Removal Of Protein-bound Uremic Toxins Research Articles

Pruritus and protein-bound uremic toxins in patients undergoing hemodialysis: a cross-sectional study.

Patients undergoing hemodialysis frequently experience pruritus; its severity is associated with poor quality of life and mortality. Recent progress in hemodialysis treatment has improved the removal of small- and middle-molecular-weight molecules; however, the removal of protein-bound uremic toxins (PBUTs) remains difficult. It is possible that pruritus is associated with serum PBUTs in patients undergoing hemodialysis. We conducted a multicenter cross-sectional study in patients undergoing hemodialysis (n=135). The severity of pruritus was assessed using the 5D-itch scale and medication use. Serum PBUTs, including indoxyl sulfate, p-cresyl sulfate, indole acetic acid, phenyl sulfate, and hippuric acid, were measured using mass spectrometry; the PBUT score was calculated from these toxins using principal component analysis. Univariate and multiple regression analyses were performed to examine independent predictors of pruritus. Pruritus was reported by 62.2%, 21.5%, and 13.3%, 1.5% and 0.7% as 5 (not at all), 6-10, 11-15, 16-20, and 21-25 points, respectively. The PBUT score was higher in patients undergoing dialysis having pruritus than those without pruritus (0.201 [-0.021 to 0.424] vs -0.120 [-0.326 to 0.087]; P=0.046). The PBUT score was shown to have an association with the presence of pruritus (coefficient 0.498[Formula: see text]0.225, odds ratio: 1.65 [1.06-2.56]; P=0.027). Uremic pruritus was frequently found and associated with the PBUT score in patients undergoing hemodialysis. Further studies are required to clarify the impact of PBUTs on uremic pruritus and to explore therapeutic strategies in patients undergoing hemodialysis.

Effect of Membrane Permeance and System Parameters on the Removal of Protein-Bound Uremic Toxins in Hemodialysis.

Inadequate clearance of protein-bound uremic toxins (PBUTs) during dialysis is associated with morbidities in chronic kidney disease patients. The development of high-permeance membranes made from materials such as graphene raises the question whether they could enable the design of dialyzers with improved PBUT clearance. Here, we develop device-level and multi-compartment (body) system-level models that account for PBUT-albumin binding (specifically indoxyl sulfate and p-cresyl sulfate) and diffusive and convective transport of toxins to investigate how the overall membrane permeance (or area) and system parameters including flow rates and ultrafiltration affect PBUT clearance in hemodialysis. Our simulation results indicate that, in contrast to urea clearance, PBUT clearance in current dialyzers is mass-transfer limited: Assuming that the membrane resistance is dominant, raising PBUT permeance from 3 × 10-6 to 10-5ms-1 (or equivalently, 3.3 × increase in membrane area from ~ 2 to ~ 6m2) increases PBUT removal by 48% (from 22 to 33%, i.e., ~ 0.15 to ~ 0.22g per session), whereas increasing dialysate flow rates or adding adsorptive species have no substantial impact on PBUT removal unless permeance is above ~ 10-5ms-1. Our results guide the future development of membranes, dialyzers, and operational parameters that could enhance PBUT clearance and improve patient outcomes.

Adsorption- and Displacement-Based Approaches for the Removal of Protein-Bound Uremic Toxins.

End-stage renal disease (ESRD) patients rely on renal replacement therapies to survive. Hemodialysis (HD), the most widely applied treatment, is responsible for the removal of excess fluid and uremic toxins (UTs) from blood, particularly those with low molecular weight (MW < 500 Da). The development of high-flux membranes and more efficient treatment modes, such as hemodiafiltration, have resulted in improved removal rates of UTs in the middle molecular weight range. However, the concentrations of protein-bound uremic toxins (PBUTs) remain essentially untouched. Due to the high binding affinity to large proteins, such as albumin, PBUTs form large complexes (MW > 66 kDa) which are not removed during HD and their accumulation has been strongly associated with the increased morbidity and mortality of patients with ESRD. In this review, we describe adsorption- and displacement-based approaches currently being studied to enhance the removal of PBUTs. The development of mixed matrix membranes (MMMs) with selective adsorption properties, infusion of compounds capable of displacing UTs from their binding site on albumin, and competitive binding membranes show promising results, but the road to clinical application is still long, and further investigation is required.

