**1. Introduction**

208 Chronic Kidney Disease

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Anaemia is a frequent complication associated with stage 5 chronic kidney disease (CKD), and is mainly due to insufficient production of erythropoietin by the kidneys. Accumulation of uremic toxins, excessive toxic storage of aluminium in the bone marrow (Miyoshi, 2006), blood loss (either iatrogenic, from the puncture sites of the vascular access and blood sampling, or from other sources, such as the gastrointestinal tract), and premature erythrocyte destruction have also been frequently associated with anaemia in stage 5 CKD patients (Medina, 1994; Pisoni, 2004).

The erythrocyte, presenting a limited biosynthesis capacity, suffers and accumulates physical and/or chemical changes, which become more pronounced with cell aging, and whenever an unusual physical or chemical stress develops (Locatelli, 2004a). Erythrocytes are physically stressed during the haemodialysis process, and metabolically stressed by the unfavourable plasmatic environment, due to metabolite accumulation, and by the high rate of haemoglobin autoxidation, due to the increase in haemoglobin turnover, a physiologic compensation mechanism triggered in case of anaemia (Lucchi, 2000; Stoya, 2002). The erythrocytes are, therefore, continuously challenged to sustain haemoglobin in its reduced functional form, as well as to maintain the integrity and deformability of the membrane.

Leukocytosis is essential as the primary host defence, and neutrophils, the major leukocyte population of blood in adults, play a primordial role. It is well known that neutrophils have mechanisms that are used to destroy invading microorganisms. These cells use oxygen-dependent and oxygen-independent microbicidal artillery to destroy and remove infectious agents (Witko-Sarsat, 2000). Activated neutrophils also undergo degranulation, with the release of several components, namely, proteases and cationic proteins (Witko-Sarsat, 2000).

In this book chapter we review the cross-talk between changes in erythrocyte membrane protein composition and the release of neutrophil activation products.

Neutrophil Activation and Erythrocyte Membrane

destruction (An & Mohandas, 2008).

**3. Neutrophil activation**

their phagocytic capacities.

Ley, 2007).

Protein Composition in Stage 5 Chronic Kidney Disease Patients 211

rigidity of the cell membrane that may lead to premature spleen sequestration and

Leukocytosis and recruitment of circulating leukocytes into the affected areas are hallmarks of inflammation. Leukocytes are chimio-attracted to inflammatory regions and their transmigration from blood to the injured tissue is primarily mediated by the expression of cell-adhesion molecules in the endothelium, which interact with surface receptors on leukocytes (Muller, 1999; Sullivan, 2000). This leukocyte-endothelial interaction is regulated by a cascade of molecular steps that lead to the morphological changes that accompany adhesion. At the inflammatory site, leukocytes release their granular content and may exert

In acute inflammation, the leukocyte infiltration is predominantly of neutrophils, whereas in chronic inflammation an infiltration predominantly of macrophages and lymphocytes is observed. Leukocyte-endothelial cell interactions are important for leukocyte transmigration and trafficking in physiological conditions. There is increasing evidences that changes in those leukocyte-endothelial interactions, due to endothelium damage or dysfunction, might be implicated in the pathogenesis of diseases, such as inflammatory diseases (Harlan, 1985;

Leukocytosis is essential as the primary host defence, and neutrophils, the major leukocyte population of blood in adults, play a primordial role. It is well known that neutrophils have mechanisms that are used to destroy invading microorganisms. These cells use an extraordinary array of oxygen-dependent and oxygen-independent microbicidal weapons to destroy and remove infectious agents (Witko-Sarsat, 2000). Oxygen-dependent mechanisms involve the production of reactive oxygen species (ROS), which can be microbicidal (Roos, 2003), and lead to the development of oxidative stress. Oxygen-independent mechanisms include chemotaxis, phagocytosis and degranulation. The generation of microbicidal oxidants by neutrophils results from the activation of a multiprotein enzyme complex, known as the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the formation of superoxide anion (O2·–). Activated neutrophils also undergo degranulation, with the release of several components, namely, proteases (such as

elastase) and cationic proteins (such as lactoferrin) (Saito, 1993; Brinkmann, 2004).

Elastase is a member of the chymotrypsin superfamily of serine proteinases, expressed in monocytes and mast cells, but mainly expressed by neutrophils, where it is compartmentalized in the primary azurophil granules. The intracellular function of this enzyme is the degradation of foreign microorganisms that are phagocytosed by the neutrophil (Brinkmann, 2004). Elastase can also degrade local extracellular matrix proteins (such as elastin), remodel damaged tissue, and facilitate neutrophil migration into or through tissues. Moreover, elastase also modulates cytokine expression at epithelial and endothelial surfaces, up-regulating the production of cytokines, such as IL-6, IL-8, transforming growth factor β (TGF-β) and granulocyte-macrophage colony-stimulating factor (GM-CSF); it also promotes the degradation of cytokines, such as IL-1, TNF-α and IL-2. There is evidence in literature that high levels of elastase are one of the major pathological factors in the development of several chronic inflammatory lung conditions (Fitch, 2006).
