Bilirubin Removal Research Articles

Bilirubin adsorption on amine/methyl bifunctionalized SBA-15 with platelet morphology

To remove bilirubin from human plasma, amine/methyl bifunctionalized SBA-15 materials were directly synthesized from the co-condensation of 3-aminopropylmethyldiethoxysilane and tetraethoxysilane with an amphiphilic block copolymer P123 as template. XRD, N(2) sorption analysis, FTIR and (29)Si MAS NMR were used to identify their well-ordered mesostructure and the grafting of amine and methyl groups on the surface of as-synthesized materials. Both SEM and TEM indicated that the bifunctionalized SBA-15 possessed platelet morphology. This might be attributed to the charge repulsion brought by protonated amine groups and the diminution of hydroxyl groups on the end of silicate-micelles, which passivated the end-to-end anchoring of silicate-micelles along the longitudinal axis. Such a material was investigated as the adsorbent for selective bilirubin removal from human plasma, which showed a high bilirubin clearance of 51.4% within 1.5 h with a little amount of albumin adsorption. The results of hemolysis assay suggested that the bifunctionalized SBA-15 caused serious hemolysis of red blood cells. However, in practical application, plasma separation technique could avoid direct contact between the adsorbent and red blood cells. The further hemeolysis assay proved that the plasma after contacting with the bifunctionalized SBA-15 could not lead to the hemolysis of red blood cells. Thus, the bifunctionalized SBA-15 is expected to be a potential candidate as a clinical hemoperfusion material.

Efficient Removal of Bilirubin from Human Serum by Monosize Dye Affinity Beads

Cibacron Blue F3GA (CB) was covalently attached onto poly(glycidyl methacrylate) (PGMA) monosize beads for removal of bilirubin from hyperbilirubinemia human serum. PGMA beads were produced by dispersion polymerization (1.6 μm in diameter). CB loading was 1.73 mmol/g. Bilirubin adsorption experiments were performed by stirred-batch adsorption. The non-specific adsorption of bilirubin was low (0.4 mg/g polymer). CB attachment onto the PGMA beads significantly increased the bilirubin adsorption (241.5 mg/g) from aqueous solutions. The maximum bilirubin adsorption was observed at pH 6.0. With an increase of the aqueous phase concentration of sodium chloride, the adsorption amount of bilirubin decreased drastically. The equilibrium adsorption of bilirubin significantly increased with increasing temperature. Much higher adsorption values up to 332 mg bilirubin/g were achieved in the case of the PGMA/CB beads from human plasma.

50 Years Ago in T he J ournalof P ediatrics: Human Albumin in Exchange Transfusion: A Quantitative Study of the Influence of Added Human Albumin in the Bilirubin Removal

50 Years Ago in T he J ournalof P ediatrics: Human Albumin in Exchange Transfusion: A Quantitative Study of the Influence of Added Human Albumin in the Bilirubin Removal

Molecular adsorbent recirculating system in hepatic failure patients with a ventricular assist device

The study we performed focuses on the removal of bilirubin in hepatic failure patients with a ventricular assist device (VAD). Bilirubin is a risk factor revealing the severe hepatic insufficiency and the alteration of the clinical status. The mortality rate of patients developing liver failure in the cardiac ICU is very high. The molecular adsorbent recirculating system (MARS) is the hepatic failure treatment in patients with no other therapeutic options. It is a liver support system that uses an albumin-enriched dialysate to facilitate the removal of albumin-bound toxins. Conventional hemodialysis techniques have little or no effect on liver detoxication and cannot improve these patients' prognosis. The study aims to prove the decrease of the mortality rate in hepatic failure patients with VAD as a result of using MARS.