PS-C09-13: NEW COMPREHENSIVE THERAPEUTIC STRATEGY FOR HYPERTENSION AND UREMIA USING INORGANIC SUBSTANCES WITH SPECIAL ADSORPTION PROPERTIES

Background: In order to remove uremic toxins accumulated in patients with chronic kidney disease (CKD), removal of uremic toxin-causing substances from the intestinal tract by administration of spherical adsorbed charcoal and removal of uremic toxins from the blood by hemodialysis are being performed. However, existing treatment methods are still inadequate for the removal of protein-bound uremic toxins (PBUT) and other medium- to large-sized uremic toxins, which leads to a decreased quality of life and worse prognosis in CKD patients. In order to solve this remaining problem, we are currently investigating the use of inorganic materials for the treatment of uremia. Methods: To evaluate the adsorption performance of our inorganic material, we compared the adsorption performance of various uremic substances in solution, healthy subjects’ plasma, and hemodialysis patients’ plasma, using Kremezin® as a control. Results: Kremezin® was able to adsorb small molecular weight substances in each solution and plasma, while medium to large molecules were poorly adsorbed. On the other hand, the inorganic material we are developing has high adsorption performance not only for small molecules but also for medium to large molecules including inflammatory cytokines and PBUT, and selectively adsorbs cations such as sodium, potassium, and inorganic phosphorus. Conclusion: Inorganic substances with special adsorption performance adsorbed not only uremic substances but also cations, whose accumulation is a problem in CKD patients. Therefore, the inorganic adsorbent may contribute not only to the treatment of uremia but also to the comprehensive treatment of hypertension, hyperkalemia, and CKD-MBD, which are common complications in CKD patients.

Effectively Decontaminating Protein-Bound Uremic Toxins in Human Serum Albumin Using Cationic Metal-Organic Frameworks.

In the field of replacement of conventional dialysis treatment, searching superior materials for removal of protein-bound uremic toxins is a challenge on account of strong interactions between proteins and uremic toxins. Herein, we first adopted cationic metal-organic frameworks (MOFs), ZJU-X6 and ZJU-X7, as sorbents to decontaminate uremic toxins (p-cresyl sulfate and indoxyl sulfate). ZJU-X6 and ZJU-X7 exhibited innate advantage for sequestration of uremic toxins by utilizing a positive charge framework with exchangeable anions. Especially, ZJU-X6 showed a higher sorption capacity and faster sorption kinetics than those of most reported materials. Moreover, the cationic MOF materials could selectively remove uremic toxins even if in the presence of competitive chloride ions and proteins. Meanwhile, pair distribution function (PDF) and density functional theory (DFT) were employed to elucidate the sorption mechanism between uremic toxins and sorbents. This work suggests an attractive avenue for constructing new types of sorbents to eliminate uremic toxins for uremia treatment.

The Medium Cut-Off Membrane Does Not Lower Protein-Bound Uremic Toxins.

The accumulation of protein-bound uremic toxins (PBUT) is associated with increased cardiovascular outcomes in patients on dialysis. However, the efficacy of PBUT removal for a medium-cutoff (MCO) membrane has not been clarified. This study was designed to assess the efficacy of PBUT clearance according to dialysis modalities. In this prospective and cross-over study, we enrolled 22 patients who received maintenance hemodiafiltration (HDF) thrice weekly from three dialysis centers. The dialysis removal of uremic toxins, including urea, beta 2-microglobulin (B2MG), lambda free light chain (λ-FLC), indoxyl sulfate (IS), and p-cresyl sulfate (pCS), was measured in the 22 patients on high-flux HD (HF-HD), post-dilution online HDF (post-OL-HDF), and MCO-HD over 3 weeks. The average convection volume in post-OL-HDF was 21.4 ± 1.8 L per session. The reduction rate (RR) of B2MG was higher in post-OL-HDF than in MCO-HD and HF-HD. The RR of λ-FLC was the highest in MCO-HD, followed by post-OL-HDF and HF-HD. The dialysate albumin was highest in MCO-HD, followed by post-OL-HDF and HF-HD. Post-dialysis plasma levels of IS and pCS were not statistically different across dialysis modalities. The total solute removal and dialytic clearance of IS and pCS were not significantly different. The clearance of IS and pCS did not differ between the HF-HD, post-OL-HDF, and MCO-HD groups.

