Removal Of Protein-bound Toxins Research Articles

#885 Combination of medium cut-off dialyzer membrane and diet modification to reduce serum concentrations of p-cresyl sulfate and indoxyl sulfate

Abstract Background and Aims Online hemodiafiltration (ol-HDF) may be considered currently as the best choice for chronic hemodialysis (HD) treatment, but medium cut-off (MCO) membranes may provide similar efficiency for larger and protein-bound toxin removal. P-cresyl sulfate (PCS) and indoxyl-sulfate (IS) concentration depends mainly on residual renal function and diet. Increased dietary fiber intake and short-chain fatty acid (SCFA) supplementation were associated with decreased production of PCS and IS. The aim of this study was to pragmatically combine MCO use with diet modification in an attempt to reduce serum concentration of PCS and IS and compare this strategy to online HDF use. Method We report preliminary results from a subset of a study sample with 42 chronic prevalent HD patients in a prospective randomized controlled interventional study. Two weeks after standard bicarbonate HD (BHD), patients were randomized to hemodialysis with MCO membrane (EXP group) or ol-HDF with a standard "high-flux" (HF) dialyzer membrane (CON group). After 4 weeks, both groups were supplemented by a change in the diet with increase of the daily intake of dietary fiber to 30g and addition of a SCFA propionate in the dose of 1g daily for 8 weeks. Two main outcomes were serum concentrations of PCS and IS. Measurements were taken at baseline (after 2 week wash-in period), after 4 weeks of the first intervention phase (MCO vs. ol-HDF; T1), after 8 weeks of the second intervention phase (fiber and SCFA supplementation; T2) and finally, after 4 weeks of wash-out period with BHD (T3). Results From 42 participants, 38 completed the study (63.2% men, 66.4±10.9 years, Charlson comorbidity index 5.7±2.3). In the CON group, serum concentrations of PCS (in μg/ml) were 36.8±19.6 (baseline), 36.9±20.8 (T1), 32.4±17.4 (T2) and 38.6±22.1 (T3). Serum concentrations of IS (in μg/ml) were 31.8±13.0 (baseline), 32.9±14.7 (T1), 29.5±9.1 (T2) and 35.5±16.8 (T3). In the EXP group, serum concentrations of PCS were 33.5± 16.6 (baseline), 35.9±17.8 (T1), 34.0±16.1 (T2) and 37.4±21.5 (T3). Serum concentrations for IS were 39.6±12.6 (baseline), 37.3±12.9 (T1), 42.3±13.5 (T2) and 41.0±12.8 (T3). Repeated measures ANOVA revealed no significant time*group interaction for PCS (F(1,33)=0.479, p=0.698, ŋ2=0.014) and IS (F(1,33)=2.392, p=0.073, ŋ2=0.068). There was a significant within-group increase in serum IS concentration between T2 and T3 in CON group (p=0.042). There was a trend towards a decrease in PCS concentration between T1 and T2 and increase between T2 and T3 in CON group. Conclusion The results of the study suggest both hemodialysis methods are equivalent in eliminating PCS and IS. Additional fiber and SCFA propionate supplementation did not decrease serum PCS and IS concentrations significantly, although there was a trend towards lower serums concentration of PCS after diet modification in CON group.

Effect of hemoperfusion with hexadecyl-immobilized cellulose beads on myocardial fatty acid imaging in hemodialysis patients: a case series study