Lysine-attached anodic aluminum oxide (AAO)–silica affinity membrane for bilirubin removal

Anodic aluminum oxide (AAO)–silica composite membrane was prepared by depositing silica onto the AAO membrane through sol–gel method. The obtained composite membrane exhibited excellent uniformities, low nonspecific adsorption and good hydraulic permeability. Lysine (Lys) as ligand was immobilized onto the AAO–silica composite membranes by activating with glutaraldehyde. The content of Lys of Lys-attached affinity membranes was ∼5.6 mg/g membrane. Such Lys-attached affinity membranes were used to adsorb bilirubin from the bilirubin–phosphate solution and bilirubin–albumin solution. The adsorption mechanism of bilirubin and the effects of temperature, initial concentration of bilirubin, albumin concentration and ionic strength on adsorption were investigated by batch experiments. The results showed that the adsorption capacity increased with increasing the temperature while decreased with increasing the NaCl concentration and albumin concentration, and the adsorption isotherm fitted the Langmuir model well. The result of dynamic experiment showed Lys-attached affinity membranes can well remove the bilirubin from the bilirubin–albumin solution.

Bilirubin removal from albumin‐containing solutions: dynamic adsorption on anionic resin

AbstractIn this paper, kinetics of unconjugated bilirubin adsorption in fixed‐bed anionic resin columns was investigated. Experimental breakthrough curves were determined at different feed flow rates and using inlet solutions with different bilirubin and albumin concentrations. A mathematical model is provided to describe the effect of albumin on bilirubin adsorption equilibrium and kinetics in a fixed‐bed column.Breakthrough curves show that a significant bilirubin concentration is present in the column outlet stream even in the early operating time. This result shows that, with the flowrates used in this work, adsorption is slow with respect to the axial convection in the column and, as a consequence, bilirubin is never completely removed from the liquid phase.The results obtained in this paper may be useful for the design of liver support devices such as Molecular Adsorbent Recirculating System (MARS), which implement anion‐exchange columns to remove albumin‐bound toxins from concentrated albumin solutions. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd.

Preparation of grafted polytetrafluoroethylene fibers and adsorption of bilirubin

AbstractBACKGROUND: A successful hemoperfusion technique requires that the adsorbent for bilirubin should have a high specificity, adsorption capacity and adsorption rate, blood compatibility and no toxicity. Compared with polymer microbeads, polytetrafluoroethylene (PTFE) fibers have many advantages. The aim of the work reported here was to prepare a new polytetrafluoroethylene‐graft‐poly(glycidyl methacrylate)‐block‐polyethyleneimine (PTFE‐g‐PGMA‐b‐PEI) adsorbent for bilirubin based on PTFE fibers by the 60Co radiation‐induced graft polymerization of GMA followed by the chemical modification of the epoxy groups on the PTFE‐g‐PGMA fibers with PEI. In addition, the adsorption properties of this novel adsorbent for bilirubin were examined.RESULTS: The highest content of amino groups obtained on the PTFE‐g‐PGMA‐b‐PEI fibers was 1.87 mmol g−1. The maximum adsorption capacity of the grafted fibers was 9.6 mg g−1 at pH = 6.5. Bilirubin adsorption on these fibers obeyed the Langmuir model. Also, these fibers possessed the ability to selectively adsorb bilirubin in the presence of bovine serum albumin.CONCLUSION: The PTFE‐g‐PGMA‐b‐PEI fibers have a high adsorption capacity for bilirubin and excellent adsorption properties. In addition, this new adsorbent is inexpensive, easy to prepare and has no toxicity. So the PTFE‐g‐PGMA‐b‐PEI fibers as a biomedical adsorbent are promising for the removal of bilirubin through the hemoperfusion technique. Copyright © 2009 Society of Chemical Industry

Albumin dialysis improves hepatic encephalopathy and decreases circulating phenolic aromatic amino acids in patients with alcoholic hepatitis and severe liver failure

IntroductionThe aim of this study was to assess the effects of albumin dialysis on hepatic encephalopathy and circulating levels of amino acids in severe alcoholic hepatitis.MethodsThe study was carried out in nine patients with severe alcoholic hepatitis and four with primary biliary cirrhosis treated with the molecular adsorbent recirculating system. Besides standard liver function tests, circulating levels of ammonia, total, branched chain and aromatic amino acids, the presence and severity of hepatic encephalopathy, and number connection test were measured before and after each treatment.ResultsThere were eight episodes of encephalopathy in patients with alcoholic hepatitis. Albumin dialysis was associated with significant improvement in encephalopathy (p = 0.02), and a decrease in total amino acid levels (2490 ± 152 μM to 2229 ± 114 μM, p < 0.001). Moreover, the Fischer's ratio, which was significantly lower in patients with alcoholic hepatitis (1.32 ± 0.08) than in controls (3.20 ± 0.16), increased by 17% after albumin dialysis (p < 0.02) because of a significant decrease in phenolic aromatic amino acids (193 ± 17 μM to 165 ± 9 μM, p = 0.04). No differences were observed in circulating ammonia. Changes in phenolic aromatic amino acids and the Fischer's ratio were more prominent in patients with encephalopathy and higher bilirubin removal. Albumin dialysis did not significantly affect the amino acid profile in the controls.ConclusionsAlbumin dialysis results in a significant decrease in circulating phenolic aromatic amino acids and improvement of hepatic encephalopathy in patients with severe liver failure.

