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

Causes of Anemia in Chronic Kidney Disease

Primary Cause

The fundamental cause of anemia in CKD is insufficient erythropoietin (EPO) production by the diseased kidneys, which leads to apoptotic collapse of early erythropoiesis and prevents normal red blood cell production. 1, 2 This results in the characteristic normocytic, normochromic anemia seen in the majority of CKD patients. 1

Pathophysiology of EPO Deficiency

• Specialized interstitial cells in the kidney cortex normally sense tissue oxygenation and produce erythropoietin in response to hypoxia. 1
• As kidney function declines, these cells become impaired and cannot produce adequate EPO to salvage early erythroid colony-forming units from programmed cell death. 1
• Without sufficient EPO binding to receptors on erythroid precursors, early erythroblasts undergo apoptosis rather than surviving and dividing. 1
• Anemia develops relatively early in CKD, with significant anemia noted when GFR falls below 20-35 mL/min/1.73 m². 1

Iron Deficiency: The Most Common Contributing Factor

Iron deficiency—both absolute and functional—is the most common cause of inadequate response to erythropoietin therapy and a critical contributor to anemia in CKD. 3, 4

Absolute Iron Deficiency

• Blood losses from repeated laboratory testing account for approximately 428 mL per year. 3
• Dialysis-related losses include blood retention in dialyzers and tubing (165 mL/year with conventional hemodialysis). 3
• Double-lumen catheter care represents the single largest source of blood loss at 2,680 mL per year due to purge protocols requiring 7-10 mL per catheter branch at each session. 3
• Uremic enteropathy, platelet dysfunction, and anticoagulation contribute to approximately 2,257 mL of occult gastrointestinal blood loss annually. 3
• Patients with double-lumen catheters lose nearly twice as much blood annually (5,320 mL/year) compared to those with native fistulas (2,680 mL/year). 3

Functional Iron Deficiency

• Inflammation-induced hepcidin elevation blocks both iron absorption in the gut and iron release from macrophages, causing functional iron deficiency even when total body iron stores appear adequate. 1, 2, 3
• Hepcidin-25, the master hormone of iron metabolism, is enhanced by inflammation via interleukin-6, further restricting iron availability. 3
• This creates a state where adequate iron stores exist but cannot be mobilized for erythropoiesis. 1

Diagnostic Criteria for Iron Deficiency in CKD

• Absolute iron deficiency is defined as transferrin saturation (TSAT) ≤20% and serum ferritin ≤100 ng/mL in predialysis and peritoneal dialysis patients, or ≤200 ng/mL in hemodialysis patients. 4
• Functional iron deficiency is characterized by TSAT ≤20% with elevated ferritin levels. 4

Chronic Inflammation

Chronic inflammation impairs erythropoiesis through multiple distinct mechanisms beyond just iron dysregulation. 2, 3

• Inflammatory cytokines directly inhibit erythropoietin production by the kidneys. 2
• These cytokines directly impair growth of early erythroblasts. 2
• Inflammation promotes ligand-mediated death of immature erythroblasts in the absence of adequate EPO. 1
• Elevated C-reactive protein levels predict resistance to erythropoietin therapy. 3
• Infection and inflammation (including vascular access infections and surgical inflammation) markedly impair responsiveness to erythropoietin. 3

Nutritional Deficiencies

Folate Deficiency

• Folate deficiency impairs DNA synthesis in rapidly dividing erythroblasts, leading to apoptosis and macrocytic anemia. 1, 2, 3
• Ongoing deficiency results in disordered DNA synthesis, maturation arrest, and ineffective early erythropoiesis. 1

Vitamin B12 Deficiency

• Vitamin B12 deficiency causes similar DNA synthesis impairment and maturation arrest as folate deficiency. 2, 3
• This also typically produces macrocytic anemia. 1

Additional Contributing Factors

Severe Hyperparathyroidism

• Severe hyperparathyroidism (osteitis fibrosa) replaces active marrow erythroid elements with fibrosis. 1, 3
• This directly impairs the bone marrow's capacity for red blood cell production. 1

Shortened Red Blood Cell Survival

• The uremic environment causes shortened red blood cell survival. 1, 2, 3
• This accelerates the turnover of existing red blood cells, compounding the production deficit. 1

Hypothyroidism

• Hypothyroidism impairs erythropoiesis through hormonal mechanisms. 1, 2, 3

Aluminum Toxicity

• Aluminum toxicity from dialysate or phosphate binders suppresses bone marrow function. 1, 2, 3
• This is less common with modern dialysis practices but remains a consideration. 3

Hemoglobinopathies

• Hemoglobinopathies such as thalassemia and sickle cell anemia may coexist with CKD. 1, 3
• These inherited disorders of hemoglobin synthesis contribute independently to anemia. 5

Critical Clinical Pitfalls to Avoid

Failing to quantify and address blood losses from catheter care protocols represents a major missed opportunity to reduce iron requirements and improve anemia management. 3

• Not evaluating iron status before initiating erythropoiesis-stimulating agents is a critical error, as iron demands frequently exceed availability during treatment. 2, 3
• Attributing all anemia solely to erythropoietin deficiency without investigating other reversible causes (infection, inflammation, nutritional deficiencies, hyperparathyroidism) leads to suboptimal treatment. 3
• Overlooking occult gastrointestinal bleeding as a significant contributor to ongoing iron losses. 3
• Ignoring the impact of vascular access type on blood loss—patients with catheters require more aggressive iron supplementation strategies. 3
• Not recognizing that the anemia of CKD is normochromic and normocytic, making it indistinguishable from anemia associated with other chronic conditions without proper workup. 5

Evaluation Approach

A complete blood count assessing all three cell lines (white blood cells, hemoglobin, and platelets) is essential, as abnormalities in two or more cell lines warrant hematology consultation. 5

• Low mean corpuscular volume suggests iron, folic acid, or vitamin B12 deficiencies, or inherited hemoglobin synthesis disorders. 5
• Reticulocyte count (absolute or adjusted for anemia severity) evaluates the appropriateness of bone marrow response. 5
• A low reticulocyte count in CKD patients replete with iron, folate, and vitamin B12 most commonly indicates either insufficient erythropoietin production or inflammation. 5
• Iron status evaluation is mandatory as part of the initial anemia workup, since iron deficiency (absolute or functional) is a common contributor. 5