Abstract
Comparative studies of the potency of long- and short-acting erythropoiesis-stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L-ESAs are used in many countries. We performed a retrospective analysis of non-dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age ≥60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia.
In chronic kidney disease (CKD), insufficient production and secretion of erythropoietin (EPO) due to destruction of kidney tissue are known to lead to anaemia (nephrogenic anaemia)1); therefore, treatment with erythropoiesis-stimulating agents (ESAs) represents a primary therapy for nephrogenic anaemia in CKD patients. The haemoglobin (Hb) level is used as a diagnostic criterion for nephrogenic anaemia, and the Japanese guidelines1) recommend controlling the Hb level in the range of 11–13 g/dL in ESA therapy for nephrogenic anaemia in non-dialysis (ND) patients with chronic kidney failure. Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines2) in the United States also set a target Hb level of 11–12 g/dL.
In recent years, long-acting ESAs (L-ESAs) such as darbepoetin and epoetin beta pegol have been commonly used in Japan. Studies on short- and long-acting ESAs (S-ESAs and L-ESAs, respectively) are dominated by investigations of doses when switching formulations3–7) and comparative studies of the effect on Hb variability8,9); no studies comparing their effect on the period until the Hb level is stabilised within the reference range are available. This is probably because a sufficient number of patients have not been available to conduct comparative studies; while S-ESAs have a long history of clinical use since the 1990s, L-ESAs have been developed only recently. For the treatment of renal anaemia, it is very meaningful to compare the difference in advantage of S-ESA- and L-ESA-treated groups. Therefore, we compared the period required for Hb stabilisation between two groups of patients that were divided according to the type of ESA administered as initial therapy. The results indicate that the L-ESA-treated group required a shorter period than the S-ESA-treated group. We then decided to determine whether this difference was simply due to differences between the formulations or if some other factors were involved.
Macdougall10) reported that factors involved in low therapeutic responsiveness to ESAs included iron deficiency, bleeding, infection, inflammatory diseases, malignant tumours and deficiency in VB12/folic acid. Rossert et al.11) conducted a study involving 93 patients with chronic kidney failure including those on dialysis, and they showed that factors associated with low responsiveness to the ESA epoetin alfa included advanced age, high body mass index (BMI), low serum iron, concomitant use of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor antagonist (ARB) and complication with diabetes mellitus (DM). Minutolo et al.12) explored factors affecting the therapeutic responsiveness in 194 ND patients divided into three groups based on changes in the Hb level (high, moderate and low responders), and they reported that less advanced age among elderly patients, low glomerular filtration rate (GFR) and high urinary protein affected the responsiveness. In these previous studies, different results may have been because of differences in patient background and conditions, although a variety of factors are likely to be involved in low responsiveness to ESA treatment. Therefore, we conducted this study to identify risk factors for delayed Hb stabilisation in ND patients.
SUBJECTS AND METHODS
SubjectsPatients visiting the department of nephrology of Fujita Health University Hospital between April 1, 2010, and March 31, 2012, who were found to have an estimated GFR (eGFR) of less than 90 mL/min or who were diagnosed with ND kidney failure, those receiving ESA at least once every 4 weeks and whose Hb was maintained at 11 g/dL or higher but less than 13 g/dL for at least three months were included in this study. Patients who underwent haemodialysis or peritoneal dialysis; those who underwent drug switching or change in the dose of the antidiabetic agent, iron supplement, ACE inhibitor, or ARB during the study period; those who hospitalised during the study period (including other hospitals) and those who had undergone red blood cell transfusion within four weeks before or during the study period were excluded from the study population. Patients with conditions predicted to affect this study, i.e., malignant tumours (including haematological malignant tumours), severe infections, systemic blood disorders (such as myelodysplastic syndrome and haemoglobinopathy), haemolytic anaemia, obvious haemorrhagic lesions such as gastrointestinal bleeding, myocardial infarction, pulmonary infarction, cerebral infarction, congestive heart failure (Class III or higher in the New York Heart Association (NYHA) cardiac function classification), unstable angina, angina poorly controlled by drug therapy or interventional treatment, arteriosclerosis obliterans (Stage II or higher in the Fontaine classification), iron deficiency anaemia, or complication with VB12/folic acid deficiency were also excluded. Further, patients with a history of myocardial infarction, pulmonary infarction or cerebral infarction were excluded.
