by Peter Bárány

Introduction

The anaemia associated with chronic renal failure has many causes. The main reason is deficient erythropoietin synthesis with serum levels of erythropoietin which are too low for the degree of anaemia. Blood loss, either iatrogenic from the puncture sites of the vascular access and blood sampling, or from other sources such as the gastrointestinal tract are contributive. As a result, iron requirements are often increased more than fivefold in dialysis patients. Most patients with chronic renal failure achieve the desired target haemoglobin (Hb) level when supplemented with relatively low doses (50–150 IU/kg/week) of recombinant human erythropoietin (epoetin) and parenteral iron (usually             1500–3000 begin_of_the_skype_highlighting            1500–3000      end_of_the_skype_highlighting       mg/year) [1]. About a quarter of the dialysis patients, however, have a poor response and need higher doses (>200 IU/kg/week) to reach the target Hb level. This relative resistance to epoetin and iron is often associated with co‐morbid conditions, particularly inflammatory conditions. The inflammatory process may be acute, leading to transient resistance to epoetin, or chronic, with a persistently poor response to epoetin.

Inflammation and the acute‐phase response

Acute inflammatory disease is classically accompanied by signs and symptoms such as fever, anorexia, and somnolence. The endocrine and metabolic response to acute inflammation includes the release of hormones which induce catabolism and gluconeogenesis such as glucagon, insulin, adrenocorticotropic hormone, growth hormone, thyroxin, and catecholamines [2]. The concentrations of iron and zinc in plasma decrease, while those of copper increase. The haematopoietic response includes leukocytosis, thrombocytosis, and anaemia secondary to decreased erythropoiesis [3].

Similarly, surgical trauma induces a state of inflammation with an acute‐phase reaction and anaemia [4]. The severity of this response is related to the extent of the trauma. When the Hb concentration acutely decreases in patients with normal renal function, erythropoietin secretion is increased for 4–10 days. The reactive increase in erythropoietin secretion is diminished in patients undergoing an acute‐phase response [3]. This has been attributed to the inhibition of erythropoietin secretion by pro‐inflammatory cytokines [5].

A narrow definition of the acute‐phase response to inflammation is based on the characteristic changes in the concentrations of several plasma proteins [2,3] secondary to altered hepatic transcription and synthesis of excretory proteins. The plasma concentrations of the two major human acute‐phase proteins, C‐reactive protein (CRP) and serum amyloid A, increase 100–1000‐fold in response to severe infections. The concentrations of other positive acute‐phase proteins increases less, e.g. complement factors, fibrinogen, ferritin, haptoglobin and α‐1 protease inhibitor. Among the negative acute‐phase proteins, of which the synthesis and secretion is decreased, are albumin, transferrin, α‐fetoprotein, and transthyretin [3].

The acute‐phase response is regulated by a number of pro‐inflammatory cytokines such as interleukin‐1 (IL‐1), tumour necrosis actor‐α (TNF‐α), interleukin‐6 (IL‐6), β‐ and γ‐interferon [2,3]. The cytokines are to a large extent produced locally by tissue macrophages, but in severe inflammation, systemic effects occur as well.

The prevalence of inflammation in uraemic patients is high [6]. Potential causes include bacterial or viral infections, surgical trauma including vascular access surgery, heart failure, and renal or systemic inflammatory diseases. It is likely but not proven that the compromised immune system contributes to the high prevalence of inflammation in uraemic patients.

Effects on erythropoiesis

The erythropoiesis‐suppressing effect of inflammation is mainly due to increased activity of the proinflammatory cytokines [3,7]. In vivo, the cytokines act in concert to affect precursor cells at different stages of erythropoiesis. Of the above‐mentioned cytokines, TNF‐α and IL‐1 have been extensively studied [3,7]. In experimental animal studies and in humans, administration of both cytokines causes a hypoproliferative anaemia by direct action on erythroid progenitor cells or indirectly by stimulating interferon production [810]. Despite the overall suppressive effect on erythropoiesis, some studies have shown that TNF‐α and IL‐1 stimulate the growth of early progenitors (burst‐forming units‐erythroid, BFU‐E), while suppressing the growth of later stages (colony‐forming units‐erythroid, CFU‐E) [3]. The inhibitory effect of TNF‐α and IL‐1 on erythropoiesis can be overcome in a dose‐dependent fashion by administering epoetin. It is thought that the direct inhibitory effect on erythroid precursors is primarily due to alterations in sensitivity to erythropoietin [3].

Other cytokines, including IL‐6 and interferons, have been shown to suppress erythropoiesis as well [3,10]. γ‐Interferon inhibits the growth of CFU‐E [7]. This can be corrected by high doses of erythropoietin [9].

Effects on erythrocyte survival

Macrophages normally remove senescent erythrocytes from the circulation. Erythrocytes coated with immunoglobulins or immune omplexes are cleared more efficiently from the circulation [11]. Macrophages, activated by inflammatory signals, are responsible for accelerated disposal of erythrocytes, shortening of the life‐span of erythrocytes and decreasing the Hb concentration.

Effects on iron metabolism

Inflammation and the acute‐phase response interact with iron metabolism at several levels. Inflammation reduces the serum concentrations of iron and transferrin. Kooistra et al. [12] found that iron absorption from the gut was impaired in patients with renal failure and elevated serum CRP levels (>8 mg/l). This is consistent with the notion that the synthesis of transferrin is reduced during the acute‐phase response. Less apotransferrin is secreted in the bile and delivered to the gut. As a result less iron is delivered to the transferrin receptors of the mucosal cells [11].

