What are the effects of iron deficiency on cardiovascular risk in a patient with Chronic Kidney Disease (CKD) stage 2?

Cardiovascular Effects of Iron Deficiency in CKD Stage 2

Iron deficiency in CKD stage 2 significantly increases cardiovascular risk, including higher rates of cardiovascular hospitalizations, mortality, myocardial infarction, stroke, and heart failure, even when anemia is not present. 1

Direct Cardiovascular Impact

Iron deficiency (defined as TSAT <20%) is independently associated with adverse cardiovascular outcomes in CKD patients, separate from its role in anemia 1. The cardiovascular effects include:

• Increased cardiovascular hospitalizations and mortality - Observational data demonstrate that TSAT <20% correlates with higher rates of cardiovascular-related hospital admissions and death 1
• Higher risk of major adverse cardiac events - Iron deficiency contributes to increased incidence of myocardial infarction, stroke, and heart failure hospitalizations 1
• Impaired cardiac function independent of hemoglobin levels - The detrimental cardiac effects occur even without anemia, suggesting iron has direct effects on myocardial tissue beyond oxygen-carrying capacity 1

Mechanisms of Cardiac Dysfunction

While the evidence focuses primarily on clinical outcomes, iron deficiency likely impairs cardiac function through multiple pathways 1:

• Reduced myocardial energy metabolism - Iron is essential for mitochondrial function and cellular energy production in cardiac myocytes 1
• Impaired skeletal and cardiac muscle function - Functional iron deficiency affects muscle performance beyond anemia-related oxygen delivery 1

Clinical Significance in CKD Stage 2

For patients with CKD stage 2 (GFR 60-89 mL/min/1.73m²), iron deficiency is particularly important because 1, 2:

• High prevalence - Between 15-72.8% of non-dialysis CKD patients have either ferritin <100 μg/L or TSAT <20%, with 8-20% having both parameters below threshold 1
• Progressive worsening - Iron deficiency prevalence increases with advancing CKD stages 1, 2
• Anemia develops early - 21-62% of non-dialysis CKD patients have anemia, which compounds cardiovascular risk 1, 2

Evidence for Treatment Benefits

Correcting iron deficiency improves cardiovascular outcomes in CKD patients, with benefits seen regardless of anemia status 1, 3, 4:

• Heart failure outcomes - Multiple RCTs demonstrate that IV iron in heart failure patients with iron deficiency improves exercise capacity, quality of life, NYHA class, and reduces hospitalizations 1, 3
• CKD subgroup benefits - Within heart failure trials, CKD patients showed similar cardiovascular improvements with iron therapy 1
• Reduced composite cardiovascular events - Meta-analyses suggest IV iron lowers the risk of recurrent cardiovascular or heart failure hospitalizations and mortality 1, 5
• Recent systematic review - A 2025 meta-analysis of 45 trials found iron therapy reduced the primary composite endpoint of heart failure hospitalization or cardiovascular death (RR 0.84,95% CI 0.75-0.94), with consistent effects across dialysis and non-dialysis CKD 5

Diagnostic Approach for CKD Stage 2

Screen for iron deficiency using transferrin saturation and ferritin levels 1, 2, 6:

• Absolute iron deficiency - TSAT ≤20% and ferritin <100 μg/L in non-dialysis CKD patients 1, 7
• Functional iron deficiency - TSAT ≤20% with ferritin >100 μg/L, often due to inflammation and hepcidin-mediated iron sequestration 1, 8, 7
• Annual screening minimum - All CKD patients should be screened for anemia and iron deficiency at least yearly 2, 6

Important Caveats

Current iron parameters have significant limitations in CKD 1, 6:

• Ferritin is an acute phase reactant and may be falsely elevated in inflammatory states 1, 6
• The truly independent cardiovascular risk of iron deficiency remains somewhat uncertain due to confounding comorbidities 1
• Newer biomarkers (reticulocyte hemoglobin content, percentage of hypochromic RBCs) may provide better assessment but lack standardized clinical decision limits 1

Theoretical risks of iron therapy exist but appear manageable 1:

• Iron may promote oxidative stress through the Fenton reaction, potentially contributing to cardiovascular disease 1
• Concern exists about increased infection risk, particularly with gram-negative bacteria 1
• However, clinical trial data are reassuring regarding safety at recommended doses 1
• Withhold IV iron during active infections as these patients were excluded from RCTs 1, 3