Adsorption and photocatalytic degradation of bilirubin on hydroxyapatite coatings with nanostructural surface

Bilirubin produced from hemoglobin metabolism and normally conjugated with albumin is a kind of lipophilic endotoxin, and can cause various diseases when its concentration is high. Bilirubin adsorption on nanostructural hydroxyapatite coatings was investigated using quartz crystal microbalance (QCM) technique, and factors affecting its adsorption such as bilirubin concentration and thickness of hydroxyapatite coatings were discussed in detail. The adsorption kinetic parameter estimated from the in situ frequency measurement is about 3.59 × 10 7 M −1. With the present method, the photocatalytic degradation of adsorbed bilirubin under UV irradiation was investigated and discussed as well, and a photocatalytic mechanism has been proposed. The obtained information suggests that QCM is a useful method for monitoring the adsorption/degradation behavior of bilirubin on nanostructural hydroxyapatite coatings, and that nanostructural hydroxyapatite coatings which is used as adsorbent for the removal of bilirubin can be photochemically regenerated due to the degradation of adsorbed bilirubin.

Depurative capacity of molecular adsorbent recycling system (MARS): A focus on bilirubin removal

The molecular adsorbent recycling system (MARS) is now widely used in the treatment of patients with hepatic failure (HF). A great deal of interest has been directed toward its effect on clinical outcome, whereas its depurative capacity also needs attention. Bilirubin, a tightly albumin-bound toxin accumulating in patients with HF, is regarded as a surrogate to evaluate the depurative capacity of albumin-bound toxins by blood purification modalities. The removal of bilirubin by MARS is difficult to predict, because both the clearance of bilirubin and the reduction ratio of bilirubin after a single session differ between patients and sessions. A reduction of depurative capacity over the course of a treatment is observed. Furthermore, the later sessions are likely less efficient than previous ones. It cannot be taken for granted that the reduction of depurative capacity is due to the saturation and reduced efficiency of the adsorbent columns used in MARS. The answer lies in the property of bilirubin/albumin binding. The removal of bilirubin by MARS is a diffusion process, dependent on the free bilirubin concentration. Bilirubin binds to albumin in 3 ways with different affinity. High-affinity binding bilirubin is difficult to dissociate from albumin and is accompanied by a smaller free fraction, which means it is also difficult for MARS to remove. The factors affecting the free fraction of bilirubin will impact on bilirubin removal by MARS. Among them, the molar ratio of bilirubin to albumin is the most important one. Other factors include the interaction of other agents with bilirubin/albumin binding, the albumin concentration, plasma ion strength, and pH.

Desferrioxamine dehydrogenates bilirubin in two stages, leading to a 1:1 red‐coloured adduct. Characterization of the products by high‐performance liquid chromatography/electrospray ionization mass spectrometry

