Clinical and Experimental Nephrology
https://doi.org/10.1007/s10157-024-02511-9

ORIGINAL ARTICLE

The comparison of four hypoxia‑inducible factor prolyl hydroxylase
inhibitors on drug potency and cost for treatment in patientswith renal anemia
Enyu Imai1,2,3· Atsuhiro Imai4

Received: 27 March 2024 / Accepted: 2 May 2024
© The Author(s), under exclusive licence to Japanese Society of Nephrology 2024

Abstract
Background Five hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved for marketing inJapan. However, marked differences exist in terms of drug potency, dose requirement, and pharmacokinetics.
Methods The primary evaluation in this study was the changes in hemoglobin levels, dose escalation, drug potency, andcost among HIF-PHIs, 3 months after the initiation of treatment.
Results All patients treated with HIF-PHI between August 2020 and December 2023 were enrolled in this study. In total,
124 patients were administered daprodustat (N = 37), enarodustat (N = 44), molidustat (N = 13), or vadadustat (N = 30).
The mean hemoglobin levels of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 11.7 g/dL, 11.8 g/
dL, 12.2 g/dL, and 11.3 g/dL, respectively. At 3 months, the mean doses of daprodustat, enarodustat, molidustat, and vadadustat increased by 110%, 177%, 125%, and 152%, respectively, from the initial dose. The HIF-PHI potency indices (HPI)of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 0.168, 0.307, 0.184, and 0.254, respectively. At
3 months, the mean daily costs of daprodustat, enarodustat, molidustat, and vadadustat were JPY 345, JPY 434, JPY 206,
and JPY 565, respectively.
Conclusion The difference in dose escalation for anemia treatment among HIF-PHIs is due to differences in drug potency,
where the HPI significantly differs among HIF-PHIs. The disparity between the HPI and the cost of the initial dose accounts
for the variance in the daily costs of renal anemia treatment among HIF-PHIs.
Keywords CKD · HIF-PHI · Renal Anemia

Introduction
Renal anemia is a common comorbidity of advanced chronic
kidney disease (CKD) [1]. Anemia associated with CKD
can cause heart failure and exacerbate CKD [2]. In 1996,
erythropoiesis-stimulating agents (ESAs) were introduced
to treat renal anemia in Japan. In 2019, renal anemia could* Enyu Imaiads12069@nifty.com
1

Nakayamadera Imai Clinic, Takarazuka, Japan2

Department of Nephrology, Fujita Health University,
Toyoake, Aichi, Japan3

Department of Nephrology and Rheumatology, Aich Medical
University, Nagakute, Aichi, Japan

4

Department of Nephrology, Osaka University Graduate
School of Medicine, Suita, Osaka, Japanbe treated with the hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Roxadustat was the first HIF-PHI
approved for clinical use in patients undergoing dialysis [3].
In 2020, daprodustat [4] and vadadustat [5] were approvedfor clinical use, followed by enarodustat [6] and molidustat [7] in 2022. Currently, five compounds are approved formarketing in Japan; however, marked differences exist interms of drug potency, dose requirements, and pharmacokinetics. Roxadustat is administered thrice weekly, whereas
the other treatments are administered daily. Our previous
study showed heterogeneous pharmacological actions of
daprodustat and vadadustat [8]. In a network meta-analysis,
the increase in hemoglobin (Hb) levels after treatment wasinconsistent among HIF-PHIs [9].
We were interested in the relationship between differences in drug potency and the daily cost of HIF-PHIs. In
this study, we have compared four HIF-PHIs (daprodustat,Vol.:(0123456789)

Clinical and Experimental Nephrology

enarodustat, molidustat, and vadadustat) in terms of the Hb
increase rate, drug potency, and treatment cost.

