Whether Prolyl Hydroxylase Blocker—Roxadustat—In the Treatment of Anemia in Patients with Chronic Kidney Disease Is the Future?

Abstract

In patients with chronic kidney disease (CKD), anemia develops gradually, which is primarily due to an inadequate synthesis of erythropoietin by the kidneys, as well as to iron disorders in the body, blood loss, shortened erythrocyte survival and inflammation. The currently accepted treatment employs iron, vitamin B12, folic acid supplementation and the use of erythropoiesis stimulants, which are administered only parenterally. Research is currently underway on the new erythropoiesis drugs that can be orally administered, i.e., hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI) inhibitors which temporarily block propyl hydroxylase [PHD] catalysis and promote a transient increase in the expression of genes regulated by HIF, including kidney and liver erythropoietin [EPO ]. Roxadustat is the first oral drug in this class and a potent HIF-PHD inhibitor, exerted to treat anemia in patients with CKD. In phase 1, 2 and 3 studies with CKD-affected patients, roxadustat was more effective to stimulate erythropoiesis for anemia correction than previously used drugs. Roxadustat can be orally given, unlike other erythropoiesis drugs with parenteral administration only, which grants roxadustat a considerable advantage. Our paper presents the results of studies with roxadustat applied for the treatment of anemia in CKD patients with or without dialysis. We are currently not yet able to know the exact role of roxadustat in the treatment of anemia in patients with CKD, but time will tell. It is possible that roxadustat has benefits an iron metabolism and cardiovascular risk.

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

“…Several phase 3 trials further evaluating the efficacy and safety of HIF-PHI in CKD patients including the long-term cardiovascular risk are currently ongoing. Interestingly, roxadustat also raised hemoglobin levels in CKD patients with immune activation [323][324][325], which suggests that HIF-PHI might be a possible treatment strategy for anemia in patients with other chronic inflammatory disease, a notion that needs to be experimentally and clinically verified.…”

Platelets in Renal Disease

“…Accordingly, correcting anemia appears to lower the risk of bleeding, while stimulating hematopoiesis using erythropoietin increases platelet reactivity and, correspondingly, increases the occurrence of ischemic events [132][133][134]. Nonetheless, compared to traditional treatments, roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors have recently been approved for treating chronic renal anemia, and are associated with a relatively low risk of cardiovascular events compared to traditional treatments [135][136][137]. Furthermore, they can ameliorate systemic inflammation and potentially benefit iron and lipid metabolism [138][139][140].…”

Roxadustat: Not just for anemia

“…Inflammation suppresses the response to an ESA, but the effects of roxadustat on Hb appear to be unaffected by inflammation (Bradbury et al, 2009;Akizawa et al, 2020d). Compared with ESAs, roxadustat appears to cause greater suppression of hepcidin (Ogawa et al, 2020;Grzeszczak et al, 2021). As a likely consequence, roxadustat is effective in some individuals who are relatively resistant to ESAs.…”

“…This drug stabilizes the level of HIF and stimulates erythropoiesis in a dose-dependent manner ( Chang et al, 2019 ). Clinical trials of roxadustat began in November 2005 ( Grzeszczak et al, 2021 ) and it was first approved in China for treatment of anemia patients receiving hemodialysis or peritoneal dialysis in December 2018 ( Dhillon, 2019 ). In August 2019, roxadustat was approved for the treatment of anemia in Chinese patients with chronic kidney disease (CKD) but not receiving dialysis ( Li et al, 2020a ).…”