What is the most likely cause of severe anemia with normal serum iron in a 68‑year‑old woman who has atrial fibrillation, diabetes, chronic kidney disease with impaired renal function, and recurrent infections?

Chronic Kidney Disease with Anemia of Chronic Disease

The most likely cause of this patient's chronic anemia (Hb 70-80 g/L) with normal serum iron is anemia of chronic kidney disease (CKD), driven primarily by erythropoietin deficiency from her severely impaired renal function (eGFR 23 mL/min/1.73m²), compounded by functional iron deficiency and chronic inflammation from recurrent infections. 1, 2

Primary Mechanism: Erythropoietin Deficiency

• With an eGFR of 23 mL/min/1.73m² (CKD stage 4), this patient has severe renal impairment where anemia prevalence reaches 22-27%, and erythropoietin (EPO) deficiency is the dominant cause. 2

• The diseased kidneys cannot produce sufficient EPO, leading to apoptotic collapse of early erythroid progenitors and decreased red blood cell production. 2

• Anemia develops when GFR falls below 60 mL/min/1.73m² and becomes especially likely when GFR is <30 mL/min/1.73m², as in this patient. 1

Why "Normal" Iron is Misleading in CKD

• The statement that "iron is normal" requires critical reinterpretation because iron parameters in CKD patients must be assessed using CKD-specific thresholds, not general population values. 1

• In CKD, absolute iron deficiency is defined as transferrin saturation ≤20% with ferritin ≤100 μg/L (for predialysis patients like this one), which differs substantially from general population thresholds. 1, 3

• Functional iron deficiency (adequate stores but insufficient availability) is extremely common in CKD and is characterized by transferrin saturation ≤20% even with elevated ferritin levels. 1, 4, 5

• The inflammatory state in CKD elevates ferritin levels, making interpretation difficult—ferritin may appear "normal" while true iron deficiency exists. 1

Contributing Factors in This Specific Patient

Chronic Inflammation and Recurrent Infections

• This patient's recurrent hospital admissions for infections (current pyelonephritis, prior ESBL infections, COVID-19) drive chronic inflammation that directly suppresses erythropoiesis and increases hepcidin production. 6, 5, 7

• Elevated hepcidin blocks iron absorption from the gut and iron release from macrophages, creating functional iron deficiency despite potentially adequate total body stores. 6, 5

• Her elevated CRP (110.0) confirms active inflammation, which directly impairs erythroid progenitor proliferation and EPO responsiveness. 6, 7

Blood Loss and Anticoagulation

• She is on apixaban 5 mg twice daily for atrial fibrillation, which increases risk of occult gastrointestinal bleeding—a major contributor to iron deficiency in CKD. 1, 3

• Recurrent phlebotomy from frequent hospitalizations compounds blood loss. 1

• The discharge summary notes she is only on ferrous sulfate 300 mg twice weekly, which is grossly inadequate for CKD-related anemia and suggests prior recognition of iron issues. 1

Additional Mechanisms

• Reduced iron absorption due to pantoprazole 40 mg twice daily (proton pump inhibitors impair iron absorption). 3

• Poor nutritional intake documented during this admission ("poor PO intake"). 1

• Chronic inflammation from CKD itself, independent of acute infections. 2, 7

Critical Diagnostic Pitfall

The most important pitfall here is accepting "normal iron" at face value without obtaining CKD-specific iron studies: transferrin saturation and ferritin levels interpreted using CKD thresholds. 1, 3

• Serum iron alone is inadequate—it reflects only immediately available iron, not total stores or functional availability. 1, 3

• Both transferrin saturation and ferritin must be measured and interpreted using CKD-specific cutoffs to distinguish absolute from functional iron deficiency. 1, 3

Recommended Diagnostic Workup

Immediate Laboratory Assessment

• Measure transferrin saturation and serum ferritin to properly assess iron status using CKD thresholds (TSAT ≤20%, ferritin ≤100 μg/L for absolute deficiency in predialysis patients). 1, 3

• Check vitamin B12 and folate levels, as deficiencies can coexist and cause macrocytic anemia. 1, 2

• Assess thyroid function (TSH) to exclude hypothyroidism, which causes normocytic anemia mimicking EPO deficiency. 1, 2

• Review peripheral smear for red cell morphology (microcytosis suggests iron deficiency; macrocytosis suggests B12/folate deficiency). 1

Gastrointestinal Investigation

• Given anticoagulation with apixaban and chronic anemia, stool guaiac testing for occult blood is mandatory to screen for GI bleeding. 1, 3

• If iron deficiency is confirmed (even with CKD), both upper endoscopy and colonoscopy should be considered in consultation with nephrology, as CKD patients frequently have coexisting GI pathology including malignancy. 1, 3

• The decision about endoscopic evaluation must weigh risks versus benefits given her multiple comorbidities, but most CKD patients with confirmed iron deficiency anemia warrant GI investigation if fit for procedures. 1

Exclude Other Causes

• Rule out hemolysis (reticulocyte count, LDH, haptoglobin). 1, 2

• Consider plasma cell dyscrasia screening (SPEP/UPEP) given age and CKD. 1

• Assess for severe hyperparathyroidism (PTH level), which contributes to anemia in CKD. 2

Management Approach

Iron Repletion

• If absolute iron deficiency is confirmed, intravenous iron is preferred over oral iron in predialysis CKD patients, as oral iron is poorly absorbed due to gut edema, inflammation, and hepcidin elevation. 1, 6

• Her current regimen of ferrous sulfate 300 mg twice weekly is inadequate and suggests poor tolerance or absorption of oral iron. 1

Erythropoiesis-Stimulating Agents

• Once iron stores are optimized (TSAT >20%, ferritin >100 μg/L), erythropoiesis-stimulating agents (ESAs) should be initiated by the nephrology team to address EPO deficiency. 1, 2

• ESAs require adequate iron availability to be effective; treating iron deficiency first is essential. 6, 8, 4

Address Inflammation

• Optimize management of recurrent infections and consider urology follow-up for definitive stone management to prevent recurrent pyelonephritis. 6

• Ensure adequate dialysis if/when indicated, as inadequate dialysis contributes to ESA hyporesponsiveness. 6

Medication Review

• Review continuation of apixaban versus bleeding risk, and consider adding proton pump inhibitor optimization (though already on pantoprazole, which may impair iron absorption). 3

• Discontinue any nephrotoxic medications or those that suppress erythropoiesis. 2

Key Clinical Pearls

• Anemia in CKD is multifactorial: EPO deficiency is primary, but iron deficiency (absolute or functional), inflammation, blood loss, and nutritional deficiencies all contribute. 1, 2

• "Normal" iron studies using general population reference ranges are meaningless in CKD—always use CKD-specific thresholds. 1, 3

• Functional iron deficiency is extremely common in CKD and is exacerbated by chronic inflammation from recurrent infections, as in this patient. 1, 6, 4, 5

• Coordination with nephrology is essential for both diagnostic workup and management of anemia in CKD. 1, 3