Three-dimensional conductive PEDOT:PSS-based mixed-matrix scaffolds for efficient removal of protein-bound uremic toxins and high-throughput collection of circulating tumor cells

The troubling connection between chronic kidney disease (CKD) and cancer may result from, for example, CKD patients being exposed to a number of major risk factors for cancers (due to residual uremic toxins in the body) or cancer patients experiencing chronic kidney failure (as an adverse effect of their therapy). Herein, we report a novel three-dimensional (3D) organic bioelectronic interface (OBEI) platform for CKD treatment, by way of hemoperfusion, that can also diagnose the levels circulating tumor cells (CTCs, the precursors of metastatic cancer) at the point of care, with high-throughput collection of targeted cells. We engineered conductive poly(3,4-ethylenedioxythiophene):polystyrenesulfonate-based mixed-matrix scaffolds, prepared through freeze-drying/cross-linking, with various adsorbents, including multiwalled carbon nanotubes, graphene oxide, and chitosan, and evaluated their removal efficiency toward protein-bound uremic toxins (PBUTs) as well as their use in the isolation of targeted CTCs and white blood cells (WBCs). Upon processing with 4 h of simulated perfusion treatment, our 3D-OBEI devices provided not only a high removal rate (ca. 40 %) of p-cresol (as a model PBUT) but also average capture efficiencies of at least 80 % (cell release efficiency: ca. 90 %) for the breast cancer cell line MCF7 and for monocytic leukemia THP-1 cells spiked in 50 mL of circulatory cell culture medium. This demonstration highlights a next-generation 3D bioelectronic device platform that enhances the removal of PBUTs while facilitating the isolation and recovery of a large number of targeted CTCs and WBCs under electrical operation with an unlimited volume capacity, with a potential for use in personalized precision medicine.

Hierarchically structural layered double oxides with stretchable nanopores for highly effective removal of protein-bound uremic toxins

The global outbreak and prevalence of coronavirus disease 2019 (COVID-19) has triggered an urgent demand for family hemodialysis equipment. It is particularly vital to design and apply superior adsorbents to adsorb toxins for reducing the usage of dialysate. In this work, hierarchically structural MgAl layered double oxides (LDO) with stretchable nanopores were exploited through a facile one-pot trisodium citrate (TSC) assistant hydrothermal reaction followed by calcination treatment for effectively adsorbing protein-bound uremic toxins such as hippuric acid (HA) or indoxyl sulfate (IS). The optimized MgAl LDO possessed flower-like spherical morphology, ultrahigh specific surface area (187.3 m2/g) and uniquely stretchable nanopores, which were more conducive to incorporating anions due to their unique memory effect endowing them with promising adsorption capacities for HA or IS. And the adsorption data could be better conformed to pseudo-second-order kinetic model and Langmuir isotherm determining that the maximum adsorption capacity of HA and IS was 129.8 mg/g and 63.1 mg/g, respectively. Furthermore, the computation of molecular size paired with the analysis of adsorption mechanism accurately revealed that high-efficiency toxin capture was mainly attributed to electrostatic interaction for internal intercalation and surface adsorption. Therefore, the application of such delicate LDO as new premium adsorbent would facilitate the development and popularization of family hemodialysis equipment.

Perfluorooctanesulfonate Can Cause Negative Bias in Creatinine Measurement in Hemodialysis Patients Using Polysulfone Dialysis Membranes.

