**4.1.1.1 Systemic Chronic Inflammation**

Inflammatory mechanisms play a relevant role in the development and progression of atherosclerosis (Ross, 1999) and heart failure (Vasan et al., 2003). Epidemiological studies in the general population have shown that even minor elevations of C-reactive protein (CRP), an acute phase reactant that markedly increases during an inflammatory response (Ridker PM, et al., 1997) predict the development of coronary heart disease and cardiac failure

The Evolution of Biocompatibility: From Microinflammation to Microvesiscles 101

which lead to the synthesis of many acute-phase reactants, is a better marker for the inflammatory burden affecting the development of CVD (Panichi et al., 2011). A frequently asked question is what is the contribution of HD bioincompatibility to the chronic inflammatory state. In this context, the evolution of HD technology has moved the focus from membrane bioincompatibility only to a more complex and integrated view of the HD system. The possibility that HD may be shift to a "cardioprotective'' therapy is inherent to

Originally introduced as an elegant concept in 1986 (Bingel et al., 1986), the "interleukin hypothesis" was first coined to indicate the production of interleukin-1, the endogenous pyrogen as produced by the result of complement-activated mononuclear cells. Indeed, the interleukin hypothesis explained much more than was initially predictable. Several studies have ever since reported an increased cytokine production secondary to blood interaction with contaminated dialysate. Interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a) and mainly IL-6 are the 3 proinflammatory cytokines that are involved in the pathogenetic aspects of HD-related disease (as reviewed by Lonnemann, 2004, Panichi et

new technologies in machines, water treatment, dialysis fluids and blood tubings.

Fig. 5. Here are schematically depicted the mechanisms related to the

*Limulus amoebocyte* lysate, UF, ultrafiltrate.

backdiffusion/backfiltration of bacteria-derived contaminants from the dialysate into the blood. Their interaction with circulating monocytes/macrophages leads to the activation of innate immunity and to the attendant triggering of proinflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor-. Abbreviations: CIS, cytokine-inducing substances; LAL,

**4.1.1.2 The Interleukin Hypothesis** 

al., 2000 (**Figure 5**).

(Liuzzo et al 1994, Lagrand et al., 1999, Badht et al, 2002). C-reactive protein may directly promote the development of atherosclerosis, through complement activation, tissue damage and activation of endothelial cells. Recent studies performed in CKD patients have shown that CRP is a strong predictor of cardiovascular death (Stenvinkel, 2001, Kaysen, 2005). The link between CRP and cardiovascular risk was initially thought to be indirect, reflecting circulating CRP only to the extent of the acute phase reaction in response to nonspecific stimuli such as confounding risk factors, atherosclerosis, vascular injury, ischemia and necrosis. **(Figure 4).** 

Fig. 4. Acute phase response is a defence response which occurs as a consequence of an inflammatory stimulus occurring in the blood or at tissue level. The enhanced production of interleukin-6 (IL-6), the most potent inducer of this reaction at the level of the liver, triggers the synthesis of newly synthesized proteins, e.g., C-reactive protein (which plasma levels may increase up to 50-to 100-fold the normal levels) as well as to the shut-down of the translation of genes coding for proteins, e.g., albumin.

Stenvinkel et al (1999) first convincingly showed that the malnutrition-inflammation complex syndrome described as MIA syndrome is associated with the highest mortality rates in ESRD. Their results were confirmed and extended (Panichi et al. 2008). As reviewed by Stenvinkel & Barany (2002), there is consensus on a link between CKD and inflammation. A number of studies have highlighted the association between increased inflammatory indexes and a reduced response to Erythropoietin-stimulating agents (ESAs), in particular, high CRP levels were found in HD patients requiring higher ESAs doses (Singh et al., 2007; Bradbury et al. 2009). However, the association between ESAs resistance and increased CRP levels (Barany et al. 1997; Gunnell et al. 1999) is unclear. Plasma IL-6 rather than CRP seem to better predict outcomes in CKD patients (Panichi et al., 2004). Various possible explanations may underline the advantage of IL-6 over CRP as a predictor of ESAs resistance. One possibility is that IL-6, being located upstream in the cascade of events which lead to the synthesis of many acute-phase reactants, is a better marker for the inflammatory burden affecting the development of CVD (Panichi et al., 2011). A frequently asked question is what is the contribution of HD bioincompatibility to the chronic inflammatory state. In this context, the evolution of HD technology has moved the focus from membrane bioincompatibility only to a more complex and integrated view of the HD system. The possibility that HD may be shift to a "cardioprotective'' therapy is inherent to new technologies in machines, water treatment, dialysis fluids and blood tubings.
