Version June 2024
INTRODUCTION — The contact of blood with dialysis membranes elicits a systemic inflammatory response with involvement of leukocytes; platelets; and complement, inflammatory, and coagulation systems. A biocompatible membrane (BCM) has traditionally been defined as "one that elicits the least amount of inflammatory response in patients exposed to it" [1]. It has been suggested, however, that "adsorption" (ie, binding) of low-molecular-weight proteins or peptides on certain types of dialysis membranes may also be important in defining the biocompatibility of a dialysis membrane [2,3].
This topic will review the pathways activated during the interaction of blood with the membrane materials used for hemodialysis filters and the contribution of adsorption to modifying the inflammatory response resulting from this interaction. The known interactions between blood and the new hemodialysis membranes will be emphasized, with only limited attention to the effect of reuse. Because hemodialysis is a repetitive procedure, minor reactions induced by the membrane at each treatment can eventually lead to adverse long-term clinical sequelae. The acute and chronic clinical sequelae of blood-membrane interactions are discussed separately. (See "Reactions to the hemodialysis membrane" and "Clinical consequences of hemodialysis membrane biocompatibility".)
In the broadest sense, all aspects of the dialysis treatment affect biocompatibility. These include dialysate composition and temperature, the permeability of the dialysis membrane, the type of clearance (diffuse or convective), the initial sterilant (eg, ethylene oxide), reuse procedure and sterilant (formaldehyde, hypochlorite, peroxyacetic acid/hydrogen peroxide), and residual materials from the manufacturing process. However, it is the biocompatibility of the membrane itself that is most important and that has been most closely studied.
COMPOSITION OF DIALYSIS MEMBRANES — Dialysis membranes can be classified into multiple groups [4]:
●Regenerated cellulose (cuprophane)
●Modified cellulose
●Synthetic (noncellulose)
Synthetic and modified cellulose dialysis membranes have become standard in most settings, both of which are more biocompatible than regenerated cellulose.
Cellulosic membranes are made up of a sequence of repetitive polysaccharide units containing hydroxyl groups, similar to bacterial cell walls. These free hydroxyl groups lead to complement activation upon exposure to blood. Modified cellulose membranes have up to 80 percent of the hydroxyl groups replaced by acetate (with cellulose triacetate being more biocompatible than cellulose acetate or diacetate), aromatic benzyl groups, or tertiary amines, reducing complement activation (Hemophane) [5,6].
The side group modifications on substituted cellulose membranes and the composition and high adsorptive capacity of synthetic membranes generally lead to a decrease in the intensity of blood-membrane interactions. Synthetic membranes are made from various polymers, such as polycarbonate, polysulfone (PS), polyamide, polyethersulfone, polyacrylonitrile (PAN), polymethylmethacrylate (PMMA), and others. Some of these membranes are hydrophilic (polyether/polycarbonate) and have a greater tendency to activate complement while others are hydrophobic and have a greater tendency to promote thrombogenicity. Hydrophobic membranes include PAN, PAN/AN69 (copolymer of acrylonitrile and methallyl sulfonate), PS, polyethersulfone, and PMMA.
PERMEABILITY OF THE DIALYSIS MEMBRANE — The permeability of the dialysis membrane may affect one aspect of biocompatibility. High-flux membranes tend to activate complement and the coagulation systems less and lead to lower production of interleukin (IL)-6 and other acute-phase reactants. One consequence of the increased pore size of high-flux dialyzers is the potential for backfiltration or backdiffusion from dialysate to blood, with movement of dialysis water impurities, such as endotoxin, into the blood stream during dialysis. To the extent that this backfiltration or backdiffusion creates a bio-incompatible treatment that may contribute to an inflammatory response, it may be considered to be one aspect of biocompatibility, particularly if ultrapure water is not being used for dialysis. (See "Ultrapure dialysis fluid".)
BLOOD-MEMBRANE INTERACTIONS — When blood encounters the hemodialysis membrane, several reactions are triggered, including the complement cascade, the coagulation cascade, and the contact-phase reaction. In addition to these protein-mediated pathways, cellular mechanisms can also be activated during hemodialysis due to direct contact of cells with the membrane and to byproducts of complement activation. These pathways are often interrelated, and activation of one system leads to participation of others.
