Anemia Treatment by Erythropoiesis-stimulating Agents during the 6 Months before the Initiation of Hemodialysis: Comparison of Darbepoetin Alfa and Continuous Erythropoietin Receptor Activator

Abstract

Anemia in chronic kidney disease (CKD) is a risk factor for cardiovascular diseases and is treated by long-acting erythropoiesis-stimulating agents (ESAs). Although the results of previous studies have shown that hemoglobin levels could not be maintained at the initiation of dialysis in CKD patients treated with recombinant human erythropoietin, it remains undetermined whether long-acting ESAs are effective in preventing the progression of anemia at the initiation of dialysis. In the present study, hemoglobin levels in 40 CKD patients treated with darbepoetin alfa (DA) and 15 CKD patients treated with a continuous erythropoietin receptor activator (CERA) were retrospectively compared during the 6 months period before the initiation of dialysis. Results showed that DA and CERA both maintained hemoglobin levels at around 10 g/dL from 6 months to 1 month before dialysis. However, hemoglobin levels at the initiation of dialysis significantly decreased to 9.1 ± 1.2 g/dL in the DA group and to 9.0 ± 1.0 g/dL in the CERA group. Although the total doses of ESAs used during the 6-month period were similar between the two groups, DA-treated CKD patients received subcutaneous injections more frequently than did patients treated with CERA. These results suggest that CKD patients require more intense ESA therapy to prevent a decline in hemoglobin levels at the initiation of dialysis, including those treated with long-acting ESAs. The results also raise the possibility that CERA is more useful than DA for reducing the number of injections during the pre-dialysis period.

Background

Anemia is a common complication of chronic kidney disease (CKD) that occurs as a result of inadequate erythropoietin production by the damaged kidneys. Anemia develops early in the course of CKD¹ and is associated with a reduced quality of life,² the development of cardiovascular diseases (such as left ventricular hypertrophy³ and congestive heart failure),⁴ and increased mortality⁵ in pre-dialysis CKD patients. Anemia in CKD is treated by erythropoiesis-stimulating agents (ESAs). Correction of anemia with ESAs has been shown to improve the quality of life, ameliorate left ventricular hypertrophy,⁶ and prolong kidney survival.^7,8 Currently, the guidelines published by the Japanese Society for Dialysis Therapy recommend a target hemoglobin (Hb) concentration of 11.0–13.0 g/dL for pre-dialysis CKD patients.⁹

Two long-acting ESAs, darbepoetin alfa (DA) and a continuous erythropoietin receptor activator (CERA, also known as methoxy polyethylene glycol-epoetin-β), have been approved for the treatment of anemia in patients with CKD. Whereas DA exhibits a half-life of 24–48 h in peritoneal dialysis patients,¹⁰ CERA has unique pharmacologic properties that result in a long half-life of approximately 130 h.¹¹ In fact, CERA acts differently to recombinant human erythropoietin (epoetin) and DA at the erythropoietin receptor level. These half-life values are markedly longer than epoetin’s half-life of 8.5 h. Both DA and CERA have been shown to successfully correct anemia and maintain stable Hb levels within the recommended target range in non-dialysis CKD patients at extended administration intervals.^12,13,14,15 However, it has not been fully elucidated whether DA and CERA are also effective in preventing the progression of anemia at the initiation of dialysis, a time at which Hb levels decrease severely. Indeed, the results of previous studies have shown that the Hb level declined to 8.35 g/dL at the initiation of dialysis in Japanese CKD patients treated with epoetin.¹⁶ Therefore, in the present study, we compared the efficacy of CERA and DA for the treatment of anemia in pre-dialysis CKD patients during the 6 months prior to the initiation of hemodialysis.

Methods

Patients

This retrospective study was conducted at a single center in Japan. The study protocol was approved by the Ethics Committee of Keio University. Outpatients who started hemodialysis therapy between January 1, 2014, and October 31, 2015, and who visited Keio University Hospital for the treatment of CKD for more than 6 months prior to the initiation of dialysis were recruited. They were divided into two groups, the DA group and CERA group, based on the use of ESAs during the pre-dialysis period. There were no restrictions on their primary physicians regarding the selection of ESA. Patients with malignancies, hematological disorders, or liver cirrhosis; patients who received red blood cell transfusions; and patients who were administrated both DA and CERA during the pre-dialysis period were excluded.

Variables

Baseline characteristics (age, gender, height, body weight, primary cause of CKD, and history of cardiovascular disorders), clinical data (systolic and diastolic blood pressure, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, use of iron supplementation, and dates and doses of injection of ESAs), and laboratory data [Hb, mean corpuscular volume, total protein, albumin, urea nitrogen, creatinine, estimated glomerular filtration rate (eGFR), calcium, inorganic phosphate, iron, total iron binding capacity, ferritin, transferrin saturation, C-reactive protein, and cardio-thoracic ratio] were obtained from medical records.

