Introduction: Roxadustat, the first-in-class drug for the treatment of renal anemia, has demonstrated efficacy in renal anemia with microinflammation. Additional data are needed regarding the efficacy of roxadustat on renal anemia with systemic macroinflammation. Methods: Three cohorts of renal anemia based on the basic level of high-sensitivity CRP were included. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group; 2< hsCRP ≤10 mg/L as microinflammation (MI) group; hsCRP≥10 mg/L as macroinflammation (MA) group. Patients received oral roxadustat three times per week for 52 weeks. The primary end point was the hemoglobin level over weeks 12–52. The second end point was the cumulative proportion of patients achieving hemoglobin response by the end of week 12. Results: A total of 107 patients with chronic kidney diseases (CKDs) were enrolled. Overall, the baseline hemoglobin level of patients was 79.99 ± 11.20 g/L. Roxadustat could significantly increase the hemoglobin level in all of the three groups and did not show any significant difference (p > 0.05, respectively). Meanwhile, compared with that of the NI group, there was no significant difference in hemoglobin response rate in the MA group both at week 12 (p = 0.06; 95% confidence interval [CI], 0.9531–13.75) and week 52 (p = 0.37; 95% CI, 0.5080–7.937). Moreover, the hemoglobin response was independent of baseline hsCRP level (p = 0.72, 95% CI, −0.1139 to 0.0794). More importantly, roxadustat significantly reduced ferritin and serum iron levels and increased total iron-binding capacity in the three groups, which showed no significant differences among the three groups (p > 0.05, respectively). Conclusion: Roxadustat significantly improves anemia in CKD patients with systemic macroinflammation.

Anemia is one of the most common complications in patients with chronic kidney diseases (CKDs), which is associated with increased morbidity and mortality. Currently, the combination of erythropoiesis-stimulating agents (ESAs) and iron supplementation is the mainstay of treatment for anemia in patients with CKDs [1]. However, management of anemia in CKDs is still challenging, specifically for those with micro- or macroinflammation [2, 3]. So far, there is no definite treatment for renal anemia with macroinflammation.

Inflammation or infection is one of the important complications in CKD patients, which is also a critical factor to exacerbate anemia (also referred to as inflammatory anemia) [2, 4]. In patients with CKDs, inflammation may induce a poor response to iron therapy, most likely due to reduced intestinal iron absorption and disturbed iron utilization [5]. More importantly, inflammation or infection is also associated with poor response to ESA therapy in patients with anemia in CKDs (called ESA hyporesponsiveness); therefore a higher ESA dosage is usually needed, which is subsequently associated with an increased risk of cardiovascular events and death [6]. Therefore, finding a new strategy for inflammatory anemia in patients with CKDs is an unmet need.

Roxadustat, an orally bioavailable hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics the natural response to hypoxia, is a new class of drug for anemia in CKDs with a novel mechanism [7]. Roxadustat not only promotes renal and hepatic erythropoietin (EPO) expression but also improves disturbed iron homeostasis, thereby coordinating erythropoiesis physiologically [7‒9]. Therefore, roxadustat therapy represents a novel therapeutic alternative for the management of anemia in CKDs, particularly among patients with difficult-to-treat anemia.

Previous phase 3 trial indicated that the dosage of roxadustat required to maintain target hemoglobin in CKD patients with microinflammation was not impacted [10]. These data suggested that roxadustat may potentially become a useful therapeutic option for the treatment of anemia with inflammation in patients with CKDs. However, its exact effect on anemia with macroinflammation is yet to be confirmed. Here, we reported our recent findings that roxadustat could improve anemia in CKD patients with systemic inflammation based on a retrospective cohort study.

Study Design

This was a single-center, retrospective cohort study of roxadustat for the treatment of anemia in patients with CKDs, which was conducted at Zhong Da Hospital, Southeast University (ChiCTR2200065159, WHO ICTRP). The study was reviewed and approved by Zhong Da Hospital, Southeast University (2019ZDSYLL193-P01).

