Prolyl hydroxylase inhibitors for the treatment of anemia in chronic kidney disease

Anemia is common in chronic kidney disease (CKD) and has been associated with reduced quality of life, the need for red blood cell transfusions and poor outcomes. The main cause of anemia in CKD is an inadequate renal production of erythropoietin (EPO). Treatment with erythropoiesis-stimulating agents (ESAs) and iron are currently the mainstays of anemia therapy in CKD. However, ESAs are not devoid of adverse events and there is a need for newer and safer therapies. Hypoxia-inducible factor (HIF) is a transcription factor that stimulates EPO production and improves iron homeostasis. HIF is regulated by prolyl hydroxylase (PHD) enzymes, whose inhibition stabilizes HIF, increasing the expression of HIF-regulated genes, such as EPO. Several small, orally active, PHD inhibitors (PHDIs) are being investigated for the treatment of renal anemia. PHDIs have demonstrated to effectively increase and maintain hemoglobin levels in ESA-naive patients or patients converted from an ESA, respectively, and to improve iron homeostasis, with no safety issues in CKD patients reported in short-term phase II clinical trials. However, there are potential concerns over the long-term effects of systemic HIF stabilization, such as its effect on carcinogenesis or on diabetic retinopathy. Therefore, the long-term efficacy and safety of PHDIs in renal anemia therapy needs to be demonstrated in the ongoing phase III clinical trials.