Aleksandra Jung

Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure

IntroductionCytokines are believed to play an important role in acute-on-chronic liver failure (ACLF). Extracorporeal liver support systems may exert beneficial effects in ACLF via removal of cytokines. At present, two systems are commercially available, the Molecular Adsorbent Recirculating System (MARS™) and Fractionated Plasma Separation, Adsorption and Dialysis (Prometheus™). The aim of this study was to compare the effects of MARS and Prometheus treatments on serum cytokine levels and their clearances.MethodsEight patients with ACLF underwent alternating treatments with either MARS or Prometheus in a randomized cross-over design. Thirty-four treatments (17 MARS, 17 Prometheus) were available for analysis. Serum cytokines were measured before and after each treatment, and cytokine clearance was calculated from paired arterial and venous samples and effective plasma flow one hour after the start of treatment.ResultsBaseline serum levels of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and soluble TNF-α receptor 1 were significantly elevated in patients with ACLF. Measurable plasma clearances were detected for all cytokines tested, but no significant changes in serum levels of any cytokine were found after treatments with MARS or Prometheus. In MARS treatments, IL-10 was cleared from plasma more efficiently than IL-6. Clearance of IL-10 was higher in Prometheus than in MARS treatments.ConclusionCytokines are cleared from plasma by both MARS and Prometheus, but neither system is able to change serum cytokine levels. This discrepancy is probably due to a high rate of cytokine production in patients with ACLF.

Removal of bile acids by two different extracorporeal liver support systems in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is accompanied by marked intrahepatic cholestasis leading to accumulation of cytotoxic bile acids. Extracorporeal liver support systems efficiently remove bile acids, but their effect on bile acid composition in ACLF is unknown. The aim of the present study was to compare elimination of individual plasma bile acids by albumin dialysis (Molecular Adsorbents Recirculating System, MARS) and fractionated plasma separation (Prometheus). Eight consecutive patients with ACLF underwent alternating 6-hour sessions with MARS or Prometheus in a randomized, cross-over design. Serum samples were obtained before, during, and after each treatment, and individual bile acids including cholic acid and chenodeoxycholic acid (CDCA) were measured by gas chromatography. MARS and Prometheus removed total bile acids to a similar extent (reduction ratio, 45% and 46%, respectively). Both devices cleared cholic acid more efficiently than did CDCA. The molar fraction of CDCA (fCDCA) was elevated at baseline and correlated with the degree of liver dysfunction. Prometheus but not MARS treatments further increased fCDCA. Although both devices eliminate total bile acids to a similar extent, clearance of individual bile acids is different, leading to a slight change of the bile acid profile toward hydrophobic bile acids during Prometheus treatments.

Bilirubin Kinetic Modeling for Quantification of Extracorporeal Liver Support

Background/Aim: To provide a measure of treatment dose for extracorporeal liver support (ELS). Methods: The kinetics of conjugated bilirubin were described by a two-compartment model (Vc, Vp) with central elimination (K) and constant generation rate (G). The transfer of solute between compartments was modeled by intercompartmental clearance (Kpc). The central compartment (Vc) was assumed as a constant fraction of total volume (Vc = 0.3*Vt). Results: Eight patients were studied during 35 treatments lasting 6 h each. The average K, Vt, Kpc, G, and mass of conjugated bilirubin removed were 18.6 ± 3.9 ml/min, 9.1 ± 3.8 liters, 103 ± 108 ml/min, 0.33 ± 0.15 mg/min, and 641 ± 275 mg, respectively. The reduction ratio (48 ± 10%) measured as the change in post- to pre-treatment concentrations underestimated the modeled fraction of bilirubin mass removed (54 ± 13%) essentially because of significant conjugated bilirubin appearance during treatments. Conclusions: Kinetic analysis provides an improved measure of treatment dose as generation, distribution, and elimination of conjugated bilirubin are jointly considered.

Relationship between kinetics of albumin-bound bilirubin and water-soluble urea in extracorporeal blood purification

BACKGROUND The purpose of the study was to examine the relationship between urea and conjugated bilirubin kinetics during extracorporeal liver support (ELS) therapy and to determine the dose of therapy for urea and conjugated bilirubin as markers for water-soluble and protein-bound solutes, respectively. METHODS Kinetics of urea and bilirubin were described by standard two-compartment models with central clearance, constant intercompartment clearance, constant generation rate and constant volume. While the concentration of urea was assumed as equilibrated between compartments at the beginning of ELS therapy, the concentration of conjugated bilirubin between compartments was assumed to follow the partition of albumin between plasma and interstitial spaces. Treatment dose was calculated as removed solute mass and fractional solute removal. RESULTS Seven patients were studied during 15 treatments lasting at least 6 h. Bilirubin distribution volume of 14.8 ± 5.4 L was not different from urea extracellular water volume of 15.0 ± 2.8 L. The correspondence between models was used to predict the mass of bilirubin removed based on extracellular volume obtained from urea kinetics, average data from bilirubin kinetics, as well as selected treatment and patient information. The prediction of bilirubin mass removed based on this reduced information was not different from the mass of solute removed based on complete bilirubin kinetic analysis. CONCLUSIONS The correspondence between kinetics of urea and conjugated bilirubin can be used to identify the bilirubin distribution volume from urea kinetic analysis. This information is then useful to estimate and predict the solute removal of conjugated bilirubin in ELS.