Eligible patients with CKDs, including pre-dialysis, hemodialysis, and peritoneal dialysis, were≥18 years of age, had hemoglobin values ≤100 g/L, and had also screened the high-sensitivity CRP (hsCRP) level before enrollment. A list of inclusion and exclusion criteria is provided in the online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000538372).

In total, 107 patients with CKDs, from December 1, 2019 to December 31, 2021, were enrolled here. We created three analysis cohorts based on the baseline level of hsCRP. Patients with hsCRP ≤2 mg/L were selected as non-inflammation (NI) group (n = 26). Patients with 2< hsCRP ≤10 mg/L were selected as microinflammation (MI) group (n = 28). Patients with hsCRP≥10 mg/L were selected as macroinflammation (MA) group (n = 53). The etiology of the macroinflammation is as follows: pneumonia (n = 23); peritonitis (n = 8); catheter-related infection (n = 6); urinary tract infection (n = 7); other infections (n = 9).

Treatment

Enrolled patients received oral roxadustat three times per week for 52 weeks. The starting dose of roxadustat was either 70 mg (body weight 45–60 kg) or 100 mg (body weight ≥60 kg). Hemoglobin was measured every 2 weeks. Doses were titrated every 4 weeks according to the patient’s response and to achieve a hemoglobin level of 100–120 g/L. Oral iron or intravenous iron therapy was prescribed if necessary.

Data Collection and Assessments

The baseline demographic and clinical characteristics of patients, the data of hemoglobin, ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation were extracted from electronic medical records. The missing data are shown in online supplementary Table 1. Hepcidin was measured using an enzyme-linked immunosorbent assay method according to the manufacturer's instructions (ZCIBIO Technology Co., Ltd., Shanghai, China).

Serum EPO Assay

Concentration of serum EPO was assessed using the human EPO Quantikine IVD enzyme-linked immunosorbent assay commercial kit (Catalog#: DEP00; R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s protocol.

End Points

The efficacy of roxadustat for the treatment of anemia was assessed by hemoglobin level over time. The primary end point was the change in the hemoglobin level over weeks 12–52. The second end point was the cumulative proportion of patients in each cohort achieving hemoglobin response (hemoglobin increase by ≥10 g/L) by the end of week 12. To evaluate the full treatment effect in evaluable patients with 52 weeks of treatment, hemoglobin response rates through the end of treatment were also presented.

Statistical Analyses

Inverse probability of treatment weighting was used to adjust the baseline patient characteristics. Multiple imputation was used to deal with missing data. One-way analysis of variance and χ2 test were used as appropriate. All analyses used SAS/STAT (V15.2) or SPSS (V20.0; International Business Machines Corporation, NY, USA). Statistical significance was set at p < 0.05 as significant. Results are presented as means ± standard deviation, means ± standard error, or median (interquartile range).

Patient Characteristics at Baseline

After adjustment using inverse probability of treatment weighting, the baseline characteristics of the patients were similar except for serum EPO level in the three groups (Table 1). Overall, the baseline hemoglobin level of the patients was 79.99 ± 11.2 g/L. The baseline hsCRP levels in the three groups were 0.86 ± 0.33 mg/L, 5.74 ± 1.99 mg/L, and 50.17 ± 43.88 mg/L, respectively.

Table 1.

