Erythropoiesis is an intricate, multistage process of differentiation of early pluripotent erythroid progenitors to mature enucleated erythrocytes. The process is dependent on numerous exogenous and endogenous factors, such as iron homeostasis, hypoxia, stress, growth and transcription factors (1). As erythropoietin is one of the strongest molecules stimulating erythropoiesis, its low production in diseased renal tissue may explain why anaemia is a prevalent complication of chronic kidney disease (CKD). However, iron deficiency-limited erythropoiesis is a compelling problem, contributing to the development of anaemia in chronic kidney disease and limiting efficacy of treatment with erythropoiesis stimulating agents (ESAs).

It is estimated that 2.4 x 10⁶ new erythrocytes should be produced each second to maintain adequate haematocrit in 5 L of blood of a healthy adult individual (2). Therefore, nearly 80% of average 25 mg of daily iron requirement is used for erythropoiesis (3). In physiological conditions daily intake of iron ranges from 10 to 15 mg and the maximum absorption is about 20%, thus normal diet provides only 2-3 mg of iron. The remaining part comes in greatest proportion from effete erythrocytes undergoing eryptosis (2). Iron deficiency has deleterious impact not only on tissue oxygenation through impaired haemoglobin synthesis, but also on various metabolic processes including accumulation of muscle energy or oxygen storage in myoglobin, neuron myelination, and DNA synthesis (4). According to American data from the National Health and Nutritional Examination Survey (NHANES III) 60-73% of persons with an estimated glomerular filtration rate < 60 ml/min/1.73 m² are iron deficient, while iron deficiency anaemia affects 8.8% of the general world population (5, 6). Iron depletion is even more accentuated in patients with end-stage renal failure on maintenance haemodialysis, where blood loss during the procedure, frequent blood sampling and occult or overt gastrointestinal bleeding may diminish scant iron stores. Moreover, iron malabsorption may be exacerbated by poor appetite, low-protein diet and various drugs frequently used in CKD patients (proton pump inhibitors, phosphate binders). Despite absolute iron deficiency in CKD patients, functional iron deficiency (FID) is also prevalent. According to Macdougall’s definition, FID is a state in which there is insufficient iron incorporation into erythroid precursors in the face of apparently adequate iron stores (7). This applies to the partial block in iron transport being the major cause of anaemia of chronic disease observed in inflammatory, infectious and malignant diseases, and to the second type of FID frequently occurring when erythroid marrow is stimulated with ESAs (8). Albeit multifactorial, both absolute and functional iron deficiencies may be partly assigned to impaired hepcidin – ferroportin axis.

Hepcidin and ferroportin are two crucial proteins that in cooperation with hemojuvelin, hephaestin, iron transporter DMT1 and duodenal cytochrome B (Dcytb) regulate plasma iron concentration (9). Ferroportin is the only known mammalian iron exporter (10). This basolateral transmembrane efflux channel in combination with ferroxidases (hephaestin, ceruloplasmin) enables absorption of ferric ions from duodenal enterocytes. Apart from that, ferroportin facilitates transfer of iron from hepatocytic storage to plasma and retrieval of iron from macrophages of the mononuclear phagocyte system, which phagocyte senescent erythrocytes. Hepcidin in turn, is a peptide hormone produced by hepatocytes in response to increased iron levels. In a negative feedback loop hepcidin causes internalization and ubiquitination of ferroportin, thus limiting intestinal iron absorption and causing iron entrapment in macrophages, hepatocytes and enterocytes (11, 12). Decreased iron absorption is the only known mechanism preventing from iron overload, for iron loss is not regulated in any defined pathway and may occur mainly through cell shedding or bleeding (11, 13). Hence, hepcidin expression is modulated by various endogenous and exogenous factors. Tissue iron stores and transferrin saturation regulate hepcidin transcription by BMP-SMAD pathway with hemojuvelin as a co-factor. Inflammation is another hepcidin transcriptional regulator, through the JAK-STAT3 pathway initiated by Il-6 (12, 13). As a consequence, in numerous patients with chronic renal failure, hepcidin levels are elevated due to an underlying inflammatory process (14). Moreover, in the end-stage renal failure hepcidin may be not efficiently eliminated, neither by kidneys nor by dialysis. In addition, the dialysis procedure may initiate inflammatory-mediated hepcidin transcription (14). Therefore in CKD patients hepcidin levels consecutively rise, compromising iron homeostasis.

Taking into account all the pathophysiological aspects of iron absorption and storage in patients with CKD, screening for iron deficiency should be performed, and iron supplementation considered, especially in the view of poor responsiveness to ESA treatment.

Nevertheless, iron supplementation has certain disadvantages. Oral supplementation in CKD patients is frequently inefficient, while intravenous supplementation is associated with various adverse effects, including anaphylactic reactions and tissue toxicity. Iron is a redox-active transition metal and it may exist in two ionic states: ferrous – Fe(II), and ferric – Fe(III), thus enabling electron transfer among molecules. This redox activity is potentially damaging and free, unbound iron easily triggers it. Human organism limits free forms of iron ions by binding them to transferrin in plasma or to ferritin intracellularly, before incorporating it into heme and non-heme proteins (15, 16). Transferrin with two iron-binding sites may exist as four molecular forms – apotransferrin, monoferric A and B transferrin, and diferric transferrin, depending on the level of saturation (16). The saturation of transferrin is calculated with an equation:

TSAT = Fe (mg/dl)/TIBC(mg/dl) x 100%