Maintenance hemodialysis is the main treatment for end-stage renal disease, which can prolong the survival time of patients, but easily leads to renal anemia. Erythropoietin is an important drug for the treatment of anemia in hemodialysis patients. However, there are many patients with erythropoietin-hyporesponsive anemia. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has been shown to be effective in treating patients with anemia due to chronic kidney disease. This study indicated for that roxadustat significantly increased hemoglobin levels, improved iron absorption and utilization and reduced cholesterol, with good short-term safety in hemodialysis patients with erythropoietin-hyporesponsive anemia.
Hypoxia-inducible factor (HIF) is a transcriptional factor that regulates gene expression in RBC production, angiogenesis, and anaerobic metabolism under hypoxia[7, 8, 19]. Roxadustat, the only new drug marketed by HIF-PHI, has been shown to be effective in the treatment of renal anemia in both dialysis and non-dialysis patients with CKD anemia in phase I-III clinical studies[9–11, 15, 20]. The results of this study showed that in hemodialysis patients with erythropoietin-hyporesponsive anemia, the levels of hemoglobin and HCT in 44 patients after 12 weeks of roxadustat treatment were significantly higher than baseline values. Moreover, hemoglobin began to increase significantly after taking roxadustat, especially at week 12, indicating that roxadustat can quickly and effectively improve anemia index level in renal anemia patients with maintenance hemodialysis.
This study also showed that in hemodialysis patients with erythropoietin-hyporesponsive anemia, roxadustat significantly reduced serum ferritin and maintained TSAT stability. This corroborates studies evaluating the safety and efficacy of roxadustat in the treatment of non-dialysis and dialysis-dependent patients with chronic kidney disease[9–11, 14, 15]. However, no significant difference in TSAT was observed in this study, which may be related to the small sample size of this study. Hemodialysis patients have an imbalance of iron homeostasis due to a variety of reasons, including decreased appetite in CKD patients, commonly used drugs (such as phosphorus binding agents and antacids) affecting the uptake of iron by small intestinal epithelial cells, concurrent inflammatory state and so on. In particular, the relative iron supply is insufficient due to the increased iron demand during the use of erythropoietin[16, 21, 22]. Roxadustat improves anemia by reducing serum ferritin amounts, increasing total iron-binding and increasing iron utilization[6, 23, 24]. It has a potential clinical application value in erythropoietin hyporesponsive anemia patients with iron metabolism disorder.
In addition to the erythropoietic effects of roxadustat, it was associated with lower plasma lipid levels in this study. This was consistent with previous studies of roxadustat in patients with non-dialysis-dependent and dialysis-dependent CKD[16, 25–27]. This is the first time that roxadustat was found to have the same cholesterol and triglyceride lowering effects in hemodialysis patients with erythropoietin-hyporesponsive anemia. None of the enrolled patients took lipid-lowering drugs during the whole study period. The underlying mechanisms of roxadustat involved in lowering lipid levels may be related to HIF1α directly regulating the expression of a number of genes possibly affecting lipid metabolism[16, 25, 28, 29].
In addition, no statistically significant difference was observed in hsCRP levels after 12 weeks of roxadustat treatment in this study, while WBC and neutrophil amounts were significantly increased. These findings are inconsistent with previous studies assessing the effect of roxadustat in patients with inflammation[11, 26]. This may indicate that inflammation does not affect the therapeutic effect of roxadustat in hemodialysis patients with erythropoietin-hyporesponsive anemia.
Of the 56 subjects administered roxadustat, 44 (78.6%) completed the 12-week treatment period and 12 (21.4%) were withdrawn. The reasons for withdrawal were death (n = 1), kidney transplantation (n = 1), blood transfusion (n = 1), drug discontinuation caused by adverse events (n = 2), and loss to follow-up (n = 7). There were no significant differences in liver function, iPTH, and hsCRP among the 44 patients treated with roxadustat at 12 weeks from baseline. The short-term safety of roxadustat is good. Studies have shown that the main adverse reactions of roxadustat include mild diarrhea, nausea, and headache[30, 31]. Such adverse reactions were not recorded in this study, which may be related to the short observation time. Closer attention should be paid to the safety of roxadustat, especially regarding its potential effects on tumor formation and the cardiovascular system. In addition, long-term clinical trials are warranted to examine the long-term safety of roxadustat.
This study had some limitations, including the small sample size and insufficient observation time. As a new drug, the long-term efficacy and safety of HIF-PHI in patients with erythropoietin-hyporesponsive anemia need to be further clarified; specifically, in terms of long-term treatment, more evidence-based findings are needed.
This study indicate that roxadustat can significantly increase hemoglobin levels, improve iron absorption and utilization and reduce lipid levels, with a good short-term safety profile in hemodialysis patients with erythropoietin-hyporesponsive anemia. Moreover, the drug is an oral preparation and easy to use, has good compliance, and can be popularized in patients with erythropoietin hyporesponsiveness.