The characteristics of the patients at baseline

NI (n = 26)MI (n = 28)MA (n = 53)p value
Age, years 50.5±12.5 46.2±19.8 54.7±18.3 0.087 
Weight, kg 61.7±7.9 59.8±12.7 63.1±12.7 0.440 
States 
 Pre-dialysis, n (%) 7 (26.92) 5 (17.86) 5 (9.43) 
 Hemodialysis, n (%) 5 (19.23) 13 (46.43) 38 (71.70) 
 Peritoneal dialysis, n (%) 14 (53.85) 10 (35.71) 10 (18.87)  
Baseline of Hb, g/L 79.9±7.5 81.7±11.4 80.1±11.3 0.760 
Dose of Rox, mg per kg 1.58±0.40 1.58±0.33 1.55±0.40 0.959 
Ferritin, μg/L 124.7 (38.40, 267.0) 182.1 (50.00, 307.4) 195.3 (65.85, 523.3) 0.067 
Folic acid, ng/mL 21.1±16.3 24.1±23.9 16.8±17.0 0.198 
Vitamin B12, pg/mL 478.0 (304.0, 650.8) 527.5 (358.2, 1,019) 486.0 (322.5, 802.0) 0.648 
Serum EPO, mIU/mL 7.765 (6.163, 15.45) 10.89 (6.993, 19.85) 19.88 (8.895, 73.07) 0.005 
Triglyceride, mmol/L 1.4±0.6 1.4±1.2 1.5±0.8 0.902 
Cholesterol, mmol/L 4.2±0.7 3.8±1.2 4.0±1.0 0.349 
NI (n = 26)MI (n = 28)MA (n = 53)p value
Age, years 50.5±12.5 46.2±19.8 54.7±18.3 0.087 
Weight, kg 61.7±7.9 59.8±12.7 63.1±12.7 0.440 
States 
 Pre-dialysis, n (%) 7 (26.92) 5 (17.86) 5 (9.43) 
 Hemodialysis, n (%) 5 (19.23) 13 (46.43) 38 (71.70) 
 Peritoneal dialysis, n (%) 14 (53.85) 10 (35.71) 10 (18.87)  
Baseline of Hb, g/L 79.9±7.5 81.7±11.4 80.1±11.3 0.760 
Dose of Rox, mg per kg 1.58±0.40 1.58±0.33 1.55±0.40 0.959 
Ferritin, μg/L 124.7 (38.40, 267.0) 182.1 (50.00, 307.4) 195.3 (65.85, 523.3) 0.067 
Folic acid, ng/mL 21.1±16.3 24.1±23.9 16.8±17.0 0.198 
Vitamin B12, pg/mL 478.0 (304.0, 650.8) 527.5 (358.2, 1,019) 486.0 (322.5, 802.0) 0.648 
Serum EPO, mIU/mL 7.765 (6.163, 15.45) 10.89 (6.993, 19.85) 19.88 (8.895, 73.07) 0.005 
Triglyceride, mmol/L 1.4±0.6 1.4±1.2 1.5±0.8 0.902 
Cholesterol, mmol/L 4.2±0.7 3.8±1.2 4.0±1.0 0.349 

Data are described as means ± standard deviation or mean (Q25, Q75). The baseline patient characteristics were adjusted using IPTW. There were no significant differences between the groups.

NI, non-inflammation; MI, microinflammation; MA, macroinflammation; Hb, hemoglobin; Rox, roxadustat; EPO, erythropoietin; IPTW, inverse probability of treatment weighting.

Of note, the levels of hsCRP at week 12 were still significantly elevated in the MI and MA groups, indicating that there was persistent inflammation during follow-up (online suppl. Fig. 1). In addition, there was no statistically significant difference in the roxadustat dose across all three groups at baseline, 12, 24, or 52 weeks, and the exact roxadustat dose is provided in the online supplementary Table 2.

Hemoglobin Levels

Roxadustat treatment resulted in a significant increase in the hemoglobin level over time in all the three groups (Fig. 1) and did not show any significant difference (all p > 0.05, respectively). At week 12, the mean hemoglobin level was 101.27 ± 2.76 g/L in the NI group; 107.17 ± 3.40 g/L in the MI group (hemoglobin level of 95% confidence interval [CI], −4.6 to 15.3); 97.98 ± 2.39 g/L in the MA group (hemoglobin level of 95% CI, −12.4 to 5.6). Similar outcomes were also observed at weeks 24 and 52. Overall, roxadustat treatment could significantly increase the hemoglobin level during the follow-up period in all the three groups.

