What is the role of HIF-PHI (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors) inhibitors versus iron supplementation in managing anemia in patients with Chronic Kidney Disease (CKD)?

HIF-PHI vs Iron in CKD Anemia Management

Iron supplementation remains the first-line treatment for anemia in CKD patients, while HIF-PHIs represent an emerging alternative that is non-inferior to ESAs for hemoglobin correction but carries concerning cardiovascular and thrombotic risks that limit their role to specific clinical scenarios where traditional therapies fail or are contraindicated. 1, 2

Treatment Algorithm: Iron First, Then Consider HIF-PHIs

Step 1: Assess Iron Status and Initiate Iron Therapy

• Measure TSAT and ferritin in all CKD patients with anemia (Hb <12 g/dL in women, <13 g/dL in men) 3, 2
• Start IV iron as first-line therapy when TSAT ≤30% and ferritin ≤500 ng/mL in advanced CKD patients, as IV iron alone can significantly improve hemoglobin without requiring ESAs 2
• For non-dialysis CKD with milder anemia: use oral iron if TSAT <20% and ferritin <100 mg/L 2
• For hemodialysis patients: IV iron is first-line; target TSAT ≥20% and ferritin ≥200 mg/L 2
• Withhold iron if ferritin >500 ng/mL and/or TSAT >30% to avoid iron overload 2

Step 2: When to Consider HIF-PHIs

HIF-PHIs should be considered only after optimizing iron therapy, particularly in these scenarios:

• ESA hyporesponsiveness (requiring higher than usual ESA doses despite adequate iron stores) 1, 4
• Chronic inflammatory states where ESAs are less effective (though evidence for HIF-PHI superiority here remains controversial) 1, 4
• Non-dialysis CKD patients who prefer oral therapy over ESA injections 1
• Patients requiring reduced IV iron supplementation burden 1

Step 3: Populations Where HIF-PHIs Should Be AVOIDED

Exercise extreme caution or exclude HIF-PHIs in: 1

• Diabetic nephropathy with retinopathy (risk of worsening retinopathy) 1
• Autosomal dominant polycystic kidney disease (potential cyst growth promotion) 1
• Active malignancy or recent cancer history (theoretical tumor growth enhancement) 1, 5
• Vascular calcifications 1
• Pulmonary arterial hypertension 1
• Pediatric patients (insufficient safety data) 1

Key Mechanistic Differences

Iron Supplementation

• Directly replenishes iron stores for erythropoiesis 1, 2
• Addresses absolute iron deficiency (TSAT <20%, ferritin <100-200 mg/L) and functional iron deficiency (TSAT <20% with higher ferritin) 1, 2
• No systemic cardiovascular risks when used appropriately 2
• IV formulations: iron sucrose (200-500 mg/infusion) or ferric carboxymaltose (up to 1000 mg/week) 2

HIF-PHIs

• Stabilize HIF complex, stimulating endogenous erythropoietin production even in end-stage kidney disease 6, 7
• Reduce hepcidin levels, improving iron mobilization from stores and increasing intestinal iron absorption 5, 4, 8
• Produce more modest, sustained increases in endogenous EPO compared to ESAs 4
• Oral administration offers convenience advantage over injectable ESAs 1, 7

Critical Safety Concerns with HIF-PHIs

The 2023 KDIGO conference concluded that HIF-PHIs are inferior to, or at best similar to, conventional ESAs regarding cardiovascular safety: 1

• Increased cardiovascular and thrombotic risks observed across phase 3 trials 1
• Different HIF-PHIs showed varying safety signals, with persistent concerns about major adverse cardiovascular events (MACE) 1
• Theoretical oncogenic potential due to HIF pathway activation in tumor cells 5, 8
• Risk of hyperkalemia and retinopathy progression 5

What the Evidence Does NOT Support

Current data do NOT support these commonly assumed HIF-PHI advantages: 1

• No reduction in IV or oral iron supplementation needs compared to standard therapy 1
• No proven superior efficacy in chronic inflammatory states (despite theoretical advantages via hepcidin suppression) 1
• Insufficient evidence for quality of life improvements in non-dialysis CKD patients 1

Monitoring Requirements

For Iron Therapy

• Monitor hemoglobin every 3 months in CKD patients with eGFR <30 mL/min/1.73 m² 3, 2
• Check iron parameters (TSAT, ferritin) before and after iron therapy 3, 2
• Assess reticulocyte hemoglobin content for more accurate iron status assessment 1

For HIF-PHI Therapy (if used)

• Novel diagnostic parameters needed: reticulocyte hemoglobin (retHb) and % hypochromic RBCs 1
• Determine upper limits of concurrent IV iron therapy (ferritin, TSAT, iron dose) 1
• Monitor for cardiovascular events and thrombosis more vigilantly than with ESAs 1
• Long-term post-market surveillance required for cancer risk, retinopathy, and other adverse effects 1

Critical Knowledge Gaps Requiring Further Research

The KDIGO conferences identified these urgent research needs: 1

• Optimal iron-dosing strategies with HIF-PHIs (oral vs IV, dosing levels, targets) 1
• Head-to-head trials comparing different HIF-PHIs and iron formulations 1
• Ferrokinetic properties of HIF-PHIs and their effects on the erythroferrone/hepcidin axis 1
• Long-term cardiovascular and oncologic safety data 1
• Whether hemoglobin targets should differ when using HIF-PHIs vs ESAs 1

Common Pitfalls to Avoid

• Do not reflexively use HIF-PHIs as first-line therapy—optimize iron status first 2
• Do not assume HIF-PHIs eliminate iron supplementation needs—current evidence refutes this 1
• Do not use HIF-PHIs in high-risk populations (diabetic retinopathy, ADPKD, active malignancy) without compelling justification 1
• Avoid blood transfusions based solely on hemoglobin levels—reserve for symptomatic patients or ESA/HIF-PHI failure 2
• Do not exceed ferritin >500 ng/mL or TSAT >30% with iron supplementation to prevent toxicity 2