We have used open-chain tetrapyrroles, such as bilirubin, as molecular probes to investigate the pro-oxidant activity of desferrioxamine (DES) and its modulation by Trolox. On exposure to Fe-EDTA/H2O2, bilirubin and mesobilirubin underwent bleaching. When DES was present, bleaching was prevented and both rubins were converted into green-coloured derivatives and then into red pigments. Trolox added with DES inhibited the colour changes induced by DES. The oxidative products were resolved from their parent compounds by high-performance liquid chromatography (HPLC) and studied by electrospray ionization mass spectrometry and by UV/visible spectroscopy. The green products were identified as biliverdin or mesobiliverdin; the red pigments as the 1:1 molar adduct of DES with biliverdin or mesobiliverdin, less two hydrogens in both cases. It is concluded that DES exercises its oxidative activity through nitroxyl oxidizing radicals capable of efficient hydrogen abstraction, dehydrogenating either rubin to the corresponding verdin. A diradical derivative of DES (bearing two nitroxyl radicals in the same molecule) may be involved in the oxidation of verdins to red pigments, through concerted dehydrogenation and adduct formation. These results shed further light on the redox properties of bilirubin, DES and Trolox, and their interactions. They provide further evidence of the pro-oxidant activity of DES and suggest a more general biological significance, as rapid removal of bilirubin by bleaching or dehydrogenation may have pharmacological/toxicological implications in severe jaundice.

Supermacroporous poly(hydroxyethyl methacrylate) based cryogel with embedded bilirubin imprinted particles

Molecular imprinted polymers are artificial, template-made materials with the ability to recognize and to specifically bind the target molecule. The aim of this study is to prepare supermacroporous cryogel with embedded bilirubin-imprinted particles which can be used for the selective removal of bilirubin from human plasma. N-methacryloyl-( l)-tyrosinemethylester (MAT) was chosen as the pre-organization monomer. In the first step, bilirubin was complexed with MAT and the bilirubin-imprinted poly(hydroxyethyl methacrylate- N-methacryloly-( l)-tyrosine methyl-ester) [MIP] monolith was produced by bulk polymerization. MIP monolith was smashed and the particles ground and sieved through 100 μm sieves. In the second step, the supermacroporous poly(hydroxyethyl methacrylate) (PHEMA) cryogel with embedded MIP particles [PHEMA/MIP composite cryogel] was produced by free radical polymerization initiated by N, N, N′, N′-tetramethylene diamine (TEMED) and ammonium persulfate (APS) pair in an ice bath. After that, the template (i.e., bilirubin) molecules were removed using sodium carbonate and sodium hydroxide. Compared with the PHEMA cryogel (0.2 mg/g polymer), the bilirubin adsorption capacity of the PHEMA/MIP composite cryogel (10.3 mg/g polymer) was improved significantly due to the embedded MIP particles into the polymeric matrix. The relative selectivity coefficients of PHEMA/MIP composite cryogel for bilirubin/cholesterol and bilirubin/testosterone were 8.6 and 4.1 times greater than the PHEMA cryogel, respectively. The PHEMA/MIP composite cryogel could be used many times without decreasing the bilirubin adsorption capacity significantly.

Selective Albumin Exchange: A Novel and Simple Method to Remove Bilirubin

Owing to its non-selectivity, plasma exchange has limited use in the treatment of patients with hepatic failure, although it is effective in removal of protein-bound toxins. This study reports a novel way to perform selective albumin exchange (SAE) by using a secondary plasma separator and aims to study its depurative capacity in the removal of bilirubin. In ex vivo experiments, the sieving coefficients (SCs) of plasma proteins for two secondary plasma separators, EC20W and EC30W (Asahi Medical, Tokyo, Japan), were measured. The EC20W membrane was chosen for use in clinical treatment because of its higher selectivity in separating albumin from plasma than the EC30W. The SCs of albumin, immunoglobumin G, A and M (IgG, IgA, IgM) for the EC20W were 0.3+/-0.021, 0.017+/-0.012, and 0, respectively. Five inpatients with plasma total bilirubin (TB) more than 200 micromol/L were enrolled in the present study and received a total of 10 SAE therapy sessions. Each session lasted 10 hours. SAE using the EC20W was conducted, making it similar to post-dilution continuous veno-venous hemofiltration (CVVH), with a filtrate rate of 2000 ml/h. Replacement fluid was composed by adding human albumin into conventional CVVH replacement fluid, with a final albumin concentration of 0.6%. During each treatment, the parameters of plasma and filtrate TB, direct bilirubin (DB), indirect bilirubin (IDB), and proteins were dynamically monitored. Hemostasis parameters were measured before and after sessions. The reduction ratio of plasma TB, DB, and IDB after a single session was 29.1+/-3.0%, 31.3+/-4.5%, and 18.7+/-10.2%, respectively. The clearance of TB at initiation was 11.1+/-1.3 mL/min and declined to 4.4+/-0.5 ml/min at the end (p<0.01). This decline was accompanied by a reduction in albumin SC from 0.3+/-0.021 to 0.13+/-0.05. The molar ratio of bilirubin to albumin in filtrate was comparable to that in plasma. After a single treatment, plasma protein concentration including total protein, albumin, IgA and IgM remained unaffected, except for globulin and IgG, which were reduced by 11.5+/-7.8% and 11.1+/-2.3%, respectively. An improvement in hemostasis parameters, including plasma fibrinogen, prothrombase time and INR, was found after treatment. No obvious side effects were reported during any of the sessions. Selective albumin exchange is a simple and effective method to remove bilirubin. However, further studies are required to verify its effects on clinical outcome.