Serum creatinine is an important clinical marker for renal clearance. However, two conventional methods (Jaffe and enzymatic) are prone to interferences with organic compounds as compared to the standard method (isotope dilution–liquid chromatography–mass spectrometry) and can cause a significant negative bias. Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two common perfluorochemicals (PFCs) that can easily be accumulated in humans. We aimed to verify whether this bias is the result of an accumulation of PFCs. The serum creatinine values of 124 hemodialysis patients were analyzed using the three methods. We also aimed to evaluate which biochemical parameters will influence the difference between the conventional methods and the standard method. We found that a significant underestimation occurred when using the conventional methods. Albumin is an independent factor associated with negative bias, but it loses this correlation after dialysis, likely due to the removal of protein-bound uremic toxins. PFOS can cause negative bias when using the enzymatic method. Furthermore, this linear correlation is more significant in patients who used polysulfone-based dialysis membranes, possibly due to the better clearance of other uremic toxins. The serum creatinine of uremic patients can be significantly underestimated when using conventional methods. PFCs, as well the type of dialysis membrane being used, can be influencing factors.

Interaction of Human Serum Albumin with Uremic Toxins: The Need of New Strategies Aiming at Uremic Toxins Removal.

Chronic kidney disease (CKD) is acknowledged worldwide to be a grave threat to public health, with the number of US end-stage kidney disease (ESKD) patients increasing steeply from 10,000 in 1973 to 703,243 in 2015. Protein-bound uremic toxins (PBUTs) are excreted by renal tubular secretion in healthy humans, but hardly removed by traditional haemodialysis (HD) in ESKD patients. The accumulation of these toxins is a major contributor to these sufferers’ morbidity and mortality. As a result, some improvements to dialytic removal have been proposed, each with their own upsides and drawbacks. Longer dialysis sessions and hemodiafiltration, though, have not performed especially well, while larger dialyzers, coupled with a higher dialysate flow, proved to have some efficiency in indoxyl sulfate (IS) clearance, but with reduced impact on patients’ quality of life. More efficient in removing PBUTs was fractionated plasma separation and adsorption, but the risk of occlusive thrombosis was worryingly high. A promising technique for the removal of PBUTs is binding competition, which holds great hopes for future HD. This short review starts by presenting the PBUTs chemistry with emphasis on the chemical interactions with the transport protein, human serum albumin (HSA). Recent membrane-based strategies targeting PBUTs removal are also presented, and their efficiency is discussed.

Removal of Protein-Bound Uremic Toxins Using Binding Competitors in Hemodialysis: A Narrative Review.

Removal of protein-bound uremic toxins (PBUTs) during conventional dialysis is insufficient. PBUTs are associated with comorbidities and mortality in dialysis patients. Albumin is the primary carrier for PBUTs and only a small free fraction of PBUTs are dialyzable. In the past, we proposed a novel method where a binding competitor is infused upstream of a dialyzer into an extracorporeal circuit. The competitor competes with PBUTs for their binding sites on albumin and increases the free PBUT fraction. Essentially, binding competitor-augmented hemodialysis is a reactive membrane separation technique and is a paradigm shift from conventional dialysis therapies. The proposed method has been tested in silico, ex vivo, and in vivo, and has proven to be very effective in all scenarios. In an ex vivo study and a proof-of-concept clinical study with 18 patients, ibuprofen was used as a binding competitor; however, chronic ibuprofen infusion may affect residual kidney function. Binding competition with free fatty acids significantly improved PBUT removal in pre-clinical rat models. Based on in silico analysis, tryptophan can also be used as a binding competitor; importantly, fatty acids or tryptophan may have salutary effects in HD patients. More chemoinformatics research, pre-clinical, and clinical studies are required to identify ideal binding competitors before routine clinical use.

