How should iron studies be interpreted in patients with Chronic Kidney Disease (CKD)?

Iron Study Interpretation in Chronic Kidney Disease

In CKD patients, interpret iron studies using different thresholds than the general population: absolute iron deficiency is defined as TSAT ≤20% with ferritin ≤100 ng/mL in non-dialysis patients or ≤200 ng/mL in hemodialysis patients, while functional iron deficiency is TSAT ≤20% despite elevated ferritin levels. 1, 2, 3

Key Diagnostic Thresholds

Absolute Iron Deficiency

• Non-dialysis CKD patients: TSAT ≤20% AND ferritin ≤100 ng/mL 1, 2, 3
• Hemodialysis patients: TSAT ≤20% AND ferritin ≤200 ng/mL 1, 2, 3
• Peritoneal dialysis patients: TSAT ≤20% AND ferritin ≤100 ng/mL 1, 3

Functional Iron Deficiency (Iron-Restricted Erythropoiesis)

• TSAT ≤20% with ferritin >100 ng/mL (non-dialysis) or >200 ng/mL (hemodialysis) 2, 3
• This reflects adequate iron stores but insufficient iron availability for erythropoiesis, typically due to inflammation and elevated hepcidin 1, 3

Treatment Thresholds Based on Iron Studies

When to Initiate Iron Therapy (Not on ESA)

• Consider IV iron trial when TSAT ≤30% AND ferritin ≤500 ng/mL 1, 2
• For non-dialysis patients, oral iron is an alternative if TSAT <20% and ferritin <100 ng/mL 1, 2
• The goal is to increase hemoglobin without starting ESA therapy 1

When to Initiate Iron Therapy (On ESA)

• Initiate iron when TSAT ≤30% AND ferritin ≤500 ng/mL 1
• For hemodialysis patients, target TSAT ≥20% and ferritin ≥200 ng/mL before considering ESA dose adjustments 2
• For pediatric patients on ESA, maintain TSAT >20% and ferritin >100 ng/mL 1

Upper Safety Limits

• Withhold IV iron if ferritin >500 ng/mL and/or TSAT >30% 2, 4
• Evidence from the PIVOTAL trial suggests holding iron at ferritin thresholds of 400-1200 ng/mL requires further study 1

Monitoring Frequency

Baseline and Routine Monitoring

• Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy 1, 2
• Measure hemoglobin at least every 3 months in CKD patients with anemia not on ESA 2, 4

Intensive Monitoring Situations

• Test iron status more frequently when: 1
  • Initiating or increasing ESA dose
  • Blood loss occurs
  • Monitoring response after IV iron course
  • Iron stores may become depleted

Critical Interpretation Pitfalls

Ferritin Limitations in CKD

• Ferritin is an acute-phase reactant and may be falsely elevated by inflammation, independent of iron stores 1, 5
• In hemodialysis patients, ferritin interpretation is particularly difficult due to chronic inflammation 1
• Consider assessing C-reactive protein or subjective global assessment to evaluate inflammation's contribution to elevated ferritin 1

TSAT as a More Reliable Marker

• TSAT is less affected by inflammation than ferritin and better correlates with iron availability for erythropoiesis 1, 5
• TSAT represents iron available to bone marrow for red cell production 1

Emerging Markers (Not Yet Standard)

• Reticulocyte hemoglobin content (RetHb) and percent hypochromic red blood cells may provide more accurate assessment than traditional parameters 1, 2, 5
• These require specialized equipment and standardized assays not yet widely available 1, 5
• Hepcidin and soluble transferrin receptor show promise but require further validation 1, 5

Clinical Context for Interpretation

Before Initiating ESA Therapy

• Evaluate and correct iron deficiency before starting ESA 1, 6
• Supplemental iron is required when ferritin <100 mcg/L or TSAT <20% 6
• The majority of CKD patients will require supplemental iron during ESA therapy 6

Functional Iron Deficiency Recognition

• Two distinct etiologies exist: 1
  • Inflammation/hepcidin-mediated reticuloendothelial system iron sequestration
  • Kinetic iron deficiency from bursts of erythropoiesis stimulated by ESAs
• Both present with low TSAT despite adequate ferritin 1, 3

Bone Marrow Iron as Gold Standard

• Peripheral iron indices (TSAT, ferritin) have limited diagnostic accuracy (AUROC ~0.75) compared to bone marrow iron stores 7
• Nearly half of anemic non-dialysis CKD patients have depleted bone marrow iron stores despite variable peripheral markers 7
• This underscores the imperfect nature of standard iron studies in CKD 7