Surface modifying of microporous PTFE capillary for bilirubin removing from human plasma and its blood compatibility

In this study, human serum albumin (HSA) was covalently immobilized onto the inner surface of microporous poly(tetrafluoroethylene) (MPTFE) capillaries for direct bilirubin removal from human plasma. To obtain active binding sites for HSA, the MPTFE capillaries were chemically functionalized by using a coating of poly(vinyl alcohol) (PVA)–glycidyl methacrylate (GMA) copolymers. Characterization of grafted MPTFE capillaries was verified by XPS, Fourier transform infrared spectroscopy (FT-IR), scanning electronic microscopy (SEM). Non-specific adsorption on the PVA–GMA coated capillary remains low (< 0.38 mg bilirubin/g), and higher affinity adsorption capacity, of up to 73.6 mg bilirubin/g polymer was obtained after HSA is immobilized. Blood compatibility of the grafted MPTFE capillary was evaluated by SEM and platelet rich plasma (PRP) contacting experiments. The experimental data on blood compatibility indicated that PVA-coated and PVA–GMA–HSA coated PTFE capillary showed a sharp suppress on platelets adhesion. The proposed method has the potential of serving in bilirubin removal in clinical application.

Selective Bilirubin Removal by Plasma Treatment With Plasorba BR-350 for Early Cholestatic Graft Dysfunction

Early cholestatic graft dysfunction is a frequent cause of morbidity after orthotopic liver transplantation (OLT). We analyze the role of selective bilirubin plasma absorption (PAP) using Plasorba BR-350 in 4 OLT patients who had experienced early severe cholestatic graft dysfunction within 15 days after transplantation. Patients were treated with 3 consecutive cycles of PAP with Plasorba BR-350. The median amount of plasma treated was 7500 mL. Median treatment duration was 231 minutes. The average plasma bilirubin level was 37 ± 1 mg/dL before PAP and decreased to 15 ± 0.2 mg/dL at the end of the third cycle of PAP; 3 of 4 cases had progressive bilirubin normalization after PAP. The average amount of bilirubin removed from the plasma of the patients during each PAP treatment was 143 ± 24 mg. At the beginning of each cycle of PAP, the Plasorba BR-350 was able to remove >90% of the total plasma bilirubin, a percentage that decreased to 60%, 50%, and 40% after 2 L, 4 L, and 7 L of plasma were treated, respectively. Liver biopsies performed after the third treatment showed reduced cholestasis when compared with the pretreatment biopsy specimen. The preliminary data suggested that PAP selective for bilirubin removal may not only reduce the bilirubin level, but may also improve the histological pattern of the graft in terms of reduced cholestatic signs.

Selective Removal of Bilirubin from Human Plasma with Bilirubin-Imprinted Particles

The objective of this study is to prepare bilirubin-imprinted polymeric particles for the selective removal of bilirubin from hyperbilirubinemic human plasma. N-methacryloyl-(l)-tyrosine methyleste...