Improved Dialysis Removal of Protein-Bound Uraemic Toxins with a Combined Displacement and Adsorption Technique

Introduction: Protein-bound uraemic toxins (PBUTs) are poorly removed by conventional dialytic techniques, given their high plasma protein binding, and thus low, free (dialysable) plasma concentration. Here, we evaluated and compared PBUTs removal among conventional haemodialysis (HD), adsorption-based HD, displacement-based HD, and their 2 combinations both in vitro and in vivo. Methods: The removal of PBUTs, including 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), p-cresyl sulphate (PCS), indoxyl sulphate (IS), indole-3-acetic acid (3-IAA), and hippuric acid, was first evaluated in an in vitro single-pass HD model. Adsorption consisted of adding 40 g/L bovine serum albumin (Alb) to the dialysate and displacement involved infusing fatty acid (FA) mixtures predialyser. Then, uraemic rats were treated with either conventional HD, Alb-based HD, lipid emulsion infusion-based HD or their combination to calculate the reduction ratio (RR), and the total solute removal (TSR) of solutes after 4 h of therapy. Results: In vitro dialysis revealed that FAs infusion prefilter increased the removal of PCS, IS, and 3-IAA 3.23-fold, 3.01-fold, and 2.24-fold, respectively, compared with baseline and increased the fractional removal of CMPF from undetectable at baseline to 14.33 ± 0.24%, with a dialysis efficacy markedly superior to Alb dialysis. In vivo dialysis showed that ω-6 soybean oil-based lipid emulsion administration resulted in higher RRs and more TSRs for PCS, IS, and 3-IAA after 4-h HD than the control, and the corresponding TSR values for PCS and IS were also significantly increased compared to that of Alb dialysis. Finally, the highest dialysis efficacy for highly bound solute removal was always observed with their combination both in vitro and in vivo. Conclusions: The concept of combined displacement- and adsorption-based dialysis may open up new avenues and possibilities in the field of dialysis to further enhance PBUTs removal in end-stage renal disease.

Fabrication of a novel nitrogen-containing porous carbon adsorbent for protein-bound uremic toxins removal

Protein-bound uremic toxins (PBUTs), the presence of which in the blood is an important risk factor for the progression of chronic kidney disease (CKD), have not been cleared efficiently via traditional hemodialysis methods until now. In this study, biosafe and efficient nitrogen-containing porous carbon adsorbent (NPCA) beads for the clearance of PBUTs were prepared from porous acrylonitrile/divinylbenzene cross-linked copolymer beads followed by pyrolysis. The resulting NPCA beads were characterized via SEM, XPS and nitrogen adsorption/desorption tests. The results demonstrated that the NPCA beads possessed a mesoporous/microporous hierarchical structure with rich nitrogen functional groups on their surfaces and realized efficient PBUTs adsorption in human plasma. More importantly, the efficacy of PBUTs removal was substantially higher than those of commercial adsorbents that are commonly used in clinical uremia treatments. The NPCA beads also exhibited satisfactory removal efficacy towards middle-molecular-weight uremic toxins. The PBUTs removal mechanism of the NPCA beads is ascribed to effective competition between nitrogen-containing NPCA and proteins for PBUT binding. According to hemocompatibility assays, the NPCA beads possessed satisfactory in vitro hemocompatibility. This nitrogen-containing porous carbon adsorbent is an attractive and promising material for blood purification applications in the treatment of clinical uremia.

Hemocompatible MOF-decorated pollen hemoperfusion absorbents for rapid and highly efficient removal of protein-bound uremic toxins

Heparin-modified NU-1000/pollen nanoporous hollow microspheres were synthesized and achieved a significantly improved toxin removal efficiency of 85% within 10 s.

The impact of intradialytic cycling on the removal of protein-bound uraemic toxins: A randomised cross-over study.

