Short-term impact of switching from erythropoiesis-stimulating agents and roxadustat to daprodustat among patients undergoing hemodialysis

doi:10.21203/rs.3.rs-1500147/v1

Daprodustat is a novel oral agent for renal anemia. This retrospective study examined 124 maintenance patients undergoing HD who had shifted from erythropoiesis-stimulating agents (ESA) or roxadustat to daprodustat (4mg daily). Anemia control, iron metabolism markers, and doses of daprodustat within 3 months after the shifting therapies were assessed. We used multivariate logistic regression analysis to determine the factors associated with the use of high doses of daprodustat 3 months after. The serum hemoglobin level significantly decreased after shifting therapies. Similarly, the proportion of patients who achieving a hemoglobin level within the appropriate range was also significantly lower, and median doses of daprodustat gradually increased. A significant increase in the serum iron, total iron-binding capacity, and transferrin saturation levels were found, but the serum ferritin level did not differ during the study period. Multivariate regression analysis showed that diabetes, a low Hb level, and use of high doses of ESA/roxadustat were independent predictors for the use of high doses of daprodustat 3 months after shifting therapies. We concluded that renal anemia control may worsen after shifting to daprodustat. Patients with diabetes, a low Hb level at baseline, and those receiving high doses of ESA/roxadustat may require high doses of daprodustat.

anemia

daprodustat

hypoxia-inducible factor

dialysis

Renal anemia, which is caused by a relative deficiency in erythropoietin (EPO) production and shortened red cell survival, is one of the major complications in patients with chronic kidney disease and is associated with increased mortality^1,2. Aside from abnormal hemoglobin (Hb) levels, Hb variability was also associated with increased all-cause mortality^3–5. Thus, maintaining stable Hb levels within target ranges is important to improve clinical outcomes.

Renal anemia was treated by blood transfusions until approximately 1990; thereafter, erythropoiesis-stimulating agents (ESA) have become the mainstay of treatment. Recently, hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors, which stimulate endogenous EPO production and enhance iron metabolism, has become a novel option in clinical practice for the treatment of renal anemia. Daprodustat was first approved in Japan in June 2020⁶, and it is the second HIF-PH inhibitor to be approved in the country. A phase 3 study showed that daprodustat may improve ESA hyporesponsiveness through better iron mobilization and utilization without being inferior to darbepoetin alfa⁷. However, since randomized controlled study was well-structured and included more ideal patient (by using inclusion/ exclusion criteria), the results immediately cannot be expanded to clinical practice.

To bridge the gap between research and clinical practice, the aim of this study was to investigate the short-term impact of daprodustat in clinical practice among patients undergoing hemodialysis with renal anemia maintained on ESA and roxadustat. We also explored predictors of the use of high doses of daprodustat 3 months following the shift of medications.

Patients

This single-center retrospective cohort study was approved by the Showa University Ethics Committee. The study was conducted in accordance with the ethical standards for human experimentation established by the principles of the Declaration of Helsinki and with the ethics guidelines in Japan. Informed consent was obtained by using an opt-out approach. For better renal anemia control on based on several clinical trials^7–9, our hospital attempted to use daprodustat first instead of ESA/roxadustat. Among the 237 outpatients undergoing HD therapy 3 times a week in our hospital from February 2021 to June 2021, 197 had received ESA or roxadustat. Of these, 22 were unable to shift to daprodustat due to following reasons: (1) inability to receive anything by mouth; (2) refusal to switch to daprodustat; (3) presence of myelodysplastic syndrome; and (4) had contraindications for HIF-PH inhibitor use. Thus, 175 outpatients undergoing HD therapy who shifted from ESA or roxadustat to daprodustat were eligible for enrollment. The exclusion criteria were as follows: (1) patients who had been receiving HD therapy for less than 3 months; (2) patients who had received blood transfusions after the shift; (3) patients with low compliance to medications; and (4) patients who did not take daprodustat for 3 months. After applying the exclusion criteria, 124 patients undergoing HD were included in this study (Fig. 1).

Clinical assessment and management of renal anemia

Anemia was managed according to the Guidelines for Renal Anemia published by the Japanese Society for Dialysis Therapy^10− 12. An intravenous (IV) iron preparation (Fesin® 40 mg, Nichiiko Pharmaceutical, Toyoma City, Japan) was administered once a week to maintain the transferrin saturation (TSAT) > 20% and/or serum ferritin > 100 ng/mL when there was difficult maintaining the Hb level within 10.0–12.0 g/dL. After switching to daprodustat, patients received the recommended initial daprodustat dose⁶ (4 mg orally once daily) for the first 2 weeks. Subsequent doses of daprodustat were adjusted at the beginning of every second week before HD and after evaluating the iron status using TSAT and serum ferritin levels to maintain the Hb within the target range.