Statistical analysis

Data are reported as percentages or the mean ±standard deviation. Categorical data were compared using the chi-square test or Fisher’s exact test. Continuous variables were tested by the unpaired t test or one-way factorial analysis of variance with a post hoc Fisher’s protected least significant difference test. When the data failed to pass the normality test, the Wilcoxon rank sum test or the Kruskal–Wallis test with Dunn’s post hoc test was performed. The association between Hb levels and creatinine levels and the association between changes in Hb levels in the 1-month period before the initiation of dialysis and creatinine levels were assessed by Pearson’s regression analysis. P values <0.05 were considered significant.

Results

A total of 90 CKD patients started hemodialysis therapy between January 1, 2014, and October 31, 2015, in our hospital. Of the 90 patients included in the study, 36 were excluded from the analysis because they had visited our hospital for less than 6 months before starting dialysis; they had malignancies, hematological disorders, or liver cirrhosis; they had received red blood cell transfusions; or they had been treated by the combined use of DA and CERA. Consequently, 40 CKD patients treated with DA and 15 CKD patients treated with CERA over 6 months prior to the initiation of hemodialysis were analyzed in the present study.

Fig. 1

Monthly changes in serum creatinine levels, Hb levels, and ESA doses in pre-dialysis CKD patients treated with DA or CERA.

A-C: Serum creatinine levels increased in CKD patients treated with DA (A) and CERA (B) and in all patients (C) from 6 months before the initiation of dialysis (−6) to the initiation of dialysis (0). D-F: Hb levels remained constant from 6 months before the initiation of dialysis to 1 month before dialysis, but decreased at the initiation of dialysis in CKD patients treated with DA (D) and CERA (E) and in all patients (F). G, H: Monthly ESA doses did not significantly change in CKD patients treated with DA (G) and CERA (H). DA: n=40; CERA: n=15. *P<0.05 compared with the levels at 6 months before the initiation of dialysis.

The patient characteristics showed no significant differences between the DA and CERA groups in terms of gender, height, weight, systolic and diastolic blood pressures, the primary cause of CKD, history of cardiovascular diseases, the use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and iron supplement use; however, the DA group was significantly older than the CERA group (Table 1). Laboratory data at the initiation of dialysis also showed no significant differences between the two groups in serum levels of urea nitrogen, creatinine, total protein, albumin, calcium, inorganic phosphate, iron, total iron binding capacity, transferrin saturation, ferritin, or C-reactive protein (Table 2). Although the parameters for iron deficiency, such as iron, total iron binding capacity, transferrin saturation, and ferritin, were not different between the DA and CERA groups, the mean corpuscular volume was smaller in the CERA group than in the DA group. Reticulocyte levels were unavailable in most patients. The cardio-thoracic ratio and eGFR did not differ between the two groups.

Table 1. Patient characteristics of at the initiation of dialysis

	DA (n=40)	CERA (n=15)	P value
Age (years)	69.4 ± 12.4	59.7 ± 14.2	0.016
Male (%)	70.0	66.6	1.000
Height (cm)	161.0 ± 8.6	160.4 ± 7.3	0.794
Body weight (kg)	58.9 ± 15.4	63.4 ± 9.7	0.302
Systolic blood pressure (mmHg)	136 ± 22	145 ± 21	0.172
Diastolic blood pressure (mmHg)	74 ± 15	73 ± 14	0.738
CKD etiology
Diabetes (%)	32.5	40.0	0.888
Hypertension (%)	27.5	26.7	1.000
Primary glomerular diseases (%)	25.0	20.0	1.000
Polycystic kidney disease (%)	5.0	0.0	1.000
Others (%)	10.0	13.3	0.660
History of CVD (%)	17.5	26.7	0.468
ACEI or ARB use (%)	30.0	46.7	0.401
Iron supplement use (%)	22.5	26.7	0.734

CVD: cardiovascular disease; ACEI: angiotensin converting enzyme inhibitors; ARB: angiotensin receptor blockers

