Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

Abstract

Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 ​mg/kg, IP, single dose) and turpentine oil (5 ​mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 ​μg/kg) and desidustat (15 or 30 ​mg/kg) for eight weeks. Separately, rhEPO (1-5 ​μg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 ​mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 ​μg/kg) for two weeks and then desidustat (15 ​mg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1β, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.

Keywords: Antibody; Desidustat; EPO resistance; Inflammation.

Graphical abstract

Fig. 1

Effect of desidustat on development of EPO-resistance in anemia induced by cisplatin and turpentine oil in rats. A, hemoglobin response over time, B, serum iron, C, liver iron, D, spleen iron, E, serum hepcidin, F, hepcidin expression in liver, G, ferroportin (FPN1) expression in liver, H, serum IL-6, I, serum IL-1β. The serum and tissue parameters (B to H) were measured at the end of 8 weeks treatment. The data expressed as mean ​± ​SEM, n ​= ​9 per group. ∗ indicate P ​< ​0.05 compared with vehicle control, $ indicate P ​< ​0.05 compared with rhEPO treatment.

Fig. 2

Effect of desidustat on bone marrow histology on development of EPO-resistance in anemia induced by cisplatin and turpentine oil in rats. A, repsentative image Myeloid: Erythroid and Lymphoid: Erythroid cells ratio, The data expressed as mean ​± ​SEM, n ​= ​9 per group. B, representative images of the bone marrow cell population at the end of the treatment period. ∗ indicate P ​< ​0.05 compared with vehicle control, $ indicate P ​< ​0.05 compared with rhEPO treatment.

Fig. 3

Desidustat protected against EPO refractory state in anemia induced by cisplatin and turpentine oil in rats. A, hemoglobin response over time, B, cumulative rhEPO dose given over time, C, antibody titer, and D, Serum EPO, at the end of 8 weeks of rhEPO and desidustat treatment. The data expressed as mean ​± ​SEM, n ​= ​9 per group. ∗ indicates P ​< ​0.05 compared with vehicle control, $ indicates P ​< ​0.05 compared with rhEPO treatment.

Fig. 4

Effect of desidustat on hemoglobin after switching from rhEPO therapy in anemia induced by cisplatin and turpentine oil in rats. A, hemoglobin response over time, B, serum iron, C, liver iron, and D, spleen iron. Iron levels in serum, spleen and liver was measured at the end of experiment. The data expressed as mean ​± ​SEM, n ​= ​9 per group. ∗ indicates P ​< ​0.05 compared with vehicle control, $ indicates P ​< ​0.05 compared with rhEPO treatment.