Clinical Parameters, TSAT, and ferritin

Blood examinations were performed in the supine position prior to HD sessions at the beginning of the week. White blood cell count, levels of Hb, hematocrit, blood urea nitrogen, creatinine, albumin (Alb), C-reactive protein (CRP), ferritin, and iron, total iron-binding capacity (TIBC), and reticulocyte count were measured; serum iron level, TIBC, ferritin level, and reticulocyte count were measured once a month. Similarly, the serum Hb level was assessed once every two weeks. A low Hb level was defined as < 10 g/dL. Absolute iron deficiency was defined as TSAT ≤ 20% and ferritin ≤ 100 ng/mL^10–12. A high dose of ESA/roxadustat was defined as epoetin ≥ 6,000 IU or darbepoetin alfa ≥ 30 µg or roxadustat ≥ 210 mg/week¹³.

Statistical Analysis

Demographic data are presented as median values (range from 25th to 75th percentile, IQR) for continuous variables unless otherwise noted and as numbers (percentage) for categorical variables. The Shapiro–Wilk test was used to assess the normality of the distributions of continuous variables. The values of Hb, reticulocyte count, iron, TIBC, TSAT, and ferritin are also presented as median (IQR). The differences between baseline and 3-months values after shifting to daprodustat were examined by the Wilcoxon rank sum test. Non-parametric Spearman’s rank correlation analysis was used to determine associations between continuous and ordinal variables. We used multivariate logistic regression analysis to assess which factors were associated with high daprodustat doses (≥ 6 mg) at 3 months following the therapy shift after adjusting for several confounders, including gender, age, dialysis vintage, body mass index, diabetes, low Hb level at baseline (≥ 6 mg), Alb, CRP, high dose of ESA/roxadustat before therapy shift, and iron supplementation.

For all tests, the level of significance was set at p < 0.05. Statistical analyses were performed using Stata 16.0 (StataCorp LLC, College Station, TX, USA) and SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).

Characteristics and clinical parameters

Table 1 shows the patients’ characteristics and clinical parameters. The median age was 71 years, and 64.5% of patients were male. The median dialysis duration was 55 months. The most common cause of end-stage renal disease was diabetes nephropathy (48%) followed by chronic glomerulonephritis (24%). Regarding anemia management, approximately 60% of the patients were treated with epoetin. The median weekly dosages of epoetin, darbepoetin alfa, and roxadustat were 4,500, 20, and 300, respectively. When high weekly doses of ESA/roxadustat were defined as epoetin ≥ 6,000 IU or darbepoetin alfa ≥ 30 µg or roxadustat ≥ 210 mg, 49% of the patients required high doses of these treatments. The median Hb level was 10.9 g/dL; however, 16.1% of the patients had Hb levels < 10 g/dL. The median serum TSAT and ferritin were 25% and 91 ng/mL, respectively. The proportion of patients with absolute iron deficiency (TSAT ≤ 20% and ferritin ≤ 100 ng/mL) was 28%. Regarding iron supplementation, 36% and 23% of the patients received IV iron supplementation and ferric citrate hydrate, respectively.

