When should iron therapy be initiated in patients with chronic kidney disease (CKD) and iron deficiency anemia?

When to Start Iron Therapy in CKD Patients

Iron therapy should be initiated in CKD patients when transferrin saturation (TSAT) is ≤20-30% and ferritin is ≤500 ng/mL, regardless of whether they are on erythropoiesis-stimulating agents (ESAs), with the goal of correcting iron deficiency before considering ESA therapy. 1, 2

Diagnostic Thresholds for Absolute Iron Deficiency

The definition of iron deficiency differs in CKD compared to the general population due to chronic inflammation affecting iron parameters 1, 3:

• Pre-dialysis and peritoneal dialysis patients: TSAT ≤20% AND ferritin ≤100 ng/mL 1, 3
• Hemodialysis patients: TSAT ≤20% AND ferritin ≤200 ng/mL 1, 3

Functional Iron Deficiency Recognition

Normal or elevated ferritin does not exclude iron deficiency in CKD patients—always check TSAT to assess functional iron availability. 2

• Functional iron deficiency is defined as TSAT ≤20-30% despite ferritin >100 ng/mL, which is extremely common in CKD 2
• Ferritin acts as an acute-phase reactant in CKD and can be falsely elevated by inflammation, masking true functional iron deficiency 2
• TSAT reflects iron availability to bone marrow for erythropoiesis, while ferritin only reflects storage 2

Treatment Algorithm Based on Iron Status

Step 1: Assess Iron Parameters

• Measure both TSAT and ferritin before initiating any anemia treatment 1, 2
• Check hemoglobin level to determine severity of anemia 1

Step 2: Initiate Iron Therapy When Indicated

Start iron therapy when TSAT ≤30% and ferritin ≤500 ng/mL 1, 2, 4:

• For pre-dialysis CKD patients (stages 3-5): Trial oral iron for 1-3 months OR preferentially use IV iron 1, 4

  • Oral iron: 200 mg elemental iron daily, divided into 2-3 doses, taken on empty stomach 4
  • IV iron is preferred as it bypasses hepcidin-mediated absorption block 2

• For hemodialysis patients: IV iron is required, as oral iron is ineffective due to elevated hepcidin and ongoing blood losses 1, 5

  • Administer 100 mg IV iron per hemodialysis session, typically totaling 1000 mg over course of treatment 6

• For peritoneal dialysis patients: IV iron in divided doses over 28 days 6

Step 3: Trial IV Iron Before ESA Therapy

Address iron deficiency prior to initiating ESA therapy 1:

• 59.4% of non-dialysis CKD patients respond to IV iron alone without ESA, with hemoglobin increases of 7-10 g/L 2
• Administer IV iron as a course (e.g., 500 mg initially, then 500 mg 4 weeks later) 2
• Check hemoglobin 2-4 weeks after completing iron course to assess response 2

Step 4: Consider ESA Only After Adequate Iron Repletion

• If hemoglobin remains <10 g/dL despite adequate iron repletion (TSAT >20%, ferritin >100 ng/mL), then consider ESA therapy 1, 2
• For patients already on ESA therapy, maintain TSAT >20% and ferritin >100 ng/mL with ongoing iron supplementation 1

Target Iron Parameters During Treatment

• Maintenance targets: TSAT ≥20% and ferritin ≥100 ng/mL 1, 2
• Upper safety limits: Stop iron when ferritin >500 ng/mL or TSAT >50%, as further hemoglobin increases are unlikely 4, 7
• Targeting ferritin 400-600 ng/mL is superior to 100-200 ng/mL for achieving hemoglobin increases in non-dialysis CKD 2

Monitoring Schedule

• Before starting treatment: Check TSAT, ferritin, and hemoglobin 1, 2
• During treatment: Monitor hemoglobin at least every 3 months 8, 4
• Iron parameters: Check TSAT and ferritin at least every 3 months once treatment is established 1, 4
• After IV iron administration: Wait 4-8 weeks before rechecking ferritin, as it becomes falsely elevated immediately post-infusion 2

Critical Pitfalls to Avoid

• Never assume normal ferritin means adequate iron in CKD—always check TSAT to assess functional iron availability 2
• Do not withhold iron if TSAT is low despite normal ferritin—this represents functional iron deficiency requiring treatment 2
• Avoid checking ferritin within 4 weeks of IV iron administration—results will be falsely elevated and misleading 2
• Do not start ESA therapy without first optimizing iron status—this leads to ESA hyporesponsiveness and higher ESA doses 1, 9
• Avoid excessive iron supplementation—withhold IV iron if ferritin >500 ng/mL and/or TSAT >30% to prevent iron overload 4, 7

Route of Administration Considerations

IV iron is superior to oral iron in CKD, particularly for dialysis patients and those approaching dialysis 1, 2:

• IV iron achieves hemoglobin increases of 7-10 g/L compared to only 4-7 g/L with oral iron 2
• Oral iron is poorly absorbed in CKD due to elevated hepcidin blocking intestinal absorption 2, 5
• For pre-dialysis patients, oral iron may be attempted first, but switch to IV iron if inadequate response after 1-3 months 1, 4
• For hemodialysis patients, IV iron is mandatory as oral iron is ineffective 1, 5