Fig. 1.

Change in hemoglobin levels after treatment with roxadustat. (The error bars indicate standard errors.) N.S., no significance. Upper, MI versus NI; lower, MA versus NI.

Fig. 1.

Change in hemoglobin levels after treatment with roxadustat. (The error bars indicate standard errors.) N.S., no significance. Upper, MI versus NI; lower, MA versus NI.

Close modal

Hemoglobin Response Rate

The percentage of patients with a hemoglobin response was 88.46% in the NI group, 57.14% in the MI group, and 67.92% in the MA group at week 12. At week 52, the percentage of patients with a hemoglobin response was 88.46% in the NI group, 71.43% in the MI group, and 79.25% in the MA group. We found that there was no significant difference in the hemoglobin response rate between the NI and MA groups both at weeks 12 and 52 (MA vs. NI: 67.92% vs. 88.46%, p = 0.06; hemoglobin response rate of 95% CI, 0.9531–13.75 at week 12 and 79.25% vs. 88.46%, p = 0.37; hemoglobin response rate of 95% CI, 0.5080–7.937 at week 52). Furthermore, a correlation study showed that the hemoglobin response was independent of the hsCRP level (p = 0.72; response rate of 95% CI, −0.1139 to 0.0794; Figure 2), indicating that the improvement of hemoglobin by roxadustat is not influenced by the severity of inflammation.

Fig. 2.

Correlation study showed the relationship between hemoglobin response and hsCRP level. Shown is the relationship between the change from baseline in the hemoglobin level and hsCRP level at week 12.

Fig. 2.

Correlation study showed the relationship between hemoglobin response and hsCRP level. Shown is the relationship between the change from baseline in the hemoglobin level and hsCRP level at week 12.

Close modal

Iron and Hepcidin Levels

The levels of ferritin and serum iron were significantly decreased, whereas the level of TIBC was significantly increased over time in all the three groups. However, the transferrin saturation level was stable in all the three groups (Fig. 3). Of note, there was no significant difference in all iron metabolism parameters among the three groups at the corresponding time (all p > 0.05). Furthermore, the level of hepcidin in patients in the MA group was significantly decreased at week 12 (p = 0.0018; 95% CI, 7.212–26.33; Fig. 4).

Fig. 3.

Effects of roxadustat on iron metabolism levels among the three groups at the corresponding time. Levels of ferritin (a), serum iron (b), TIBC (c), and TSAT (d). The error bars indicate standard errors. N.S., no significance. a Upper, MA versus NI; lower, MI versus NI; b upper, MA versus NI; lower, MI versus NI; c upper, MI versus NI; lower, MA versus NI; d upper, MA versus NI; lower, MI versus NI.

Fig. 3.

Effects of roxadustat on iron metabolism levels among the three groups at the corresponding time. Levels of ferritin (a), serum iron (b), TIBC (c), and TSAT (d). The error bars indicate standard errors. N.S., no significance. a Upper, MA versus NI; lower, MI versus NI; b upper, MA versus NI; lower, MI versus NI; c upper, MI versus NI; lower, MA versus NI; d upper, MA versus NI; lower, MI versus NI.

Close modal
Fig. 4.

Effects of roxadustat on hepcidin levels. The data shown are the mean hepcidin levels at week 12 in the inflammation group. There was a significant reduction in the hepcidin level after the treatment (p = 0.0018; 95% CI, 7.212–26.33). The error bars indicate standard errors.

Fig. 4.

Effects of roxadustat on hepcidin levels. The data shown are the mean hepcidin levels at week 12 in the inflammation group. There was a significant reduction in the hepcidin level after the treatment (p = 0.0018; 95% CI, 7.212–26.33). The error bars indicate standard errors.

Close modal

In addition, it appears that fewer patients needed oral iron supplementation in the MA group (n = 24, 45.28%) compared to those in the NI group (n = 16, 61.54%) and MI group (n = 14, 50.0%). The amounts of oral iron prescribed per month are equivalent (ferrous succinate 200 mg twice per day). No one was prescribed intravenous iron.