Table 1

Baseline clinical and biochemical characteristics of patients in the study
	Total patients (n = 124)
Demography and clinical characteristics
Age (years)	71 (62–80)
Males, n (%)	80 (64.5%)
Dialysis vintage (months)	55 (27–99)
BMI (kg/m²)	22 (20–26)
Diabetes mellitus, n (%)	67 (54.0%)
Hypertension, n (%)	87 (70.2%)
OMI, n (%)	19 (15.3%)
Cancer, n (%)	6 (4.8%)
Cause of ESKD
CGN	30 (24.2%)
DMN	59 (47.6%)
BNS	10 (8.1%)
ADPKD	2 (1.6%)
other	23 (18.5%)
ESA/HIF-PhD inhibitors (roxadustat)
Epoetin	74 (59.7%)
Weekly dose (IU)	4500 (4,500–9,000)
Darbepoetin Alfa	32 (25.8%)
Weekly dose (µg)	20 (10–30)
Roxadustat	18 (14.5%)
Weekly dose (mg)	300 (278–300)
High dose of ESA/roxadustat^a, n (%)	61 (49.1%)
Circulating biomarkers
WBC (/µL)	5650 (4,630–7,230)
Reticulocyte (%)	16 (12–20)
Hb (g/dL)	10.9 (10.2–11.6)
Low Hb levels (< 10 g/dL) ^b, n (%)	20 (16.1%)
Ht (%)	33 (30.3–34.9)
BUN (mg/dL)	61 (53–70)
Cr (mg/dL)	10.5 (8.7–12.4)
Alb (g/dL)	3.6 (3.3–3.8)
CRP (mg/dL)	0.105 (0.04–0.33)
Iron (µg/dL)	59 (45–73)
TIBC (µg/dL)	237 (215–285)
TSAT (%)	25 (18–33)
Ferritin (ng/mL)	91 (57–149)
Absolute iron deficiency ^c, n (%)	35 (28.2%)
Medications
Iron supplementation	63 (50.8%)
IV iron supplementation, n (%)	44 (35.5%)
Ferric Citrate Hydrate, n (%)	28 (22.6%)
Sucroferric oxyhydroxide, n (%)	4 (3.2%)
Continuous variables are presented as median (25th–75th percentile). Categorical variables are presented as number (n)/percentage (%). ^aDefined as epoetin ≥ 6,000 IU or darbepoetin alfa ≥ 30 µg or roxadustat ≥ 210 mg. ^bDefined as Hb levels < 10 g/dL. ^cDefined as TSAT ≤ 20% and ferritin ≤ 100 ng/mL.
Abbreviations: BMI, body mass index; OMI, old myocardial infarction; ESKD, end-stage kidney disease; CGN, chronic glomerulonephritis; DMN, diabetic nephropathy; BNS benign nephrosclerosis; ADPKD, autosomal dominant polycystic kidney disease; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin; Ht, hematocrit; BUN, blood urea nitrogen; Cr, creatinine; Alb, albumin; CRP, C-reactive protein; TIBC, total iron-binding capacity; TSAT, transferrin saturation; IV, intravenous.

Impacts on anemia and daprodustat dose

Figure 2 shows the changes in anemia status 2 months before and 3 months after shifting therapy. After the shift, Hb levels significantly decreased (except at 1 month after), was maintained after 2 months, and thereafter gradually attenuated, but its level 3 months after the shift was different from that at baseline (Fig. 2a). Regarding the reticulocyte count, it significantly increased 3 months after shifting therapies (Fig. 2b).

A trajectory for the proportion of patients with an Hb level within normal range (10 ≤ Hb < 12 g/dL) as recommended in the JSDT guidelines¹² was similar to the time course of Hb changes (Fig. 2c). On the contrary, the proportion of patients using high-dose daprodustat gradually increased (Fig. 2d).

Changes in iron metabolism

Figure 3 shows the impact on iron metabolism 2 months before and 3 months after shifting therapies. The serum iron, TIBC, and TSAT levels were significantly increased at 1, 2, and 3 months after shifting therapies, respectively. However, the serum ferritin level did not differ.

Univariate correlation analysis and multivariable predictors of high-dose daprodustat use

In the Spearman rank correlation analysis (Table 2), high doses of daprodustat 3 months after shifting therapies was associated with diabetes (rho 0.18, p < 0.05), receiving high doses of ESA/roxadustat (rho 0.32, p < 0.001), and low Hb levels (< 10 g/dl) (rho 0.30, p < 0.001). Interestingly, serum Alb and CRP levels, absolute iron deficiency, and iron supplementation were not associated with a high-dose daprodustat use.

Table 2

Univariate Spearman's Rho correlations of high dose of Daprodustat (≥ 6 mg) with selected variables.
Variables	High-dose Daprodustat Rho correlations	P-value
Age (years)	−0.1071	0.2442
Males	−0.1603	0.0804
Dialysis vintage	−0.0744	0.4196
BMI	0.0137	0.8818
Diabetes mellitus	0.1827	0.0459
OMI, n (%)	−0.1214	0.1866
Hypertension, n (%)	−0.0635	0.4908
Cancer, n (%)	−0.0038	0.9669
Cause of ESKD	0.1316	0.152
High dose of ESA/roxadustat	0.3229	0.0003
WBC (/µL)	−0.1655	0.0708
Low Hb levels	0.2999	0.0007
BUN (mg/dL)	−0.0306	0.7403
Cr (mg/dL)	−0.0946	0.3043
Alb (g/dL)	0.0131	0.8875
CRP (mg/dL)	−0.0988	0.283
Reticulocyte (%)	0.0287	0.7557
Absolute iron deficiency	−0.0486	0.9315
Iron supplementation	−0.0971	0.2835
Abbreviations: BMI, body mass index; OMI, old myocardial infarction; ESKD, end-stage kidney disease; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin; BUN, blood urea nitrogen; Cr, creatinine; Alb, albumin; CRP, C-reactive protein.