Methods
Study protocol
This was a retrospective, observational study. The Nakayamadera Imai Clinic treats approximately 1,800 patients
per month, 95% of whom have chronic non-communicablediseases (mainly diabetes and CKD). All patients treatedwith HIF-PH inhibitors between August 2020 and December
2023 were enrolled in this study.
Clinically, we treated patients with HIF-PHIs by targeting a Hb level of 11 to 13 g/dL and transferrin saturationof ≥ 20% or ferritin level of ≥ 100 ng/mL, according to the2018 Guidelines for the Diagnosis and Treatment of Chronic
Kidney Disease (as published by the Japanese Society ofNephrology) [10].
In 2023, the costs of the initial dose of daprodustat,enarodustat, molidustat, and vadadustat were JPY 179.70(2 mg) or JPY 316.80 (4 mg), JPY 270.50 (2 mg), JPY
163.80 (25 mg), and JPY 366.00 (300 mg), respectively.
The study protocol was approved by the Ethics Committee of Hyogo Medical Association (R4-005). As this was a
retrospective study, we used an opt-out approach and waived
the requirement for written informed consent. This study was
conducted in accordance with the Declaration of Helsinki.

Patients’ follow‑up and study outcomes
Patients visited the clinic every month for the treatment of
CKD, including renal anemia. Clinical data were obtained
from patients’ clinical records. We compared Hb levels,
HIF-PHI dose, and daily cost of HIF-PHIs among patientstreated with HIF-PHIs. The primary evaluation of this study
was the difference in dose, drug potency, and cost among
HIF-PHIs 3 months after the initiation of treatment. Drugpotency was defined using the HIF-PHI potency index (HPI)
as follows: HPI = (drug dose/starting dose) × 100/Hb (g/dL)/BW (kg).

Statistical analyses
One-way analysis of variance or Fisher’s exact test wasused to evaluate the significant differences among thebackgrounds of the four groups. We evaluated the Hb timeseries data using repeated-measures analysis of variance,
but the sphericity assumption was violated by Mauchly’s
tests. In the repeated-measures analysis, we used the Greenhouse–Geisser correction. To evaluate HIF-PHI dose, HIFPHI cost, and HPI, we performed a Kruskal–Wallis test. If

there was a significant difference, we performed Dunn’s
multiple comparison test or pairwise comparisons using theMann–Whitney U test with Bonferroni’s P-value adjustment
method.
Statistical significance was set at P < 0.05. Statisticalanalyses were performed using GraphPad Prism 10.2.1 software program (GraphPad Software, San Diego, CA, USA) or
EZR 1.55. Data are expressed as the mean ± standard deviation or median (interquartile range).

Results
Participants
All patients treated with HIF-PHI between August 2020 and
December 2023 at Nakayamadera Imai Clinic were enrolled
in this study. In total, 124 patients were administered daprodustat (N = 37), enarodustat (N = 44), molidustat (N = 13),or vadadustat (N = 30). The mean age of the participants
was 74.4 years, and 55.6% were male. The clinical characteristics relevant to renal anemia were similar between thegroups, except for the pre-medicated individuals (Table 1).
The participants had advanced CKD, with a mean estimatedglomerular filtration rate of 22.3 mL/min/1.73 ­m2. The meanbaseline Hb was 10.7 g/dL. At baseline, the mean transferrin saturation was 29.3%, with a mean serum ferritin levelof 153 ng/mL, indicating that the iron status for erythropoiesis was adequate. The number of patients who received
pre-medication with ESA or HIF-PHIs differed significantly
between the HIF-PHI groups. The proportion of patients premedicated with ESA or HIF-PHI was 59.5%, 36.4%, 30.8%,
and 80.0% in the daprodustat, enarodustat, molidustat, andvadadustat groups, respectively.

Outcomes
Changes in Hb levels after HIF-PHI treatment are shown in
Fig. 1. The mean Hb at 1 month did not change from baseline in the enarodustat and vadadustat groups but increasedin the daprodustat and molidustat groups. The mean Hblevels of daprodustat, enarodustat, molidustat, and vadadustat at 3 months were 11.7 g/dL, 11.8 g/dL, 12.2 g/dL,
and 11.3 g/dL, respectively. The percentage of participants
who reached the target Hb level of 11–13 g/dL was 59.5%,
45.4%, 76.9%, and 33.3% for daprodustat, enarodustat, molidustat, and vadadustat, respectively. Given that the target Hblevel was 10–13 g/dL, according to the 2023 Guidelines forthe Diagnosis and Treatment of Chronic Kidney Disease,the percentages of participants who reached the target Hblevel of 10–13 g/dL were 81.1%, 65.9%, 84.6%, and 63,3%
for daprodustat, enarodustat, molidustat, and vadadustat,
respectively.

