cellulitis/gangrene.
Facility practices associated with lower haemoglobin concentrations
Two different facility practices were examined for their effect on the odds of a patient having a haemoglobin 11 vs <11 g/dl. The first practice, level of facility rHuEpo, indicated a 1.6-fold higher AOR (P = 0.06) of a patient having a haemoglobin
11 g/dl if the patient dialysed in a unit within the highest quartile of rHuEpo use (
92% of patients prescribed rHuEpo) compared with those treated in a facility within the lowest quartile of rHuEpo use (>3776% of patients prescribed rHuEpo).
The second facility practice examined was the policy in some units to require a patient's haemoglobin concentration to fall below a predetermined level before rHuEpo was prescribed. A survey completed by 97 Euro-DOPPS medical directors indicated that 55% of these haemodialysis units have such a policy. The AOR of having a haemoglobin concentration 11 g/dl was 53% higher (P = 0.05) for patients treated in facilities initiating rHuEpo treatment at a haemoglobin concentration of
10.0 g/dl compared with dialysis facilities initiating treatment at a haemoglobin threshold concentration of <10 g/dl (data not shown).
Morbidity and mortality associated with anaemia
The relationship between mortality or hospitalization with patient haemoglobin concentration was examined in models adjusted for patient demographic and co-morbid characteristics (Figure 5). Higher haemoglobin concentrations were associated with a 5% lower RR of mortality (RR = 0.95) for every 1 g/dl increase in haemoglobin (95% CI = 0.900.99, P = 0.03, Figure 5). A similar RR of mortality was seen if the analysis was restricted to patients on dialysis >180 days (RR = 0.94) for every 1 g/dl higher haemoglobin (95% CI = 0.890.99, P = 0.01, n = 2609). Furthermore, a significant relationship between mortality and haemoglobin was found (RR = 0.92 per 1 g/dl higher haemoglobin, 95% CI = 0.860.99, P = 0.02) if the adjusted mortality analyses excluded patients having a history of cancer or peripheral vascular disease or gastrointestinal bleeding in the past 12 months. These were the only co-morbidities (indicated in the previous section) to be significantly associated with a lower mean haemoglobin concentration.
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The sample size in Euro-DOPPS was not large enough to show, by individual country, the relationship between patient haemoglobin concentrations and risk of mortality or hospitalization with the numerous adjustments used in these models. Consequently, these analyses were performed only for the five Euro-DOPPS countries combined into one model. However, these analyses were stratified by country, so the results reflect the mean relationship across all five countries.
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Discussion |
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Large variations were observed in the median haemoglobin value across the Euro-DOPPS countries. With the current study sample size, the mean haemoglobin concentration in Italy was significantly lower than that of all five Euro-DOPPS countries combined. This was observed both with and without adjustment for patient mix and differences in i.v. iron use.
The country with the highest median haemoglobin value, Spain (median = 11.6 g/dl vs <11.1 g/dl for the four other Euro-DOPPS countries, Figure 1) had relatively high values in the three major categories of anaemia management practice: rHuEpo use (91%), mean rHuEpo dose (114 IU/kg body weight/week) and prevalence of i.v. iron use (66%) (Table 3). The facility practice patterns analyses indicated that initiating rHuEpo therapy at higher haemoglobin threshold values was associated with attaining a higher mean haemoglobin concentration. The survey responses from Euro-DOPPS unit medical directors indicated that the majority of Spanish dialysis units had a policy of initiating rHuEpo therapy at relatively high haemoglobin threshold values. The high mean haemoglobin concentration observed for Spanish haemodialysis patients would appear to be largely a consequence of a country-wide practice of initiating rHuEpo use at a relatively high haemoglobin threshold value in conjunction with high use of rHuEpo, at a moderately high dose and maintaining sufficiently high iron levels for haemodialysis patients. Spanish dialysis units also displayed the highest prevalence of comprehensive monitoring of patient iron status through widespread use of serum iron, serum ferritin and TIBC measurements.
Large differences were seen between some of the Euro-DOPPS countries regarding the type of i.v. iron preparation prescribed for patients. However, this difference may be a reflection of what preparations are available for use in a given country, rather than preferences of the nephrologist for a particular type of i.v. iron.
The present cross-sectional study includes patients at various stages of ESRD therapy. This allowed evaluation of patterns at different time points of dialysis. The low mean haemoglobin concentration of 9.4 g/dl displayed by new ESRD patients when initiating haemodialysis underscores the failure of pre-ESRD health care programmes to adequately address the anaemia management needs of this patient population. As a consequence of their high level of anaemia, new ESRD patients require 35 months of rHuEpo therapy after initiating haemodialysis in order to achieve a mean haemoglobin concentration comparable with that of patients on haemodialysis therapy for longer times (Figure 4). Clearly, much greater efforts are needed to ensure a seamless correction of anaemia from the earliest stages of progressive CKD into renal replacement therapy. Most analyses in the present study adjust for years with ESRD and adjust additionally for being in the first 180 days of ESRD, due to the lack of steady state for haemoglobin in this early phase of ESRD.
It is apparent from the findings of the present study that a patient's haemoglobin concentration affects morbidity and mortality. The risk of hospitalization was 4% lower for every 1 g/dl higher haemoglobin concentration. Higher cardiac-related morbidity has been associated with lower haemoglobin values [36,10]. The question arises to what extent cardiac-related hospitalization could be reduced if higher haemoglobin concentrations or levels >11 g/dl were obtained for haemodialysis patients. Moreover, the risk of mortality in these patients was 5% lower for each 1 g/dl higher haemoglobin concentration (Figure 5). These statistically significant results are in agreement with previous reports of the Lombardy Registry [23] and USRDS [2,7,24].
The data clearly indicate a strong association of higher haemoglobin concentration with improved health outcomes. Although observational studies cannot prove causality, this study suggests that, if the EBPG guidelines are followed, a trend for improved outcomes in anaemic CKD patients may be expected. The EBPG on anaemia, based on expert review of evidence, thus receives additional supportive evidence from the present study. Despite the dissemination of the EPBG, many European haemodialysis patients still have haemoglobin concentrations below the minimum recommended level of 11 g/dl. This suggests a major opportunity for improved anaemia management for haemodialysis patients.
This study and two companion papers reviewing treatment and mortality in the Euro-DOPPS countries seek to present a comprehensive overview of the haemodialysis and anaemia practices and outcomes for the European study population [25,26]. The findings of this study indicate that anaemia control according to the EBPG is significantly associated with lower morbidity and mortality in haemodialysis patients. Although a trend toward increasing haemoglobin concentrations is evident over recent years, further efforts are required if the EBPG target of a haemoglobin concentration 11 g/dl in 85% of patients is to be achieved. Moreover, anaemia management should be particularly improved in pre-dialysis patients.
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Acknowledgments |
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Conflict of interest statement. F. Locatelli has participated in expert advisory groups and in clinical trials and received lecture honoraria from the manufacturers of epoetin alfa, epoetin beta and darbepoetin alfa (Johnson and Johnson, F. Hoffman-La Roche and Amgen). R. L. Pisoni, F. K. Port and P. J. Held are conducting research funded by unrestricted grants from Amgen Inc. The remaining authors declared no conflict of interest.
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References |
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