HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia.

Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state.

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 â€‹mg/kg, IP, single dose) and turpentine oil (5 â€‹mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 â€‹µg/kg) and desidustat (15 or 30 â€‹mg/kg) for eight weeks. Separately, rhEPO (1-5 â€‹µg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 â€‹mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 â€‹µg/kg) for two weeks and then desidustat (15 â€‹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-1ß, 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.