Anemia of Chronic Disease with Functional Iron Deficiency
The most likely diagnosis in this patient is anemia of chronic disease (ACD) with functional iron deficiency (FID), secondary to chronic kidney disease and diabetes mellitus. The combination of high ferritin, low iron, and macrocytic anemia in the setting of CKD and diabetes is characteristic of this condition, though the macrocytosis requires additional investigation for vitamin B12 or folate deficiency 1, 2.
Diagnostic Reasoning
Iron Studies Interpretation in CKD
In patients with chronic inflammation (such as CKD), ferritin >100 μg/L with transferrin saturation <20% defines anemia of chronic disease 1. This patient's high ferritin indicates adequate iron stores but the low serum iron reflects functional iron deficiency—iron is sequestered and unavailable for erythropoiesis due to inflammation-induced hepcidin elevation 1, 2.
- In CKD patients, absolute iron deficiency is defined as transferrin saturation ≤20% and ferritin ≤100 ng/mL (predialysis) or ≤200 ng/mL (hemodialysis) 2
- When ferritin is >100 μg/L with transferrin saturation <20%, this indicates functional iron deficiency where inflammation prevents iron utilization despite adequate stores 1
- The inflammatory state in CKD causes hepcidin upregulation, which reduces iron export from macrophages and creates functional iron deficiency for erythropoiesis 1
The Macrocytic Component
The macrocytic anemia requires evaluation for vitamin B12 or folate deficiency, which commonly coexists with anemia of chronic disease 1.
- Macrocytosis in this context may indicate B12 deficiency (common in diabetes due to metformin use or gastric atrophy) or folate deficiency 1
- A combined deficiency picture (iron deficiency plus B12/folate deficiency) can occur in malabsorption states 1
- Check B12, red cell folate, and consider reticulocyte count to differentiate causes 1
The Cardio-Renal-Anemia Syndrome
This patient exemplifies the cardio-renal-anemia syndrome, where CKD, anemia, and cardiovascular disease (hypertension, likely heart failure given dyspnea) form a vicious cycle 3.
- Anemia in CKD is associated with increased morbidity and mortality, and the severity correlates with worse outcomes 2, 3
- Anemia worsens heart failure and accelerates CKD progression, while untreated heart failure further deteriorates renal function 3
- The dyspnea on minimal exertion likely reflects both anemia and cardiac dysfunction 3
Key Diagnostic Pitfalls
Do not misinterpret the high ferritin as excluding iron deficiency in the setting of chronic inflammation 1.
- Ferritin is an acute-phase reactant and rises with inflammation, potentially masking true iron deficiency 1
- In inflammatory states, ferritin up to 100 μg/L may still be consistent with iron deficiency 1
- Always assess inflammatory markers (CRP, ESR) alongside iron studies to properly interpret ferritin levels 1
Do not overlook diabetes mellitus as an independent risk factor for iron deficiency 4, 5.
- Diabetes is independently associated with iron deficiency even without nephropathy 4, 5
- Iron deficiency is more frequent in diabetic CKD patients compared to non-diabetic CKD patients 4
- The prevalence of iron deficiency in type 2 diabetes without nephropathy can be as high as 55% 5
Additional Workup Required
Obtain transferrin saturation, vitamin B12, folate, reticulocyte count, and inflammatory markers (CRP) to complete the evaluation 1.
- Transferrin saturation <20% confirms functional iron deficiency in the setting of elevated ferritin 1
- Reticulocyte count helps classify the anemia and assess bone marrow response 1
- B12 and folate levels are essential given the macrocytosis 1
- CRP or ESR confirms the inflammatory state affecting iron metabolism 1
Clinical Implications
Anemia in CKD requires screening at initial evaluation and treatment when present 2. The association between anemia severity and mortality in CKD necessitates aggressive management 2, 3. Correcting anemia with erythropoietin and iron supplementation improves cardiac function, reduces hospitalization, stabilizes GFR decline, and enhances quality of life 3.