Erythropoietin stimulating agents had a long haul in Lithuania—we had no epoetin till 1994 and there was no intravenous iron in 2001–2004. The aim of this study was to assess the changes of renal anemia control in hemodialysis patients from early independence of Lithuania till nowadays and to evaluate the link of anemia with hospitalization rates and survival and hemoglobin variability in association with mortality. In December of each year since 1996 all hemodialysis centers have been visited and data has been collected using special questionnaires. The history of renal anemia control in Lithuania was complicated; however, a significant improvement was achieved: 54.7% of hemodialysis patients reached the target hemoglobin; all patients have a possibility of treatment with epoetin and intravenous iron. The involuntary experiment with an intravenous iron occurred in Lithuania because of economic reasons and confirmed the significant role of intravenous iron in the management of renal anemia. Hemoglobin below 100 g/L was associated with a 2.5-fold increase in relative risk of death and 1.7-fold increase in relative risk of hospitalization in Lithuanian hemodialysis patients. Although hemoglobin variability was common in Lithuanian hemodialysis patients, we did not find the association between hemoglobin variability and all-cause mortality in our study.
Lithuania is a country in Northern Europe, the largest of the three Baltic States. It is situated along the southeastern shore of the Baltic Sea with a territory of 65 200 km2 and a population of 3 million inhabitants. Starting in 1940, Lithuania was occupied by the Soviet Union. On March 11, 1990, the year before the breakup of the Soviet Union, Lithuania became the first Soviet republic to declare independence. In the early period of independence (1991–1993) hemodialysis (HD) was only acetate and available only for recipients waiting for transplantation. There were old HD machines, no water treatment, lack of nephrology literature in English and no competent training in nephrology. This was followed by tremendous progress in renal replacement therapy later on: full renovation and expansion of HD service, start of peritoneal dialysis, establishment of a second center of kidney transplantation, development of a Western model of nephrology with the help of European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and International Society of Nephrology (ISN).
The introduction of erythropoiesis stimulating agents (ESAs) has changed the management of renal anemia, leading to substantial reduction in the blood transfusion requirements, improvement in energy and physical function and improvement in health-related quality of life. However introduction of ESAs had a long haul in Lithuania: we did not have epoetin until 1994 and there were no intravenous iron in the period of 2001–2004 and very strict limitations by Lithuanian Ministry of Health for the prescription of epoetin. The Lithuanian anemia management guidelines were revised only in August 2011 and correspond to European Renal Best Practice (ERBP) statements today, but, until then, hemoglobin (Hb) target range of 100–105 g/L was recommended. Maintaining Hb levels within such a narrow target range was a challenge in our clinical practice, so Hb variability was highly prevalent in our dialysis patients.
First data about control of renal anemia in HD patients in Lithuania were published in 2003 [ to analyse the changes of renal anemia control in HD patients depending on local protocols from early independence of Lithuania till nowadays; to evaluate the link of anemia with hospitalization rate and survival; to evaluate Hb variability in association with mortality.
In the absence of official Renal Registry in Lithuania, in December of each year starting from 1996, all HD centers of the country have been visited and data has been collected using special paper questionnaires. Information about the number of patients and HD stations, demographic characteristics, etiology of end stage renal disease (ESRD), data about dialysis quality, blood tests, and the medicines used have been obtained. Changes of renal anemia control in HD patients depending on local protocols were evaluated from early independence of Lithuania till nowadays.
Influence of anemia on hospitalization rate was evaluated in a prospective study performed in 2002–2006. We investigated 559 patients from Kaunas region of Lithuania. The Kaunas region accounts for 12% of the Lithuanian territory and for 20% of the population. During the study 27% of all Lithuanian ESRD patients were hemodialysed in Kaunas region. Kaunas HD patients were representative of overall Lithuanian HD population: a comparative analysis using all Lithuanian data showed no statistically significant differences in age, gender, primary cause of ESRD, and hospitalization rate. Patients were followed prospectively 12 month for hospitalization rate, length of hospital stay, and causes of hospitalization.
Using data, collected at annual visits to HD centres, study on mortality of HD patients was performed. All patients who started chronic HD due to ESRD in Lithuania, between January 1, 1998 and December 31, 2005, were enrolled in our study. Outcomes and mortality and survival rates were analysed in the study.