InvestigationsThis was a retrospective study in which subject information was collected using electronic medical records at the Fujita Health University Hospital. As patient background, demographics when drug administration was initiated (sex, age, BMI [calculated from body height and weight]), various clinical laboratory test values at the time of the initiation of administration (serum creatinine, eGFR, quantitative urinary protein corrected for creatinine, Hb), type of ESA used for treatment, initial doses of ESA, period required to obtain a stable Hb level and medical record information related to exclusion criteria were collected. Therapeutic efficacy was assessed based on laboratory test values obtained in the period between the initiation of administration and the efficacy assessment. ESA doses by weight were converted to a standard unit based on previous reports8,9,13,14) and information in the package inserts, as follows: darbepoetin 15 µg, 3000 IU; 20 µg, 4500 IU; 30 µg, 6000 IU; 40 µg, 9000 IU; 50 µg, 10500 IU; 60 µg, 12000 IU; 80 µg, 18000 IU; 100 µg, 21000 IU; 120 µg, 24000 IU; and 180 µg, 36000 IU. Doses of epoetin beta pegol were converted linearly as 250 IU/µg.
This study was conducted according to a protocol approved by the Ethics Review Committee for Epidemiology and Clinical Studies of the Fujita Health University, with adequate ethical considerations to patients.
AssessmentStudy subjects were divided into two groups according to the type of ESA initially used, i.e. L-ESA or S-ESA, and the period from initial ESA administration to Hb stabilisation was compared between the two groups. The period required for Hb stabilisation refers to the period of treatment required to accomplish the maintenance of the Hb level at 11 g/dL or above but less than 13 g/dL for at least three months. In addition, the period from initiation of ESA treatment to Hb stabilisation was obtained for the whole subject population and the median value computed. Subjects were then divided into the short-term group, which comprised patients with a period equal to or shorter than the median period, and the long-term group with a period longer than the median period to investigate factors associated with ESA treatment resistance.
Statistical AnalysisVariables that follow a normal distribution are expressed as mean±standard deviation (S.D.). Variables that do not follow a normal distribution are expressed as median (interquartile range). The unpaired t-test and Mann–Whitney U-test were used for an inter-group comparison of numeric values following and not following a normal distribution, respectively. Proportions between groups were compared with the chi-squared test. To identify risk factors for a prolonged period of treatment to stabilise the Hb level, a univariate analysis was conducted using the objective variable that the period from the initial ESA administration to Hb stabilisation was at least 252 d and the following explanatory variables: male; age of 60 years or older; BMI, 25 or higher; serum creatinine; eGFR; quantitative urinary protein corrected for creatinine; haemoglobin; use of S-ESA in the initial treatment; initial ESA dose; concomitant use of an ACE inhibitor or an ARB; complications with DM; diabetic nephropathy, nephrosclerosis or immunoglobulin A (IgA) nephropathy as the primary disease. We used the age of 60 years for age-based grouping of subjects because diagnostic criteria for patients above and below this age are substantially different in the Japanese guidelines for renal anaemia treatment.1) A multivariate logistic regression analysis was used to explore for risk factors for the therapeutic effect of ESA treatment. The analysis software used was Statmate IV, and differences with a significance level of less than 5% were considered statistically significant.
RESULTS
Subject SelectionA total of 878 patients received ESAs during the study period. Of these, 356 patients who were on haemodialysis or peritoneal dialysis were excluded. Further, patients with any conditions predicted to affect the study were excluded: 33 patients with cancer; 32 with severe infection; 12 with a haematological disorder; 26 with a cardiac disease; 19 with a brain disease; and 20 with any other condition as defined in the exclusion criteria. From the remaining 380 patients, those who met exclusion criteria during the study period were excluded, and, as a result, the number of patients whose Hb level remained between 11 g/dL and 13 g/dL for at least three months was 74.
Comparison of the Effect of ESA Judging from Difference of Reaction TimeBaseline Patient CharacteristicsSubjects were divided into L-ESA-treated and S-ESA-treated groups based on the type of ESA used initially, and the two groups were compared. The S-ESA used was epoetin alfa or epoetin beta, and the L-ESA was darbepoetin alfa or epoetin beta pegol. In total, 74 patients were studied. Table 1 shows the patient backgrounds and clinical laboratory test values of each group. Significant differences were not found between the two groups in any item.