Complement activation — Complement activation proceeds primarily via the alternate pathway during hemodialysis [7]. A role for the classical and lectin pathways has also been proposed [8]. New, unused cuprophane membranes activate complement to the greatest degree, compared with the other membrane materials discussed above [9]. C3 activation occurs early in the hemodialysis treatment, peaking in the first 10 to 15 minutes, while terminal pathway activation occurs later and results in formation of C5a and C5b-9, the membrane attack complex. The free hydroxyl group on the surface of cuprophane membranes is thought to promote the deposition and covalent bonding of C3b and the association of C3b with factor B. This is followed by the activation of factor B by factor D, eventually resulting in formation of the C3 convertase C3bBb and the C5 convertase, which cleaves C5 to produce C5a, an anaphylatoxin, and C5b, which leads to generation of the membrane attack complex (C5b-9). (See "Complement pathways".)
C3a and C5a are potent, biologically active agents capable of producing intense vascular smooth muscle contraction, increased vascular permeability, and the release of histamines from mast cells. Complement activation also leads to recruitment and activation of neutrophils and monocytes. Neutrophil activation leads to release of inflammatory cytokines, including various interleukins (IL-1, IL-6, IL-8), tumor necrosis factor (TNF)-alpha, interferon-gamma, and monocyte chemoattractant factor-1 [4,10]. Myeloperoxidase and elastase are released from neutrophils, and there is also upregulation of adhesion molecules and expression of tissue factor and granulocyte colony-stimulating factor [8]. Transient granulocytopenia results from these effects on neutrophils upon hemodialysis initiation. (See 'Activation of cellular components' below.)
Substitution of as little as 1 percent of the hydroxyl ions results in significant attenuation of complement activation. However, other membranes that do not contain hydroxyl moieties such as polyacrylonitrile (PAN) can also activate complement.
As noted above, activation of complement is maximum at approximately 10 to 15 minutes, after which the rate of complement activation decreases. The mechanisms for this decrease have not been well defined, but coating of the membrane with protein films is thought to be important. These films consist of fibrin, albumin, and C3 fragments, particularly C3b (covalently bound), C3c, and C3d (noncovalently bound).
While dialyzer reprocessing for reuse is rarely performed anymore, cellulose membranes processed for reuse with a mixture of peroxyacetic acid/hydrogen peroxide remain coated with protein, improving the membrane biocompatibility with repeated use, while reprocessing with hypochlorite (in addition to formalin) removes the membrane-coated protein, therefore abrogating the potential benefits of reuse [11]. (See "Reuse of dialyzers".)
Activation of the lectin pathway has been proposed to be initiated through binding of mannose-binding lectin and ficolin-2 to certain hemodialysis membranes, resulting in C5a production and leukopenia [12]. Furthermore, alternative pathway complement activation has been suggested to follow from adsorption of factor H and clusterin; the former is a C3 inhibitor while the latter is an inhibitor of C5a and C5b-9 formation. The importance of classical and/or lectin pathway activation in the responses to blood-dialysis membrane (cuprophane) interaction is suggested by attenuation of the response in patients with C4 deficiency [13].
Importance of factor D — Factor D is the essential, rate-limiting enzyme of the alternate pathway of complement activation [2]. Its molecular weight is 23 kD, and its plasma concentration is increased approximately 10-fold in patients with end-stage kidney disease (ESKD) due to reduced renal excretion [14]. The high level of functionally active factor D is directly responsible for enhanced activation of the alternate pathway in the plasma of these patients, a problem that can be enhanced by many dialysis membranes.
In vitro and in vivo studies using specific blocking antibodies against factor D have shown that blockade of factor D function impairs alternate pathway activation [15]. It is therefore possible that adsorption of factor D onto dialysis membranes could inhibit complement activation. Both PAN/AN69 and polymethylmethacrylate (PMMA) membranes remove large amounts of factor D due primarily to adsorption. Circulating factor D levels are reduced at the end of a regular hemodialysis session, the degree of which is membrane dependent: 80 percent with PAN/AN69, 50 percent with PMMA, and <10 percent with cellulose acetate; adsorption accounts for 98 and 85 percent of factor D removal by PAN and PMMA, while no adsorption occurs on cellulose membranes [16,17].
Contact pathway activation — The contact pathway is activated via Hageman factor (factor XII). Negatively charged surfaces are potent activators of this pathway. PAN, with a negative charge of -153.9, induces a greater degree of activation of this pathway than the neutral cuprophane membranes. It is thought that the negative surface charge induces a conformational change of factor XII, which promotes interaction between factor XII and prekallikrein, which is facilitated by surface-bound high-molecular-weight kininogen (HMWK). Once activated, kallikrein is potent in liberating bradykinin from HMWK [18,19]. This sequence probably explains the high frequency of anaphylactoid reactions seen when PAN membranes are used in conjunction with angiotensin-converting enzyme (ACE) inhibitors. ACE is also a kininase; thus, its inhibition can lead to persistence of kinins activated by the PAN membrane. Support for this hypothesis is provided by the finding that administration of a bradykinin B2 receptor antagonist prevents this reaction in sheep dialyzed with an AN69 membrane and treated with an ACE inhibitor [20]. (See "Reactions to the hemodialysis membrane".)