Multivariate logistic regression analysis showed that diabetes (OR = 2.64, p < 0.05), receiving high doses of ESA/roxadustat (OR = 5.33, p < 0.01), and low Hb levels (OR = 10.13, p < 0.01) independently predicted the use of high doses of daprodustat (Table 3).

Table 3

Predictors of the use of high doses of daprodustat 3 months after shifting therapies based on multivariate logistic regression analysis
Variables	Odds Ratio	Lower 95%CI	Upper 95%CI	P-value
Gender	0.44	0.18	1.09	0.076
1-SD of Age	0.81	0.52	1.28	0.37
1-SD of dialysis vintage	1.01	0.99	1.01	0.955
1-SD of BMI	1.18	0.76	1.84	0.464
Diabetes mellitus	2.64	1.09	6.41	0.032
Low Hb levels	10.13	2.32	44.26	0.002
1-SD of Alb	1.218	0.73	2.02	0.446
1-SD of CRP	0.96	0.61	1.50	0.857
High dose of ESA/roxadustat	5.33	2.03	13.95	0.001
Iron supplementation	0.51	0.21	1.23	0.134
Abbreviations: BMI, body mass index; Hb, hemoglobin; Alb, albumin; CRP, C-reactive protein; ESA, erythropoiesis-stimulating agents;

Among maintenance hemodialysis dialysis patients using ESA or roxadustat who shifted to daprodustat, we found that the serum Hb levels and proportion of patients who achieved Hb levels within the target range significantly decreased, and the daprodustat dose gradually but significantly increased from the recommended initial dose of 4 mg. The serum iron level and TSAT significantly increased, whereas no significant changes in the serum ferritin level was observed during the study period. Furthermore, we identified diabetes, low Hb level, and use of high doses of ESA/roxadustat as factors that were significantly associated with the use of high doses of daprodustat 3 months after shifting therapies.

Our major finding in our study was the initial decrease in Hb levels 3 months after shifting to daprodustat, which was different from those in other studies regarding HIF-PH inhibitors^8,14,15. In a phase 3 trial assessing the noninferiority of roxadustat to darbepoetin alfa in Japanese patients undergoing hemodialysis, a decline in Hb levels was not reported¹⁴. Regarding the initial roxadustat dose, the initial dose was not specified and was only based on the patient’s previous ESA dose¹⁴. Other phase 3 trials of daprodustat in patients undergoing dialysis that had starting doses between 4 and 12 mg based on the patient’s previous ESA dose also showed no initial decrease in the mean Hb levels after shifting to daprodustat⁸. The median starting dose of daprodustat was 6 mg (IQR, 4–8)⁸, which was greater than that in a study conducted in Japan. On the other hand, in a previous study investigating the efficacy and safety of daprodustat among Japanese patients undergoing hemodialysis, the initial dose of daprodustat was uniformly set at 4 mg for the first 4 weeks, regardless of the patient’s previous ESA dose⁷. After shifting from ESA to daprodustat, the mean Hb level among the patients declined during the first 16 weeks but returned to normal levels thereafter⁷, which was similar with the findings in our study. Additionally, the proportion of patients requiring high daprodustat doses in our study gradually increased, which may result in a subsequent increase in reticulocyte levels after 3 months and an improvement in the ratio of patients who will reach their target Hb levels. Hence, the initial dose of 4 mg/day of daprodustat may be not sufficient for some patients. To improve anemia treatment, the starting dose after shifting therapies should be considered based on pretreatment conditions.

Polypharmacy in patients undergoing dialysis is well-known¹⁶. Compared to ESA/oral roxadustat, which is taken three times weekly, taking daprodustat once daily may result in lower adherence and compliance of patients undergoing hemodialysis, which may cause difficulty in achieving the target Hb range. Considering that 10 patients who switched to daprodustat showed low tolerance in our study (Fig. 1), ESA/roxadustat may be more suitable in some patients to reduce polypharmacy and promote better adherence, thereby resulting in better clinical outcomes^16–18.

