How does chronic kidney disease cause anemia?

How Chronic Kidney Disease Causes Anemia

The primary mechanism by which chronic kidney disease causes anemia is insufficient erythropoietin production by the diseased kidneys, leading to apoptotic collapse of early erythropoiesis and preventing normal red blood cell production. 1, 2

Primary Pathophysiologic Mechanism: Erythropoietin Deficiency

• Specialized interstitial cells in the kidney cortex normally sense tissue hypoxia and produce erythropoietin in response to decreased oxygen delivery. 3, 2
• As kidney function declines, these cells become impaired and cannot produce adequate erythropoietin, which is the fundamental hormonal defect in CKD-related anemia. 1, 2
• Erythropoietin normally binds to receptors on erythroid colony-forming units (CFU-Es) in the bone marrow, salvaging these early red blood cell progenitors from preprogrammed cell death (apoptosis). 3, 2
• Without sufficient erythropoietin, CFU-Es and subsequent erythroblast generations succumb to apoptosis, causing the collapse of early erythropoiesis and resulting in normocytic, normochromic anemia in the majority of CKD patients. 1, 2

Timing and Prevalence

• Mean hemoglobin levels decrease consistently only when GFR falls below 60 mL/min/1.73 m² (CKD stage 3). 3
• Anemia prevalence increases dramatically with declining kidney function: 5-7.5% at stage 3,22-27% at stage 4, and 33-52% at stage 5 CKD. 2
• Patients with diabetes develop anemia earlier in the course of CKD and have 2-3 times higher anemia prevalence at any given GFR level compared to non-diabetic patients. 3, 2

Iron Deficiency and Dysregulation

Iron deficiency is the most common cause of inadequate response to erythropoietin therapy and represents a critical secondary mechanism. 1

Absolute Iron Deficiency

• Blood losses from repeated laboratory testing account for approximately 428 mL per year. 4
• Modern dialysis membranes and blood-line losses result in approximately 165 mL of blood loss per year with conventional hemodialysis. 4
• Double-lumen catheter care represents the single largest source of blood loss, accounting for approximately 2,680 mL per year due to purge protocols. 4
• Uremic enteropathy, platelet dysfunction, and anticoagulation contribute to 2,257 mL of occult blood loss annually. 4

Functional Iron Deficiency

• Chronic inflammation stimulates hepatic release of hepcidin, which simultaneously blocks iron absorption in the gut and iron release from resident macrophages, causing functional iron deficiency even when total body iron stores appear adequate. 3, 1, 4
• This inflammation-induced hepcidin elevation decreases transferrin saturation and promotes iron-deficiency erythropoiesis despite normal ferritin levels. 3, 1

Chronic Inflammation

• Inflammatory cytokines inhibit erythropoietin production by the kidneys, compounding the deficiency caused by kidney disease itself. 3, 1
• These cytokines directly impair growth of early erythroblasts and promote their death through ligand-mediated destruction, especially in the absence of adequate erythropoietin. 3, 1
• The anemia of inflammation is characteristically hypoproliferative and frequently includes features suggesting iron-deficiency erythropoiesis. 3

Nutritional Deficiencies

• Folate deficiency impairs DNA synthesis in rapidly dividing erythroblasts during the period of rapid cell division, leading to apoptosis, disordered DNA synthesis, maturation arrest, and macrocytic anemia. 3, 1
• Vitamin B12 deficiency causes identical DNA synthesis impairment and maturation arrest, producing macrocytic anemia. 3, 1
• Iron deficiency affects the later hemoglobin-building steps following rapid cell division, slowing both heme and globin synthesis, resulting in hypochromic microcytic anemia. 3

Additional Contributing Factors

• Severe hyperparathyroidism (osteitis fibrosa) replaces active marrow erythroid elements with fibrosis, directly impairing the bone marrow's capacity for red blood cell production. 1, 4
• Shortened red blood cell survival in the uremic environment accelerates turnover of existing red blood cells, compounding the production deficit. 1, 2
• Hypothyroidism impairs erythropoiesis through hormonal mechanisms. 1, 2
• Aluminum toxicity from dialysate or phosphate binders suppresses bone marrow function, although this is less common with modern dialysis practices. 1, 4
• Hemoglobinopathies such as thalassemia and sickle cell anemia may coexist with CKD, contributing independently to anemia. 1, 2

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—patients with catheters lose nearly twice as much blood annually (5,320 mL/year) compared to those with native fistulas (2,680 mL/year). 4
• Not evaluating iron status before initiating erythropoiesis-stimulating agents is a critical error, as iron demands frequently exceed availability during treatment. 1, 4
• Attributing all anemia solely to erythropoietin deficiency without investigating other reversible causes such as infection, inflammation, nutritional deficiencies, or hyperparathyroidism. 4
• Overlooking occult gastrointestinal bleeding as a significant contributor to ongoing iron losses. 4