Table 2. Laboratory data at the initiation of dialysis

	DA (n=40)	CERA (n=15)	P value
Urea nitrogen (mg/dL)	99 ± 29	83 ± 24	0.056
Creatinine (mg/dL)	9.9 ± 2.9	10.0 ± 3.1	0.828
eGFR (mL/min/1.73 m2)	4.8 ± 1.8	4.9 ± 1.6	0.712
Total protein (g/dL)	6.0 ± 0.8	5.9 ± 0.7	0.615
Albumin (g/dL)	3.2 ± 0.7	3.2 ± 0.6	0.872
Calcium (mg/dL)	7.9 ± 1.0	7.5 ± 1.0	0.279
Inorganic phosphate (mg/dL)	6.8 ± 1.8	6.3 ± 1.6	0.512
Iron (μg/dL)	63.6 ± 42.1	60.9 ± 27.5	0.736
Total iron binding capacity (μg/dL)	242.1 ± 58.5	238.2 ± 48.9	0.832
Transferrin saturation (%)	27.2 ± 18.3	26.2 ± 12.3	0.705
Ferritin (ng/mL)	146.0 ± 103.7	190.0 ± 126.1	0.305
Mean corpuscular volume (fL)	92.6 ± 3.7	87.8 ± 4.4	0.003
C-reactive protein (mg/dL)	1.78 ± 2.57	1.21 ± 1.72	0.642
Cardio-thoracic ratio (%)	56.4 ± 7.7	56.2 ± 7.4	0.705

During the 6-month pre-dialysis period, serum creatinine levels gradually increased in both groups (Figs. 1A–1C). Indeed, serum creatinine levels 6 months before dialysis were 6.0 ± 1.6 mg/dL in the DA group and 5.0 ± 1.7 mg/dL in the CERA group (Table 3), and this difference was not significant (P = 0.056). At the initiation of hemodialysis, serum creatinine levels were 9.9 ± 2.9 mg/dL in the DA group and 10.0 ± 3.1 mg/dL in the CERA group, also not significantly different (P = 0.828). Hb levels remained constant from 6 months before dialysis to 1 month before dialysis; however, Hb levels had significantly decreased at the initiation of dialysis in both groups (Figs. 1D–1F). Hb levels at the initiation of dialysis were similar in the DA group (9.1 ± 1.2 g/dL) and the CERA group (9.0 ± 1.0 g/dL). The monthly doses of ESAs did not change significantly from 6 months before dialysis to the initiation of dialysis in either group (Figs. 1G and 1H). In addition, the total amounts of ESAs and the total costs of ESAs used during the 6-month pre-dialysis period were not different between the two groups (Figs. 2A and 2B). However, as shown in Fig. 2C, the DA group received subcutaneous injections of ESAs more frequently (6.6 ± 2.5 times/6 months) than did the CERA group (4.3 ± 2.3 times/6 months).

Table 3. Laboratory data at 6 months before the initiation of dialysis

	DA (n=40)	CERA (n=15)	P value
Urea nitrogen (mg/dL)	62 ± 18	51 ± 20	0.060
Creatinine (mg/dL)	6.0 ± 1.6	5.0 ± 1.7	0.056
Albumin (g/dL)	3.6 ± 0.8	3.6 ± 0.7	0.873
Calcium (mg/dL)	8.4 ± 0.7	8.3 ± 0.7	0.621
Inorganic phosphate (mg/dL)	5.2 ± 0.9	4.8 ± 0.7	0.963
C-reactive protein (mg/dL)	0.45 ± 0.84	0.14 ± 0.22	0.191

Fig. 2

The doses, costs, and frequency of ESA injections in pre-dialysis CKD patients treated with DA and CERA in the 6-month pre-dialysis period. The total amounts of ESAs (A), the total costs of ESAs (B), and the frequency of subcutaneous injections of ESAs (C) in the 6 months before the initiation of hemodialysis were compared among CKD patients treated with DA (n=40) and CERA (n=15). *P<0.05 compared with DA-treated CKD patients.

The guidelines published by the Japanese Society for Dialysis Therapy⁹ recommend a dose reduction or interruption of ESA therapy if Hb levels exceed 13 g/dL in pre-dialysis CKD patients (or exceed 12 g/dL in pre-dialysis CKD patients with a history of serious cardiovascular disease). We examined the number of pre-dialysis CKD patients whose Hb levels were elevated above these levels. One in 40 CKD patients treated with DA and 1 in 15 CKD patients treated with CERA had an episode of Hb overshoot. The incidence of Hb overshoot was not significantly different between the DA and CERA groups.

Finally, we examined the relationship between Hb levels and serum creatinine levels at the initiation of dialysis in both groups combined. No significant correlation was observed between these parameters (r =0.074, P = 0.590, n =55). In addition, no significant correlation was observed between changes in Hb levels during the 1 month before the initiation of dialysis and serum creatinine levels at the initiation of dialysis (r =0.201, P = 0.297, n =55), suggesting that the decline in Hb levels at the initiation of dialysis was not simply caused by a decline in kidney function.