Table 1. Baseline Characteristics According to ESA in Initial Treatment
| Total | ESA | p Value |
|---|
| L-ESA | S-ESA |
|---|
| (n=74) | (n=18) | (n=56) | |
| Sex (male, female) | 42, 32 | 9, 9 | 33, 23 | 0.51 |
| Age (years) | 72.5 (60.3–80.0) | 72.0 (58.0–80.3) | 72.5 (63.0–80.0) | 0.61 |
| Body mass index (kg/m2) | 22.2 (19.6–25.0) | 23.0 (21.4–25.1) | 21.8 (19.4–25.1) | 0.43 |
| Serum creatinine (mg/dL) | 2.86 (2.11–3.68) | 2.82 (2.03–4.30) | 2.87 (2.18–3.52) | 0.63 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 14.9 (11.7–21.8) | 13.5 (11.4–19.9) | 15.4 (11.8–22.1) | 0.90 |
| Urinary protein adjusted for creatinine (mg/g·Cr) | 930 (346–2483) | 1223 (678–3208) | 806 (250–2448) | 0.24 |
| Haemoglobin (g/dL) | 8.19±2.03 | 8.19±2.32 | 8.18±1.95 | 0.99 |
| Initial dosage of ESA (IU) | 9000 (6000–12000) | 12000 (9000–12000) | 9000 (6000–12000) | 0.077 |
| ACEi/ARB | 54 | 16 | 38 | 0.15 |
| Diabetes mellitus | 30 | 8 | 22 | 0.70 |
| Primary diseases | | | | 0.42 |
| Diabetic nephropathy | 29 | 6 | 23 | |
| Nephrosclerosis | 20 | 4 | 16 | |
| IgA nephropathy | 7 | 3 | 4 | |
| Others | 8 | 2 | 6 | |
| Unknown | 10 | 3 | 7 | |
| CKD classification | | | | 0.90 |
| G3a | 1 | 0 | 1 | |
| G3b | 4 | 1 | 3 | |
| G4 | 32 | 7 | 25 | |
| G5 | 37 | 10 | 27 | |
Variables with a normal distribution are expressed as the mean±S.D., and other data are shown as the median (interquartile range). ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Table 2 shows the period of ESA treatment required to stabilise the Hb level in the L-ESA-treated and S-ESA-treated groups. The period required for Hb stabilisation was significantly shorter in the L-ESA-treated group than in the S-ESA-treated group.
Table 2. Period to Reach Hb Stabilisation by Initially Administrated ESA
| ESA | p Value |
|---|
| L-ESA | S-ESA |
|---|
| Period for Hb stable | 126 (104–257) | 368 (109–693) | 0.0086 |
Data are shown as the median (interquartile range).
The period of ESA treatment required to obtain a stable therapeutic effect was investigated in a group of 40 subjects, in whom the type of ESA remained unchanged throughout the study period. The treatment periods in L-ESA-treated and S-ESA-treated groups were 126 (104–257) days and 131 (79–313) days, respectively, showing no significant difference (data not shown, p=0.99).
Comparison of a Short Term Group and a Long Term GroupBaseline Patient CharacteristicsA total of 74 subjects analysed above were divided into two groups based on the median period of treatment required to stabilise the Hb level in the whole subject population, which was 252 d. In a comparison between the short-term group, in which the treatment period was equal to or shorter than the median period, and the long-term group, in which the treatment period was longer than the median, significant differences were found in age (p<0.0001), type of ESA (p=0.017) and primary disease (p=0.028), while no significant differences in other parameters were noted (data not shown).
Investigation of Risk FactorsThe three factors for which significant differences were found in the univariate analysis were subjected to a multivariate analysis. Table 3 shows the results, indicating that an age of 60 years or older and the use of S-ESA in the initial treatment were the factors that affected the period required for Hb stabilisation.