Functional iron deficiency is defined as low availability of iron for erythropoiesis despite normal or high iron stores in the body [1]. A state of functional iron deficiency often occurs when erythropoiesis is stimulated by erythropoietin, but the rate of iron delivery to the bone marrow is insufficient. Theoretically, functional iron deficiency may occur in one of two ways: (i) when high doses of epoetin stimulate erythropoiesis so much that it exceeds the maximal capacity to deliver iron, or (ii) when the delivery of iron from the reticuloendothelial cells to haematopoietic cells is inhibited or blocked [13]. In clinical practice it is not always possible to distinguish between these two mechanisms.

Serum ferritin is an acute‐phase protein and increases two‐to fourfold in response to inflammation. IL‐1 and TNF‐α cause an increase in ferritin synthesis directly at the transcriptional level [14]. Cytokines may also induce ferritin synthesis indirectly by increasing iron uptake into hepatocytes [11]. The increase in ferritin synthesis by hepatocytes and reticuloendothelial cells underlies the increase in the iron storage pool during inflammation. The circulating ferritin contains only minute amounts of iron and its role in iron metabolism is uncertain. It may have a protective detoxifying effect by taking up free iron at sites of inflammation.

Lactoferrin is present in polymorphonuclear leukocytes and acts as an iron scavenger with bactericidal activity [3]. As a part of the acute‐phase reaction, lactoferrin synthesis increases during inflammation. It can bind large amounts of free iron [11]. The iron bound to lactoferrin is taken up by activated macrophages, which express specific lactoferrin receptors. During inflammation, this causes iron deprivation of the erythroid precursors, which fail to express lactoferrin receptors.

Iron is essential for the growth of some microbes and sequestration of iron in the form of insoluble compounds, such as lactoferrin and haemosiderin, is thought to be part of the host defence against bacterial and viral infections [15]. However, a decrease in erythropoiesis may also reflect a relative deficit of erythropoiesis in the face of an increased demand to produce neutrophil granulocytes and other immunocompetent cells.

Serum CRP predicts epoetin resistance

CRP is secreted by the liver and inflammation causes a rapid increase in its serum concentration. It plays a role in host defence by interacting with complement. Compared to measurements of other markers of inflammation and the acute‐phase reaction, serum CRP has several advantages. It is a simple, reliable, readily available and inexpensive test. It is also a long‐term predictor of cardiovascular risk and mortality in the general population and in chronic renal failure patients [6]. About one‐third of patients with chronic renal failure have serum CRP concentrations >10 mg/l [16]. In dialysis patients, high CRP levels are associated with low Hb levels and/or epoetin resistance [1618]. Other acute‐phase proteins that have been shown to correlate to epoetin resistance in dialysis patients are albumin [18] and fibrinogen [19]. Although there is a relationship between the degree of systemic inflammation and epoetin resistance, in the presence of chronic inflammation the effect is highly variable between patients and variable over time in individual patients.

Treatment with epoetin and iron in patients with inflammation

On average, the required epoetin dose to maintain a certain Hb level may be increased by 30–70% in dialysis patients with serum CRP >20 mg/l as compared to those with a lower CRP concentration ([17], and unpublished data from the European Survey of Management of Anaemia). In patients with an acute intercurrent illness and in those who undergo surgery, the current recommendation is to continue epoetin treatment [1]. Hb concentrations may decrease to critically low levels if epoetin is discontinued. When the degree of systemic inflammation is severe, the response to epoetin may be totally blunted and blood transfusion may be needed.

The use of parenteral iron in patients with inflammation is controversial. The potential risks of iron excess have been extensively discussed, but available data are inconclusive [20,21]. It is recommended that intravenous iron should be discontinued in patients with bacteraemia because iron may promote bacterial growth [1]. In patients with systemic inflammation of other aetiology, who often have functional iron deficiency, it has been suggested that repeated continuous administration of low doses may be safe and effective [20,21]. This approach may be more effective than loading with higher doses, since the effect of intravenous iron on transferrin saturation is only transient in such patients [22].

Future aspects and conclusions

It is obvious that controlled trials are necessary before evidence‐based recommendations can be given for the management of inflammation‐induced epoetin resistance. The risks and benefits of intravenous iron and the effects of various iron dosage schedules warrant further careful evaluation in prospective studies. In patients with acute intercurrent illness or surgery, it would be of interest to compare different epoetin regimens. Mimicking of the normal secretion of erythropoietin after surgery by transiently increasing the epoetin dose for 4–10 days seems theoretically attractive.

In conclusion, in patients with chronic renal failure, inflammation is associated with a relative resistance to epoetin. In most patients with mild to moderate inflammation it can be overcome by increasing the dose. So far, serial measurements of serum CRP are the best way to monitor the acute‐phase response in clinical practice. In the future, novel inflammatory markers such as procalcitonin and neopterin may give more specific information. The inflammation‐induced low concentration of iron contributes to epoetin hyporesponsiveness. Intravenous iron in combination with epoetin increases erythropoiesis, but the optimal management of anaemia in chronic renal failure patients with inflammation has not yet been determined.

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