Clinical and Experimental Nephrology
Table 1  Baseline Characteristics of PatientsAgeSex (%)
Body weight (kg)Hb baseline (g/dL)
Ferritiin
TSAT (%)
Premedication (%)
Darbepoetin alpha
Epoetin beta pegol
PIF-PHIab

Daprodustat (N = 37)

Enarodustat (N = 44)

Molidustat (N = 13)

Vadadustat (N = 30)

P value75.3 ± 10.9
22 (59.5)
58.0 ± 12.4
10.6 ± 1.1
156 ± 100
29.4 11.5
22 (59.5)0
15
7

72.0 ± 13.6
22 (44.9)
57.2 ± 10.0
10.7 ± 1.2
155 ± 10627.3 ± 11.5
16 (36.4)
3
121

78.2 ± 9.0
7 (53.8)
53.4 ± 9.1
11.0 ± 1.2
133 ± 12031.3 ± 12.7
4 (30.8)
04
075.2 ± 11.2
18 (60)57.2 ± 10.0
10.7 ±0.8
154 ± 9031.1 ± 8.5
24 (80.0)
2
21
1

a

0.318
0.474
a
0.62
a
0.789
a
0.927
a
0.447
b
0.001
b

one-way ANOVAFisher’s exact test

Fig. 1  Change in Hemoglobin
levels during the study. The
mean hemoglobin ± standard
deviation is shown for 3 months
after treatment with each
HIF-PHI: daprodustat (N = 37),
enarodustat (N = 44), molidustat (N = 13), and vadadustat(N = 30). Greenhouse–Geisser
correction for departure fromsphericity was performed after
univariate type III repeatedmeasures analysis of variance,
assuming sphericity. A timedependent effect was observed(P < 0.0001); however, there
were no significant differencesin drug efficacy (P = 0.2647).
HIF-PHI, hypoxia-inducible
factor prolyl hydroxylase inhibitor

Daprodustat 37
Enarodustat 44
Molidustat 13
Vadadustat 30

The HIF-PHI dose at 3 months is shown in Fig. 2. After
3 months, the mean doses of daprodustat, enarodustat, molidustat, and vadadustat increased by 110%, 177%, 125%,and 152%, respectively, from the initial dose. The treatment
doses of enarodustat and vadadustat were significantly
higher than that of daprodustat.
The HPI at 3 months is shown in Fig. 3. The HPIs of
daprodustat, enarodustat, molidustat, and vadadustat at
3 months were 0.168, 0.307, 0.184, and 0.254, respectively (Fig. 3a). The HPI of daprodustat was significantly lower than those of enarodustat and vadadustat.
In non-pre-medicated patients, the HPIs of daprodustat,enarodustat, molidustat, and vadadustat at 3 months were0.169, 0.287, 0.158, and 0.237, respectively (Fig. 3b).
The HPIs of daprodustat and molidustat tended to be

34
44
13
30

35
43
13
26

36
43
13
24

lower than those of enarodustat and vadadustat but notsignificantly. The HPI at 6 and 12 months are shown in
Fig. 3c and Fig. 3d. The HPIs of daprodustat, enarodustat, molidustat, and vadadustat at 6 months were 0.141,
0.296, 0.154, and 0.222, respectively (Fig. 3c). The HPIsof daprodustat, enarodustat, molidustat, and vadadustat at
12 months were 0.158, 0.297, 0.148, and 0.235, respectively (Fig. 3d).
The daily costs of HIF-PHI treatment are shown in
Fig. 4. At 3 months, the mean daily costs of daprodustat,enarodustat, molidustat, and vadadustat were JPY 335,
434, 206, and 565, respectively. The cost of treatment withmolidustat was significantly lower than that of vadadustat
and enarodustat. The cost of daprodustat is significantly
lower than that of vadadustat.