Hb variability in HD patients was evaluated in another single-center, retrospective study (
For the statistical analysis we used Statistical Package for Social Science, version 20.0. Variables included in the study were expressed as percentages or position (mean, median) and dispersion parameters as appropriate for the type of variable. For evaluation of continuous variables the statistical mean and standard deviation were used. Kolmogorov-Smirnov statistics were used to evaluate sample normality distribution. Comparison between groups was performed using the Student’s
Tremendous changes were observed in HD service of Lithuania during this period. There was an increase in number of HD centres (from 17 to 61) and HD stations (from 25 p.m.p. to 201 p.m.p.) in 1996–2010. The prevalence of HD patients increased from 60 p.m.p. in 1996 to 467 p.m.p. in 2010 and the incidence rate of HD patients increased from 54.3 p.m.p. in 1997 to 115 p.m.p. in 2010. The mean age of the prevalent HD patients increased from
Changes of treatment and control of renal anemia in hemodialysed patients in Lithuania.
Year | The mean Hb concentration (g/L ± SD) | Percentage of HD patients with Hb > 100 g/L | Percentage of HD patients receiving epoetin | The mean dosage of epoetin (U/week ± SD) | Percentage of HD patients receiving i/v iron |
---|---|---|---|---|---|
1997 |
|
27.5 | 78 |
|
7.5 |
1998 |
|
44.1* | 89.5* |
|
27.6* |
1999 |
|
52.9 | 92.4 |
|
35.1 |
2000 |
|
62.9 | 96.1 |
|
70.8# |
2001 |
|
64 | 94.6 |
|
|
|
|
|
|
|
Only single patient |
2003 |
|
49.7 | 91.1 |
|
Only single patient |
2004 |
|
53.6 | 89 |
|
Only single patient |
|
|
|
|
|
|
2006 |
|
62.4 | 78.8 |
|
70.8 |
2007 |
|
66.6 | 81.4 |
|
85.1 |
2008 |
|
66.3 | 76.6 |
|
80.3 |
2009 |
|
64.4 | 75.9 |
|
78.2 |
2010 |
|
67.8 | 76.6 |
|
69.9 |
In 2010 76.6% of patients received epoetin in Lithuania. This percentage was low as compared to results of DOPPS study in 2010: lowest percentage was observed in Japan (87.3%) and Austria (87.7%) and ranged from 89.2% (France) till 96% (Belgium) in other countries [
The oral route of iron administration was popular in Lithuania before 1997. Only 7.5% of patients received intravenous iron. After the increased use of intravenous iron in the year 2000 the mean Hb concentration increased significantly without serious changes in the doses of epoetin (Hb
Relationship between iron deficiency and dose of erythropoietin in the treatment of renal anemia of hemodialysed patients in 2002–2005.
Year | The mean Hb concentration (g/L ± SD) | Percentage of HD patients with ferritin <100 mcg/L | Percentage of HD patients receiving epoetin | The mean dosage of epoetin (U/week ± SD) |
---|---|---|---|---|
2002 |
|
30.5 | 88.8 |
|
2003 |
|
|
91.1 |
|
2004 |
|
|
89 |
|
2005 |
|
|
|
|
Changes of mean hemoglobin concentration of hemodialysis patients due to influence of national algorithm and deficiency of iron in 1997–2010.
There is no unified opinion about the influence of anemia to hospitalization rate of HD patients. Big retrospective study of dialysis patients showed that higher concentration of Hb associated with lower rate of hospitalization [
Relation between hemoglobin level and hospitalization in Lithuanian hemodialysis patients.
Annual data collection allows us to analyse associations between anemia and mortality in incident HD patients in Lithuania in 1998–2005. Analysis revealed that the mean Hb value of all these patients was
Multivariate Cox proportional hazards analysis revealed that anemia was an independent risk factor of death (RR = 0.952, 95% CI 0.945–0.959,
As shown in Table
Relative risk of death for hemoglobin categories.
