Clinical bottom line
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) represent a promising oral therapeutic class for anemia management in patients with dialysis-dependent chronic kidney disease (CKD). Recent meta-analyses and clinical experience suggest that HIF-PHIs effectively increase hemoglobin levels and improve iron utilization with a safety profile comparable to erythropoiesis-stimulating agents (ESAs). However, long-term cardiovascular and mortality outcomes remain incompletely characterized, warranting cautious integration into clinical practice alongside established anemia treatments.
What the evidence shows
Systematic reviews and meta-analyses of randomized controlled trials (RCTs) provide the most comprehensive evidence on HIF-PHIs in dialysis-dependent CKD anemia. Tyagi et al. (2025) conducted a meta-analysis focusing exclusively on dialysis-dependent patients, demonstrating that HIF-PHIs significantly increased hemoglobin levels compared to placebo or ESAs. Improvements in iron metabolism markers, including reductions in hepcidin and increased total iron-binding capacity, were also observed, suggesting enhanced iron availability for erythropoiesis. Similarly, Nasiri et al. (2025) performed a network meta-analysis including both dialysis and non-dialysis CKD populations, confirming that HIF-PHIs improve hemoglobin and iron parameters with no significant increase in major adverse cardiovascular events compared to ESAs.
Clinical experience from single-center observational data supports these findings. Saxena et al. (2024) reported a 1-year real-world experience with desidustat, a HIF-PHI, in dialysis-dependent patients, noting effective anemia correction and a tolerable safety profile. This study adds practical insights into patient characteristics and treatment adherence outside of controlled trial settings.
Mechanistically, HIF-PHIs stabilize hypoxia-inducible factors, promoting endogenous erythropoietin production and modulating iron metabolism pathways, including downregulation of hepcidin. This dual action contrasts with ESAs, which primarily stimulate erythropoiesis without directly affecting iron homeostasis (Parfrey et al., 2021). The oral administration route of HIF-PHIs offers convenience over injectable ESAs, potentially improving patient adherence.
Caveats and uncertainty
Despite encouraging efficacy and short-term safety data, several uncertainties remain. Most RCTs included in meta-analyses have relatively short follow-up durations, limiting assessment of long-term cardiovascular safety and mortality outcomes. The heterogeneity of HIF-PHI compounds and dosing regimens complicates direct comparisons and generalizability. Additionally, the impact of HIF-PHIs on inflammation and potential off-target effects requires further elucidation.
Real-world data, while valuable, are limited by observational design and potential confounding. Saxena et al.’s (2024) single-center experience, for example, may not reflect broader patient populations or practice settings. Furthermore, patient subgroups such as those with active malignancy or severe cardiovascular disease were often excluded from trials, leaving questions about safety in these higher-risk groups.
Regulatory approvals and guideline endorsements vary globally, reflecting ongoing evaluation of benefit-risk profiles. Clinicians should remain vigilant for emerging data, particularly from large phase 4 post-marketing surveillance studies.
How this may change practice
HIF-PHIs offer a novel oral alternative to ESAs for anemia management in dialysis-dependent CKD, potentially simplifying treatment regimens and improving iron utilization. Clinicians may consider HIF-PHIs for patients with suboptimal response or intolerance to ESAs, or those preferring oral therapy. Integration into practice should be guided by individual patient risk assessment, local regulatory status, and emerging evidence on long-term outcomes.
Routine monitoring of hemoglobin, iron parameters, and adverse events remains essential. Given current uncertainties, HIF-PHIs are unlikely to fully replace ESAs imminently but may complement existing therapies. Multidisciplinary collaboration and patient education on the novel mechanism and safety considerations are recommended.
Ongoing research and pharmacovigilance will clarify optimal patient selection, dosing strategies, and long-term safety, informing future guideline updates and clinical decision-making.