**1. Introduction**

92 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Zhao W, et al. (2008). Fabrication of antifouling polyethersulfone ultrafiltration membranes

*Membrane Science*, Vol. 318, No. 1-2 (June 2008), pp. 405-412, ISSN 0376-7388 Zhu LP, et al. (2008a). Molecular design and synthesis of amphiphilic copolymers, and the

Zhu LP, et al. (2008b). Amphiphilic graft copolymers based on ultrahigh molecular weight

Zou W, et al. (2010). Poly (methyl methacrylate-acrylic acid-vinypyrrolidone) terpolymer

Zwirner J, Dobos G & Gotze O. (1995). A novel elisa for the assessment of classical pathway

2008), pp. 309-317, ISSN 1000-3304

pp. 76-84, ISSN 0376-7388

44, No. 6 (June 2008), pp. 1907-1914, ISSN 0014-3057

using Pluronic F127 as both surface modifier and pore-forming agent. *Journal of* 

performances of their blend membranes. *Acta Polymerica Sinica*, Vol. 1, No. 4 (April

poly(styrene-alt-maleic anhydride) with poly(ethylene glycol) side chains for surface modification of polyethersulfone membranes. *European Polymer Journal*, Vol.

modified polyethersulfone hollow fiber membrane with pH-sensitivity and protein antifouling property. *Journal of Membrane Science*, Vol. 358, No. 1-2 (August 2010),

of complement activation in-vivo by measurement of c4-c3 complexes. *Journal of Immunological Methods*, Vol. 186, No. 1 (October 1995), pp. 55-63, ISSN 0022-1759

Haemodialysis (HD) is a life-saving treatment for patients with chronic kidney disease (CKD) stage 5. CKD persists as a chronic worldwide epidemic and HD is the more frequently (70%) adopted treatment modality. Exponential growth trend continues on a global scale. The HD population becomes every year increasingly older (average age: 75 yrs) and sicker due to the associated co-morbidities such as cardiovascular disease (heart failure, coronary heart disease, and peripheral vascular disease), diabetes, hypertension, and peripheral vascular disease. Most of the complications associated with HD involve the cardiovascular system (Go et al., 2004; Culleton et al., 1999, Goodkin et al., 2003, Foley 2004; Barret, 2002). The evolution in the history of HD technology has greatly helped to make the HD procedure a safe and more biocompatible extracorporeal therapy. However, it must be admitted that despite significant improvements in HD technology and in the management of patients due to a better understanding of uremia toxicity, improvements in dialysis technology, better correction of anaemia and metabolic abnormalities, implementation of best practice guidelines, no significant improvement has been achieved in patient survival over the last decade (Rayner et al., 2004). The extracorporeal circuit offers a large surface of contact of the blood with foreign materials, namely the dialysis membrane, the tubings and the large volumes of the dialysate. The concept of biocompatibility has greatly evolved in the last two decades. Initially, numerous studies focused on the blood-dialyzer membrane interaction, leading to the activation of plasma systems (complement, coagulation, fibrinolysis). These studies helped in the understanding of some unknown effects occurring in the early stages of the HD session leading to pulmonary sequestration of leukocytes (mainly neutrophils) that explained the profound neutropenia associated with the cuproammonium membranes. The availability of reliable testing of complement-activated

<sup>\*</sup>*1Biologics Research, Intl Research and Development, Fresenius Medical Care, Bad Homburg, Germany. 2Doctoral School of Biotechnology, University of Torino, Torino, Italy.* 

*<sup>3</sup>Department of Medicine, Nephrology and Dialysis Unit, CTO Hospital, Torino, Italy. 4Department of Internal Medicine, Centre for Molecular Biotechnology and Centre for Research in Experimental Medicine (CeRMS), Torino, Italy.* 

*<sup>5</sup>Chair of Nephrology and Department of Nephrology, Dialysis and Transplantation, University of Torino, Italy 6Danube University, Center for Biomedical Technology, Krems, Austria.*

The Evolution of Biocompatibility: From Microinflammation to Microvesiscles 95

complement activation (C3a or C5a plasma levels) by highly sensitive ELISA tests has become a standard requirement for the evaluation of biocompatibility ever since along with the precise characterization of the polymer structure (Krieter et al, 2008). It also became clear that synthetic polymers had a very low neutropenia-inducing effect. In some cases such as the polyacrylonitrile membrane, this was also due to the capacity of the membrane to adsorb C3b and the anaphylytoxins thus masking in fact complement

Fig. 1. Pathways involved in blood-membrane interactions. LTB4 denotes leukotriene B4,

Numerous acquired hemostatic abnormalities have been identified in chronic renal failure. HD adds to these disturbances as it repetitively implies turbulent blood flow, high shear stress, and contact of blood to artificial surfaces. Anticoagulation in HD is targeted to prevent activation of coagulation during the procedure. Most anticoagulant agents inhibit the plasmatic coagulation cascade. Still commonly used is unfractionated heparin, followed by low-molecular-weight heparin preparations with distinct advantages. Immune-mediated heparin-induced thrombocytopenia constitutes a potentially life-threatening complication of

PAF, platelet-activating factor, IL-1, interleukin-1, TNF-, tumor necrosis factor.

**2.2 Activation of the coagulation system** 

activation (Pascual et al 1993) (**Figure 1**).

products (C3a and C5a and their desarginated products) guided the development of less neutropenia-inducing membranes and ultimately to the final development of fully synthetic membranes which have very low if at all capacity to induce complement activation. At that time, coagulation was an important reason for frequent interruptions and delays in the HD sessions. Due to the complex interplay known to occur between the activation of the complement and coagulation systems, it became of great interest to try to reduce the propensity for intravascular coagulation. The development of high-flux membranes and growing awareness of the benefits of convective and convective/diffusive under several contexts (intradialytic cardiovascular stability, better control or the uremic status and fluid control) gave impetus to a large number of enlightening studies on another mechanism of HD bio**IN**compatibility. The contamination by bacterial products, particularly with the widespread use of bicarbonate-based dialysates opened a new era in the field of biocompatibility. The formulation of the "interleukin hypothesis" was *a posteriori* not only the basis for further studies on the monocyte stimulation during HD, but also provided a link between biocompatibility and chronic inflammation. Basically, the evolution of biocompatibility has led us to consider two sides of the same coin: on one side, the biological responses at the blood-membrane interface; on the other hand, the consequences derived from the contact on the membrane performances (e.g. hydraulic permeability and sieving coefficients).

In this review, we will summarize the most important steps in the evolution from the concept of the blood-dialyzer membrane interaction to that of the whole HD system compatibility. In face of very recent developments of cell-to-cell communication and signal transduction, we will also discuss the new hypothesis for a role of microvesicles (MVs) in cell activation, as well as in tissue and vascular repair. We will not deal with other important aspects of biocompatibility such as the oxidant stress, the relevant role of additives in dialyzer manufacturing, and of leachables and the effects of different sterilization modes.
