Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF‐PH inhibitors

Abstract

Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard‐of‐care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF‐prolyl hydroxylase inhibitors (HIF‐PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia‐Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF‐PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia‐Pacific region who have clinical experience or have been investigators in HIF‐PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF‐PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF‐PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.

Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference

“…Recent recommendations by the Asian Pacific Society of Nephrology emphasized the importance of avoiding excessive serum iron lowering by HIF-PHIs to minimize the risk of associated adverse effects. 181 Additional areas of uncertainty. Several mechanistic knowledge gaps and high-priority research areas regarding HIF-PHIs were identified (Table 1).…”

HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review

“…It remains to be seen whether such selectivity affects the malignancy risk of individual PHDs. Among various drugs that have been developed, at least five HIF-PHIs, approved for the treatment of renal anemia in Japan, are being used in clinical practice as of 2021 [ 24 ].…”

“…Absorption of orally administered HIF-PHIs from the intestinal tract can result in HIF activation in most cells in the body. HIF-PHIs are clinically used for the treatment of renal anemia [ 24 , 25 , 113 ].…”

“…In addition, for HD patients, it was stated that it is desirable to start ESA therapy when the Hb level does not fall below 9.0 g/dL, as it is not reasonable to maintain Hb levels above 11.5 g/dL [ 116 ]. It is now advocated that renal anemia should be managed with adequate iron supplementation followed by ESA or HIF-PHIs [ 24 , 116 ]. The target hemoglobin level for CKD in the conservative phase is 11–13 g/dL and that for CKD in the hemodialysis phase is 10–12 g/dL.…”

“…In this review, I describe the process of molecular cloning of HIF and HIF-PH, which explains the induction of EPO expression by hypoxia; the development of HIF-PH inhibitors (HIF-PHIs) that artificially activate HIF by inhibiting HIF-PH; medical interventions that utilize HIF-PHIs; and the implications and significance of these interventions [ 24 , 25 ]. In addition, this review will specifically describe HIF-PHIs, which are currently prescribed in medical practice, and explain its biological effects in addition to its anemia-alleviating effects in relation to its molecular mechanism.…”