BackgroundHexadecyl-immobilized porous cellulose beads (HICBs) can be used to remove β2-microglobulin, as well as several inflammatory cytokines and free protein-binding uremic toxins (PBUTs). Interleukin-6 and PBUT levels have been associated with oxidative stress and/or cardiovascular disease. In this retrospective study, we investigated the potential of direct hemoperfusion with HICBs to improve impaired myocardial fatty acid imaging in hemodialysis patients.MethodWe evaluated 24 hemodialysis patients who did not undergo percutaneous coronary intervention or coronary artery bypass grafting during the observation period. Among these patients, 12 who had been treated using HICB columns for more than 4 years were assigned to the HICBs group (mean observation period, 61.9 ± 16.3 months), while the remaining patients who had never undergone treatment with HICB columns were assigned to the non-HICBs group (mean observation period, 58.0 ± 12.2 months). Impaired myocardial fatty acid metabolism was assessed by single-photon emission computed tomography (SPECT) using 123I-β-ethyliodophenyl pentadecanoic acid (BMIPP). Uptake on SPECT was graded in 17 segments on a 5-point scale (0, normal; 4, absent) and assessed as the BMIPP summed score (SS).ResultsWhile the HICBs group showed a lower mean β2-MG than the non-HICBs group, the other baseline clinical patient characteristics did not differ between the two groups. In the HICBs group, the second BMIPP SS was decreased significantly compared with the first BMIPP SS. A decrease in the BMIPP SS was observed in nine (75%) patients with the first BMIPP SS ≥ 6, and no change was observed in three patients with BMIPP SS ≤ 2. In the non-HICBs group, the second BMIPP SS was increased significantly compared with the first BMIPP SS.ConclusionThe improvement in myocardial fatty acid imaging suggests an improvement in the impaired myocardial microcirculation. We suggest that the use of direct hemoperfusion with HICBs may have improved the impaired myocardial microcirculation in hemodialysis patient through the removal of protein-bound toxins and inflammatory cytokines and might contribute towards improving the survival of dialysis patients.

SlipSkinTM based hollow fiber membranes for protein-bound toxin removal

SlipSkinTM based hollow fiber membranes for protein-bound toxin removal

Removal of asymmetric dimethylarginine during artificial liver support using fractionated plasma separation and adsorption

Objective. Asymmetric dimethylarginine (ADMA) is the most potent endogenous nitric oxide synthase inhibitor. Elevated ADMA levels have been linked to increased mortality in different patient populations. Key regulation of ADMA levels mainly takes place in the liver. Hence, ADMA is elevated in liver disease. There is no specific pharmacological treatment to lower the elevated ADMA levels. Hemodialysis is of limited efficiency in removing ADMA as it is highly protein bound. Prometheus® is an extracorporeal liver support system which allows the removal of protein-bound toxins. We assessed the efficiency of the Prometheus® system in reducing high ADMA levels in patients with liver failure. Material and methods. We studied nine patients with acute-on-chronic liver failure and concomitant renal failure already necessitating hemodialysis. Seven patients needed intensive care treatment. Two consecutive sessions of Prometheus® therapy of each 4 h were performed in all patients. ADMA and its structural isomer symmetrical dimethylarginine (SDMA) were determined using liquid chromatography–mass spectrometry. Results. ADMA levels correlated to model for end stage liver disease (MELD) score (rs = 0.62; p < 0.0001). Before Prometheus® was started, levels of ADMA and SDMA were elevated (1.36 ± 0.5 μmol/l and 1.90 ± 0.4 μmol/l, respectively). During Prometheus® treatments, plasma levels of ADMA dropped by a mean 25% (p < 0.0001) and SDMA levels by 22% (p < 0.0001). However, there was a significant rebound of ADMA levels between the two therapy sessions (p < 0.01). Conclusions. This study shows for the first time that plasma levels of ADMA can be effectively lowered by an artificial liver support system (Prometheus®). Effective elimination of ADMA might explain some of the beneficial clinical effects of these systems in patients with liver failure.

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.

The elusive goal of liver support – quest for the Holy Grail

The history of liver support devices is traced from early attempts with dialysis based on the known dialysability of ammonia--the major identified toxin in liver failure--and exchange transfusion with removal of protein-bound toxins, to the later techniques based on whole organ perfusion in extracorporeal circuits. Perfusion through charcoal as an adsorbent represented a major advance and remains a component of more recently introduced devices based on bioreactors of cultured hepatocytes and in the albumin dialysis techniques of molecular adsorbent recirculating system and the Prometheus device. The latter are the most highly efficient to date in toxin removal but whether survival is improved and the need for liver transplantation remain to be proven.

