Hallmarks for Thrombotic and Hemorrhagic Risks in Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is a global health issue causing a significant health burden. CKD patients develop thrombotic and hemorrhagic complications, and cardiovascular diseases are associated with increased hospitalization and mortality in this population. The hemostatic alterations are multifactorial in these patients; therefore, the results of different studies are varying and controversial. Endothelial and platelet dysfunction, coagulation abnormalities, comorbidities, and hemoincompatibility of the dialysis membranes are major contributors of hypo- and hypercoagulability in CKD patients. Due to the tendency of CKD patients to exhibit a prothrombotic state and bleeding risk, they require personalized clinical assessment to understand the impact of antithrombotic therapy. The evidence of efficacy and safety of antiplatelet and anticoagulant treatments is limited for end-stage renal disease patients due to their exclusion from major randomized clinical trials. Moreover, designing hemocompatible dialyzer membranes could be a suitable approach to reduce platelet activation, coagulopathy, and thrombus formation. This review discusses the molecular mechanisms underlying thrombotic and hemorrhagic risk in patients with CKD, leading to cardiovascular complications in these patients, as well as the evidence and guidance for promising approaches to optimal therapeutic management.

Alleviation of Oxidative Stress during Hemodialysis Sessions by Hemodialysis Membrane Innovation: A Multidisciplinary Perspective.

Oxidative stress is prevalent in end-stage kidney disease patients receiving chronic hemodialysis and is associated with heavy cardiovascular disease burdens and increased mortality risks. Hemoincompatible hemodialysis membranes per se contribute to the activation of oxidative reactions and the generation of oxygen free radicals. Since the early 1990s, vitamin E-coated membranes have been extensively used in hemodialysis patients to reduce oxidative stress during hemodialysis sessions. However, the beneficial effects of vitamin E-coated membranes versus unmodified synthetic membranes on long-term patient-centered outcomes, such as survival, quality of life, and prevalence of cardiovascular diseases, remain controversial. Accordingly, novel antioxidant hemodialysis membranes were prepared to replace the use of vitamin E-coated membranes despite the translational research on these membranes unfortunately coming to a standstill. In this review, we first summarize the state-of-the-art on the use of vitamin E-coated membranes in hemodialysis patients to highlight their strengths and limitations. Then, we discuss the latest advances in fabricating antioxidant hemodialysis membranes and provide perspectives to bridge knowledge gaps between laboratorial investigations and clinical practice in fabricating antioxidant hemodialysis membranes.

Pushing the boundaries of hemodialysis: innovations in membranes and sorbents.

Membranes and sorbents play a crucial role in extracorporeal blood purification therapies, which aim to remove harmful molecules and toxins from the blood. Over the years, advancements in hemodialysis (HD) membranes and sorbents have significantly enhanced their safety and effectiveness. This review article will summarize the latest breakthroughs in the development and clinical application of HD membranes and sorbents. We will commence with a concise examination of the mechanisms involved in solute transport across membranes and sorbents. Subsequently, we will explore the evolutionary path of HD membranes, from early cellophane membranes to high-flux membranes, including the development of high-cutoff membranes and the emergence of medium- cutoff membranes. We will discuss each type of HD membrane's advantages and limitations, highlighting the most promising advancements in novel biomaterials and biocompatibility, technologies, research in membrane performance, and their clinical applications. Furthermore, we will delve into the evolution and progress of sorbent technology, tracing its historical development, outlining its key characteristics, examining the mechanism involved in the adsorption process, and exploring its clinical application. This review aims to underscore the growth and future landscape of HD membranes and sorbents in extracorporeal blood purification techniques.

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

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.

The biocompatibility and bioactivity of hemodialysis membranes: their impact in end-stage renal disease.

