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Assessment of polyethersulfone and polyacrylonitrile hemodialysis clinical membranes: In situ synchrotron-based imaging of human serum proteins adsorption, interaction analyses, molecular docking and clinical inflammatory biomarkers investigations
Graphical Abstract
Introduction
Biological interactions of certain human serum proteins with non-physiologic synthetic surfaces (e.g., hemodialysis (HD) membranes) during their adsorption have become an important aspect in understanding biocompatibility of dialysis membranes, implant materials, drug-delivery conjugates etc., as it affects cardiac complications [1]. In fact, adsorption studies involving these proteins (e.g., human serum albumin, fibrinogen and transferrin proteins) have been regarded as the initial step in the assessment of hemocompatibility of materials [2]. The clinical application in this study is restricted to kidney HD as an effective and widely utilized therapy for renal disease affecting millions of patients globally. The population of chronic kidney disease (CKD) patients among Canadian adults has increased over the years. Between 2007 and 2009, the figure was 13% and has continued to increase since then [3]. One in 10 Canadians (~4 M people) are affected by CKD, which is typically irreversible [4]. More than 50% of diabetic Canadian patients will also have renal failure during their lifetime [5]. However, the present HD therapy still leads to adverse health complications during HD treatments, especially with engineered polymeric membranes [6].
When in contact with blood, hemodialyzer membranes imitate biological events that contribute to pro-inflammatory cytokines as they are complement, leukocyte and coagulation activators. These events also lead to several cardiovascular diseases due to their bioincompatibility. The health complications may also result in hypertension in renal disease patients periodic undergoing HD sessions [7]. Upon adsorption of serum proteins on surfaces of HD membranes, the initial seconds witness activation of platelet and coagulation factors as adsorption layers are formed [8]. This subsequently leads to platelet thrombosis, and within the first minutes, cascades of events leading to fibrin polymerization are imminent [9], [10]. These biological events are rapid and also in quick successions, hence the formation of thrombi is almost immediately. Membrane-surface protein interactions significantly contributes to platelet and complement activations when their adhesions are irreversible according to Vroman effect [11], [12]. Between the first batch of small protein adsorption and their subsequent substitution by those of higher molecular weights (e.g., kininogen) [13], a combination of inherent conformation changes and produced enzymatic mediators facilitate biological activations within the body as more blood platelets continue fouling each membrane surface [14], [15]. Coagulation activation then leads to more fibrin formation while platelet aggregation results in thrombocyte activation [15], [16]. These biological events may not have a predesigned order, but their pathway during blood/membrane interaction is the key reason for hemoincompatibility in hemodialyzer membranes.
The use of synthetic HD membranes (e.g., PES and PAN) has attracted measurable attention in HD blood purification due to factors related to their chemical and thermal stabilities, surface and mechanical properties [17]. The difference in intrinsic surface energies between both membranes may contribute to protein and platelet adsorption and their subsequent interactions on membrane surfaces, that, results in thrombosis formation and other biological reactions within the immune system [18], [19], [20], [21]. As synthetic membranes, PAN and PES are not susceptible to activation of a complement system compared to their unmodified hydroxylated cellulosic counterparts utilized in most HD dialyzers, since they possess poor hydrophilic and blood-compatible properties. Adsorption of human serum proteins on surfaces of the membrane fibers clogs their pores and affects filtration processes [22], [23] by altering membrane-surface forces (e.g., van der Waals forces and hydrogen bonds) [24], [25], [26].
Recently, our research group has reported issues surrounding bio-incompatibility of hemodialysis membranes with their chemistries and morphologies in terms of recommendations and selection criteria [14], [15], [27]. We have also reported the improved biocompatibility of PES clinical HD membranes modified with novel zwitterionic copolymers [6] as well as unmodified CTA and polyethersulfone PES membranes [28]. These undesired reactions are related to the bio-incompatibility of dialysis membranes We have also reported the effects on defined surface parameters (e.g., hydrophilicity) on the enhancement in the use of polyvinylidene fluoride (PVDF) [29] and PES membranes [30] by means of computational study and theoretical simulation, with and without zwitterionic materials coatings. The quest to develop safer modalities of HD membranes continues to be the goal of our research group since acute and chronic complications in patients undergoing dialysis could be traced to membrane bioincompatibility. The findings within the present study will highlight a key understanding of the origins of side effects experienced by CKD patients on hemodialysis as it relates to the hemocompatibility of dialyzer membranes. It shades light into the consequences of effects of blood-membrane interactions on biocompatibility from both experimental and theoretical standpoints.