BOUND SOLUTE DIALYSIS WITH ULTRAFILTRATION

Bound solute dialysis (BSD), as practiced by MARS (“albumin dialysis”) and the Biologic-DT (“sorbent dialysis”), is directed toward removal of protein-bound toxins and has shown some clinical efficacy in treatment of liver failure patients. Semicontinuous ultrafiltration with dialysis (SCUF-D), rather than dialysis, is used to maintain or reduce patient volume. Objective: Understand the impact of ultrafiltration (UF) volume removal from a patient in conjunction with BSD on protein-bound toxin reduction. Methods: A thermodynamically-based engineering model of SCUF-D coupled with BSD (SCUF-BSD) in which the bound toxin, but not the binding protein, can cross the membrane is developed. Four dimensionless ratios (κ; membrane extraction/perfusion rate; α: dialysate/perfusate rate; β: dialysate/perfusate albumin ratio; γ: fractional UF rate) govern the ability of SCUF-BSD to remove albumin-bound solutes from the blood stream. Results: UF of protein-bound toxin removes some toxin mass but leads to an increase in toxin concentration because the binding protein concentration increases with decreasing volume. For any SCUF-BSD UF cartridge, toxin mass removal from a patient is insensitive to α when α >0.2. Toxin mass removal is also insensitive to dialysate albumin concentration once β >0.02. At that point, SCUF-BSD toxin removal doubles in comparison SCUF-D. Also, when β >0.02 bound toxin removal increases with decreasing UF rate, at equivalent volume reduction, because higher UF rates lower the total time available for BSD treatment and it is BSD that promotes bound toxin removal. Conclusion: SCUF-BSD is more efficacious than SCUF-D for bound solute toxin removal.

The removal of uremic toxins

Three major groups of uremic solutes can be characterized: the small water-soluble compounds, the middle molecules, and the protein-bound compounds. Whereas small water-soluble compounds are quite easily removed by conventional hemodialysis, this is not the case for many other molecules with different physicochemical characteristics. Continuous ambulatory peritoneal dialysis (CAPD) is often characterized by better removal of those compounds. Urea and creatinine are small water-soluble compounds and the most current markers of retention and removal, but they do not exert much toxicity. This is also the case for many other small water-soluble compounds. Removal pattern by dialysis of urea and creatinine is markedly different from that of many other uremic solutes with proven toxicity. Whereas middle molecules are removed better by dialyzers containing membranes with a larger pore size, it is not clear whether this removal is sufficient to prevent the related complications. Larger pore size has virtually no effect on the removal of protein-bound toxins. Therefore, at present, the current dialytic methods do not offer many possibilities to remove protein-bound compounds. Nutritional and environmental factors as well as the residual renal function may influence the concentration of uremic toxins in the body fluids.

Hemodiabsorption in Treatment of Acute Hepatic Failure and Chronic Cirrhosis with Ascites

Hemodiabsorption is a selective chemical removal process during which blood passes through dialysis membrane packages surrounded by a suspension of fine sorbent particles. The BioLogic-DT system contains charcoal and cation exchangers in a suspension that passes through dialysate spaces of a cellulosic membrane plate dialyzer. The system has proven effective in treatment of patients with serious drug overdose and has demonstrated positive effects in treatment of stage 4 coma due to hepatic failure. Recently, the charcoal in this system has been preloaded with branch chain amino acids to return these acids to patients while aromatic amino acids are removed. Further improvements include addition of osmotically active agents to the priming fluid and sorbent to increase blood oncotic pressure and transfer of ascitic fluid to blood while ultrafiltration transfers fluid out of the blood. Clinical testing of these improvements is now beginning in patients with ascites and encephalopathy due to chronic hepatic insufficiency and cirrhosis. Future improvements will include protein permeable membranes to increase removal of protein-bound toxins and addition of hepatic cells downstream from the hemodiabsorption unit.

Removal of protein-bound toxins from critical care patients.

AbstractThe coma which develops during acute hepatic failure has been attributed to the accumulation of toxic metabolites, since coma is potentially fully reversible without residual sequelae and there are no important structural changes in the brain of these patients [1]. Removal of these toxins might accelerate arousal and thereby improve survival by preventing cerebral edema and other complications of coma. Ultimately these complications are often the cause of death in many instances of acute hepatic failure, even in patients whose livers are beginning to regenerate [2].