End-stage renal disease is a growing health problem with increasing prevalence and high health care costs. Patients suffering from end-stage renal disease exhibit higher morbidity and mortality rates compared to the general population. These patients, who are treated using hemodialysis, typically suffer from anemia, inflammation, and oxidative stress. Inadequate dialyzer membrane biocompatibility exacerbates these negative side effects. Modifications of the composition of hemodialysis membranes have improved their biocompatibility and improve the patients' quality of life. Recently, the use of dialyzer membranes coated with bioactive compounds has also been proposed to further ameliorate dialysis-associated problems. Based on a survey of the current literature, application of bioactive membranes decreases the inflammation and oxidative stress of patients treated with hemodialysis.

Dialysis treatment, in vitro, and anticoagulation activity of polysulfone-polyacrylamide based-blend membranes: an experimental study.

The majority of treatments are performed with polysulfone (PSf) membranes. The main issue of the PSf membrane is its lack of endothelial function, leading to various processes like platelet adhesion, protein adsorption, and thrombus formation when comes in contact with blood. The crucial aspect in the development of hemodialysis (HD) membrane materials is a biocompatibility factor. This study aims to improve the performance and biocompatibility of PSf membranes by utilizing polyethylene glycol (PEG) as a pore-forming agent and polyacrylamide (PAA) as a multifunctional modifying additive owing to its non-toxic, and biocompatible nature. The formulated HD membranes were characterized using Fourier Transform Infrared (FTIR) spectroscopy, Scanning Electron Microscopy (SEM), and Water Contact Angle (WCA) measurements. The biocompatibility results showed that PSf-PAA membranes reduced the adsorption of bovine serum albumin (BSA) protein, hemolysis process, thrombus formation, and platelets adhesion with improved in vitro cytotoxicity results as well as anticoagulation performance. The protein separation results showed that PSf-PAA membranes were able to reject 90.1% and 92.8% of BSA protein. The membranes also showed better uremic waste clearance for urea (76.56% and 78.24%) and creatinine (73.71% and 79.13%) solutes, respectively. It is conceivable that these modern-age membranes may surpass conventional HD membranes regarding both efficiency and effectiveness.

Influence of UV-irradiation intensity and exposure duration on the hemobiocompatibility enhancement of a novel synthesized phosphobetaine zwitterions polyethersulfone clinical hemodialysis membranes.

To improve the biocompatibility of polyethersulfone (PES) membranes utilized for biomedical hemodialysis (HD) applications, surface grafting with hydrophilic polymers has become a reliable modification strategy. Like most photochemical catalyzed reactions, UV-assisted grafting is distinctly advantageous for inducing permanent surface chemistry, enhancing hydrophilicity, improving morphology, and surface charge of membranes. PES membranes may be hydrophilic and chemically stable; however, they also have low protein-binding capacity and very susceptible to fouling and target analyte binding. In this study, novel zwitterionic polymers (PVP-ZW) have been synthesized by UV-assisted grafting PVP to a phosphobetaine monomer in a reaction involving dimethylamino and dioxaphospholane-2-oxide terminal groups in an NVP monomer solution at varying UV exposure conditions. The highlight of the present study is the investigation of the hemocompatibility of coated PES HD membranes at varying UV exposure conditions with respect to membrane chemistry and morphology and its influence on human serum protein adsorption. A clinical investigation of inflammatory biomarker release from incubated coated membranes within uremic blood samples of HD patients reveals they are weak complement and coagulation activators compared to bare PES membrane. The trend of fibrinogen adsorption on coated PES membranes was observed to increase with reducing UV intensity and exposure duration. Fibrinogen adhesion only increased with roughened membrane surfaces, and this also led to the formation of biological activation pathways hindering biocompatibility. Resistance against fibrinogen absorption on zwitterionic modified PES membrane could be linked with the creation of electrostatically induced neutral zwitterionic PVP-phosphobetaine hydration layer with hydrophilic character. Experimental results are accompanied by spectroscopic and morphological imaging evidence. Zwitterion coated PES membranes (PES-PVP-ZW) fabricated from higher UV intensities through longer exposure durations showed significant presence of surface deformations in the forms of inherent exfoliations due to harsh UV reaction conditions. The zeta potential and surface roughness of coated membranes also played significant role in the fibrinogen adsorption on PES membranes during ultrafiltration.

