Iron deficiency is a prevalent issue in chronic kidney disease (CKD), affecting approximately 30–50% of patients across various stages. Traditionally associated with anemia, iron deficiency in CKD is now increasingly recognized as a contributor to cardiovascular complications, fatigue, reduced quality of life, and disease progression. Recent studies, including a 2025 meta-analysis published in Kidney International Reports, have reinforced the idea that iron therapy in CKD extends beyond hematological correction—it is a potential therapeutic avenue to reduce hospitalizations, cardiovascular events, and mortality.
Understanding Iron Deficiency in CKD
Iron is essential for oxygen delivery, cellular metabolism, and immune function. In CKD, factors such as chronic inflammation, reduced gastrointestinal absorption, blood losses (especially during dialysis), and functional iron sequestration due to elevated hepcidin levels contribute to iron deficiency. The typical laboratory thresholds for initiating iron therapy include transferrin saturation (TSAT) <20% and serum ferritin <100 ng/mL in non-dialysis CKD and <300 ng/mL in dialysis-dependent patients.
Clinical Case: Real-World Insight
A 63-year-old woman with stage 3 CKD complained of progressive fatigue and exertional dyspnea. Despite normal hemoglobin levels, her TSAT was 17% and ferritin 80 ng/mL, confirming iron deficiency. She received two doses of 1000 mg ferric carboxymaltose IV, spaced two weeks apart. After the infusions, her energy improved, and she reported less breathlessness. For the next six months, she remained stable with no hospitalizations. Her nephrologist noted that even in the absence of anemia, correcting iron deficiency had meaningful clinical effects.
Evidence from the 2025 Meta-Analysis
The systematic review included 45 randomized controlled trials examining the impact of iron supplementation—both oral and intravenous—on various clinical outcomes in CKD patients. The most significant findings were:
| Outcome | Relative Risk (RR) | 95% Confidence Interval | Evidence Level |
|---|---|---|---|
| Heart failure hospitalization or CV death | 0.84 | 0.75–0.94 | Moderate |
| Heart failure hospitalization alone | 0.77 | 0.61–0.96 | Moderate |
| Cardiovascular mortality | 0.81 | 0.65–1.02 | Low |
| Myocardial infarction | 0.66 | 0.50–0.88 | Low |
| All-cause mortality | 0.85 | 0.74–0.98 | Low |
| Serious adverse events | 0.90 | 0.82–0.98 | Moderate |
These results suggest that iron therapy may reduce cardiovascular and all-cause mortality risks, particularly in patients with heart failure.
Commonly Used Iron Products Worldwide
Several iron formulations are approved globally for CKD-related iron deficiency. Their characteristics vary by administration route, safety profile, and clinical efficacy:
Intravenous (IV) Iron
| Product Name | Strengths | Notes |
| Ferric carboxymaltose | High-dose (1000 mg), fewer infusions, CV benefits | Well-studied in AFFIRM-AHF, IRONMAN trials |
| Ferric derisomaltose | Single 1000 mg dose, low hypersensitivity | Rapid iron repletion |
| Iron sucrose | Long safety record, inexpensive | Requires multiple 100–200 mg doses |
| Iron dextran | Cost-effective | Risk of anaphylaxis; test dose needed |
Oral Iron
| Product Name | Strengths | Notes |
| Ferrous sulfate | Cheap, widely available | GI side effects common |
| Ferric citrate | Dual function (iron + phosphate binder) | Shown to delay dialysis in non-dialysis CKD |
| Ferric maltol | Well tolerated, suitable for maintenance | More expensive; limited access in some countries |
Indications for Iron Therapy
| Condition | Threshold or Criteria | Notes |
| Transferrin Saturation | < 20% | Common trigger for iron therapy |
| Ferritin | < 100–300 ng/mL depending on CKD stage | Consider inflammation and dialysis status |
| ESA response | Poor | Suggests need for concurrent iron therapy |
| Clinical symptoms | Fatigue, shortness of breath | Especially with coexisting heart failure |
Mechanistic Insights
Iron replenishment improves mitochondrial function, reduces cardiac stress, and supports erythropoiesis. IV iron bypasses the hepcidin-mediated block of iron absorption in CKD and achieves more predictable replenishment. Trials like PIVOTAL (in hemodialysis) and AFFIRM-AHF (in heart failure) have demonstrated that IV iron not only corrects laboratory values but also reduces hospitalizations and improves quality of life.
Expert Opinion
“Heart failure and CKD are two sides of the same coin. Iron therapy helps break this vicious cycle and should be a central component of management.”
— Dr. B.L. Neuen, Lead Author, 2025 Meta-analysis
Practical Takeaways for Clinicians
- Assess iron status regularly, not only hemoglobin
- Treat iron deficiency even in non-anemic CKD patients, especially if symptomatic or with heart failure
- Prefer IV iron in patients with intolerance to oral iron or those needing rapid repletion
- Ferric citrate may offer added value in non-dialysis CKD by reducing phosphate and delaying dialysis
Conclusion
Iron therapy in CKD is underutilized but has robust evidence supporting its broader role in cardiovascular protection, symptom improvement, and disease progression delay. Clinicians should move beyond hemoglobin thresholds and adopt a proactive approach to iron repletion in appropriate patients.