Safety

The mean systolic pressure level was stable through 52 weeks in all the three groups, and there was no significant difference among the three groups. Meanwhile, the mean diastolic pressure levels were also similar among the three groups (Table 2).

Table 2.

The change in blood pressure and serum potassium levels after treatment with roxadustat

Week 12Week 24Week 52
SBP, mm HgDBP, mm Hgserum K+, mmol/LSBP, mm HgDBP, mm HgSerum K+, mmol/LSBP, mm HgDBP, mm HgSerum K+, mmol/L
NI 142.0±12.3 76.6±6.5 4.45±0.81 143.4±11.3 80.5±9.5 4.34±0.72 142.1±10.9 78.2±6.0 4.07±0.54 
MI 139.9±16.4 78.1±7.9 4.11±0.56 143.5±10.4 79.6±6.0 4.34±0.53 138.1±14.5 80.8±7.2 4.13±0.51 
MA 137.6±12.3 77.5±8.6 4.27±0.59 140.1±13.1 77.0±9.3 4.35±0.47 138.9±9.8 78.9±6.7 4.65±0.48 
p value 0.56 0.91 0.38 0.63 0.30 0.36 0.61 0.88 0.10 
Week 12Week 24Week 52
SBP, mm HgDBP, mm Hgserum K+, mmol/LSBP, mm HgDBP, mm HgSerum K+, mmol/LSBP, mm HgDBP, mm HgSerum K+, mmol/L
NI 142.0±12.3 76.6±6.5 4.45±0.81 143.4±11.3 80.5±9.5 4.34±0.72 142.1±10.9 78.2±6.0 4.07±0.54 
MI 139.9±16.4 78.1±7.9 4.11±0.56 143.5±10.4 79.6±6.0 4.34±0.53 138.1±14.5 80.8±7.2 4.13±0.51 
MA 137.6±12.3 77.5±8.6 4.27±0.59 140.1±13.1 77.0±9.3 4.35±0.47 138.9±9.8 78.9±6.7 4.65±0.48 
p value 0.56 0.91 0.38 0.63 0.30 0.36 0.61 0.88 0.10 

Plus-minus values are means ± standard deviation. There were no significant differences among the groups.

SBP, systemic blood pressure; DBP, diastolic blood pressure; K+, potassium; NI, non-inflammation; MI, microinflammation; MA, macroinflammation.

Mean serum potassium level was also stable throughout 52 weeks. At week 12, the mean serum potassium level was 4.45 ± 0.81 mmol/L in the NI group, 4.11 ± 0.56 mmol/L in the MI group, and 4.27 ± 0.59 mmol/L in the MA group. The treatment difference was similar among the three groups (all p > 0.05). Similar outcomes were also observed at weeks 24 and 52 (Table 2).

For acidosis, at week 12, the incidence of acidosis was 11.53% in the NI group, 10.71% in the MI group, and 11.32% in the MA group. The difference was similar among the three groups (all p > 0.05). Similar outcomes were also observed at weeks 24 and 52. In addition, there was no significant difference in the major adverse cardiovascular events (2/26 in NI group, 3/28 in MI group, and 6/53 in MA group) and thrombosis (3/26 in NI group, 2/28 in MI group, and 4/53 in MA group) among the three groups.

Anemia is a critical complication of CKDs, causing high mortality and morbidity. Although ESAs have greatly reduced the opportunity of blood transfusion, the number of patients resistant to this therapy due to systemic inflammation is still a big challenge for clinicians [11]. Concurrent inflammation is always associated with a poor response to ESA therapy (ESA hyporesponsiveness) [12], which stimulates clinicians to use a higher ESA dosage to maintain hemoglobin levels and subsequently induces a higher cardiovascular risk. Moreover, the disturbance of iron metabolism is also frequently presented in inflammation, via the increase of hepcidin, thereby inhibiting the absorption of intestinal iron, iron mobilization, and utilization [13]. More recently, roxadustat, the first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor, has been demonstrated to improve the hemoglobin level in renal anemia by many clinical trials [14‒16], which was even shown effective in patients with microinflammation. However, its exact efficacy on renal anemia with macroinflammation has not been studied previously.

