Efficacy of daprodustat on anemia in hemodialysis patients with sustained inflammation: a case report

Abstract

Hypoxia-inducible factor prolyl hydroxylase inhibitors improve anemia in CKD and dialysis patients and were approved for anemia treatment with these populations in Japan. An 89 year-old man with anemia and on maintenance hemodialysis was successfully treated with a dose-up of darbepoetin alfa from 10 to 20 μg per week, and the dose was gradually tapered to 5 μg. Later, serum hemoglobin levels decreased with the newly occurring sustained inflammation and left pleural effusion of an unknown cause, and the darbepoetin alfa dose was increased again to 20 μg per week, which was not effective. Darbepoetin alfa was switched to 4 mg of daprodustat daily, which was fairly effective under sustained inflammation, with serum hemoglobin levels maintained at 11–12 g/dL. The increase in hemoglobin levels was ascribed to the increase in the number of red blood cells, not the mean corpuscular hemoglobin level. During the inflammatory state, despite the contrasting effect on anemia by the 20 μg of darbepoetin alfa weekly and 4 mg of daprodustat daily, the reticulocyte counts were equivalent. The serum erythropoietin levels during daprodustat administration were within the physiological range (8.5–18.8 mIU/mL). For anemia treatment in hemodialysis patients, daprodustat is less influenced by the inflammatory status than darbepoetin alfa, and one of the possible reasons for this includes the extended red blood cell lifespan.

Introduction

Anemia is common in hemodialysis patients, and the relative deficiency of erythropoietin (EPO) is the main cause [1]. Anemia management in hemodialysis patients was revolutionized by the introduction of erythropoietin-stimulating agents (ESAs) in the late 1980 s, which have become the mainstay of anemia treatment [2]. Hypoxia-inducible factor stabilization stimulates erythropoietin (EPO) synthesis and decreases hepcidin, which regulates iron homeostasis [3]. In Japan, five agents of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are available, and it has been reported that compared with erythropoiesis-stimulating agents (ESAs), their effect on anemia is less influenced by inflammatory status [4].

In a hemodialysis patient for whom darbepoetin alfa (DA) was not effective, likely due to pleurisy inflammation, we administered daprodustat. Daprodustat was effective for anemia treatment, and we considered the possible mechanisms of this effect.

Case report

An 89 year-old man newly introduced to maintenance hemodialysis due to nephrosclerosis was transferred to our clinic. At the start of hemodialysis treatment in our clinic, he was iron deficient (iron, 18 μg/dL; transferrin saturation, 7.34%; and ferritin, 23.2 ng/mL), and oral (50 mg of sodium ferrous citrate daily) and intravenous (40 mg of ferric oxide saccharate, twenty times) iron was administered. Iron administration was effective, hemoglobin levels increased to 13.5 g/dL, and DA was temporarily discontinued. The increase in hemoglobin levels was due to the increase in the mean corpuscular hemoglobin (MCH) level, not in the red blood cells (RBCs) (*1 to *3 in Fig. 1 and Table 1).

Fig. 1.

Changes in hemoglobin and C-reactive protein levels, mean corpuscular hemoglobin levels, red blood cell count, reticulocyte count, erythropoietin levels, and representative chest X-ray during the anemia treatments. The dashed square represents the period when darbepoetin alfa and daprodustat were administered concomitantly. W week, D day

Table 1.

