Inhibition of alternative complement system and prolyl hydroxylase ameliorates anaemia of inflammation

Chronic diseases associated with inflammation cause early destruction of RBCs. Complement system, part of innate immunity, is involved in such RBC destruction. Persistent inflammation causes kidney injury, leading to reduced erythropoietin release and functional iron deficiency, causing anaemia. We have investigated effect of iptacopan, a factor B inhibitor, and desidustat, a prolyl hydroxylase inhibitor in anaemia induced by peptidoglycan polysaccharide (PGPS) treatment in rats. Inflammation, haemolysis and its diagnostic markers (LDH, total bilirubin, and RBC lifespan) were evaluated after three days of PGPS challenge. Haemoglobin, RBC, iron homeostasis, and RBC destruction were evaluated fourteen days after PGPS challenge. Desidustat (15 mg/kg) and iptacopan (20 mg/kg) were given along with PGPS and continued for two weeks. Iptacopan and its combination with desidustat prevented LDH, total bilirubin, complement protein-C3a and haemolysis. Combination treatment caused an early normalization of haemoglobin and RBC. Combination also reduced WBC, alkaline phosphatase, aspartate aminotransferase, and rat paw volume. Serum iron was increased by desidustat and its combination treatment. Spleen weight, tissue iron, and serum hepcidin were reduced by combination treatment. Effect of desidustat alone was prominent on iron (serum and tissue) and hepcidin. Thus, combination of iptacopan and desidustat can be a potentially useful therapeutic option for treatment of anaemia of inflammation.