Blood-incompatibility in haemodialysis: alleviating inflammation and effects of coagulation

Abstract

Blood-incompatibility is an inevitability of all blood-contacting device applications and therapies, including haemodialysis (HD). Blood leaving the environment of blood vessels and the protection of the endothelium is confronted with several stimuli of the extracorporeal circuit (ECC), triggering the activation of blood cells and various biochemical pathways of plasma. Prevention of blood coagulation, a major obstacle that needed to be overcome to make HD possible, remains an issue to contend with. While anticoagulation (mainly with heparin) successfully prevents clotting within the ECC to allow removal of uraemic toxins across the dialysis membrane wall, it is far from ideal, triggering heparin-induced thrombocytopenia in some instances. Soluble fibrin can form even in the presence of heparin and depending on the constitution of the patient and activation of platelets, could result in physical clots within the ECC (e.g. bubble trap chamber) and, together with other plasma and coagulation proteins, result in increased adsorption of proteins on the membrane surface. The buildup of this secondary membrane layer impairs the transport properties of the membrane to reduce the clearance of uraemic toxins. Activation of complement system-dependent immune response pathways leads to leukopenia, formation of platelet-neutrophil complexes and expression of tissue factor contributing to thrombotic processes and a procoagulant state, respectively. Complement activation also promotes recruitment and activation of leukocytes resulting in oxidative burst and release of pro-inflammatory cytokines and chemokines, thereby worsening the elevated underlying inflammation and oxidative stress condition of chronic kidney disease patients. Restricting all forms of blood-incompatibility, including potential contamination of dialysis fluid with endotoxins leading to inflammation, during HD therapies is thus still a major target towards more blood-compatible and safer dialysis to improve patient outcomes. We describe the mechanisms of various activation pathways during the interaction between blood and components of the ECC and describe approaches to mitigate the effects of these adverse interactions. The opportunities to develop improved dialysis membranes as well as implementation strategies with less potential for undesired biological reactions are discussed.

Keywords: biocompatibility; blood haemocompatibility; clinical outcomes; coagulation; complement activation; haemodialysis membranes; inflammation.

Figure 1:

Multiple stimuli (orange arrows) arising from the entire ECC contribute to the haemo-incompatibility equation in haemodialysis therapies. Although the dialyser membrane is the focal point of most discussions around the haemocompatibility debate, activation of blood protein and cellular pathways occurs by venipuncture (needles), different types of polymers used for the ECC and is influenced by factors such as anticoagulation and blood flow rates. Blood trauma (caused by pumps or frothing) and blood–air interfaces contribute to the overall system haemo-incompatibility.

Figure 2:

Rapid adsorption of plasma proteins is the initial step of blood–material interactions. Depending on various physiochemical properties of the inner blood-contacting membrane surface, a series of biological pathways are triggered. Only the main pathways most relevant to HD (coagulation, complement and immune) are shown. There is significant interaction of pathways during blood–material interactions, involving adhesion and activation of platelets and several types of white cells.

Figure 3:

The various biochemical pathways that are activated during the interaction of blood components (plasmatic and cellular) with artificial surfaces. The protein adsorption-dependent activation involves activation and adhesion of both platelets and leukocytes. The figure emphasizes the interplay of the coagulation cascade and the complex complement pathways that collectively induce a local pro-inflammatory response. Modified from reference 125 (with permission of authors and publishers).

Figure 4:

The complex dialysis membrane-dependent activation of complement and leukocytes culminating not only in triggering the inflammatory response but also in inducing the procoagulant state.

Figure 5:

Some strategies to mitigate the effects of blood-incompatibility in HD. Dialyser membranes (and other components of the ECC) need to have an optimal balance between different parameters that induce minimal activation of various plasmatic biological pathways and of platelets and leukocytes. Although several novel surface modification techniques have been attempted for blood-contacting biomaterials, few can be extrapolated to the HD field because of the amount (surface areas) that need to be passivated due to the associated effort and related costs.