Protein-bound uremic toxins (PBUTs) in chronic kidney disease (CKD) patients: Production pathway, challenges and recent advances in renal PBUTs clearance.

Uremic toxins, a group of uremic retention solutes with high concentration which their accumulation on the body makes several biological problems, have recently gained a large interest. The importance of this issue more targets patients with compromised kidney function since the presence of these toxins in their bodies contributes to serious illness and death. It is reported that around 14% of people are subjected of CKD's problems. Among different classifications of uremic toxins, protein bound uremic toxins are poorly removed from the body as they tightly bind to proteins like serum albumin. A deeper and closer understanding of methods for removing protein bound uremic toxins and their efficiency is of paramount importance. This article discussed the most critical protein bound uremic toxins from different points of view including their chemistry, binding sites, interactions, and their biological impacts. Concerning the toxicity and high concentration, p-cresyl sulfate (PCS), Indoxyl sulfate (IS), 3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), and Indole- 3-acetic acid (IAA) was chosen to study in this article. Results offered that the functional groups of mentioned PBUTs and the way that they interact with the adsorbent play an important role in finding substances for removal of them. Furthermore, the development of nanoparticle (NPs) for promising biomedical purposes has been explored. However, there is still a need for further investigation to find biocompatible substances focusing on the removal of PBUTs. PBUTs are a unique class of uremic toxins whose renal clearance mechanisms and role in uremic pathophysiology are still unclear. This review outlines the biochemical aspects of PBUT/protein binding in a view to explaining their renal formation to elimination mechanisms; some examples are drawn from routes involving albumin-binding with indoxyl sulphate, p-cresyl sulfate, p-cresyl glucuronide and hippuric acid. We have also highlighted the kinetic behaviors during dialytic removal of PBUTs to address future concerns regarding dialytic therapy.

Cellulose acetate-polyvinyl alcohol blend hemodialysis membranes integrated with dialysis performance and high biocompatibility.

Hemodialysis considered as therapy of end-stage renal disease (ESRD) for the separation of protein and uremic toxins based on their molecular weights using semi-permeable membranes. Cellulose Acetate (CA) hemodialysis membrane has been widely used in the biomedical field particularly for hemodialysis applications. The main issue of CA membrane is less selectivity and hemocompatibility. In this study, to enhance the filtration capability and biocompatibility of CA hemodialysis membrane modified by using Polyvinyl Alcohol (PVA) and Polyethylene Glycol (PEG) as additives. CA-PVA flat sheet membranes were cast by phase inversion method, and separation was done by dead-end filtration cell. The synthesized membranes were described in terms of chemical structure using Fourier Transform Infrared Spectroscopy (FTIR) and morphology by Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), pure water flux, solute permeation, and protein retention. Biocompatibility of the membranes was tested by the platelet adherence, hemolysis ratio, thrombus formation, and plasma recalcification time. SEM images exposed that the CA-PVA membrane has a uniform porous structure. 42.484 L/m2 h is the maximum pure water flux obtained. The CA-PVA rejected up to 95% of bovine serum albumin (BSA). A similar membrane separated 93% of urea and 89% of creatinine. Platelet adhesion and hemolysis ratio of casted membranes were less than the pure CA membrane. Increased clotting time and less thrombus formation on the membrane's surface showed that the fabricated membrane is biocompatible. CA-PVA hemodialysis membranes are more efficient than conventional reported hemodialysis membranes. It revealed that CA-PVA is high performing biocompatible hemodialysis membrane.

Nano architectured cues as sustainable membranes for ultrafiltration in blood hemodialysis.

