How can I differentiate anemia caused by chronic kidney disease from pure iron‑deficiency anemia?

Differentiating Anemia of Chronic Kidney Disease from Pure Iron-Deficiency Anemia

The key to distinguishing kidney-related anemia from pure iron deficiency lies in using different ferritin and transferrin saturation thresholds: in CKD, absolute iron deficiency is defined by ferritin ≤100 ng/mL (predialysis/peritoneal dialysis) or ≤200 ng/mL (hemodialysis) with TSAT ≤20%, whereas in patients without CKD, ferritin <30 ng/mL with TSAT <16-20% confirms iron deficiency. 1, 2

Laboratory Thresholds That Distinguish CKD-Related Anemia

In Chronic Kidney Disease Patients

• Absolute iron deficiency in CKD is diagnosed when TSAT ≤20% and serum ferritin ≤100 ng/mL (for predialysis and peritoneal dialysis patients) or ≤200 ng/mL (for hemodialysis patients). 1, 2

• Functional iron deficiency in CKD (iron-restricted erythropoiesis) is characterized by TSAT ≤20% with elevated ferritin levels (>100-200 ng/mL depending on dialysis status), indicating adequate iron stores but insufficient iron availability due to elevated hepcidin from chronic inflammation. 1, 2, 3

• The higher ferritin thresholds in CKD reflect that ferritin is an acute-phase reactant and becomes falsely elevated by the chronic inflammatory state inherent to kidney disease. 1

In Patients Without CKD (Pure Iron Deficiency)

• Pure iron deficiency is diagnosed when ferritin <30 μg/L without clinical, endoscopic, or biochemical evidence of inflammation. 1

• When inflammation is absent, ferritin <15 μg/L provides 99% specificity for depleted iron stores. 4

• TSAT <16-20% confirms iron deficiency in non-CKD patients, particularly when ferritin may be falsely elevated by concurrent inflammation. 1

Clinical Context That Points to CKD as the Cause

Assess Kidney Function First

• Measure serum creatinine and estimated GFR to establish whether CKD is present; anemia in CKD typically appears when eGFR falls below 60 mL/min/1.73m² (stage 3 or higher). 2, 5

• The presence of CKD fundamentally changes the diagnostic criteria for iron deficiency, requiring higher ferritin thresholds. 1, 2

Look for Functional Iron Deficiency Pattern

• TSAT ≤20% with ferritin 100-700 ng/mL suggests functional iron deficiency from CKD-related inflammation, where iron stores are adequate but unavailable for erythropoiesis due to elevated hepcidin. 1, 2

• In contrast, pure iron deficiency shows both low ferritin (<30 ng/mL) and low TSAT (<20%). 1

• If serial ferritin levels decrease during erythropoietin therapy while remaining >100 ng/mL, this confirms functional iron deficiency; an abrupt increase in ferritin with sudden TSAT drop indicates an inflammatory block. 1

Bone Marrow Examination Provides Definitive Distinction

• In CKD patients with anemia, bone marrow biopsy showing absent iron stores despite ferritin 100-300 ng/mL confirms that the elevated ferritin is falsely elevated by inflammation and true iron deficiency exists. 6

• This finding is common: 46 of 47 consecutive CKD patients with anemia had no bone marrow iron deposits despite mean ferritin of 236 μg/L. 6

Algorithmic Approach to Differentiation

1. Obtain baseline labs: hemoglobin, MCV, serum creatinine, eGFR, ferritin, TSAT, and C-reactive protein. 1, 2, 5

2. Determine if CKD is present:

   • eGFR ≥60 mL/min/1.73m² → use standard iron deficiency criteria (ferritin <30 ng/mL, TSAT <20%)
   • eGFR <60 mL/min/1.73m² → use CKD-specific criteria (ferritin ≤100-200 ng/mL, TSAT ≤20%) 1, 2

3. Interpret ferritin in context of kidney function:

   • No CKD + ferritin <30 ng/mL → pure iron deficiency 1
   • CKD + ferritin ≤100 ng/mL (or ≤200 if on hemodialysis) + TSAT ≤20% → absolute iron deficiency in CKD 1, 2
   • CKD + ferritin >100 ng/mL + TSAT ≤20% → functional iron deficiency from CKD 1, 2

4. If ferritin is 30-100 ng/mL without CKD:

   • Measure CRP to assess for inflammation
   • If CRP elevated, ferritin up to 100 μg/L may still indicate iron deficiency 1
   • TSAT <20% with ferritin >100 μg/L suggests anemia of chronic disease 1

5. Consider trial of IV iron to distinguish functional from inflammatory block:

   • Give 50-125 mg IV iron weekly for 8-10 doses
   • Erythropoietic response (hemoglobin increase) confirms functional iron deficiency
   • No response suggests inflammatory block 1

Critical Pitfalls to Avoid

• Do not use the same ferritin threshold (<30 ng/mL) for CKD patients as for those without kidney disease; this will miss the majority of iron-deficient CKD patients whose ferritin is falsely elevated by inflammation. 1, 2

• Do not assume ferritin 100-300 ng/mL excludes iron deficiency in CKD; bone marrow examination often reveals absent iron stores at these ferritin levels due to chronic inflammation. 6

• Do not rely on ferritin alone when inflammation is present (elevated CRP); always calculate TSAT, as it more accurately reflects iron available for erythropoiesis. 1

• Recognize that normocytic anemia can occur in both conditions; CKD typically causes normocytic anemia of chronic disease, while combined iron and folate/B12 deficiency can mask microcytosis. 1

• In CKD patients with TSAT <20% and ferritin 100-700 ng/mL, distinguish functional iron deficiency from inflammatory block by monitoring serial ferritin trends or giving a trial of IV iron. 1