Table 3. Risk Factors for Delayed Hb Stabilisation
| Univariate analysis | Multivariate analysis |
|---|
| Odds ratio (95% CI) | p Value | Odds ratio (95% CI) | p Value |
|---|
| Male | 1.12 | 0.81 | | |
| (0.44–2.82) | | | |
| Age (≥60 years) | 4.47 | 0.018 | 3.65 | 0.041 |
| (1.30–15.41) | | (1.06–12.63) | |
| BMI (≥25 kg/m2) | 0.63 | 0.41 | | |
| (0.21–1.89) | | | |
| Serum creatinine (mg/dL) | 0.66 | 0.046 | 0.76 | 0.25 |
| (0.44–0.99) | | (0.48–1.20) | |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 1.02 | 0.30 | | |
| (0.97–1.09) | | | |
| Urinary protein adjusted for creatinine (mg/g·Cr) | 1.00 | 0.37 | | |
| (1.00–1.00) | | | |
| Haemoglobin (g/dL) | 0.99 | 0.94 | | |
| (0.79–1.24) | | | |
| S-ESA (Initial introduction) | 3.90 | 0.021 | 3.99 | 0.026 |
| (1.23–12.34) | | (1.18–13.45) | |
| Initial dosage of ESA (IU) | 1.00 | 0.43 | | |
| (1.00–1.00) | | | |
| ACEi/ARB | 0.57 | 0.30 | | |
| (0.20–1.63) | | | |
| Diabetes mellitus | 0.80 | 0.63 | | |
| (0.32–2.02) | | | |
| Diabetic nephropathy | 0.89 | 0.81 | | |
| (0.35–2.27) | | | |
| Nephrosclerosis | 1.28 | 0.62 | | |
| (0.48–3.40) | | | |
| IgA nephropathy | 0.0006 | 0.38 | | |
| (≺0.0001–0.87) | | | |
Risk factors are analysis with multivariable logistic-regression models. BMI, body mass index; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
Populations of patients whose Hb level was stabilised after switching from S-ESA to L-ESA, patients whose Hb level was stabilised by treatment with S-ESA, and patients whose Hb level was stabilised by treatment with L-ESA were compared between the two groups. Respective types of patients were 9 (24.3%), 15 (40.5%) and 13 patients (35.1%) in the short-term group and 25 (67.6%), 7 (18.9%) and 5 patients (13.5%) in the long-term group, showing a significant inter-group difference (data not shown; p=0.00092). Patients who underwent the L-ESA to S-ESA switch were found in neither of the groups.
DISCUSSION
Univariate and multivariate analyses were conducted to identify risk factors for requiring a long period to stabilise the Hb level in ESA treatment for nephrogenic anaemia in ND patients. As a result, the use of S-ESA in the initial treatment and an age of 60 years or older were revealed as two risk factors. The finding that the use of an S-ESA in the initial treatment was a risk factor for delayed Hb stabilisation suggests an advantage of initiating the treatment with an L-ESA, and this is of great significance to the treatment of renal anaemia. The conclusion that advanced age is a risk factor is in agreement with the report by Rossert et al.11) However, our study differs from theirs in that our conclusion includes a specific age boundary. This may have been possible because we analysed relatively elderly patients with a median age of 72.3 years, whereas Rossert et al. studied a patient population with a mean age of 56.8 years. In addition, a crucial difference between the two studies is that we analysed data of patients treated between 2010 and 2012, while their study period was 2002–2006. Because of this, the two studies had different target Hb levels: we studied patients with an Hb level of 11–13 g/dL, whereas they compared a group of patients with an Hb level of 11–12 g/dL and another group with an Hb level of 13–15 g/dL. The guidelines were modified based on studies demonstrating that events such as death and heart failure occur more frequently in patients with an Hb level of 13 g/dL or higher,13,14) and this modification underlies the difference in targets between the two studies. The risk factors identified in the present study are derived from the analysis of patients treated in accordance with the current guidelines, unlike those reported by Rossert et al.
Minutolo et al.12) have reported a conflicting result that elderly ND patients were good responders to ESA treatment. Similar to our study, they used a target Hb level of 11–13 g/dL. However, they divided patients into high responsiveness, moderate responsiveness and low responsiveness groups based on changes in the Hb level over 6 months to explore for differences in patient background. In contrast, the endpoint in our study design was the treatment period required to stabilise the Hb level for at least 3 months, and the follow-up period in our study was noticeably longer (up to 3 years) than in that in their study, in addition to other differences in study design. These differences in study design may have been reflected in the different results described above, but the specific cause remains unknown. The mean age of patients in their study was 63.7 years, which is seven years younger than in our study and represents another possible cause of discrepancy. Based on the results of our study, we propose that for patients who are aged 60 years or older at the time of treatment initiation, measures should be taken in advance for possible resistance to ESA treatment, including careful monitoring of changes in the Hb level, and the dose should be increased as soon as necessary. The number of patients in this study was too small to allow us to propose specific criteria for a dose increase. We could recruit only a limited number of subjects because patients with various previously reported factors for ESA resistance were excluded from this study. Dose-elevation criteria should be developed for patients whose Hb level cannot be quickly stabilised through a long-term prospective study in a larger patient population.
