**1. Introduction**

174 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Yamashita, A.C. (2007). Mechanisms of solute and fluid removal in hemodiafiltration.

Patients with chronic kidney disease and patients on renal replacement therapy, such as hemodialysis and peritoneal dialysis, have an increased susceptibility to infectious diseases compared with healthy subjects (Sarnak & Jaber 2000; Allon et al. 2003). Infection is also the second most common cause of morbidity and mortality in patients with end-stage renal disease (Bloembergen & Port 1996; Powe et al. 1999; Graff et al. 2002).

One contributing factor could be the chronic inflammatory activation seen in patients with chronic kidney disease and patients on dialysis, which causes a refractoriness of leukocytes when confronted with invading microorganisms.

### **1.1 The innate and adaptive immune responses**

The immune system is designed to defend us from invading microorganisms, such as viruses and bacteria. The first response is called the innate immune response, mostly dependent on recruitment and activation of neutrophils (Parkin & Cohen 2001). Complement activation occurs on the bacterial cell surface, triggering a cascade of proteolytic reactions that are specific in so far as they act on microbial surfaces but not on host cells. Neutrophils have receptors both for common bacterial constituents and for complement. Neutrophils become activated through complement (C3b and C5a) but can also get activated directly by bacterial peptides, such as lipopolysaccharide, lipotechoic acid, mannans and fMLP (N-formylmethionyl leucyl phenylalanine) (Parkin & Cohen 2001).

Activation of neutrophils occurs in several steps, comprising both priming and further activation, and is necessary for neutrophils to perform their specific actions at the inflammatory sites: phagocytosis and release of inflammatory mediators (Swain et al. 2002). Neutrophils are effector cells of great importance in the innate immune system. An impaired neutrophil function leads to several dysfunctions in the defense against invading microorganisms. Neutrophils have previously been regarded as wholly differentiated and static cells whose function is based on preformed receptors and soluble factors, and solely part of the innate immune system. This idea has been challenged by publications that show a high gene transcriptional activity following both activation and extravasation (Theilgaard-Monch et al. 2006). The transcriptional activation occurs at the inflammatory site and engages genes involved in multiple neutrophil functions, such as production of reactive oxygen species, hydrogen peroxide, cytokines and chemokines (Theilgaard-Monch et al. 2004; Coldren et al. 2006). Neutrophils direct both innate and adaptive immune responses,

Fig. 1. Leukocyte adhesion to the endothelium, subsequent extravasation and transmigration through a chemotactic gradient in the interstitium towards a site of

Fig. 2. Neutrophil adhesion, extravasation and transmigration.

inflammation.

by interacting with immune modulating cells (Cohen et al. 2001; Yamashiro et al. 2001; Cohen et al. 2003; Theilgaard-Monch et al. 2004). Neutrophil cytokine and chemokine production can be an important link between the innate and the adaptive immune responses. Cytokine-activated neutrophils produce and release multiple proinflammatory cytokines and chemokines, including IL-1, IL-8, monocyte chemotactic protein-1 (MCP-1/CCL2) and macrophage inflammatory protein-1α and 1β (MIP-1α/MIP-1β). MCP-1 and MIP-1α act as chemotactic and activating signals for mononuclear cells, especially monocytes, and for mobilization of other cell surface molecules involved in the adaptive immune response (Yamashiro et al. 2001; Kobayashi 2008).

Chemokines attract neutrophils and monocytes from the circulation to the inflammatory/infectious site by first making the endothelium more adhesive to the circulating cells and then through a chemokine gradient through the tissue leading the way to the site of inflammation (Janeway & Travers 2005). Circulating monocytes that extravasate and get activated rapidly develop into mature macrophages with the principal function of phagocyting microorganisms (Janeway & Travers 2005).
