J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Original Article

Volume 10, Number 6, December 2021, pages 255-265

Monthly Continuous Erythropoietin Receptor Activator Versus Weekly Epoetin-Beta, Similar Hemoglobinization but Different Anisocytosis Degree in Hemodialysis Patients: A Randomized Controlled Trial

Figure 3. Hemoglobin evolution and ESA dosage during the study. CERA: continuous erythropoietin receptor activator; Hb: hemoglobin; SD: standard deviation.

Figure 4. (a, b) RDW and MCV evolution throughout the study. *, **P < 0.05 respect to baseline. ‡P < 0.05 respect to the CERA arm. (c) Iron requirements evolution throughout the study. *P < 0.05, Cochran test. CERA: continuous erythropoietin receptor activator; RDW: red cell distribution width; MCV: mean corpuscular volume; SD: standard deviation.

Figure 5. α-Klotho associations. ∆stands for the changes between month 3 and month 6. RDW: red cell distribution width; CERA: continuous erythropoietin receptor activator; EB: epoetin-β; EPO: erythropoietin.

**Table 1.** Baseline Characteristics of the Patients Who Completed the Study Protocol in Both Treatment Arms
	EB (n = 16)	CERA (n = 15)	P
Data are presented as mean ± standard deviation (SD), median (P25 - P75) and raw numbers (percentage). U Mann-Whitney or t-tests were used for comparing continuous variables among both groups. Categorical variables were compared using the χ² or Fisher’s exact tests as necessary. Lanthanum carbonate and sevelamer hydrochloride were included as non-calcium chelators. Vitamin D deficiency was defined by circulating concentrations < 20 ng/mL. CERA: continuous erythropoietin receptor activator; EB: epoetin-β; BMI: body mass index; CCB: calcium channel blocker; ESR: erythrocyte sedimentation rate; iPTH: intact parathormone; nPCR: normalized protein catabolism rate; RAAS: renin-angiotensin-aldosterone system.
Age, years	59 ± 16	59 ± 17	0.94
Time in dialysis, months	29 (19 - 45)	32 (24 - 44)	0.54
Weight, kg	78 ± 25	76 ± 15	0.85
BMI, kg/m²	25 (21 - 31)	29 (21 - 33)	0.71
Office systolic blood pressure, mm Hg	123 ± 14	135 ± 18	0.04
Office diastolic blood pressure, mm Hg	75 ± 14	76 ± 15	0.87
Kt/V	1.5 ± 0.2	1.5 ± 0.2	0.44
nPCR, g/kg/day	0.9 ± 0.2	0.9 ± 0.2	0.52
Albumin, g/L	39 ± 4	39 ± 4	0.82
Vitamin B12, pg/mL	574 (385 - 717)	402 (290 - 512)	0.14
Folic acid, ng/mL	19 (2 - 40)	19 (5 - 32)	0.74
C-reactive protein, mg/dL	0.65 (0.43 - 1.90)	0.86 (0.24 - 1.26)	0.45
ESR, mm/h	31 ± 24	31 ± 21	0.96
Corrected calcium, mg/dL	9 ± 0.4	8.9 ± 0.4	0.6
Phosphorus, mg/dL	3.8 ± 1.2	4.4 ± 1.3	0.12
iPTH, pg/mL	228 ± 121	333 ± 196	0.12
25 (OH) vitamin D, ng/mL	17 (11 - 35)	25 (14 - 32)	0.52
1,25 (OH)₂ vitamin D, pg/mL	15 (9 - 20)	17 (13 - 23)	0.32
Comorbidities
Arterial hypertension, n (%)	13 (46)	15 (54)	0.22
Diabetes mellitus, n (%)	4 (40)	6 (60)	0.45
Dyslipidemia, n (%)	4 (40)	9 (60)	0.21
Vitamin D deficiency, n (%)	7 (54)	6 (46)	0.71
Smoking patients, n (%)	3 (33)	6 (67)	0.25
Concomitant treatments
Calcifediol, n (%)	8 (47)	9 (53)	0.57
Paricalcitol, n (%)	11 (48)	12 (52)	0.68
Cinacalcet, n (%)	3 (30)	7 (70)	0.13
RAAS inhibitors, n (%)	6 (54)	5 (46)	0.43
CCB, n (%)	5 (50)	5 (50)	0.9
Calcium acetate, n (%)	4 (33)	8 (67)	0.1
Non-calcium chelator, n (%)	13 (57)	10 (43)	0.43

Table 1. Baseline Characteristics of the Patients Who Completed the Study Protocol in Both Treatment Arms

EB (n = 16)

CERA (n = 15)