Coagulation pathway activation — The coagulation cascade is activated rapidly by surfaces of all membranes. Generation of C5a also increases expression of granulocyte colony-stimulating factor and tissue factor, which favor a procoagulant state. Evidence also suggests that there are variable degrees, depending upon the membrane material, of fibrinogen adsorption to the membrane, leading to glycoprotein IIb/IIIa-mediated platelet activation [21,22]. During hemodialysis, this cascade is purposely blunted by heparin. There is little information on the relative degree of activation of this pathway by different membranes.
Activation of cellular components — Neutrophils, monocytes, lymphocytes, red cells, and platelets are all influenced by contact with the hemodialysis membrane. Activation of neutrophils leads to upregulation of adhesion receptors and release of proteinases and other intracellular enzymes, reactive oxygen species, leukotrienes, and platelet-activating factor [4,10]. Activation of monocytes leads to production of monokines, such as IL-1 and TNF. Activation of platelets leads to release of thromboxanes [23-25]. These factors may be important determinants of the consequences of bioincompatibility. (See "Clinical consequences of hemodialysis membrane biocompatibility".)
Properties intrinsic to the cuprophane membrane may directly cause cell activation (eg, synthesis of IL-1 mRNA by monocytes); however, it is primarily complement activation products (C5a and C5b-9) that greatly enhance the synthesis of mRNA for these cytokines [26,27]. (See 'Complement activation' above.)
Although red blood cell survival is significantly reduced in dialysis patients, this abnormality has not been directly related to the biocompatibility of the dialysis membrane. However, complement activation, particularly the release of C5b-9, may induce red cell membrane fragmentation and hemolysis [28,29].
SUMMARY
●General principles – The contact of blood with dialysis membranes elicits a multipronged inflammatory response. A biocompatible membrane (BCM) is defined as one that elicits the least amount of inflammatory response. Other aspects of the dialysis treatment that affect biocompatibility include dialysate composition and temperature, the permeability/porosity of the dialysis membrane, the type of clearance (diffuse or convective), the initial sterilant, reuse procedure and sterilant, and residual materials from the manufacturing process. (See 'Introduction' above.)
●Types of dialysis membranes – Dialysis membranes can be classified into three groups including cellulose (cuprophane), substituted cellulose, and synthetic. The side group modifications on substituted cellulose membranes and the high adsorptive capacity of synthetic membranes lead to a decrease in the intensity of blood-membrane interactions. (See 'Composition of dialysis membranes' above.)
●Blood-membrane interactions – Several reactions are triggered when blood encounters the hemodialysis membrane. Such reactions include the complement cascade, the coagulation cascade, and the contact-phase reaction. Cellular mechanisms can also be activated during hemodialysis due to direct contact of cells with the membrane and to byproducts of complement activation. These pathways are often interrelated and are summarized below:
•Complement activation – The sequelae of complement activation include the release of anaphylatoxins (C3a and C5a), the formation of the membrane attack complex (C5b-9), and activation of neutrophils and monocytes, which causes intense vascular smooth muscle contraction, increased vascular permeability, and the release of histamines from mast cells. (See 'Complement activation' above.)
•Contact pathway – The contact pathway is activated by negatively charged surfaces such as the polyacrylonitrile (PAN) membrane, possibly by inducing a conformational change of factor XII, which promotes interaction between factor XII and prekallikrein, resulting in the release of bradykinin. This may explain the high frequency of anaphylactoid reactions seen when PAN membranes are used in conjunction with an angiotensin-converting enzyme (ACE) inhibitor. The inhibition of ACE may lead to persistence of PAN membrane-activated kinins. (See 'Contact pathway activation' above.)
•Coagulation pathway – The coagulation cascade is activated rapidly by surfaces of all membranes. During hemodialysis, this cascade is purposely blunted by heparin. (See 'Coagulation pathway activation' above.)
•Cellular components – Neutrophils, monocytes, lymphocytes, red cells, and platelets are all activated by contact with the hemodialysis membrane, resulting in upregulation of adhesion receptors, release of proteinases and other intracellular enzymes, reactive oxygen species, leukotrienes, platelet activating factor, interleukin (IL)-1, tumor necrosis factor (TNF), and release of thromboxanes. These factors may be important determinants of the consequences of bioincompatibility. (See "Clinical consequences of hemodialysis membrane biocompatibility" and 'Activation of cellular components' above.)
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