Discussion

We examined the effect of DA and CERA on anemia in pre-dialysis CKD patients during the 6-month period before the initiation of hemodialysis. The results showed that DA and CERA both maintained Hb levels at around 10 g/dL from 6 months before dialysis to 1 month before dialysis, but they both failed to prevent a decline in Hb levels at the initiation of dialysis. Hb levels at the initiation of dialysis decreased to 9.1 ± 1.2 g/dL in the DA group and to 9.0 ± 1.0 g/dL in the CERA group. Results also showed that CKD patients treated with DA received more subcutaneous injections than those treated with CERA, although the total doses and total costs of ESAs used during the 6-month pre-dialysis period were similar for the two groups. The reduction in the number of subcutaneous injection is of importance, because administration of ESAs is painful, and some CKD patients are afraid of the injections. The results of the present study suggest that: (1) CKD patients require attention to prevent the progression of anemia immediately before dialysis, and (2) CERA might be more useful than DA because of the reduced number of subcutaneous injections during the pre-dialysis period.

Previous studies have shown that hemodialysis patients have a high mortality rate within 120 days after the initiation of hemodialysis,¹⁷ and that the incidence of cardiovascular events in the first week after the initiation of hemodialysis is much higher than that in the subsequent period.¹⁸ Because Hb levels decrease most severely at the initiation of dialysis,¹⁶ and because anemia is a risk factor for the development of cardiovascular diseases and increased mortality,^3,4,5 it is highly possible that prevention of the decline in Hb levels at the initiation of dialysis may improve the prognosis in CKD patients. In support of this hypothesis, the results of recent studies showed that low Hb levels at hemodialysis initiation were a significant risk factor for coronary artery disease and cerebrovascular disease.¹⁹ Based on the results of these previous studies and those of the present study, it is suggested that CKD patients need larger doses and/or more frequent injections of ESAs immediately before dialysis, even when being treated with long-acting ESAs.

According to the guidelines of the Japanese Society of Dialysis Therapy, the target Hb level is 11–13 g/dL in patients with CKD stage 3–5.⁹ However, the mean Hb levels in both the DA and CERA groups did not achieve the target range in the present study. Despite the guideline recommendation, monthly ESA doses were not increased during the observation period. There are several possible explanations for this phenomenon. First, ESAs are expensive, and patients sometimes refuse to increase the doses. Second, some patients are unable to visit the hospital frequently for personal reasons. Third, some nephrologists might consider the negative effect of ESAs on the risk of cardiovascular diseases. Indeed, several studies have reported that higher Hb targets during ESA therapy did not improve the outcome in pre-dialysis CKD patients.^20,21,22 These factors may have contributed to the mean Hb levels being below 11.0 g/dL during the observation period, despite patients being treated with ESAs.

Recently, two research groups have independently reported retrospective studies similar to our present study.^23,24 Results of both of these studies showed a decline in Hb levels at the initiation of dialysis in CKD patients treated with epoetin, DA, or CERA. Each of these ESAs evidently failed to maintain target Hb levels at the initiation of dialysis. Compared to our present study, an advantage of the other two studies was that they analyzed larger numbers of CKD patients. However, a disadvantage of these studies was that they enrolled CKD patients who started dialysis from 2007 to 2014 in one study²³ and from 2009 to 2015 in the other study.²⁴ During these relatively long periods, guideline had been revised,⁹ and many articles were published that may have influenced the decisions of nephrologists regarding the choice of ESA therapy. Nonetheless, the results of the previous studies and our present study all suggest that more intense ESA therapy is needed for pre-dialysis CKD patients to avoid the progression of anemia immediately before the initiation of dialysis.

In the present study, the efficacies of DA and CERA were analyzed in terms of the equivalent ESA dose. Indeed, some previous studies used a dose conversion ratio of DA:CERA =1:0.93 for non-dialysis CKD patients,¹³ whereas others used a ratio of 1:1.^23,24 We used a ratio of 1:1; however, even if a conversion ratio of 1:0.93 had been adopted, the conclusions of the present study would have remained the same.

There are several limitations in the present study. First, the number of CKD patients treated with DA versus CERA was quite different. Second, the age was also different between the two groups. These differences may have affected the analysis of the efficiency of ESAs for anemia treatment. Moreover, although alcohol consumption and smoking can influence renal anemia, the history of these habits could not be determined accurately because of the nature of this retrospective study. Prospective randomized studies are needed in the future.

In summary, the results of the present study suggest that CKD patients need to be treated with more intense ESA therapy to prevent the progression of anemia immediately before dialysis. Additionally, CERA may be more useful than DA because fewer subcutaneous injections are required during the pre-dialysis period. In the future, we plan to determine the relationship between Hb levels and the prognosis of CKD patients enrolled in the present study.

Acknowledgments

M.H. received grants from Kyowa Hakko Kirin Co., Ltd. and Chugai Pharmaceutical Co. However, these corporations were not involved in designing or conducting this study. T.Y. has no conflicts of interest to declare.

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