What is the pathogenesis of anemia in patients with Chronic Kidney Disease (CKD)?

Pathogenesis of Anemia in Chronic Kidney Disease

The fundamental cause of anemia in CKD is insufficient erythropoietin production by the diseased kidneys, which leads to apoptotic collapse of early erythropoiesis and prevents normal red blood cell production. 1, 2

Primary Mechanism: Erythropoietin Deficiency

• Specialized interstitial cells in the kidney cortex normally sense tissue hypoxia and produce erythropoietin in response to decreased oxygen delivery. 2, 3
• As kidney function declines, these cells become impaired and cannot produce sufficient erythropoietin, with significant anemia typically developing when GFR falls below 20-35 mL/min/1.73 m². 2
• Erythropoietin normally binds to receptors on erythroid colony-forming units (CFU-Es) in bone marrow, salvaging these cells from programmed cell death and permitting their survival and division. 2, 3
• Without adequate erythropoietin, early erythroblasts undergo apoptosis, resulting in decreased red blood cell production and the characteristic normocytic, normochromic anemia seen in most CKD patients. 1, 2

Iron Deficiency: Absolute and Functional

Absolute Iron Deficiency

• Blood losses from repeated laboratory testing, dialysis-related losses (blood retention in dialyzers and tubing), and uremic enteropathy contribute to absolute iron deficiency. 1, 3
• Iron deficiency is the most common cause of inadequate response to erythropoietin therapy. 1

Functional Iron Deficiency

• Chronic inflammation stimulates hepatic release of hepcidin, which blocks iron absorption in the gut and iron release from macrophages. 1, 3, 4
• This creates functional iron deficiency where total body iron stores may appear adequate (elevated ferritin), but iron is unavailable for erythropoiesis. 1, 3
• Transferrin saturation becomes a more reliable marker than ferritin in inflammatory states, as ferritin is an acute-phase protein that elevates independently of actual iron stores. 3

Chronic Inflammation

• Inflammatory cytokines impair erythropoiesis through multiple simultaneous mechanisms: inhibition of erythropoietin production, direct impairment of early erythroblast growth, and promotion of ligand-mediated death of immature erythroblasts. 1, 3
• Inflammation-induced hepcidin elevation creates a state of iron-restricted erythropoiesis despite adequate or elevated ferritin levels. 1, 3
• The anemia of inflammation is characteristically hypoproliferative and frequently includes features suggesting iron-deficiency erythropoiesis. 3

Nutritional Deficiencies

Folate and Vitamin B12 Deficiency

• Both folate and vitamin B12 deficiencies impair DNA synthesis in rapidly dividing erythroblasts, leading to apoptosis and maturation arrest. 1, 2, 3
• These deficiencies produce macrocytic anemia through disordered DNA synthesis and ineffective early erythropoiesis. 1, 2

Iron Deficiency Effects on Hemoglobin Synthesis

• Iron deficiency affects the later hemoglobin-building steps of erythropoiesis, slowing both heme and globin synthesis. 2

Additional Contributing Factors

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

Clinical Progression and Prevalence

• Anemia prevalence increases dramatically as GFR declines: 5-7.5% at CKD stage 3,22-27% at CKD stage 4, and 33-52% at CKD stage 5. 2
• Diabetic patients develop anemia at earlier CKD stages and have 2-3 times higher anemia prevalence at any given GFR level compared to non-diabetic patients. 2

Critical Clinical Pitfalls to Avoid

• Failing to evaluate iron status before initiating erythropoiesis-stimulating agents is a critical error, as iron demands frequently exceed availability during treatment. 1, 3
• Not quantifying and addressing blood losses from catheter care protocols represents a major missed opportunity to reduce iron requirements. 1
• Overlooking the contribution of medications that may suppress erythropoiesis. 2
• A complete blood count assessing all three cell lines is essential, as abnormalities in two or more cell lines warrant hematology consultation. 1