Anemia has a major impact on patient morbidity and mortality and is a typical consequence of chronic kidney disease (CKD).

Erythropoiesis-stimulating agents (ESAs) have long been the standard treatment, but concerns over safety have prompted exploration of alternative approaches.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) emerge as promising contenders, offering a new paradigm for anemia management.

Introduction

Anemia is a common CKD consequence that affects up to 80% of patients with severe CKD and about 30–40% of people in the early stages of the disease.

The use of intravenous iron supplements and erythropoiesis-stimulating agents (ESAs) are two examples of traditional therapy techniques that have drawbacks, including potential safety issues and high costs.

Because of its critical function in the control of erythropoiesis, the hypoxia-inducible factor (HIF) pathway is a desirable target for new therapeutic interventions.

Oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), such as daprodustat and vadadustat, stimulate endogenous erythropoietin production and improve iron metabolism by imitating the physiological response to hypoxia.

It is critical to assess these medicines' safety profiles as they become more widely used in clinical practice in order to guarantee that CKD patients' anemia is managed as best they can.

Management of Anemia in CKD

Managing anemia in chronic kidney disease (CKD) requires a multifaceted approach balancing efficacy with safety.

While erythropoiesis-stimulating agents (ESAs) remain central, concerns over cardiovascular risks mandate cautious use. This class of drugs includes peginesatide, darbepoetin alfa, and epoetin alfa.

Iron supplementation, both oral and intravenous, is crucial for replenishing iron stores and enhancing ESA response, given the high prevalence of iron deficiency in CKD.

Emerging therapies like daprodustat and vadadustat, targeting the hypoxia-inducible factor (HIF) pathway, offer promising alternatives with potential advantages such as oral administration and improved iron utilization.

Mechanism Of Action

Erythropoietin analogs, or ESAs, mimic endogenous erythropoietin, boosting red blood cell production by binding to erythropoietin receptors in the bone marrow.

Erythropoietin, produced by kidney interstitial cells, prompts bone marrow precursor cells to generate red blood cells in response to low oxygen levels. However, in CKD patients, decreased erythropoietin production contributes to anemia, alongside other potential factors.

While effective in correcting anemia in CKD, ESAs increase the need for IV iron due to heightened iron demand and raise the risk of cardiovascular complications and thromboembolism.

Additionally, ESA use can lead to hypo-responsiveness and resistance, exacerbating morbidity and mortality. 

The emerging therapy, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), stabilize HIF by inhibiting PHD, thereby promising alternative by stimulating endogenous erythropoietin production within physiological limits.

By inhibiting prolyl hydroxylase and stabilizing HIF, HIF-PHIs activate erythropoiesis while potentially mitigating adverse effects associated with ESAs.

Under hypoxic conditions, the continuous expression of hypoxia-inducible factor-alpha (HIF-α) is regulated by prolyl hydroxylase (PHD) and von Hippel-Lindau (VHL) protein.

During hypoxia, PHD inhibition allows HIF-α to bind with HIF-beta (HIF-β), triggering increased erythropoietin gene expression and endogenous erythropoietin production.

This pathway also activates genes related to inflammation, vascular calcification, and angiogenesis.

This novel approach presents a paradigm shift in managing renal anemia, addressing the need for safer and more effective treatments in CKD patients.

Hepcidin, a liver-produced acute-phase reactant, plays a crucial role in iron metabolism regulation, inducing functional iron deficiency during inflammation.

Unlike ESAs, HIF-PHIs like roxadustat, vadadustat, and daprodustat effectively reduce hepcidin levels, enhancing iron parameters such as transferrin saturation and total iron binding capacity.

Studies demonstrate varied effects on iron-related parameters among HIF-PHI and ESA groups, with some showing significant reductions in hepcidin levels and IV iron use with HIF-PHIs compared to ESA. 

However, conflicting findings on iron metabolism improvement necessitate further research to ascertain the full extent of HIF-PHI benefits in renal anemia management.

Clinical Efficacy

ESA, administered via subcutaneous or intravenous routes, revolutionized anemia treatment in CKD patients, targeting a hemoglobin level of 11-12 gm/dl while avoiding levels exceeding 13 gm/dl due to increased cardiovascular risks.

However, ESA efficacy diminishes during inflammation, leading to hypo-responsiveness.

In contrast, oral HIF-PHIs like roxadustat, vadadustat, daprodustat, and molidustat offer improved iron metabolism and efficacy regardless of inflammatory status.

Roxadustat, particularly, maintains hemoglobin levels without iron supplementation in hemodialysis patients and reduces cholesterol and hepcidin levels compared to ESA.

They also raised total iron binding capacity (TIBC) in comparison to ESA, suggesting that they could be used as oral substitutes for conventional ESA therapy.

Various studies demonstrate the effectiveness of HIF-PHIs in maintaining hemoglobin levels comparable to ESA while enhancing iron parameters, presenting promising alternatives for CKD-related anemia.

Safety Profile

Administering an ESA can have common adverse effects such as:

• elevated blood pressure

• pain at the injection site

• skin rash or redness

• low iron levels

Rare side effects includes:

• red cell aplasia.

• blood clots

• allergic reactions

Comparing the safety profiles of ESA and HIF-PHI revealed varying adverse event frequencies.

Roxadustat exhibited higher rates of certain adverse events like nasopharyngitis and hyperkalemia compared to ESA, while ESA use was associated with more cases of hypertension.

However, adverse events of special interest such as cardiovascular events and retinal hemorrhage were similar between roxadustat and ESA.

Agarwal, Anand, et al. observed similar safety profiles between vadadustat and ESA groups, with comparable rates of adverse events, serious adverse events, and events leading to death.

Moreover, other studies showed no significant differences in the occurrence of common adverse events like nasopharyngitis, diarrhea, nausea, and vomiting between vadadustat and ESA treatments.

Daprodustat and molidustat also exhibited safety profiles akin to ESA, with comparable rates of adverse events and adverse events of special interest reported.

Enarodustat and roxadustat showed higher occurrence of gastrointestinal disorders compared to ESAs, while vadadustat exhibited lower occurrence of hypertension.

Roxadustat had higher incidence of vascular-access complications, whereas daprodustat had lower incidence.

However, no significant differences were observed in other events, including cardiovascular events, between HIF-PHIs and ESAs.

These findings underscore the need for individualized risk assessment when selecting between ESA and HIF-PHI therapies for renal anemia management.

Conclusion

In a nutshell, the comparative safety assessment indicates that HIF-PHIs may be a more secure option for managing anemia in patients with chronic kidney disease (CKD) than ESAs.

In order to customize treatment plans for specific patients, clinicians must consider the advantages and disadvantages of each method.