In this single-center, retrospective cohort study, we first analyzed the efficacy of roxadustat on renal anemia; specifically, we included the patients with microinflammation and macroinflammation, as assessed on the baseline of hsCRP levels. We found that roxadustat could significantly increase hemoglobin level without being influenced by the inflammatory status. There was no significant difference in the hemoglobin response rate both at weeks 12 and 52. More impressively, it was shown that the hemoglobin response was independent of baseline hsCRP level. Of note, although there was no significant difference in hemoglobin level among the three groups, the rate of hemoglobin increase in the MA group seemed to be slower. This study provided important clinical evidence that roxadustat might be a valuable choice for treatment of CKD patients with systemic inflammation.

Under the condition of inflammation or infection, functional iron deficiency is one of the most common clinical features in patients with CKDs [17]. Mechanistically, the increased hepcidin, which is stimulated by proinflammatory cytokines (including tumor necrosis factor-α, interleukin-1, and interleukin-6), is known to be the key factor [18]. Interestingly, in the present study, we found that roxadustat could significantly improve iron metabolism by reducing the ferritin level and serum iron level and increasing the TIBC. Furthermore, roxadustat significantly decreased the hepcidin level in the MA group. Although the mechanism of hepcidin-lowering effect of roxadustat remains unclear, we speculate that the improvement of internal iron stores may contribute to the beneficial effect of this new class of drug.

We realized that there are some limitations in the nature of this study. This is a single-center, retrospective study rather than a prospective randomized controlled study. Secondly, we mainly focused on the hemoglobin level of patients rather than its potential mechanism on inflammatory anemia. In viewing the lack of an efficient therapy for inflammatory renal anemia, our work may stimulate the further development of a more aggressive prospective study of roxadustat to deal with this clinically challenging issue.

In summary, this study demonstrated for the first time that roxadustat significantly improves renal anemia with macroinflammation and iron disturbance. Clearly, large-scale clinical trials are urgently needed and so is the understanding of the potential mechanism as well.

This study protocol was reviewed and approved by Zhong Da Hospital, Southeast University, approval number 2019ZDSYLL193-P01, and relevant studies were complied with the guidelines and regulations of the World Medical Association Declaration of Helsinki. Written informed consent was obtained for participation in this study.

The authors confirm that there are no conflicts of interest.

This work was supported by the Key Program of National Natural Science Foundation of China (82030024 and 82230022), the National Natural Science Foundation of China (82000648), the Natural Science Foundation of Jiangsu Province (BK20200363), the Outstanding Youth Cultivation Foundation of Southeast University (2021ZDYYYQPY07), and the Fundamental Research Funds for the Central Universities (2242023K40046).

Y.T., Z.L.L., and B.C.L. designed the study, analyzed data, and wrote and edited the paper. H.L., R.N.T., and G.H.W. collected the data, analyzed the data, and made the figures. L.L.L. and B.W. analyzed the data and edited the paper. All authors approved the final version of the paper.

Additional Information

Yan Tu and Zuo-Lin Li contributed equally to this work.

Data are not publicly available due to ethical reasons. Further enquiries can be directed to the corresponding author.