Data are presented as mean ± standard deviation (SD), median (P25 - P75) and raw numbers (percentage). U Mann-Whitney or t-tests were used for comparing continuous variables among both groups. Categorical variables were compared using the χ² or Fisher’s exact tests as necessary. Lanthanum carbonate and sevelamer hydrochloride were included as non-calcium chelators. Vitamin D deficiency was defined by circulating concentrations < 20 ng/mL. CERA: continuous erythropoietin receptor activator; EB: epoetin-β; BMI: body mass index; CCB: calcium channel blocker; ESR: erythrocyte sedimentation rate; iPTH: intact parathormone; nPCR: normalized protein catabolism rate; RAAS: renin-angiotensin-aldosterone system.

Age, years

59 ± 16

59 ± 17

0.94

Time in dialysis, months

29 (19 - 45)

32 (24 - 44)

0.54

Weight, kg

78 ± 25

76 ± 15

0.85

BMI, kg/m²

25 (21 - 31)

29 (21 - 33)

0.71

Office systolic blood pressure, mm Hg

123 ± 14

135 ± 18

0.04

Office diastolic blood pressure, mm Hg

75 ± 14

76 ± 15

0.87

Kt/V

1.5 ± 0.2

0.44

nPCR, g/kg/day

0.9 ± 0.2

0.52

Albumin, g/L

39 ± 4

0.82

Vitamin B12, pg/mL

574 (385 - 717)

402 (290 - 512)

0.14

Folic acid, ng/mL

19 (2 - 40)

19 (5 - 32)

0.74

C-reactive protein, mg/dL

0.65 (0.43 - 1.90)

0.86 (0.24 - 1.26)

0.45

ESR, mm/h

31 ± 24

31 ± 21

0.96

Corrected calcium, mg/dL

9 ± 0.4

8.9 ± 0.4

0.6

Phosphorus, mg/dL

3.8 ± 1.2

4.4 ± 1.3

0.12

iPTH, pg/mL

228 ± 121

333 ± 196

0.12

25 (OH) vitamin D, ng/mL

17 (11 - 35)

25 (14 - 32)

0.52

1,25 (OH)₂ vitamin D, pg/mL

15 (9 - 20)

17 (13 - 23)

0.32

Comorbidities

Arterial hypertension, n (%)

13 (46)

15 (54)

0.22

Diabetes mellitus, n (%)

4 (40)

6 (60)

0.45

Dyslipidemia, n (%)

4 (40)

9 (60)

0.21

Vitamin D deficiency, n (%)

7 (54)

6 (46)

0.71

Smoking patients, n (%)

3 (33)

6 (67)

0.25

Concomitant treatments

Calcifediol, n (%)

8 (47)

9 (53)

0.57

Paricalcitol, n (%)

11 (48)

12 (52)

0.68

Cinacalcet, n (%)

3 (30)

7 (70)

0.13

RAAS inhibitors, n (%)

6 (54)

5 (46)

0.43

CCB, n (%)

5 (50)

0.9

Calcium acetate, n (%)

4 (33)

8 (67)

0.1

Non-calcium chelator, n (%)

13 (57)

10 (43)

0.43

**Table 2.** Baseline Hematological Parameters and Iron Status of the Patients Who Completed the Study Protocol in Both Arms of Treatment
	EB (n = 16)	CERA (n = 15)	P
Data are presented as mean ± standard deviation (SD), median (P25 - P75) and raw numbers (percentage). U Mann-Whitney or t-tests were used for comparing continuous variables among both groups. Categorical variables were compared using the χ² or Fisher’s exact tests as necessary. Total iron deficit was calculated as follows: (10 × (target Hb (g/dL) - actual Hb (g/dL)) × (0.24 × bodyweight (kg))) + mg of iron for body stores, where mg of iron for body stores were 0 mg if bodyweight < 35 kg and 500 mg if bodyweight ≥ 35 kg. The erythropoietin resistance index (ERI) was determined as the weekly weight-adjusted dose of EPO (IU/kg/week) divided by Hb concentration (g/dL). CERA: continuous erythropoietin receptor activator; EB: epoetin-β; Fe: serum iron; IV: intravenous; Hb: hemoglobin; RDW: red cell distribution width; TSAT: transferrin saturation index; EPO: erythropoietin.
Hb, g/dL	11.9 ± 0.8	11.7 ± 1.0	0.48
Erythrocyte count, ×10⁶/µL	3.69 ± 0.30	3.63 ± 0.31	0.61
RDW, %	13.5 ± 1.1	13.0 ± 0.8	0.21
Fe, µg/dL	54 (51 - 75)	73 (68 - 85)	0.02
TSAT, %	25 (22 - 33)	28 (21 - 38)	0.18
Ferritin, ng/mL	675 (433 - 1,123)	860 (529 - 1,042)	0.54
Transferrin, mg/dL	157 (144 - 183)	166 (143 - 251)	0.40
Total iron deficit calculated, mg	1,559 ± 310	1,566 ± 344	0.95
EB dosage, IU/week	7,000 ± 3,204	6,200 ± 4,195	0.55
ERI, IU/kg /week	9.0 ± 6.8	7.4 ± 5.7	0.48
IV iron supplementation, n (%)	16 (100)	9 (60)	< 0.01