The present study offers a broader highlight and in-depth understanding into two commonly used clinical PES and PAN membranes in Canadian hospitals. The objectives of the study were to: i) critically assess membrane characteristic tendencies toward protein membrane-surface adhesion, as it relates to the induction of blood-bound complement activations and pro-inflammatory cytokines; ii) investigate the effects of surface chemistry of membranes on membrane/protein interactions; iii) comprehensively examine human serum protein adsorption in each layer of the membrane (fibrinogen, albumin, transferrin, mixture of human serum proteins) using advanced in-situ SR-µCT innovative technique; iv) theoretically access the membrane-bound chemical groups responsible for protein interactions using a molecular bioinformatics modeling tool (molecular docking); and v) examine the effects of membrane chemistry on the release of inflammatory biomarkers in uremic blood samples of CKD patients.
Section snippets
Membranes and reagents
Polyethersulfone and polyacrylonitrile membranes were provided by St. Paul’s Hospital. Both membranes have molecular weight cut-off (MWCO) 50 kDa. They were chosen based on their varying degrees of hydrophilicity, hence susceptibility toward protein interaction. PAN and PES membrane surface had a surface charge of − 41.5 mV and − 68 mV, respectively. Human serum albumin, fibrinogen and transferrin were also purchased from Sigma Aldrich as used as plasma protein components. We also had a
Effect of membrane-protein interactions on human serum proteins fouling
To probe the effects of membrane-protein interactions on both membranes, inherent changes on their surface morphologies were examined after the ultrafiltration tests. Fig. 4 depicts SEM micrographs of individual (albumin, fibrinogen and transferrin) and multiple protein-fouled PAN and PES membrane surfaces compared to their untreated matrices at two magnifications for each. The surfaces of both neat membranes show relatively clean features since they also have no adhering protein nanoparticles.
Conclusions
The key objective to this study highlights the reason for the choice of between two frequently used clinical HD membranes in terms of their tendency toward pro-inflammatory cytokines and blood activation. In this study, the extent of protein adhesion on two clinical grade PAN and PES membranes were investigated after ultrafiltration with aqueous solutions of three model human-serum proteins, individually and as a mixture. The differences in protein adhesion between both clinical membrane
Research ethics
The principal investigator of the project, Dr. Amira Abdelrasoul, has the Research Ethics Approval and the Operational Approval to conduct the research in Saskatchewan Health Authority, in Canada. She has the responsibility for the regulatory approvals that pertained to this project, and for ensuring that the authorized project was conducted according to the governing law. All the experimental protocol for involving humans was conducted according to the governing law. All the participants in
CRediT authorship contribution statement
Shaghayegh Saadati: Investigation, Formal Analysis, Writing - Original Draft. Ubong Eduok: Investigation, Visualization, Writing - Original Draft. Heloisa Westphalen: Formal Analysis. Amira Abdelrasoul: Conceptualization, Methodology, Supervision, Investigation, Data Curation, Writing - Review & Editing, Project Administration. Ahmed Shoker: Data Curation, Supervision. Phillip Choi, Huu Doan & Farhad Ein-Mozaffari: Writing - Review & Editing. Ning Zhu: Investigation, Data Curation.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to acknowledge and express their gratitude to The New Frontiers in Research Fund for supporting this project, which is administered by the Social Sciences and Humanities Research Council (SSHRC) on behalf of Canada’s three research granting agencies: SSHRC, the Canadian Institutes of Health Research (CIHR), and the Natural Sciences and Engineering Research Council (NSERC). The authors are also grateful to the University of Saskatchewan for providing all research
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