1.
Kidney Disease Improving Global Outcomes
.
KDIGO clinical practice guideline for anemia in chronic kidney disease
.
Kidney Int Suppl
.
2012
;
2
(
4
):
279
335
.
2.
Ganz
T
.
Anemia of inflammation
.
N Engl J Med
.
2019
;
381
(
12
):
1148
57
.
3.
Raichoudhury
R
,
Spinowitz
BS
.
Treatment of anemia in difficult-to-manage patients with chronic kidney disease
.
Kidney Int Suppl
.
2021
;
11
(
1
):
26
34
.
4.
Gluba-Brzózka
A
,
Franczyk
B
,
Olszewski
R
,
Rysz
J
.
The influence of inflammation on anemia in CKD patients
.
Int J Mol Sci
.
2020
;
21
(
3
):
725
.
5.
Begum
S
,
Latunde-Dada
GO
.
Anemia of inflammation with an emphasis on chronic kidney disease
.
Nutrients
.
2019
;
11
(
10
):
2424
.
6.
Koulouridis
I
,
Alfayez
M
,
Trikalinos
TA
,
Balk
EM
,
Jaber
BL
.
Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis
.
Am J Kidney Dis
.
2013
;
61
(
1
):
44
56
.
7.
Li
ZL
,
Tu
Y
,
Liu
BC
.
Treatment of renal anemia with roxadustat: advantages and achievement
.
Kidney Dis
.
2020
;
6
(
2
):
65
73
.
8.
Chen
N
,
Hao
C
,
Peng
X
,
Lin
H
,
Yin
A
,
Hao
L
, et al
.
Roxadustat for anemia in patients with kidney disease not receiving dialysis
.
N Engl J Med
.
2019
;
381
(
11
):
1001
10
.
9.
Chen
N
,
Hao
C
,
Liu
BC
,
Lin
H
,
Wang
C
,
Xing
C
, et al
.
Roxadustat treatment for anemia in patients undergoing long-term dialysis
.
N Engl J Med
.
2019
;
381
(
11
):
1011
22
.
10.
Akizawa
T
,
Iwasaki
M
,
Yamaguchi
Y
,
Majikawa
Y
,
Reusch
M
.
Phase 3, Randomized, double-blind, active-comparator (Darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan
.
J Am Soc Nephrol
.
2020
;
31
(
7
):
1628
39
.
11.
Weir
MR
.
Managing anemia across the stages of kidney disease in those hyporesponsive to erythropoiesis-stimulating agents
.
Am J Nephrol
.
2021
;
52
(
6
):
450
66
.
12.
Smrzova
J
,
Balla
J
,
Bárány
P
.
Inflammation and resistance to erythropoiesis-stimulating agents – what do we know and what needs to be clarified
.
Nephrol Dial Transplant
.
2005
;
20
Suppl 8
:
viii2
7
.
13.
Pasricha
SR
,
Tye-Din
J
,
Muckenthaler
MU
,
Swinkels
DW
.
Iron deficiency
.
Lancet
.
2021
;
397
(
10270
):
233
48
. doi: h.
14.
Fishbane
S
,
El-Shahawy
MA
,
Pecoits-Filho
R
,
Van
BP
,
Houser
MT
,
Frison
L
, et al
.
Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study
.
J Am Soc Nephrol
.
2021
;
32
(
3
):
737
55
.
15.
Fishbane
S
,
Pollock
CA
,
El-Shahawy
M
,
Escudero
ET
,
Rastogi
A
,
Van
BP
, et al
.
Roxadustat versus epoetin alfa for treating anemia in patients with chronic kidney disease on dialysis: results from the randomized phase 3 ROCKIES study
.
J Am Soc Nephrol
.
2022
;
33
(
4
):
850
66
.
16.
Barratt
J
,
Andric
B
,
Tataradze
A
,
Schömig
M
,
Reusch
M
,
Valluri
U
, et al
.
Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES)
.
Nephrol Dial Transplant
.
2021
;
36
(
9
):
1616
28
.
17.
Batchelor
EK
,
Kapitsinou
P
,
Pergola
PE
,
Kovesdy
CP
,
Jalal
DI
.
Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment
.
J Am Soc Nephrol
.
2020
;
31
(
3
):
456
68
.
18.
Agarwal
AK
.
Iron metabolism and management: focus on chronic kidney disease
.
Kidney Int Suppl
.
2021
;
11
(
1
):
46
58
.