Changes in clinical parameters during the anemia treatments

	*1	*2	*3	*4	*5	*6	*7	*8	*9	*10	*11	*12	*13
Darbepoetin alfa (μg/week)	60	60	5	10	20	20	5	5	20	20	20	0	0
Daprodustat (mg/day)	0	0	0	0	0	0	0	0	0	0	4	4	4
Ferric oxide saccharate (mg/week)	0	0	120	0	0	0	0	0	0	0	0	0	0
Sodium ferrous citrate (mg/day)	0	50	50	0	0	0	0	0	0	0	0	0	0
Ferric citrate (mg/day)	0	0	0	500	500	500	500	500	500	500	500	500	500
Creatinine (mg/dL)	6.88	7.89	9.50	7.92	8.65	9.16	7.63	8.33	7.80	7.58	6.43	6.76	7.91
Blood urea nitrogen (mg/dL)	31.9	60.6	77.3	50.6	53.2	47.8	77.4	64.3	43.9	44.1	38.5	56.9	67.7
Hemoglobin (g/dL)	10.4	10.6	13.0	8.8	9.5	10.6	9.4	7.6	7.7	7.7	10.4	11.3	12.0
MCH (pg)	25.2	24.2	29.3	31.0	32.6	32.1	30.2	30.8	30.2	29.2	30.1	29.2	30.2
RBC × 10,000/μL	413	438	444	284	291	330	311	247	255	264	345	387	398
Reticulocyte (‰)	11	13	5	15	21	11	9	6	8	8	13	9	6
Reticulocyte, /mm3/1000	45.4	56.9	22.2	42.6	61.1	36.3	28.0	14.8	20.4	21.1	44.9	34.8	23.9
C-reactive protein (mg/dL)	0.05	0.58	0.05	0.03	0.04	0.23	0.09	1.04	1.90	1.92	1.27	0.98	1.14
Ferritin (ng/mL)	23.2	17.5	N/A	N/A	183.2	N/A	177.6	145.4	N/A	N/A	N/A	196.4	225.1
Hepcidin (ng/mL)	N/A	1.6	N/A	N/A	34	N/A	69.4	105.2	N/A	N/A	N/A	30.4	N/A
Iron (μg/dL)	18	87	N/A	N/A	45	N/A	66	33	N/A	N/A	N/A	53	41
TSAT (%)	7.3	28.8	N/A	N/A	26.3	N/A	35.7	18.6	N/A	N/A	N/A	30.8	20.7

The numbers with *correspond to those in Fig. 1

MCH mean corpuscular hemoglobin, RBC red blood cell, TSAT transferrin saturation

After the discontinuation of DA, the hemoglobin levels decreased gradually to less than 9 g/dL, DA was readministered and the dose was finally increased to 20 μg weekly. The hemoglobin levels increased again (*4 to *6 in Fig. 1 and Table 1), and the DA dose was tapered to 5 μg. After that, left pleural effusion followed by inflammation with an unknown cause (thoracoabdominal pelvic computed tomography; left pleural effusion without tumors, gastroscopy and colonoscopy; no abnormalities were observed, and the QuantiFERON test was negative) occurred. Inflammation with a C-reactive protein level greater than 1.0 mg/dL was sustained for more than 12 weeks. During the deterioration of this inflammatory status, hemoglobin levels decreased to less than 8 g/dL, which was not improved despite the dose-up of DA to 20 μg per week (*8 to *10 in Fig. 1 and Table 1). His nutrition status was good, and patient’s parathyroid hormone was controlled within the appropriate range for hemodialysis patients (parathyroid hormone; 175 ~ 227 pg/mL).

We discontinued DA and switched to 4 mg of daprodustat daily. Although we mistakenly administered DA and daprodustat concomitantly for 4 weeks, after the discontinuation of DA, the patient’s hemoglobin levels were maintained at approximately 11 g/dL with 4 mg of daprodustat. The increase in hemoglobin levels during daprodustat administration was parallel to that in the RBCs but not the MCH level (*10 to *13 in Fig. 1 and Table 1).

Discussion

ESAs have become the mainstay of anemia treatment in CKD and dialysis patients [2]. Although ESAs are potent agents for the treatment of renal anemia, the injection of ESAs results in temporally nonphysiologically high-serum EPO concentrations, and a high dose of administered ESAs increases the risk of cardiovascular events, stroke and death, when targeting higher hemoglobin levels (> 13 g/dL) [5].

HIF-PHIs are being developed to treat anemia, which can improve renal anemia with physiological serum EPO concentrations [6]. It has been reported that the mechanisms of action of HIF-PHIs include the induction of erythropoiesis through direct activation of the EPO gene and the induction of a number of genes involved in iron uptake, mobilization and transport [7]; the former mechanism increases serum EPO levels and reticulocyte counts, and the latter increases MCH levels.

