What are the primary causes of anemia in Chronic Kidney Disease (CKD)?

Causes of Anemia in Chronic Kidney Disease

The primary cause of anemia in CKD is insufficient erythropoietin production by the diseased kidneys, with iron deficiency (both absolute and functional) being the most important contributing factor. 1

Primary Pathophysiologic Mechanism

• Erythropoietin deficiency is the fundamental driver of anemia in CKD, as failing kidneys cannot produce adequate amounts of this hormone needed to stimulate red blood cell production in bone marrow 1
• This deficiency leads to apoptotic collapse of early erythropoiesis, preventing the normal expansion of red blood cell production 1

Iron Deficiency: The Critical Contributing Factor

Absolute Iron Deficiency

• Severely reduced or absent iron stores occur commonly in CKD patients 2
• Defined by transferrin saturation (TSAT) ≤20% and ferritin ≤100 ng/mL in predialysis/peritoneal dialysis patients, or ≤200 ng/mL in hemodialysis patients 2
• Results from multiple mechanisms:
  • Blood losses from repeated laboratory testing, needle punctures, blood retention in dialyzers and tubing, and gastrointestinal bleeding 1
  • Impaired iron absorption in the gut 3

Functional Iron Deficiency

• Adequate iron stores exist but iron cannot be mobilized for incorporation into erythroid precursors 2
• Characterized by TSAT ≤20% with elevated ferritin levels 2
• Caused by inflammation-induced hepcidin elevation, which blocks both iron absorption in the gut and iron release from macrophages 1

Additional Contributing Factors

Inflammation

• Chronic inflammation is common in CKD and impairs erythropoiesis through multiple mechanisms 1, 4:
  • Inflammatory cytokines inhibit erythropoietin production 1
  • Direct impairment of early erythroblast growth 1
  • Promotion of immature erythroblast death through ligand-mediated destruction 1
  • Stimulation of hepatic hepcidin release, creating functional iron deficiency 1

Nutritional Deficiencies

• Folate deficiency impairs DNA synthesis in rapidly dividing erythroblasts, leading to macrocytic anemia 1
• Vitamin B12 deficiency causes similar DNA synthesis impairment and maturation arrest 1, 5

Endocrine and Metabolic Disorders

• Severe hyperparathyroidism can contribute to anemia 1
• Hypothyroidism impairs erythropoiesis 1

Toxic and Structural Factors

• Aluminum toxicity from dialysate or phosphate binders can suppress bone marrow function 1, 5
• Shortened red blood cell survival occurs in the uremic environment 1
• Hemoglobinopathies such as thalassemia may coexist with CKD 1

Clinical Pitfalls to Avoid

• Do not assume erythropoietin deficiency is the sole cause—iron status must always be assessed before initiating erythropoiesis-stimulating agents, as iron demands frequently exceed availability during treatment 1
• Recognize that normal serum creatinine does not exclude significant CKD, especially in elderly patients with poor nutrition and reduced muscle mass 5
• Screen for anemia early—it develops when GFR falls below 60 mL/min/1.73 m² and worsens progressively with declining renal function 5
• Investigate other causes systematically including malignancy, blood loss, and inflammation before attributing anemia solely to CKD 5