Causes

The causes of iron-deficiency anaemia include decreased intake or absorption of iron. Furthermore, chronic inflammatory processes reduce the release of iron from storage sites.²¹ Other typical causes for iron deficiency are blood loss or increased iron usage for RBC production in response to erythropoiesis stimulating agents (ESA).^22-24

Dialysed patients experience additional iron need in consequence of repetitive blood loss caused by frequent venous punctures (3 x per week) and blood samplings. Blood loss can be as high as 3 g of iron per year.^{10, 11, 25}

Interestingly, CKD patients show substantially higher blood loss via the gastrointestinal tract in comparison to healthy volunteers²⁶. Occult gastrointestinal bleeding (due to high rates of inflammation of gastrointestinal mucosa) is found in up to 20 % of CKD patients.^{24, 27}

Clinical signs of iron deficiency

Symptoms of iron deficiency include mouth soreness, difficulty swallowing, enlarged spleen, irritability, and spooning (softening and curling of the nails). Some patients with iron deficiency may exhibit pica, a craving to ingest peculiar substances such as clay, ice or corn starch.²⁸ Chronic iron deficiency in children is associated with developmental delays and behavioural disturbances.²⁹ In pregnant women, iron deficiency increases the risk for pre-term delivery and low-birth-weight infants.³⁰ While patients at an early stage of iron deficiency may fail to exhibit any physiological impairment,³¹ as iron deficiency progresses the signs and symptoms of anaemia generally parallel the severity of iron deficiency.³²

Generally, two different forms of iron deficiency can be identified in CKD patients: absolute and functional iron deficiency.

Absolute iron deficiency

Multiple procedural, disease- and diet-related factors may contribute to an inadequacy of total body iron stores in patients with CKD, resulting in absolute iron deficiency. In such cases, the total quantities of iron in the available stores are insufficient to cover the overall demand. This status is usually detected by performing two laboratory tests, to measure levels of serum ferritin and transferrin saturation (TSAT). Current guidelines reflect the analysis of all available evidence and an expanded scope addressing all patients with CKD, including transplant CKD, regardless of etiology, stage, or treatment modality. Guidelines state that in CKD patients with ferritin values <200 ng/mL (haemodialysis) or <100 ng/mL (non-dialysis or peritoneal dialysis), the likelihood that iron stores are depleted is high. If these patients also show TSAT <20%, iron deficiency is considered to be absolute.^33,34,48

Functional iron deficiency

In contrast to absolute iron deficiency, functional iron deficiency is a failure to release iron rapidly enough to keep pace with the demands of the bone marrow for the production of RBCs, despite adequate total body iron stores. This means that sufficient iron is in fact available in the stores but it cannot be used adequately owing to a lack of mobilisation and transport resources.
Functional iron deficiency is the most common cause of a poor response to ESA therapy. Functional iron deficiency has the following characteristics^20,33:

• Inadequate Hb response to EPO
• Serum ferritin normal or raised
• Transferrin saturation (TSAT) <20 % 

Assessing iron status

The differential diagnosis between functional and absolute iron deficiency (See table) is essential in order to understand iron values in patients with chronic renal failure. For instance, functional iron deficiency, which is the most common cause of an inadequate response to EPO therapy (Hb <11.0 g/dL), requires a treatment approach different from that for cases of absolute deficiency.