The multivariate analysis revealed an additional risk factor in ESA treatment, i.e., the initial use of S-ESA. Specifically, the group of patients initially treated with S-ESA required a longer period to accomplish Hb stabilisation than the group of patients who underwent initial treatment with L-ESA. In an analysis of the short- and long-term groups, comprising patients who were divided using the median period required to stabilise the Hb level, the number of cases where the drug was switched to L-ESA in the course of the treatment was significantly greater in the long-term group. These results suggest that a longer treatment period is required to achieve a stable effect when the treatment is initiated with S-ESA compared with that required when an L-ESA is used initially. However, when only 40 subjects in whom the type of ESA remained unchanged throughout the study period were analysed, no appreciable difference was found between patients in L-ESA-treated and S-ESA-treated groups in the treatment period required to get a stable therapeutic effect. The proportion of patients who underwent the S-ESA to L-ESA switch was nonetheless significantly greater, i.e., 67.6% vs. 24.3% in long-term and short-term groups, respectively. This result indicates that a large number of patients treated initially with S-ESA underwent switching to L-ESA because an adequate therapeutic effect was not obtained. This was likely why a longer treatment time was required to stabilize the Hb level when treatment was initiated with S-ESA. Iwasaki and Akizawa8) reported that there was no difference in the effect on the Hb level with different types of ESA. Given our result that the effect was comparable in patients treated with S-ESA or L-ESA throughout the study period, it cannot be ruled out that the convenient once-in-4-weeks regimen of L-ESA had a major effect in accomplishing the target Hb level. This could not be probed further because a retrospective study design was used. Further investigations are required to identify the causal factors. In summary, when initiating treatment for nephrogenic anaemia in ND patients, it is desirable to initiate treatment with L-ESA for early stabilisation of the Hb level in the recommended range. Early stabilisation of Hb leads not only to improved quality of life but also to prevention of complications through improvements in cardiac functions15) and protection of kidney functions16) and eventually to the provision of safe, high-quality medical care.
Previously reported risk factors for low ESA responsiveness include iron deficiency, bleeding, infection, inflammatory diseases, malignant tumours and VB12/folic acid deficiency, which were reported by Macdougall10); advanced age, high BMI, low serum iron, concomitant use of an ACE inhibitor or ARB and complications with DM, which were reported by Rossert et al.11); and less advanced age in elderly patients, low GFR and high urinary protein, which were reported by Minutolo et al.12) In the present study, all the risk factors reported by Macdougall and low serum iron reported by Rossert et al. were excluded as far as possible, and other factors were assessed. As a result, we found that BMI, concomitant use of an ACE inhibitor or ARB, complication with DM, low GFR and high urinary protein were not risk factors for low ESA treatment responsiveness. Our results, however, are not necessarily in contradiction with their previous results and may reflect differences in patient age and study design. Results from the present study indicate that the effects of BMI, concomitant use of an ACE inhibitor or ARB, GFR and proteinuria do not have to be seriously considered when ESA is used, in accordance with the Japanese guidelines. However, given that differences in the primary disease were noted between the short-term and the long-term group and that only the presence or absence of DM was included in the analysis, as was the case in the study by Rossert et al., a study from a different perspective using more precise criteria is required to determine the effects of the primary disease and DM complications. The number of patients involved in this study is expected to be insufficient to conduct such a study, and a retrospective study involving collaborating hospitals, or a long-term prospective study, is desirable.
We propose initial introduction of an L-ESA at an early stage from the viewpoint of reducing burdens to healthcare workers and preventing medical accidents, in addition to benefits of improvement in a patient’s quality of life, decrease in hospitalisation risk, suppression of occurrence of cardiocirculatory diseases17) and improvement in vital prognosis18) from adequate treatment of nephrogenic anaemia in ND patients.
Conflict of Interest
The authors declare no conflict of interest.
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