Table 2. Baseline Hematological Parameters and Iron Status of the Patients Who Completed the Study Protocol in Both Arms of Treatment

EB (n = 16)

CERA (n = 15)

Data are presented as mean ± standard deviation (SD), median (P25 - P75) and raw numbers (percentage). U Mann-Whitney or t-tests were used for comparing continuous variables among both groups. Categorical variables were compared using the χ² or Fisher’s exact tests as necessary. Total iron deficit was calculated as follows: (10 × (target Hb (g/dL) - actual Hb (g/dL)) × (0.24 × bodyweight (kg))) + mg of iron for body stores, where mg of iron for body stores were 0 mg if bodyweight < 35 kg and 500 mg if bodyweight ≥ 35 kg. The erythropoietin resistance index (ERI) was determined as the weekly weight-adjusted dose of EPO (IU/kg/week) divided by Hb concentration (g/dL). CERA: continuous erythropoietin receptor activator; EB: epoetin-β; Fe: serum iron; IV: intravenous; Hb: hemoglobin; RDW: red cell distribution width; TSAT: transferrin saturation index; EPO: erythropoietin.

Hb, g/dL

11.9 ± 0.8

11.7 ± 1.0

0.48

Erythrocyte count, ×10⁶/µL

3.69 ± 0.30

3.63 ± 0.31

0.61

RDW, %

13.5 ± 1.1

13.0 ± 0.8

0.21

Fe, µg/dL

54 (51 - 75)

73 (68 - 85)

0.02

TSAT, %

25 (22 - 33)

28 (21 - 38)

0.18

Ferritin, ng/mL

675 (433 - 1,123)

860 (529 - 1,042)

0.54

Transferrin, mg/dL

157 (144 - 183)

166 (143 - 251)

0.40

Total iron deficit calculated, mg

1,559 ± 310

1,566 ± 344

0.95

EB dosage, IU/week

7,000 ± 3,204

6,200 ± 4,195

0.55

ERI, IU/kg /week

9.0 ± 6.8

7.4 ± 5.7

0.48

IV iron supplementation, n (%)

16 (100)

9 (60)

< 0.01

**Table 3.** Iron Status Markers Evolution in Patients Who Completed the Study
ESA type: (n = 16)/CERA (n = 15)	Months of follow-up	F	P	Partial η²
Values are given as mean (standard deviation (SD)). ^aP < 0.05 respect to baseline. ^bP < 0.05 after iron adjustment. CERA: continuous erythropoietin receptor activator; EB: epoetin-β; ESA: erythropoietin-stimulating agent; Fe: serum iron; TIDC: total iron deficit calculated; TSAT: transferrin saturation index.
TSAT, %
EB	26 ± 6	24 ± 7	30 ± 19	0.98	0.38
CERA	35 ± 17	36 ± 14	29 ± 14	1.18	0.32
Ferritin, ng/mL
EB	755 ± 397	707 ± 439	632 ± 343	0.78	0.45
CERA	879 ± 542	783 ± 443	561 ± 301^a	7.17	< 0.01^b	0.33
Transferrin, mg/dL
EB	161 ± 30	162 ± 22	158 ± 24	0.25	0.77
CERA	183 ± 50	172 ± 37	164 ± 35^a	3.39	0.04	0.19
Fe, µg/dL
EB	59 ± 16	55 ± 15	67 ± 38	0.77	0.46
CERA	83 ± 33	83 ± 35	64 ± 27	1.81	0.18
TIDC, mg
EB	1,559 ± 310	1,565 ± 337	1,580 ± 299	0.05	0.95
CERA	1,566 ± 344	1,609 ± 382	1,600 ± 364	0.19	0.82

Table 3. Iron Status Markers Evolution in Patients Who Completed the Study

ESA type: (n = 16)/CERA (n = 15)

Months of follow-up

Partial η²

Values are given as mean (standard deviation (SD)). ^aP < 0.05 respect to baseline. ^bP < 0.05 after iron adjustment. CERA: continuous erythropoietin receptor activator; EB: epoetin-β; ESA: erythropoietin-stimulating agent; Fe: serum iron; TIDC: total iron deficit calculated; TSAT: transferrin saturation index.

