3.3 Effect of erythropoiesis- stimulating agents and iron

Question 3 (Interventional question)

In medical patients, what is the effect of non-transfusion interventions to increase Hb concentration on morbidity, mortality and need for RBC blood transfusion?

Hb, haemoglobin; RBC, red blood cell

The transfusion of RBCs is resource intensive, and has been associated with short and long-term morbidity in recipients. Recombinant erythropoiesis-stimulating agents (ESAs) promote bone marrow production of RBCs. However, ESAs have been associated with complications of therapy in some patients, particularly where the baseline Hb is near normal. In some patients, iron administration may also be effective. The systematic review examined the effectiveness of ESAs or iron supplementation in subgroups of anaemic patients.

Erythropoietin is secreted by the kidneys in response to hypoxia and stimulates erythropoiesis in the marrow. A reduction in renal mass may contribute to reduced erythropoietin levels, and therefore anaemia. ESAs are synthetic molecules that replicate this function. They are effective in increasing the Hb in individuals with severely impaired renal function, but have also been used to overcome reduced erythropoiesis due to a variety of other causes; these include cancer, haematological malignancies and other chronic diseases. The erythropoietic response to ESAs is reduced in primary bone marrow disorders and where chronic inflammation contributes to anaemia.

The effectiveness of ESAs in treating anaemia and their consequent potential effect on functional status must be balanced against risks associated with therapy; both the effectiveness and the risks vary in different diagnostic subgroups.

Iron deficiency results when iron losses or requirements exceed absorption; it is often multifactorial, and may be absolute or relative. Relative iron deficiency is commonly referred to as functional iron deficiency (FID). A patient with FID has adequate stores of iron, but the iron cannot be mobilised for erythropoiesis, which is mediated by elevated hepcidin. FID is commonly seen in patients with end-stage kidney disease, but may also contribute to anaemia in patients with inflammatory diseases, chronic heart failure (CHF) and cancer.

The serum ferritin level is the most readily available and useful index of iron deficiency.93 In an adult with anaemia, a ferritin level below 15 mcg/L is diagnostic of iron deficiency, and levels of 15 – 30 mcg/L are highly suggestive of the condition. However, ferritin is also an acute-phase protein and is elevated in inflammation, infection, liver disease and malignancy. This can result in misleadingly high ferritin levels in iron-deficient patients with coexisting systemic illness.

Iron therapy may be used as a primary treatment for anaemic or nonanaemic iron deficiency, or to augment the response to ESAs. When administered with ESAs, iron therapy prevents both absolute iron deficiency and FID, and minimises the dose of ESA needed to achieve target Hb concentrations.