Clinical and Experimental Nephrology

Fig. 2  Change in dose for the treatment with HIF-PHI. The percent change from the initial dose of each HIF-PHI is shown as themedian (25% and 75%). Kruskal–Wallis test was used for daprodustat (P = 0.64), enarodustat (P < 0.0001), molidustat (P = 0.6215),

and vadadustat (P < 0.0001). Pairwise comparison with Dunn’s test,*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. HIF-PHI,
hypoxia-inducible factor prolyl hydroxylase inhibitor

Discussion

the initiation of treatment in patients who have previously
used ESAs. The initial dose of vadadustat may have been too
low to increase Hb levels in the 1 month because Hb levels
increased after administering higher doses of vadadustat(450 mg or 600 mg). In a phase II study, 450 mg vadadustat
was administered as the initial dose. By the second week, themean Hb levels had increased significantly from baseline,
further increasing by 0.5 g/dL by the fourth week [14]. For
enarodustat, a starting dose of 2 mg may be too low for treating patients previously treated with ESA, as Hb increased
after eight weeks with up-titration to 4 mg at four weeks. Ina phase III study of molidustat, the Hb level increased in thefirst eight weeks with 25 mg of the initial dose of molidustat
in patients with CKD without dialysis [15]. In this study, adose–response relationship was observed between 25 and
75 mg molidustat in patients with CKD without dialysis. In
a transition study from darbepoetin alfa to molidustat, Hblevels were maintained within the target range without falling with 25 mg of molidustat [15]. In contrast, slow erythropoiesis has not been reported with daprodustat in patientswith CKD or those on dialysis [16, 17]. The effect of daprodustat on the increase in Hb was better than that of darbepoetin alfa in patients who were not previously treated with
ESA, whereas the Hb increase seemed to be comparable
between daprodustat and darbepoetin alfa groups in patientspreviously treated with ESA. Differences in the potency of
HIF-PHIs may contribute to differences in the erythropoietic
response to HIF-PHIs.
In the present study, we used HPI to indicate HIF-PHI
potency. HPI was calculated as follows: HPI = treatment
drug dose/starting dose × 100/Hb (g/dL) /BW (kg). Thisidea is based on the established HIF-PHI resistance index,
which is calculated as follows: HRI = weekly dose of HIFPHI (mg) /Hb (g/dL) /body weight (kg) [18]. HRI increased

Four HIF-PHIs, daprodustat, enarodustat, molidustat, andvadadustat, were retrospectively evaluated in 124 patientswith renal anemia between 2020 and 2023. We compared
the effects of the four HIF-PHIs on the treatment dose, drug
potency by HPI, and daily drug costs 3 months after treatment. Daprodustat and molidustat were maintained at theinitial dose for treating renal anemia, whereas the doses forenarodustat and vadadustat were increased by approximately
50%. The difference in treatment dose seems to be due tothe difference in drug potency, in which HPI significantly
differed among HIF-PHIs, as shown in this study. The difference between the HPI and the cost of the initial dose
accounts for the disparity in the daily costs of renal anemia
treatment among HIF-PHIs.
Drug potency was significantly different among the HIFPHIs. Daprodustat and molidustat were found to be morepotent than vadadustat and enarodustat. Slow erythropoiesis with vadadustat and enarodustat, particularly in patientspreviously treated with ESA, was also observed in Japanesephase III trials compared to darbepoetin alfa [11–13]. In
a Japanese phase III trial for vadadustat at a starting doseof 300 mg, Hb levels did not increase during the initial six
weeks in patients who had previously used ESAs [12]. In
patients who had not been previously treated with ESAs,
Hb levels increased after four weeks; the dose of vadadustat
needed to be increased in some patients after four weeks[12]. The vadadustat dose was increased to 450 mg/day
after eight weeks. Hb levels did not increase but tended todecrease after treatment with 2 mg/day of enarodustat during the initial eight weeks in patients who had previously
used ESAs [13]. These results suggest that slow erythropoiesis is a characteristic of vadadustat and enarodustat at

Clinical and Experimental Nephrology
Fig. 3  HIF-PHI potency index(HPI). a The HPI is shown foreach HIF-PHI in all patients at
3 months: daprodustat (N = 36),
enarodustat (N = 41), molidustat (N = 13), and vadadustat(N = 22). Kruskal–Wallis test,
P = 0.007. Pairwise comparison
with Bonferroni adjustment;*P < 0.05. b HPI for each
HIF-PHI in patients without
pre-medication. daprodustat(N = 15), enarodustat (N = 28),molidustat (N = 9), and vadadustat (N = 4). Kruskal–Wallis test, P = 0.196. HIF-PHI,
hypoxia-inducible factor prolylhydroxylase inhibitor. c The
HPI is shown for each HIF-PHI
in patients at 6 months. daprodustat (N = 25), enarodustat(N = 27), molidustat (N = 11),and vadadustat (N = 16).
Kruskal–Wallis test, P = 0.0002.
Pairwise comparison with Bonferroni adjustment; *P < 0.05,****P < 0.0001. d HPI is shownfor each HIF-PHI in patientsat 12 months. daprodustat(N = 24), enarodustat (N = 23),molidustat (N = 10), and vadadustat (N = 14). Kruskal–Wallis
test, P = 0.0009. Pairwise comparison with Bonferroni adjustment; *P < 0.05, **P < 0.01

