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 inhibitors8,14,15. 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 outcomes16–18.
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 levels7,19. 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 ESA7,20. However, stable TSAT and ferritin levels even after roxadustat and daprodustat treatment in patients undergoing hemodialysis have also been reported8,14, 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.