Using HIF-PH inhibitors, which inhibit the prolyl hydroxylase domain that results in HIF-1a and HIF-2a stabilization, could result in better iron mobilization and utilization due to erythropoiesis that can maintain appropriate Hb levels^7,19. In previous studies of Japanese patients undergoing hemodialysis and peritoneal dialysis, the decreased ferritin and TSAT levels after shifting to daprodustat was attributed to the potential shift of iron from storage to erythrocyte development, which suggests HIF-PHI drugs improve iron utilization, compared to ESA^7,20. However, stable TSAT and ferritin levels even after roxadustat and daprodustat treatment in patients undergoing hemodialysis have also been reported^8,14, which do not support the theory that HIF-PHI drugs improve iron utilization. In the present study, we also found that stable serum ferritin levels and an increase in TSAT levels were accompanied by an immediate increase in the mean serum iron level and TIBC after shifting from ESA/roxadustat to daprodustat. One possible cause for the discrepancy in the results between these studies, including ours, is the differences in anemia management, especially in the use of IV iron supplementation, which influence iron metabolism parameters. Further studies are needed to clarify if HIF-PHI drugs could promote iron utilization and attenuate ESA hyporesponsive.

In our analysis, diabetes, high doses of ESA/roxadustat, and low Hb levels in patients undergoing hemodialysis were independent predictors for high doses of daprodustat 3 months after shifting therapies. Interestingly, inflammatory (CRP) and nutritional markers (Alb) were not associated with the uses of a high daprodustat dose, which was also in line with the results of a previous study showing that the dose requirement of roxadustat is not be affected by higher hs-CRP levels¹⁴. On the other hand, another previous study pointed out the potential efficacy of daprodustat even in patients hyporesponsive to EPO⁷. However, our findings suggest that patients requiring large doses of ESA/roxadustat may require a dose of daprodustat greater than the recommended initial dose of > 4 mg. Furthermore, our analysis also showed that there was no significant association between iron deficiency and high doses of daprodustat. Our novel findings should remind clinicians that monitoring the Hb response, especially in patients with factors predictive of the use of high doses of daprodustat, is required to achieve favorable clinical outcomes.

Some limitations of the present study should be noted when interpreting the results. Information regarding several factors linked to anemia status that could have had an impact on changes in renal anemia after switching to daprodustat, such as serum concentrations of vitamin B12 and folic acid, were unavailable. We also could not exclude the possibility of gastrointestinal bleeding as upper/lower gastrointestinal endoscopy was not mandatory in all outpatients.

The present study has some strengths worth mentioning. This is the first study to investigate the short-term impact of daprodustat after shifting from ESA and roxadustat in real clinical situations. In addition, we enrolled patients regardless of comorbidities because our intention was to investigate the overall impact of daprodustat while considering the fact that patients undergoing dialysis usually have various comorbidities. In addition to the fact that not all patients always get a detailed examination such as CT and colon fiber, the aging population and major advances in the cancer treatment has led to an increasing number of people who live longer with their cancer. Swedish population-based study showed that more than 20% of the patients undergoing dialysis had the history of the cancer²¹.

In conclusion, an immediate decrease in Hb levels accompanied by worse renal anemia control compared to the baseline was observed during the transition period among patients undergoing hemodialysis who shifted to daprodustat therapy. While there was no significant change in the serum ferritin level, the mean serum iron, TIBC, and TSAT levels significantly increased. The median daprodustat dose also gradually increased compared to the baseline of 4 mg orally once daily. These findings suggested that the starting dose may be determined based on the pretreatment conditions, and heightened surveillance is warranted in patients with diabetes, low Hb level, and previous use of high doses of ESA/roxadustat. However, the external validity should be investigated in future studies.

Disclosures

None of the authors declare any conflict of interest.

Data availability

The datasets used and/or analyzed during the study available from the corresponding author on reasonable request.

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No competing interests reported.

STROBEchecklistcohort.docx

Short-term impact of switching from erythropoiesis-stimulating agents and roxadustat to daprodustat among patients undergoing hemodialysis

Status:

Version 1

Abstract

Figures

Introduction

Patients And Methods

Patients

Clinical assessment and management of renal anemia

Clinical Parameters, TSAT, and ferritin

Statistical Analysis

Results

Characteristics and clinical parameters

Impacts on anemia and daprodustat dose

Changes in iron metabolism

Univariate correlation analysis and multivariable predictors of high-dose daprodustat use

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1