Erythropoiesis-stimulating agents (ESA) are derivates of natural EPO, manufactured by recombinant DNA technology. ESA therapy stimulates the process of RBC production by erythroid cells in the bone marrow.
Prior to the introduction of ESA into the treatment of anaemia, blood transfusions were commonly given to patients with CKD in an attempt to raise the haematocrit. However, these transfusions frequently resulted in a severe iron overload. Untreated, iron overload can cause hepatic or cardiovascular dysfunction and may also increase the risk of bacterial infections.³⁴

For this reason, the administration of ESA to patients with anaemia as a consequence of CKD presents a major improvement in therapy and facilitates an increase of Hb and HCT levels with many potential benefits to the patient, including:

• Decreased need for blood transfusions
• Reduced fatigue
• Increased energy and exercise capacity³⁴
• Increased appetite
• Improved quality of life^34,37 

A reduced number of hospitalisations, associated with improved anaemia control and higher HCT levels, may furthermore result in overall cost savings in healthcare.³⁸ However, too high doses of ESA can be detrimental: e.g. an increased risk of death and an increased number of blood clots, strokes, heart failure, and heart attacks was reported in CKD patients when ESA therapy was given in an attempt to maintain haemoglobin levels of more than 12 g/dL.³⁹

A target Hb level of 11 to 12 g/dL and a target HCT level of 33 % to 36 % should be maintained in patients with CKD during ESA therapy.³⁵ However, stimulating replacement therapy with ESA also increases the demand for iron. In that context, when iron stores cannot be mobilised quickly enough to meet the enhanced need in the bone marrow for the production of new RBCs, functional and absolute iron deficiency may result, despite an adequate iron supply. Therefore, additional iron supplementation is often required in order to maintain a proper iron balance and to ensure optimal therapeutic response to ESA therapy.⁴⁰

Different iron therapies

The introduction of ESA therapy for CKD-induced anaemia in 1989 led to considerable progress in its successful treatment. However, the sufficient repletion of body iron stores emerged as a critical factor in the subsequent time period, whereby the administration route oral vs. i.v. was demonstrated to play a crucial role.⁴¹

Limitations of oral iron administration

Studies demonstrate that the oral administration of iron is unlikely to achieve target iron indices in EPO-treated patients and also insufficient for maintaining iron stores.^{18, 42, 43}

As a contributing factor, dietary absorption of iron is not only slightly lowered in dialysis patients, but is significantly reduced by approximately 50 % compared to iron deficient healthy patients.²² As intestinal iron absorption is diminished in CKD, sufficient absorption to meet iron requirements for optimal erythropoiesis is unlikely to occur.^{33, 35, 48}

Oral iron therapy is also hampered by poor compliance as a result of gastrointestinal side effects. Oral iron supplementation can be costly, ineffective and troublesome to patients.⁴⁷

It is evident that many CKD patients receiving ESA therapy will additionally require i.v. iron to reach and maintain target iron levels.³³ In addition the permanent dialysis associated blood loss and the resulting negative iron balance make continuous supplementation necessary. There are two major therapy options with i.v. iron:

1. Periodical repletion of iron stores reached by high dose administration of iron,
2. Maintenance of iron stores is done by regular administration of iron on a weekly or monthly schedule.³⁴

According to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [NKF-K/DOQI]³⁴, several important issues related to iron deficiency and its management in chronic renal failure patients receiving ESA therapy should be considered:

• Iron (blood) losses are high, especially in haemodialysis patients
• Oral iron usually cannot maintain adequate iron stores, especially in haemodialysis patients receiving ESA
• EPO stimulates erythropoiesis, often leading to iron deficiency
• Prevention of functional and absolute iron deficiency by regular use of i.v. iron improves erythropoiesis
• TSAT is a very good indicator of iron availability for erythropoiesis. Serum ferritin is an indicator of tissue iron stores. However, both indices lack sensitivity (referring to how many positive results a test can detect) and specificity (referring to the accuracy of a test without giving false-positive results). So no single value of TSAT reliably distinguishes iron-deficient from iron-sufficient erythropoiesis, and no single value of ferritin especially in an inflammatory state distinguishes depleted from adequate iron stores. Consequently, results from both tests are necessary in order to confirm the diagnosis.

Assessment and monitoring

Monitoring of the iron status on the basis of TSAT and serum ferritin levels is recommended as a crucial part of anaemia management. After the initiation of EPO therapy, iron indices should be monitored monthly. In patients who have achieved target range Hb or who are already receiving i.v. iron therapy, TSAT and ferritin levels should be monitored every three months.