Membranes with zeolites are encouraging for performing blood dialysis because zeolites can eliminate uremic toxins through molecular sieving. Although the addition of various pore-gen and adsorbent in the membrane can certainly impact the membrane production along with creatinine adsorption, however, it is not directed which pore-gen along with zeolite leads to better performance. The research was aimed at reducing the adsorption of protein-bound and uremic toxins by using mordenite zeolite as an adsorbent while polyethylene glycol and cellulose acetate as a pore generating agent. Membranes were cast by a phase-inversion technique which is cheap and easy to handle as compared to the electro-spinning technique. Through this strategy, the ability to adsorb creatinine and solute rejection percentage were measured and compared against the pristine PSU, when only PEG was used as a pore-modifier and when PEG along with CA was used as a pore-modifier along with a different concentration of zeolite. The experiments revealed that PEG membranes can give a better solute rejection percentage (93%) but with a low creatinine adsorption capacity that is 7654 µg/g and low bio-compatibility (PRT 392 s, HR 0.46%). However, PEG/CA membranes give maximum creatinine adsorption that is 9643 µg/g and also better bio-compatibility (PRT 490 s, HR 0.37%) but with a low BSA rejection (72%) as compared to the pristine PSU and PEG membranes. The present study finds that the concentration of mordenite zeolite affects the membrane performance because its entrapment and large pore size of the membrane decreases solute rejection but increases creatinine uptake level along with the better bio-compatibility.

Pushing the Boundaries of Hemodialysis: Innovations in Membranes and Sorbents

ABSTRACT Membranes and sorbents play a crucial role in extracorporeal blood purification therapies, which aim to remove harmful molecules and toxins from the blood. Over the years, advancements in hemodialysis (HD) membranes and sorbents have significantly enhanced their safety and effectiveness. This review article will summarize the latest breakthroughs in the development and clinical application of HD membranes and sorbents. We will commence with a concise examination of the mechanisms involved in solute transport across membranes and sorbents. Subsequently, we will explore the evolutionary path of HD membranes, from early cellophane membranes to high-flux membranes, including the development of high-cut-off membranes and the emergence of medium- cut-off membranes. We will discuss each type of HD membrane's advantages and limitations, highlighting the most promising advancements in novel biomaterials and biocompatibility, technologies, research in membrane performance, and their clinical applications. Furthermore, we will delve into the evolution and progress of sorbent technology, tracing its historical development, outlining its key characteristics, examining the mechanism involved in the adsorption process, and exploring its clinical application. This review aims to underscore the growth and future landscape of HD membranes and sorbents in extracorporeal blood purification techniques.

Study of uremic toxin fluxes across nanofabricated hemodialysis membranes using irreversible thermodynamics.

INTRODUCTION: The flux of uremic toxin middle molecules through currently used hemodialysis membranes is suboptimal, mainly because of the membranes' pore architecture. AIM: Identifying the modifiable sieving parameters that can be improved by nanotechnology to enhance fluxes of uremic toxins across the walls of dialyzers' capillaries. METHODS: We determined the maximal dimensions of endothelin, cystatin C, and interleukin - 6 using the macromolecular modeling software, COOT. We also applied the expanded Nernst-Plank equation to calculate the changes in the overall flux as a function of increased electro-migration and pH of the respective molecules. RESULTS: In a high flux hemodialyzer, the effective diffusivities of endothelin, cystatin C, and interleukin - 6 are 15.00 x 10(-10) cm(2)/s, 7.7 x 10(-10) cm(2)/s, and 5.4 x 10(-10) cm(2)/s, respectively, through the capillaries' walls. In a nanofabricated membrane, the effective diffusivities of endothelin, cystatin C, and interleukin - 6 are 13.87 x 10(-7) cm(2)/s, 5.73 x 10(-7) cm(2)/s, and 3.45 x 10(-7) cm(2)/s, respectively, through a nanofabricated membrane. Theoretical modeling showed that a 96% reduction in the membrane's thickness and the application of an electric potential of 10 mV across the membrane could enhance the flux of endothelin, cystatin C, and interleukin - 6 by a factor of 25. A ΔpH of 0.07 altered the fluxes minimally. CONCLUSIONS: Nanofabricated hemodialysis membranes with a reduced thickness and an applied electric potential can enhance the effective diffusivity and electro-migration flux of the respective uremic toxins by 3 orders of magnitude as compared to those passing through the high flux hemodialyzer.