The evidence on impact of intradialytic exercise on the removal of urea, is conflictive. Impact of exercise on kinetics of serum levels of protein-bound uraemic toxins, known to exert toxicity and to have kinetics dissimilar of those of urea, has so far not been explored. Furthermore, if any effect, the most optimal intensity, time point and/or required duration of intradialytic exercise to maximise removal remain obscure. We therefore studied the impact of different intradialytic cycling schedules on the removal of protein-bound uraemic toxins during haemodialysis (HD).This randomised cross-over study included seven stable patients who were dialysed with an FX800 dialyser during three consecutive midweek HD sessions of 240 min: (A) without cycling; (B) cycling for 60 min between 60th and 120th minutes of dialysis; and (C) cycling for 60 min between 150th and 210th minutes, with the same cycling load as in session B. Blood and dialysate flows were respectively 300 and 500 mL/min. Blood was sampled from the blood inlet at different time points, and dialysate was partially collected (300 mL/h). Small water soluble solutes and protein-bound toxins were quantified and intradialytic reduction ratios (RR) and overall removal were calculated per solute.Total solute removal and reduction ratios were not different between the three test sessions, except for the reduction ratios RR60-120 and RR150-210 for potassium.In conclusion, we add evidence to the existing literature that, regardless of the timing within the dialysis session, intradialytic exercise has no impact on small solute clearance, and demonstrated also a lack of impact for protein-bound solutes.

Aortic stenosis in patients with kidney failure: Is there an advantage for a PD-first policy?

Aortic stenosis (AS) is the most common valvular disease. It is twice as prevalent in patients with kidney failure as compared to the general population. In addition, AS progresses at a faster rate and is associated with a higher risk of death and poorer quality of life in patients on dialysis. Chronic kidney disease-mineral and bone disorder (CKD-MBD), inflammation, and hemodynamic disturbances contribute to the pathophysiology and progression of AS. Whether the type of dialysis modality, that is, hemodialysis (HD) versus peritoneal dialysis (PD), has a differential impact on the development and progression of AS in patients with kidney failure remains debated. Recent data indicate that the prevalence of valvular calcifications might be lower and the development of AS delayed in PD patients, as compared to those treated with HD. This could be accounted for by several mechanisms including reduced valvular shear stress, better preservation of residual kidney function (with better removal of protein-bound uremic toxins and CKD-MBD profile), and lower levels of systemic inflammation. Given the high morbidity and mortality rates related to interventional procedures in the population with kidney failure, surgical and transcatheter aortic valve replacement should be considered in selected patients with severe AS. Strategies slowing down the progression of aortic valve remodeling should remain the cornerstone in the management of individuals with kidney failure and mild to moderate AS. This review explores the potential benefits of PD in patients with kidney failure and AS and provides some clues to help clinicians in the decision-making process when options for kidney replacement therapy are considered in patients with AS.

Multi-sites polycyclodextrin adsorbents for removal of protein-bound uremic toxins combining with hemodialysis

Accumulation of protein-bound uremic toxins (PBUTs) has a high incidence in the blood of hemodialysis-treated patients with chronic kidney disease. Development of adsorbent for the high-efficient, selective, and removal of various PBUTs is still challenging because of their strong interactions to the corresponding binding proteins and the complex blood background. Herein, we reported poly-cyclodextrins adsorbents with multi adsorption-sites for PBUTs removal from plasma. Compared to poly-α-cyclodextrin and poly-γ-cyclodextrin, poly-β-cyclodextrin (PβCD) showed the best adsorption capability and the maximum p-cresol sulfate (PCS, a model PBUT) binding capacity of PβCD (263 mg g−1). Combining with hemodialysis, PβCD adsorbents added into the dialysate can remove 96 % PCS in the plasma via adsorbent once-through mode. Additionally, various PBUTs co-exsiting in the plasma could be effectively removed, exhibiting high-concentrition PBUT adsorption property of PβCD. We expect that the PCD adsorbents combining with hemodialysis therapy may become a promising potential for clinical PBUT removal.

High flux mixed matrix membrane with low albumin leakage for blood plasma detoxification

Current hemodialysis (HD) therapy removes well small sized toxins but removes less effectively middle molecules and protein-bound uremic toxins (PBUTs). This limited removal has been associated to high mortality of patients due to increased cardiovascular events. The hemodiafiltration therapy, which combines diffusive and convective transport using high flux membranes, can achieve higher removal of middle molecules. However, still the removal of PBUT is limited. Our earlier studies showed that combination of filtration and adsorption on one hollow fiber membrane, so called mixed matrix membranes (MMMs) can achieve removal of range of toxins, including PBUTs, however, these MMMs either had low flux and therefore were not suitable for convective therapies or had high flux but also albumin leakage which is undesired for the HD therapies. In this work, we present for the first time a new generation of MMM which combines high water flux with high albumin retention and very low total protein adsorption and protein leakage. The membrane fabrication conditions are optimized for achieving fibers with small diameter and optimal distribution of the sorbent particles leading to superior removal of PBUT from human plasma, in comparison to the previous MMMs, as well as, to series of commercial membranes used currently in the clinic.