We administered 4 mg of daprodustat daily after switching from a previous administration of 20 μg of DA weekly. Except for during the period when DA and daprodustat were administered concomitantly (dashed square in Fig. 1), trough serum EPO levels during the treatment with daprodustat (at the start of the hemodialysis session, which occurred 20 h after the daily daprodustat administration) were less than 20 mIU/mL. Given the serum EPO levels of healthy subjects receiving daprodustat [6], the serum fluctuation of EPO levels during the treatment of 4 mg of daprodustat daily in this case was postulated to be very small, and serum EPO levels are supposed to be consistent within the physiological range, which must not occur during DA treatment. Trough reticulocyte counts (DA: at the start of the hemodialysis session, which occurred 1 week after the DA injection; daprodustat: at the start of the hemodialysis session, which occurred 20 h after the daily daprodustat administration) during the inflammatory state were almost equivalent or slightly higher during the period of daprodustat treatment than during DA treatment (DA: *9 to *10, daprodustat: *12 to *13 in Fig. 1 and Table 1). Given the temporal increase in reticulocyte counts, which peaked around the fourth day during the weekly DA injections [8], and given that a fluctuation will not occur during the daily administration of daprodustat, it was presumed that 20 μg of DA weekly and 4 mg of daprodustat daily produced almost equivalent reticulocyte counts during the inflammatory state. Nevertheless, serum hemoglobin levels during the daprodustat treatment were higher than those during the DA treatment, which may represent the difference in RBC lifespan during both treatments.

In the current case, in contrast to the result that the efficacy of the oral and intravenous iron administration on anemia was mainly due to the increase in MCH levels, not RBC counts, the main cause of the increase in serum hemoglobin levels by both the DA and daprodustat treatments was attributed to the increase in RBC counts, not MCH levels (DA: *4 to *6, daprodustat: *10 to *12 in Fig. 1 and Table 1). The increase in RBC counts does not necessarily mean an increase in reticulocyte synthesis but may also be the consequence of the prolongation of the lifespan of RBCs. Although the main cause of anemia of inflammation is believed to be impaired erythropoiesis [9], a shortened RBC lifespan is also a possible cause of anemia of inflammation, which includes that due to pleurisy [10]. The increase in the serum hemoglobin levels with DA during the noninflammatory state (*4 to *6 in Fig. 1 and Table 1) was accompanied by an increase in the reticulocyte count, but the serum hemoglobin levels increased without an increase in reticulocyte count with daprodustat during the inflammatory state (*11 to *12 in Fig. 1 and Table 1), which could be explained by the prolongation of the lifespan of RBCs.

EPO is a survival factor for RBCs, and ESA administration prolongs the half-life of RBCs; in contrast, the sudden discontinuation of ESA administration results in a shortened half-life of RBCs [11]. Possible mechanisms of this shortened half-life of RBCs include neocytolysis: endothelial cells appear to respond to a rapid decrease in circulating EPO levels, which signal reticuloendothelial phagocytes to destroy neocytes [12]. In contrast to ESA administration, HIF-PHIs can improve anemia with physiological serum EPO levels, and the small fluctuation of serum EPO levels may prevent neocytolysis and participate in the resulting increase in serum hemoglobin levels. Although the mechanisms of HIF-PHIs are postulated to be EPO synthesis and the improvement of iron utilization [3], in our case, these mechanisms may not fully explain the improvement of anemia. Recently, it was reported that roxadustat may extend the lifespan of RBCs [13]. The lifespan of RBCs is shortened in hemodialysis patients [14], an inflammatory status may further shorten the lifespan of RBCs [10], and HIF-PHIs may improve the shortened lifespan of RBCs in hemodialysis patients including those with sustained inflammation.

Finally, although concomitant administration of HIF-PHIs and ESAs is prohibited by the Japanese Society of Nephrology [15], we mistakenly administered DA and daprodustat concomitantly for four weeks. During the period when 20 μg of DA were administered weekly and 4 mg of daprodustat were administered daily concomitantly, the increase in hemoglobin levels was steeper, and more reticulocytes were produced (*10 to *11 in Fig. 1 and Table 1) than during the period when daprodustat was administered alone (*11 to *13 in Fig. 1 and Table 1). Considering the results that DA alone was not effective during the same inflammatory state (*8 to *10 in Fig. 1 and Table 1), it is possible that HIF-PHIs prolong the lifespan of RBCs while HIF-PHIs may also improve the responsiveness to ESAs by the concomitant use of both agents, especially during the inflammatory state.

Conclusion

The refractory anemia of a hemodialysis patient with sustained inflammation was fairly treated with daprodustat switched from DA, and a prolonged lifespan of RBCs is supposed to be one of the mechanisms of anemia improvement. HIF-PHIs are newly developed and promising agents for treating anemia in CKD and dialysis patients, and further experience with and knowledge of their mechanisms of action are warranted.

Declarations

Conflict of interest

The author has declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number 2022 A-1) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from the individual participants included in the study.