Biocompatibility of the Dialysis System

Objectives

This chapter will:

1.
Present the fundamentals of biocompatibility of membranes and other factors contributing to the biocompatibility of dialysis.
2.
Discuss the findings of meta-analyses concerned with the effect of biocompatibility on treatment outcomes.

Biocompatibility may be defined as “the ability of a biomaterial to perform its desired function with respect to a medical therapy, without eliciting any undesirable local or systemic effects in the recipient of that therapy, but generating the most appropriate beneficial response (…) and optimising the clinically relevant performance of that therapy” .

In patients with severe AKI, renal replacement therapy (RRT) encompasses several modalities, including continuous RRT, prolonged intermittent RRT and intermittent hemodialysis. All these treatments expose patients' blood to nonphysiological materials, which include: dialyzer membrane and housing, tubing sets, dialysate and infusate. Contact with these materials may activate a variety of biological responses, involving humoral and cellular pathways, with clinical sequelae. Initially, biocompatibility studies mainly focused on the interaction between blood and dialysis membranes. To date, the concept of biocompatibility has greatly evolved and it may be regarded as the sum of interactions and biological responses elicited with blood exposure to all components of the hemodialysis system. This definition also includes the effects induced by manufacturing processes, sterilization modes, contaminants, leachables and particles. In this chapter we discuss the available evidence on the main issues related to the biocompatibility of the dialysis system and its clinical implications in the therapy and outcomes of patients with AKI.

Dialysis Membranes and Determinants of Biocompatibility

The dialysis membrane is the largest surface of contact between blood and a nonphysiological material, therefore it is the main device where several biological responses are elicited. From a clinical perspective, it is appropriate to classify dialysis membranes according to permeability and biocompatibility characteristics. On the basis of chemical composition, membranes are grouped in those made of unmodified cellulose (Cuprophan), those in which the cellulose structure is modified by replacing hydroxyl ions with hydrophobic substances and those based on synthetic polymers. Among cellulose membranes, only cellulose diacetate (CDA) and cellulose triacetate (CTA) are still commercially available. Except for those made of ethylene vinyl alcohol (EVAL), most of the synthetic membranes are based on hydrophobic polymers: polysulfone (PS), polyethersulfone (PES), polyester polymer alloy (PEPA) polyacrylonitrile (PAN) and polymethylmethacrylate (PMMA). Hydrophobic polymers require to be rendered hydrophilic for improving solute transport, either by blending with hydrophilic agents (e.g. polyvinylpyrrolidone in PS and PES membranes), or by being produced as copolymer with hydrophilic compounds (e.g. sodium methallyl sulfonate in the PAN membrane AN69) . Nowadays, synthetic membranes are the most frequently used in RRT and are considered more biocompatible than those based on cellulose. However, reactivity to blood contact is exhibited by all membranes to some extent, because a universal biocompatibility does not exist: the absence of response in a single biological pathway does not automatically avoid activation of others.

Protein Adsorption

Blood exposure to artificial surfaces, such as dialysis membranes, leads to the deposition of a plasma protein layer over the polymer and within the membrane pores. Protein adsorption is a complex phenomenon governed by hydrophobic and electrostatic interactions, hydrogen bonding and Van der Waals forces. Furthermore, it is influenced by several factors related to blood composition, chemical properties of proteins, physicochemical membrane characteristics (surface roughness, thickness, porosity, composition, hydrophobicity and charge) and operating conditions within the dialyzer (blood flow dynamics and temperature). It has been proposed that adsorption occurs in two ways. The first, known as Vroman effect, is a competitive deposition onto membrane surface of high molecular weight proteins, in which albumin, immunoglobulins, fibrinogen, factor XII (Hageman factor) and high molecular weight kininogen (HMWK) are sequentially adsorbed onto the membrane surface, one displacing the other. The second is a dynamic adsorption of low and medium molecular weight proteins within the membrane, which is dependent upon membrane characteristics and limited by its permselectivity .

Adsorption of plasma proteins on dialysis membranes is of critical importance for their biocompatibility. Once adsorbed, proteins undergo conformational changes with possible autoactivation. Adsorbed proteins also modulate the membrane bio-reactivity, by triggering the humoral and cellular pathways. It has been shown indeed that protein layers with a low albumin/fibrinogen ratio may increase the thrombogenicity, by enhancing platelet adhesion to different membranes. Finally, protein adsorption may either modulate the biocompatibility of some synthetic membranes with great absorptive capability, by removing cytokines, anaphylatoxins and complement factor D, or impair both diffusive and convective transport, by forming a secondary resistance to mass transfer .

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