Removal of Protein-Bound Uremic Toxins by Liposome-Supported Peritoneal Dialysis.

Background:Protein-bound uremic toxins (PBUTs) are poorly cleared by peritoneal dialysis (PD). This study aimed to enhance PBUT removal in PD by adding a binder to the peritoneal dialysate and to evaluate the feasibility and efficacy of liposome-supported PD (LSPD) to increase the removal of PBUTs compared with albumin PD.Methods:Removal of p-cresyl sulfate (PCS), indoxyl sulfate (IS), and indole-3-acetic acid (3-IAA) was first evaluated in an in vitro PD model using artificial plasma preloaded with test solutes. Male Sprague-Dawley rats (n = 24) were then subjected to 5/6 nephrectomy and fed for 16 weeks to establish end-stage renal failure, after which they were treated with either conventional glucose-based PD, albumin-based PD, or liposome-based PD. Removal of PBUTs and small water-soluble solutes was determined during a 6-hour PD dwell.Results:In vitro experiments showed that adding albumin as a toxin binder to the dialysate markedly increased the removal of PCS, IS, and 3-IAA compared with the control. The uptake capacity of liposomes was comparable with that of albumin for PCS and 3-IAA, though slightly inferior for IS. In vivo PD in uremic rats demonstrated that LSPD resulted in higher intraperitoneal concentrations and more total mass removal for PBUTs than the conventional glucose-based PD, which was comparable with albumin PD.Conclusions:Supplementing conventional glucose-based PD solutions with a binder could efficiently increase the removal of PBUTs. This preliminary study suggested that LSPD may be a promising alternative to albumin PD for increasing PBUT removal in the development of next-generation PD solutions for PD patients.

Carbon Nanotube/Conducting Polymer Hybrid Nanofibers as Novel Organic Bioelectronic Interfaces for Efficient Removal of Protein-Bound Uremic Toxins.

Protein-bound uremic toxins (PBUTs) can cause noxious effects in patients suffering from renal failure as a result of inhibiting the transport of proteins and inducing their structural modification. They are difficult to remove through standard hemodialysis (HD) treatment. Herein, we report an organic bioelectronic HD device system for the effective removal of PBUTs through electrically triggered dissociation of protein-toxin complexes. To prepare this system, we employed electrospinning to fabricate electrically conductive quaternary composite nanofiber mats-comprising multiwalled carbon nanotubes (MWCNTs), poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS), poly(ethylene oxide) (PEO), and (3-glycidyloxypropyl)trimethoxysilane (GOPS)-on conventional polyethersulfone (PES) dialysis membranes. These composite nanofiber platforms exhibited (i) long-term water resistance (due to cross-linking among PSS, PEO, and GOPS), (ii) high adhesion strength on the PES membrane (due to GOPS functioning as an adhesion promoter), (iii) enhanced electrical properties [due to the MWCNTs and PEDOT:PSS promoting effective electrical stimulation (ES) operation in devices containing bioelectronic interfaces (BEI)], and (iv) good anticoagulant ability and negligible hemolysis of red blood cells. We employed this organic BEI electronic system as a novel single-membrane HD device to study the removal efficiency of four kinds of uremic toxins [p-cresol (PC), indoxyl sulfate, and hippuric acid as PBUTs; creatinine as a non-PBUT] as well as the effects of ES on lowering the protein binding ratio. Our organic BEI devices provided a high rate of removal of PC with low protein loss after 4 h of a simulated dialysis process. It also functioned with low complement activation, low contact activation levels, and lower amounts of platelet adsorption, suggesting great suitability for use in developing next-generation bioelectronic medicines for HD.