EFFECT OF DESIDUSTAT, A PROPYL HYDROXYLASE INHIBITOR, IN EPO-REFRACTORY
ANEMIA
Amit Joharapurkar, Vishal Patel, Samadhan Kshirsagar, Maulik Patel, Hardikkumar Savsani and Mukul
Jain
Zydus Research Centre, Ahmedabad, India
Objective: Recombinant human erythropoietin (rHuEPO) and iron supplementation are the
mainstays in treating CKD-induced anemia. However, EPO-refractory anemia is found among
CKD populations caused by inflammation, deranged iron utilization, oxidative stress, older
age, and EPO antibody. Hence, there is an urgent need for the treatment of EPO-refractory
renal anemia. Treatment with desidustat, a small molecule inhibitor of hypoxia-inducible
factor prolyl hydroxylase (HIF-PHI), has shown improved renal anemia in CKD patients. Here,
we present the beneficial effects of desidustat in treating refractory renal anemia associated
with the presence of anti-EPO antibodies.
Methods: Sprague Dawley rats were treated with cisplatin (5mg/kg, IP, single dose) and
turpentine (5mL/kg, SC, once a week) to induce anemia. These anemic rats were treated
with recombinant human EPO (1μg/kg, three times a week for the next eight weeks) to
induce EPO-resistance. Desidustat (15 or 30 mg/kg, alternate day) or vehicle was co-administered
along with EPO. In a similar experiment, the EPO dose was varied between 1 to
5 μg/kg (thrice a week) to maintain the hemoglobin levels to normal.
Results: Chronic treatment with EPO induced EPO-resistance in anemic SD rats. Desidustat
co-administration reduced EPO-resistance development in a dose-related manner and
increased iron utilization by decreasing hepcidin, IL-6, and IL-1β levels in serum, which were
accompanied by a dose-related increase in ferroportin levels. Desidustat treatment also
reduced the requirement of EPO for maintaining normal hemoglobin levels and decreased
the anti-EPO antibodies.
Conclusion: The novel prolyl hydroxylase inhibitor desidustat can treat red cell aplastic
anemia caused by anti-EPO antibodies by improving the iron metabolism and decreasing
inflammation.
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