Can Chronic Kidney Disease (CKD) lead to anemia?

Can CKD Lead to Anemia?

Yes, chronic kidney disease (CKD) is a well-established cause of anemia, with inadequate erythropoietin production by diseased kidneys being the primary mechanism. 1

Primary Pathophysiology

The fundamental problem in CKD-related anemia is erythropoietin (EPO) deficiency resulting from impaired kidney function 2, 1. As kidney function declines, specialized interstitial cells in the kidney cortex that sense tissue oxygenation and produce EPO become damaged, leading to insufficient EPO production 1. Without adequate EPO to bind receptors on early erythroid cells, these precursor cells undergo apoptotic collapse rather than surviving and dividing into mature red blood cells 1.

• Anemia develops relatively early in CKD, becoming clinically significant when GFR falls below 20-35 mL/min/1.73 m² 1
• The anemia is characteristically normocytic and normochromic in the majority of patients with reduced kidney function 1
• As kidney function progressively declines, the likelihood and severity of EPO-deficiency anemia increases 1

Contributing Factors Beyond EPO Deficiency

While EPO deficiency is primary, multiple additional mechanisms contribute to anemia in CKD 2, 1:

Iron Dysregulation

• Inflammation stimulates hepatic hepcidin release, which blocks intestinal iron absorption and prevents iron release from macrophages, leading to functional iron deficiency even when total body iron stores are adequate 1
• Blood loss from laboratory testing, dialysis procedures, or gastrointestinal bleeding depletes iron stores 1

Inflammatory and Metabolic Factors

• Inflammatory cytokines directly suppress EPO production and impair erythroblast growth 1
• Severe hyperparathyroidism contributes to anemia 1
• Aluminum toxicity can suppress erythropoiesis 1
• Shortened red blood cell survival occurs in the uremic environment 1

Nutritional Deficiencies

• Folate and vitamin B12 deficiencies impair DNA synthesis in rapidly dividing erythroblasts, causing macrocytic anemia 1
• Iron deficiency affects later hemoglobin-building steps of erythropoiesis 1

Other Conditions

• Hypothyroidism contributes to anemia 1
• Hemoglobinopathies such as thalassemia may coexist 1

Clinical Consequences

Untreated CKD-related anemia causes significant physiologic derangements 1:

• Decreased tissue oxygen delivery and utilization
• Increased cardiac output leading to cardiac enlargement and ventricular hypertrophy
• Angina and congestive heart failure
• Decreased cognition and mental acuity
• Impaired immune responsiveness
• Reduced quality of life 3
• Increased risk of cardiovascular disease, hospitalization, and mortality 4, 5

Critical Diagnostic Pitfalls

Before attributing anemia solely to CKD, exclude other treatable causes 1, 6:

• Screen for hypothyroidism, vitamin B12 and folate deficiency, hemolysis, plasma cell dyscrasias, severe hyperparathyroidism, and aluminum toxicity 6
• Do not confuse anemia of CKD with anemia of chronic disease, where inflammatory cytokines are the primary driver rather than EPO deficiency 1
• Evaluate for gastrointestinal bleeding, particularly if stool is guaiac positive or absolute iron deficiency is confirmed 6
• Review medications that may suppress erythropoiesis 1

Treatment Implications

The recognition that CKD causes anemia through EPO deficiency has led to established treatment paradigms using erythropoiesis-stimulating agents (ESAs) and iron supplementation 2, 3. However, ESAs increase risks of death, myocardial infarction, stroke, and thromboembolism when targeting hemoglobin >11 g/dL 7. The goal is to use the lowest dose sufficient to reduce transfusion needs rather than normalize hemoglobin 7.

Newer hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) offer oral administration and may improve iron utilization, particularly in inflammatory states, though long-term safety data remain limited 2, 3, 8.