in proportion to increased resistance to renal anemia treatment. Thus, HPI decreased in proportion to an increase in
drug potency. A lower HPI indicates a higher potency of
HIF-PHIs in erythropoiesis. Based on this, the HPIs were in
the following order of strength of drug potency: daprodustat,molidustat, enarodustat, and vadadustat (Fig. 3a–d).
The cost of treating renal anemia using HIF-PHIs depends
on the initial dose. To reduce the daily costs of HIF-PHIs,
molidustat, daprodustat, enarodustat, and vadadustat havebeen used. Molidustat had the lowest initial daily cost oftreatment and a good PHI, contributing to the lower daily
cost of treatment at 3 months. In the present study, patientstreated with daprodustat were pre-medicated with ESAs;
however, the low daily cost and high PHI of daprodustat
contributed to the low cost of treatment at 3 months.

The target Hb level for treating renal anemia in patientswith CKD without dialysis is expected to change by 2023.
In the present study, the target Hb level was 11–13 g/dL,
set according to the 2018 Japanese CKD guidelines [10],requiring a relatively high HIF-PHIs dose. The Japanese
Guidelines for the Diagnosis and Treatment of Chronic
Kidney Disease were revised in 2023 [22], and the target
hemoglobin level for treating renal anemia was reduced to
10–13 g/dL. This may improve the gap between guideline
recommendations and real-world clinical practice. The
proportion of participants who reached the targeted Hblevel of 11–13 g/dL was less than 50%, except those treatedwith daprodustat and molidustat. Given that the target Hblevel was 10–13 g/dL according to the 2023 Guidelines forthe Diagnosis and Treatment of Chronic Kidney Disease,Clinical and Experimental Nephrology

In conclusion, heterogeneity exists among HIF-PHIs,
and differences in drug potency affect dosage changes during renal anemia treatment in patients with CKD without
dialysis. The cost of renal anemia treatment is related to theinitial daily costs of HIF-PHIs and HPI. HIF-PHIs with alower initial dose cost and lower HPI impose less economic
burden and a better clinical outcome for maintaining Hb attarget levels of 11–13 g/dL.
Acknowledgements English language editing was provided by Editage.
Author contributions Enyu Imai was responsible for the conception,
design, and interpretation of the data and writing of the manuscript.
Atsuhiro analyzed the data.
Funding This research was conducted with the help of Enyu Imai, thecorresponding author.

Declarations
Conflict of interest Enyu Imai and Atsuhiro Imai declare no conflictsof interest.

Fig. 4  Daily cost for treatment with HIF-PHI. Daily costs are presented as medians (25% and 75%). The Kruskal–Wallis test wasused for daprodustat (P = 0.64), enarodustat (P < 0.0001), molidustat(P = 0.6215), and vadadustat (P < 0.0001). Pairwise comparison with
Dunn’s test, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
HIF-PHI, hypoxia-inducible factor prolyl hydroxylase inhibitor

more than 80% of the participants reached the target Hblevel of 10–13 g/dL after treatment with daprodustat or
molidustat, and more than 60% of them maintained thetarget Hb level after treatment with enarodustat or vadadustat. This may improve the gap between guideline recommendations and real-world clinical practice.
The present study had several limitations. First, this wasa retrospective observational study conducted at a single
center. Therefore, randomization could not be performed.
Secondly, the sample size was small. Subtle changes inclinical parameters may not be detected in some patients;
therefore, a real-world prospective multicenter study iswarranted. Third, the number of patients previously treatedwith ESAs varied among HIF-PHIs. Patients previously
treated with ESAs or HIF-PHIs are often resistant to HIFPHIs. In other words, a high dose of HIF-PHIs may beneeded to treat renal anemia in patients who were premedicated. Vadadustat and daprodustat groups had a significantly higher proportion of patients with pre-medication with ESA or HIF-PHI than enarodustat and molidustat
groups. This may partly account for the requirement fordose escalation in the initial phase of vadadustat comparedwith daprodustat.