TSAT, %

26 ± 6

24 ± 7

30 ± 19

0.98

0.38

CERA

35 ± 17

36 ± 14

29 ± 14

1.18

0.32

Ferritin, ng/mL

755 ± 397

707 ± 439

632 ± 343

0.78

0.45

CERA

879 ± 542

783 ± 443

561 ± 301^a

7.17

< 0.01^b

0.33

Transferrin, mg/dL

161 ± 30

162 ± 22

158 ± 24

0.25

0.77

CERA

183 ± 50

172 ± 37

164 ± 35^a

3.39

0.04

0.19

Fe, µg/dL

59 ± 16

55 ± 15

67 ± 38

0.77

0.46

CERA

83 ± 33

83 ± 35

64 ± 27

1.81

0.18

TIDC, mg

1,559 ± 310

1,565 ± 337

1,580 ± 299

0.05

0.95

CERA

1,566 ± 344

1,609 ± 382

1,600 ± 364

0.19

0.82

**Table 4.** Hepcidin, EPO and α-Klotho Changes During the Evaluation Period
ESA type	Month 3	Month 6	P
Data are presented as median (P25 - P75). *P < 0.05 respect to EB. α-Klotho: soluble α-Klotho; CERA: continuous erythropoietin receptor activator; EB: epoetin-β; EPO: erythropoietin; ESA: erythropoietin-stimulating agent.
Hepcidin, pg/mL
EB	995 (244 - 1,308)	1,103 (161 - 1,345)	0.95
CERA	1,094 (234 - 1,390)	215 (157 - 922)	0.02
EPO, mIU/mL
EB	7.7 (4.1 - 11.6)	12.1 (4.1 - 22.4)	0.09
CERA	13.3 (10.8 - 17.1)*	22.6 (14.5 - 41.9)*	0.08
α-Klotho, pg/mL
EB	514 (417 - 584)	493 (370 - 526)	0.01
CERA	540 (455 - 741)	409 (360 - 534)	0.03

Table 4. Hepcidin, EPO and α-Klotho Changes During the Evaluation Period

ESA type

Month 3

Month 6

Data are presented as median (P25 - P75). *P < 0.05 respect to EB. α-Klotho: soluble α-Klotho; CERA: continuous erythropoietin receptor activator; EB: epoetin-β; EPO: erythropoietin; ESA: erythropoietin-stimulating agent.

Hepcidin, pg/mL

995 (244 - 1,308)

1,103 (161 - 1,345)

0.95

CERA

1,094 (234 - 1,390)

215 (157 - 922)

0.02

EPO, mIU/mL

7.7 (4.1 - 11.6)

12.1 (4.1 - 22.4)

0.09

CERA

13.3 (10.8 - 17.1)*

22.6 (14.5 - 41.9)*

0.08

α-Klotho, pg/mL

514 (417 - 584)

493 (370 - 526)

0.01

CERA

540 (455 - 741)

409 (360 - 534)

0.03

**Table 5.** Adverse Events Requiring Hospital Admission or Care in the Emergency Department
	All patients (n = 37)	Epoetin-β (n = 19)	CERA (n = 18)	P
^aVascular access complication, fistula or catheter thrombosis, post-dialysis site bleeding. AE: adverse event; SAE: serious adverse event; CERA: continuous erythropoietin receptor activator.
AE, n (%)	21	7 (33)	14 (67)	< 0.01
Required transfusion(s), n (%)	1	0	1 (100)	1.00
Any SAE, n (%)	7	1 (14)	6 (86)	0.04
Vascular access complications^a	6	2 (33)	4(67)	0.40
Suspected adverse reaction	7	2 (29)	5 (71)	0.39
Death, n (%)	2	0	2 (100)	0.22

Table 5. Adverse Events Requiring Hospital Admission or Care in the Emergency Department

All patients (n = 37)

Epoetin-β (n = 19)

CERA (n = 18)

^aVascular access complication, fistula or catheter thrombosis, post-dialysis site bleeding. AE: adverse event; SAE: serious adverse event; CERA: continuous erythropoietin receptor activator.

AE, n (%)

7 (33)

14 (67)

< 0.01

Required transfusion(s), n (%)

1 (100)

1.00

Any SAE, n (%)

1 (14)

6 (86)

0.04

Vascular access complications^a

2 (33)

4(67)

0.40

Suspected adverse reaction

2 (29)

5 (71)

0.39

Death, n (%)

2 (100)

0.22