Bilirubin adsorption on nanocrystalline titania films

Bilirubin produced from hemoglobin metabolism and normally conjugated with albumin is a kind of lipophilic endotoxin, and can cause various diseases when its concentration is high. Bilirubin adsorption on the nanocrystalline TiO 2 films was investigated using quartz crystal microbalance, UV–vis and IR techniques, and factors affecting its adsorption such as pH, bilirubin concentration, solution ionic strength, temperature and thickness of TiO 2 films were discussed. The amount of adsorption and parameters for the adsorption kinetics were estimated from the frequency measurements of quartz crystal microbalance. A fresh surface of the nanocrystalline TiO 2 films could be photochemically regenerated because holes and hydroxyl radicals were generated by irradiating the nanocrystalline TiO 2 films with UV light, which could oxidize and decompose organic materials, and the nanocrystalline TiO 2 films can be easily regenerated when it is used as adsorbent for the removal of bilirubin.

An albumin-fixed membrane for the removal of protein-bound toxins

Established methods for kidney dialysis do not work for liver failure because kidney dialysis removes only water-soluble toxins, while the liver normally removes albumin-bound toxins. In the present study, a polysulfone dialysis membrane with a −OH reactive group was prepared by hydrolyzing the chloromethylated polysulfone membrane, and the bovine serum albumin molecules were fixed into the membrane with 1,1′-carbonyldiimidazole activation. The content of albumin of the albumin-fixed membrane was 121.3 mg (g membrane)−1. The albumin-fixed dialysis membranes were used to remove protein-bound toxins, bilirubin, from the bilirubin–albumin solution. The transfer rate of bilirubin of the albumin-fixed membrane was obviously higher compared to the normal dialysis membrane. The clearance of bilirubin with the albumin-fixed membrane was 49.8%. The albumin-fixed membrane can easily be regenerated by the bovine serum albumin and NaOH solution. Regeneration of the membrane suggested good mechanical and chemical stability, as well as good clearance of bilirubin. In addition, the effects of membrane thickness and bilirubin initial concentration on the removal of bilirubin were discussed.

Molecular adsorbent recirculating system treatment for patients with liver failure: the Hong Kong experience

The molecular adsorbent recirculating system (MARS) is an extracorporeal liver dialysis system that allows selective removal of bilirubin and other albumin-bound toxins. We reported here our experience with the use of this technique for management of liver failure at Queen Mary Hospital, Hong Kong. From December 2002 to 2004, a total of 74 MARS sessions were performed on 22 patients. The cause of liver failure included acute liver failure (n = 2), acute on chronic liver failure (n = 12), posthepatectomy liver failure (n = 4), and posttransplantation allograft failure (n = 4). MARS treatment showed significant reduction in total bilirubin level, serum ammonia level and blood urea, and nitrogen (P < 0.001 for all three parameters). Five patients (22.7%) were able to bridge to transplantation and one patient (4.5%) made a spontaneous recovery. The 30-day mortality rate was 72.7%. Our results indicated that MARS can effectively improve serum biochemistry and is suitable for temporarily supporting patients with liver failure where transplantation is not immediately available. There is, however, no clear evidence showing that MARS can increase survival, improve the chance of transplantation or assist liver regeneration. Future studies in the form of randomized-controlled trials are crucial to characterize the true potential of this treatment.

A Modeling Study of Bilirubin Kinetics During Molecular Adsorbent Recirculating System Sessions

This work presents a quantitative description, by means of a mathematical model, of bilirubin removal during Molecular Adsorbent Recirculating System sessions. The model includes four compartments: two for the patient, and two for the albumin circuit. Equations in each compartment express mass preservation, mass exchange between compartments, and bilirubin-albumin binding kinetics. Model development and validation are based on in vivo data of bilirubin concentration acquired in eight sessions at different times during the session. The accuracy of the model in reproducing real data is high (error in blood = -0.3 +/- 0.93 mg/dL), if three parameters, representing the depurative efficacy of the system (the dialysance of the blood filter and the initial and final clearance of the depurative elements in the albumin circuit), are estimated on each single session. However, model accuracy is only slightly deteriorated (error in blood = -0.4 +/- 0.99 mg/dL) if a single set of parameters (fixing the three parameters at their mean values) is adopted. These results suggest that the model may be used a priori (i.e., using a single set of parameters) to achieve a satisfactory prediction of the overall bilirubin removal, as well as a posteriori for the estimation of device parameters. The latter use may allow the investigation of the dependence of these parameters on the operative and clinical conditions, in the effort to arrive at a rationalization and optimization of the treatment.