Sensitivity Analysis of Two-Compartment Model Parameters for Extracorporeal Liver Therapy Purposes

Time-stable volume two compartment conjugated bilirubin (cb) kinetics model was applied for sensitivity analysis. Model parameters variation influence on time course of cb concentration was determined. The analysis was performed for central and peripheral compartment during and between extracorporeal treatments. The analyzed model parameters were bilirubin generation G, volume V and intercompartmental clearance \(K_{pc}\). Sensitivity with respect to G had a maximum at the end of the observed period of 24 h, while the sensitivities with respect to V and \(K_{pc}\) reached their maxima during the treatment time. Sensitivity with respect to G was negligible at the beginning of the treatment and increased almost linearly after the treatment. It was similar for the central and peripheral output. Parameter V affected cb concentration the most strongly during the treatment, the sensitivity was lower for overhydrated patients. After the treatment sensitivity of V decreased almost linearly. The sensitivity with respect to \(K_{pc}\) was low and even negative. Summarizing, the analysis demonstrated that cb concentration was highly sensitive to G and V whereas it was influenced by \(K_{pc}\) to a much lesser extent. Sensitivity analysis indicates that parameters G and V may be estimated with high accuracy from cb concentration measurements for most patients but identification process must be provided more carefully for overhydrated patients. \(K_{pc}\) is estimated less accurately, similarly to hemodialysis models. The accuracy of the parameter estimation may be improved by selecting the sampling time individually for each patient near the peak values of the sensitivity.

The elemental changes occurring in the rat liver after exposure to PEG-coated iron oxide nanoparticles : total reflection x-ray fluorescence (TXRF) spectroscopy study

Abstract The main goal of this study was to evaluate in vivo effects of low dose of PEG-coated magnetic iron oxide nanoparticles (IONPs) on the rat liver. The IONPs was intravenously injected into rats at a dose equaled to 0.03 mg of Fe per 1 kg of an animal body weight. The elemental composition of liver tissue in rats subjected to IONPs action and controls were compared. Moreover, in order to determine the dynamics of nanoparticles (NPs) induced elemental changes, the tissues taken from animals 2 hours, 24 hours, and 7 days from IONPs injection were examined. The analysis of subtle elemental anomalies occurring as a result of IONPs action required application of highly sensitive analytical method. The total reflection X-ray fluorescence spectroscopy perfectly meets such requirements and therefore it was used in this study. The obtained results showed increasing trend of Fe level within liver occurring 2 hours from IONPs injection. One day after NPs administration, the liver Fe content presented the baseline level what suggests only the short-term accumulation of nanoparticles in the organ. The Ca, Cu, and Zn levels changed significantly as a result of NPs action. Moreover, the anomalies in their accumulation were still observed 7 days after IONPs injection. The level of Cu decreased while those of Ca and Zn increased in the liver of NPs-treated animals. The reduced liver Cu, followed by elevated serum level of this element, might be related in triggering the mechanisms responsible for Fe metabolism in the organism.

Evaluation of spatial and seasonal radioactivity dose fluctuations in a Wierzchowska Górna limestone cave

Measurements of the dose rate changes were carried out in order to assess seasonal and spatial radioactivity variations in the largest limestone cave of the Polish Jura Wierzchowska Górna. Thermoluminescence detectors, which were annealed, calibrated and protected against humidity were used. Measurements were repeated four times in 13 locations to observe possible changes. The external dose rate was in the range of 0.004–0.106 mGy/quarter. The results were influenced by the detector locations – lower doses were estimated closer to the cave entrance and the highest doses were in the so-called ‘primitive man room’. Doses measured in four periods were statistically significantly different. The external dose level as well as seasonal and spatial dose changes measured in the cave were low. In other caves where external doses are higher, seasonal and spatial dose changes may have a stronger impact on radiological hazard.

Clearance and rate of conjugated bilirubin removal during extracorporeal liver support therapy with FPSA PrometheusTM

The elimination of protein-bound solutes during extracorporeal liver support (ELS) therapy involves a se- quence of steps and processes such as diffusion, convection, filtration, and adsorption. It was the purpose of this study to analyze the time course and the relative contribution of these processes to overall solute removal. Eighteen treatments done in 8 acute-on-chronic liver failure patients for a duration of 8 h using fractionated plasma sepa- ration and adsorption (FPSA) were studied. Conjugated bili- rubin was measured in the extracorporeal circulation at 6 different sampling points in regular intervals. Clearance and removal rates were calculated for the whole system and for selected system components. Conjugated bilirubin concentrations decreased in the pri- mary circuit directly connected to the patient and remained stable or increased in the secondary circuit which contained the adsorbers. Bilirubin clearance declined notably during the first 2 h of therapy for the whole system as well as for the adsorbers. The clearance for bilirubin in the primary circuit provided by the FX50 dialyzer was relatively small but con- stant. In the secondary circuit clearance was larger for the anion exchanger (Prometh02™) than for the neutral resin (Prometh01™) and decreased throughout the ELS treatment. Thus, approximately 90% of overall removal rate for conju- gated bilirubin occurred in the adsorbers and about 10% in the dialyzer. The information obtained on the relative contribution of different ELS components to overall bilirubin removal could be helpful to improve the performance of selected components of FPSA and thereby of ELS as a whole.