Ethical approval All procedures performed in the studies involving
human participants were in accordance with the ethical standards ofthe institutional and/or national research committee at which the studies were conducted (Hyogo Medical Association IRB approval number
R4-005) and the 1964 Helsinki Declaration and its later amendments
or comparable ethical standards.
Informed consent As this was a retrospective study, we used an opt-out
approach and waived the requirement for written informed consent.

References
1. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc
Nephrol. 2012;23:1631–4.
2. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y,
Schwartz D. Anemia, chronic renal disease and congestive heart
failure—The cardio renal anemia syndrome: The need for cooperation between cardiologists and nephrologists. Int Urol Nephrol.
2006;38:295–310.
3. Roxadustat DS. First global approval. Drugs. 2019;79:563–72.
4. Daprodustat DS. First approval. Drugs. 2020;80:1491–7.
5. Vadadustat MA. First approval. Drugs. 2020;80:1365–71.
6. Enarodustat MA. First approval. Drugs. 2021;81:169–74.
7. Böttcher M, Lentini S, Arens ER, Kaiser A, van der Mey D, Thuss
U, Kubitza D, Wensing G. First-in-man-proof of concept study
with molidustat: A novel selective oral HIF-prolyl hydroxylase
inhibitor for the treatment of renal anaemia. Br J Clin Pharmacol.
2018;84:1557–65.
8. Imai E, Imai A. The comparison between vadadustat and daprodustat regarding dose, cost, and safety of treatment for renal anemia in non-dialysis patients with chronic kidney diseases. Intern
Med. 2023. https://​doi.​org/​10.​2169/​inter​nalme​dicine.​2501-​23.
9. Zheng Q, Yang H, Sun L, et al. Efficacy and safety of HIF prolylhydroxylase inhibitor vs epoetin and darbepoetin for anemia inchronic kidney disease patients not undergoing dialysis: A network meta-analysis. Pharmacol Res. 2020;159: 105020. https://​doi.​org/​10.​1016/j.​phrs.​2020.​105020.

Clinical and Experimental Nephrology
10. Japanese Society of Nephrology. The guideline for the diagnosis
and treatment of chronic kidney disease 2018, Tokyo Igakusya,
Topkyo 2018.
11. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat inpatients with anemia and non-dialysis-dependent CKD. N Engl J
Med. 2021;384:1589–600.
12. Nangaku M, Kondo K, Kokado Y, et al. Phase 3 randomized
study comparing vadadustat with darbepoetin alfa for anemia inJapanese patients with nondialysis-dependent CKD. J Am Soc
Nephrol. 2021;32:1779–90.
13. Akizawa T, Nangaku M, Yamaguchi T, Koretomo R, Maeda K,
Miyazawa Y, Hirakata HA. A Phase 3 study of enarodustat in anemic patients with CKD not requiring dialysis: The SYMPHONY
ND study. Kidney Int Rep. 2021;6:1840–9.
14. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH.
Vadadustat, a novel oral HIF stabilizer, provides effective anemia
treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90:1115–22.
15. Macdougall IC, Akizawa T, Berns JS, Bernhardt T, Krueger T.
Effects of molidustat in the treatment of anemia in CKD. Clin J
Am Soc Nephrol. 2019;14:28–39.
16. Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for thetreatment of anemia in patients not undergoing dialysis. N Engl J
Med. 2021;385:2313–24.

17. Nangaku M, Hamano T, Akizawa T, et al. Daprodustat comparedwith epoetin beta pegol for anemia in Japanese patients not on
dialysis: A 52-week randomized open-label Phase 3 trial. Am J
Nephrol. 2021;52:26–35.
18. Hanafusa N, Abe M, Joki N, Hoshino J, Tankguchi M, Kikuchi
S, Hasegawa T, Goto S. 2022 Annual Dialysis Data Report JSDT
Renal Data Registry. J Dial Ther. 2023;56:473–536.
19. Japanese Society of Nephrology. The guideline for the diagnosis
and treatment of chronic kidney disease. Tokyo Igakusya; 2023.
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