The Complement System in Hemodialysis Patients: Getting to the Heart of the Matter

Borst, Martin H. de

doi:10.1159/000443340

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…Repeated interactions of blood with artificial surfaces contribute to the chronic inflammation of dialysis patients, which is recognized a main component in the development and progression of CVD and mortality 2,3 . Activation of the complement system is one central aspect in the inflammatory reaction 5‐7 and is especially triggered with cellulosic membranes. Here, hydroxyl groups on the membranes’ surface activate the alterative complement pathway and induce the formation of the anaphylatoxins C3a and C5a 5,20 .…”

Section: Discussionmentioning

confidence: 99%

“…Dialysis treatment‐related factors such as dialysate contamination and the perpetuated contact of blood to artificial surfaces contribute to the persistent inflammation in these patients via repeated and sustained activation of the complement system 4‐6 . The pro‐inflammatory anaphylatoxins C3a and C5a as well as the membrane attack complex sC5b‐9 are the key elements in this process and have been linked to CVD and mortality 5,7 . Therefore, strategies to reduce complement activation and inflammatory reaction during dialysis treatment are needed to improve patients’ outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge

et al. 2021

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Activation of the complement system may occur during blood‐membrane interactions in hemodialysis and contribute to chronic inflammation of patients with end‐stage renal disease. Hydrophilic modification with polyvinylpyrrolidone (PVP) has been suggested to increase the biocompatibility profile of dialysis membranes. In the present study we compared the complement activation of synthetic and cellulose‐based membranes, including the polysulfone membrane with α‐tocopherol‐stabilized PVP‐enriched inner surface of the novel FX CorAL dialyzer, and linked the results to their physical characteristics. Eight synthetic and cellulose‐based dialyzers (FX CorAL, FX CorDiax [Fresenius Medical Care]; Polyflux, THERANOVA [Baxter]; ELISIO, SUREFLUX [Nipro]; xevonta [B. Braun]; FDX [Nikkisio Medical]) were investigated in the present study. Complement activation (C3a, C5a, and sC5b‐9) was evaluated in a 3 hours ex vivo recirculation model with human blood. Albumin sieving coefficients were determined over a 4 hours ex vivo recirculation model with human plasma as a surrogate of secondary membrane formation. Zeta potential was measured as an indicator for the surface charge of the membranes. The FX CorAL dialyzer induced the lowest activation of the three complement factors (C3a: −39.4%; C5a: −57.5%; and sC5b‐9: −58.9% compared to the reference). Highest complement activation was found for the cellulose‐based SUREFLUX (C3a: +154.0%) and the FDX (C5a: +335.0% and sC5b‐9: +287.9%) dialyzers. Moreover, the FX CorAL dialyzer had the nearest‐to‐neutral zeta potential (−2.38 mV) and the lowest albumin sieving coefficient decrease over time. Albumin sieving coefficient decrease was associated with complement activation by the investigated dialyzers. Our present results indicate that the surface modification implemented in the FX CorAL dialyzer reduces the secondary membrane formation and improves the biocompatibility profile. Further clinical studies are needed to investigate whether these observations will result in a lower inflammatory burden of hemodialysis patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge

et al. 2021

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“…A series of biochemical reactions such as the coagulation cascade and activation of the complement system trigger potential pathophysiological results including insulin resistance, lipid metabolism disorders, and coronary heart disease . In addition, high circulating levels of mannose‐binding lectin, the complement membrane attack complex inhibitor CD59, and the C5b‐9 membrane attack complex are also involved in the occurrence of coronary artery diseases . In our study, some proteins related to immunoglobulin and complement proteins were identified (Table , Figure ).…”

Section: Discussionmentioning

confidence: 65%

Proteomics Investigations into Serum Proteins Adsorbed by High‐Flux and Low‐Flux Dialysis Membranes

Han

Yang

Jian

et al. 2017

Proteomics Clinical Apps

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Hemodialysis is one of the most important therapies for patients with uremia, and the dialysis membrane is the predominant factor that impacts the efficiency of dialysis. Here, a protein adsorption on two different membranes is investigated to provide a basis for improving dialysis materials. Two cases treated with the Polyflux 14L low-flux dialyzer and the Polyflux 140H high-flux dialyzers during two continuous therapies are selected. Four used dialyzers from selected patients are infused with C12Im-Cl to elute the adsorbed proteins. Then labeled digested proteins adsorb by Polyflux 140H and Polyflux 14L with CD O and NaCNBD (light labeling, L) and CD O and NaCNBH (heavy labeling, H), respectively. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used to identify the proteins. According to the ratio (Light labeling/Heavy labeling), the eluted proteins are divided into three groups: significantly higher, significantly lower, and no significant differences with a ratio of >2, <0.5, and 0.5-2, respectively. A total of 668 proteins are identified by LC-MS/MS, among which 177 proteins are retained more by the Polyflux 140H membrane (ratio >2), 320 proteins are retained more by the Polyflux 14L membrane (ratio <0.5), and 171 proteins show no significant difference (ratio 0.5-2) between the two types of membranes. Statistical significance is shown in the percentage of adsorbed proteins with an isoelectric point (pI) ranging from 9 to 10 (19.08 versus 7.69%; χ = 11.87, p = 0.0006). Proteins with a molecular weight (MW) of 10-15 kDa tend to deposit on Polyflux 140H compared with Polyflux 14L (25 versus 9.23%; χ = 18.66, p = 0.0000) and proteins with a MW of 30-60 kDa tend to deposit on Polyflux 14L compared with Polyflux 140H (36.54 versus 22.37%; χ = 8.96, p = 0.0028). According to gene ontology analysis, the proteins adsorbed by dialysis membranes are closely related to activation of complement system and the coagulation cascade. The proteins adsorbed by Polyflux 140H and Polyflux 14L show significant differences in PI, MW, and protein class. Proteomic techniques are an effective approach for studying hemodialysis membranes.

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“…Thus, a simple clinical observation led to the study of biochemical and cell activation pathways that revealed the deleterious effects of complement activation on a range of body functions both in the short and long term. As complement activation worsens underlying conditions such as inflammation and oxidative stress, promotes coagulation and cardiovascular calcifications contributing to cardiovascular events, inhibition of complement in dialysis is still a relevant safety target today [ 74 , 88 ].…”

Section: Blood–materials Interactions: the Specific Case Of Dialysis Membranesmentioning

confidence: 99%

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

Bowry¹,

Kırçelli

Himmele

et al. 2021

Clinical Kidney Journal

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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.

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The Complement System in Hemodialysis Patients: Getting to the Heart of the Matter

Cited by 10 publications

References 28 publications

Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge

Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge

Proteomics Investigations into Serum Proteins Adsorbed by High‐Flux and Low‐Flux Dialysis Membranes

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

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