What causes anemia in patients undergoing dialysis (Dialysis)?

Causes of Anemia in Dialysis Patients

Anemia in dialysis patients results from multiple mechanisms, with erythropoietin deficiency being the primary driver, compounded by substantial blood losses inherent to the dialysis process itself, iron deficiency from chronic bleeding, and inflammatory states that impair erythropoiesis. 1, 2

Primary Mechanism: Erythropoietin Deficiency

• Insufficient erythropoietin production by diseased kidneys is the fundamental cause of anemia in chronic kidney disease patients, including those on dialysis 1, 2
• The failing kidneys cannot produce adequate amounts of this hormone needed to stimulate red blood cell production in bone marrow, leading to apoptotic collapse of early erythropoiesis 2
• This deficiency prevents the normal expansion of red blood cell production and results in normocytic, normochromic anemia in the majority of patients 1

Blood Loss: A Major Underrecognized Factor

Blood losses are a major factor in iron deficiency associated with dialysis but have largely been overlooked since the advent of erythropoiesis-stimulating agents 3

Three Cumulative Sources of Blood Loss:

1. Dialysis Technique Itself:

• Modern dialysis membranes and blood-line losses result in approximately 165 mL of blood loss per year with conventional hemodialysis (3 sessions/week) 3
• Daily dialysis increases this to 330-385 mL annually 3

2. Vascular Access Management:

• Double-lumen catheter care represents the single largest source of blood loss, accounting for approximately 2,680 mL per year due to purge protocols (7-10 mL per catheter branch at each session) 3
• This can be reduced by 77% using modified protocols (2 mL per branch), decreasing losses to 888 mL/year 3
• Accidental bleeding from arteriovenous fistulas due to insufficient compression adds additional losses 3

3. Routine Blood Sampling:

• Laboratory monitoring accounts for 428 mL of blood loss per year 3
• This volume increases substantially with participation in clinical trials 3

4. Occult Gastrointestinal Bleeding:

• Uremic enteropathy, platelet dysfunction, and anticoagulation contribute to 2,257 mL of occult blood loss annually 3

Total Annual Blood Loss:

• Patients with native fistula: 2,680 mL/year 3
• Patients with double-lumen catheter: 5,320 mL/year 3

Iron Deficiency and Dysregulation

• Iron deficiency is the most common cause of inadequate response to erythropoietin therapy 3
• Blood losses from the dialysis process, laboratory testing, and gastrointestinal bleeding deplete iron stores 2
• 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 2, 4
• Hepcidin-25, the master hormone of iron metabolism, is enhanced by inflammation via interleukin-6, further restricting iron availability 3

Inflammatory Factors

• Chronic inflammation impairs erythropoiesis through multiple mechanisms: inhibition of erythropoietin production, direct impairment of early erythroblast growth, promotion of immature erythroblast death, and stimulation of hepatic hepcidin release 2
• Infection and inflammation (including access infections, surgical inflammation) markedly impair responsiveness to erythropoietin 3
• Elevated C-reactive protein levels predict resistance to erythropoietin therapy 3

Additional Contributing Factors

Nutritional Deficiencies:

• Folate deficiency impairs DNA synthesis in rapidly dividing erythroblasts, leading to macrocytic anemia 2
• Vitamin B12 deficiency causes similar DNA synthesis impairment and maturation arrest 2

Metabolic and Endocrine Factors:

• Severe hyperparathyroidism (osteitis fibrosa) replaces active marrow erythroid elements with fibrosis 3, 2
• Hypothyroidism impairs erythropoiesis 2

Toxic Factors:

• Aluminum toxicity from dialysate or phosphate binders suppresses bone marrow function 3, 2

Hematologic Factors:

• Shortened red blood cell survival occurs in the uremic environment 2
• Hemoglobinopathies (thalassemia, sickle cell anemia) may coexist with chronic kidney disease 3, 2

Critical Clinical Pitfalls

• Failing to quantify and address blood losses from catheter care protocols represents a major missed opportunity to reduce iron requirements 3
• Not evaluating iron status before initiating erythropoiesis-stimulating agents, as iron demands frequently exceed availability during treatment 2
• Overlooking occult gastrointestinal bleeding as a significant contributor to ongoing iron losses 3
• Attributing all anemia solely to erythropoietin deficiency without investigating other reversible causes (infection, inflammation, nutritional deficiencies, hyperparathyroidism) 3
• Ignoring the impact of vascular access type on blood loss—patients with catheters lose nearly twice as much blood annually compared to those with native fistulas 3