What is the management approach for a patient with anemia of chronic disease, particularly those with underlying conditions such as chronic kidney disease, rheumatoid arthritis, or cancer?

Management of Anemia of Chronic Disease

The management of anemia of chronic disease requires first optimizing treatment of the underlying condition (CKD, rheumatoid arthritis, or cancer), followed by iron supplementation—preferably intravenous in most chronic disease states—and consideration of erythropoiesis-stimulating agents only when iron therapy and disease optimization prove insufficient. 1

Initial Diagnostic Approach

Confirm the Diagnosis and Identify Contributing Factors

• Measure ferritin and transferrin saturation to assess iron status, recognizing that ferritin is an acute phase reactant and may be falsely elevated in inflammatory conditions 1
• Check complete blood count with red cell indices to characterize the anemia (typically normocytic, normochromic in anemia of chronic disease) 1, 2
• Assess renal function (GFR/creatinine) as CKD is a major contributor to anemia in chronic disease, particularly when GFR <60 mL/min/1.73m² 1, 2
• Screen for vitamin B12 and folate deficiency only in patients with macrocytosis (MCV >100 fL) or high clinical suspicion, as deficiency rates are low (<4%) in most chronic disease populations 1
• Evaluate for occult blood loss with stool guaiac testing, especially in elderly patients or those on antiplatelet/anticoagulant therapy 1

Disease-Specific Iron Parameters

For CKD patients, iron deficiency is defined differently than the general population 1:

• Absolute iron deficiency: transferrin saturation ≤20% with ferritin ≤100 μg/L (predialysis/peritoneal dialysis) or ≤200 μg/L (hemodialysis)
• Functional iron deficiency is common in advanced CKD 1, 2

For inflammatory conditions (rheumatoid arthritis, IBD), ferritin may be elevated despite true iron deficiency due to inflammation 1

Treatment Algorithm

Step 1: Optimize Treatment of the Underlying Disease

• Prioritize aggressive management of the primary condition before initiating anemia-specific therapy, as controlling inflammation often improves hemoglobin levels 1
• In rheumatoid arthritis and inflammatory bowel disease, optimizing anti-inflammatory therapy (including biologics like infliximab) significantly improves hemoglobin independent of direct anemia treatment 1

Step 2: Iron Supplementation

Intravenous iron is preferred over oral iron in most chronic disease states 1:

• Oral iron has limited efficacy in chronic inflammatory conditions due to hepcidin-mediated blockade of intestinal iron absorption 3, 4, 5
• Intravenous iron bypasses intestinal absorption and directly replenishes iron stores 6
• Oral iron may be attempted in predialysis CKD patients, but switch to IV if not tolerated or ineffective 1

For CKD patients on dialysis, intravenous iron is required as first-line therapy 1

Step 3: Erythropoiesis-Stimulating Agents (ESAs)

Consider ESAs only after optimizing disease treatment and ensuring adequate iron stores 1, 7:

Indications for ESA therapy 1, 7:

• Anemia of chronic disease with insufficient response to IV iron
• CKD-related anemia to decrease need for RBC transfusion
• Cancer patients receiving myelosuppressive chemotherapy (with ≥2 months planned chemotherapy remaining)
• Zidovudine-induced anemia in HIV patients

Target hemoglobin: Do not exceed 12 g/dL 1:

• Use the lowest ESA dose sufficient to reduce transfusion needs rather than normalize hemoglobin
• Higher hemoglobin targets are associated with increased cardiovascular risks

ESAs are NOT indicated for 7:

• Cancer patients receiving only hormonal agents, biologics, or radiotherapy without concurrent chemotherapy
• Patients whose anemia can be managed by transfusion alone
• Patients with curative cancer treatment intent

Step 4: Novel Therapies (Emerging)

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) offer oral administration and may improve iron utilization, particularly in inflammatory states, though long-term safety data remain limited 2, 3, 8

Step 5: Red Blood Cell Transfusion

Reserve transfusions for specific situations 1:

• Hemoglobin <7 g/dL
• Hemoglobin >7 g/dL with symptomatic anemia or hemodynamic instability
• Severe acute anemia
• Failure of all other treatments

Always follow transfusions with subsequent IV iron supplementation to address the underlying iron deficiency 1

Disease-Specific Considerations

Chronic Kidney Disease

• Anemia develops when GFR <60 mL/min/1.73m², with prevalence increasing dramatically as GFR declines (5-7.5% at stage 3,33-52% at stage 5) 2
• Primary mechanism is erythropoietin deficiency from diseased kidneys 2, 3
• Management should be coordinated with nephrology, particularly regarding GI investigation decisions 1
• Most CKD patients with confirmed iron deficiency warrant GI investigation if fit for procedures 1

Rheumatoid Arthritis and Inflammatory Conditions

• Optimize anti-inflammatory therapy first, as this directly improves hemoglobin 1
• Functional iron deficiency is common due to hepcidin elevation from chronic inflammation 3, 4, 5
• IV iron is more effective than oral iron due to impaired intestinal absorption 1, 6

Cancer-Related Anemia

• Distinguish between anemia from the malignancy itself versus chemotherapy-induced anemia 1
• Screen for nutritional deficiencies (folate, B12, iron), though prevalence is low 1
• ESAs are only indicated during active myelosuppressive chemotherapy with ≥2 months remaining 7
• Avoid ESAs in curative treatment settings 7

Common Pitfalls to Avoid

• Do not rely solely on ferritin in inflammatory conditions—it may be falsely elevated; use transferrin saturation as well 1
• Do not use oral iron as first-line in dialysis patients or severe inflammatory states—it is ineffective due to hepcidin blockade 1, 3, 5
• Do not target hemoglobin >12 g/dL with ESAs—this increases cardiovascular risks without improving quality of life 1, 7
• Do not assume nutritional deficiency without testing—folate and B12 deficiency rates are <4% in most chronic disease populations 1
• Do not overlook multiple contributing causes—elderly patients and those with chronic disease often have overlapping etiologies (iron deficiency, B12/folate deficiency, occult bleeding) 1
• Do not use ESAs in cancer patients receiving curative-intent therapy or non-chemotherapy treatments 7