Mean hemoglobin concentration (g/L) | Relative risk |
|
95% CI | |
---|---|---|---|---|
Lower limit | Upper limit | |||
100–105 | 1.0 | |||
|
|
|
1.923 | 3.177 |
106–109 | 1.076 | 0.687 | 0.754 | 1.534 |
110–120 | 1.058 | 0.731 | 0.767 | 1.459 |
121–130 | 1.031 | 0.915 | 0.593 | 1.791 |
>130 | 2.356 | 0.063 | 0.953 | 5.822 |
Patients with Hb level of 100 to 105 g/L were selected as the reference group, according to national algorithm for the management of anemia in Lithuania from 2002 (the target Hb level in patients on chronic HD was between 100 g/L and 105 g/L). The Hb concentration below 100 g/L was associated with a 2.5-fold increased relative risk of death. Hb levels of >106 g/L were not associated with a lower risk of death. For Hb concentrations ≥130 g/L, a trend towards higher mortality risk was observed (RR = 2.356, 95% CI 0.953–5.822,
Since the introduction of ESA, most of the clinical trials with ESA therapy have focused on Hb targets in CKD patients; however, there is a shortage of clinical trials studying the optimal strategy for Hb monitoring in patients treated with ESA and interventions to reduce Hb variability. Several factors affect Hb variability, including those that are drug related, such as pharmacokinetic parameters, clinical practice guidelines, treatment protocols, and reimbursement policies. Strategies that consider each of these factors and reduce Hb variability may be associated with improved clinical outcomes [
We evaluated Hb concentrations and ESA doses in 100 patients—56 (56%) men and 44 (44%) women. The mean age of patients was
Mean hemoglobin concentrations during 2011 year. Influence of a new anemia management algorithm, certified in Lithuania August 2011.
We looked in detail to each month (01/2011–06/2011) Hb concentrations and found that only 17.1% of patients during this period had Hb in the target range according to local algorithm (100–105 g/L), 50.2% of patients had Hb <100 g/L, and 32.7% had Hb >105 g/L. A big part of our patients exhibited fluctuations in the Hb levels corresponding to literature data where we found that 80–90% of ESRD patients on dialysis exhibit fluctuations in the Hb levels, known as Hb variability [
Pattern of fluctuations in hemoglobin levels during a six-month period (01/2011–06/2011) in Lithuanian hemodialysis patients, classified according to Ebben’s principle (
In the United States Renal Data System analysed by Ebben et al. [
The data on the effect of Hb variability on mortality are conflicting. In our study we did not find the association between Hb variability and all-cause mortality using an adjusted Cox regression model, although the Hb concentrations of dead patients had a tendency to be lower (Figure
Comparison of mean hemoglobin concentrations during the year 2011 in dead and alive hemodialysis patients.
The study of Ebben et al. suggested that variability itself may not have a strong association with mortality. The key factors seem to be the number and timing of Hb values <110 g/L. Patients whose Hb levels were consistently within the target range of 110 to 125 g/L experienced the lowest mortality in their study. The longer the amount of time with Hb level <110 g/L was the greater the risk of death was noted [
Our study has limitations that should be considered. The sample size was small and the data were collected retrospectively in only one dialysis center. The obtained database therefore reflects only a small sample of entire Lithuanian dialysis population. Further studies are needed to clarify the relationship between provided practices, Hb variability, and mortality.
As it was mentioned before Lithuanian anemia management guidelines were revised in August 2011 and correspond to ERBP position (target Hb 100–120 g/L). The mean Hb of our HD patients was
The history of renal anemia control in Lithuania was complicated; however, a significant improvement was achieved and 54.7% of HD patients reached the target hemoglobin. The involuntary experiment with an intravenous iron occurred in Lithuania because of the economic reasons and confirmed the significant role of intravenous iron in the management of renal anemia. Hemoglobin concentration below 100 g/L increased relative hospitalization risk by 1.7-fold and it was one of the most important factors influencing hospitalization rate. Hemoglobin concentration below 100 g/L was associated with a 2.5-fold increased relative risk of death in Lithuanian hemodialysis patients. Although hemoglobin variability was common in Lithuanian hemodialysis patients, it did not independently predict mortality.
The authors declare that there is no conflict of interests.
The authors would like to thank all Lithuanian colleagues from hemodialysis centers who helped to collect the data about hemodialysis patients.