Peter Krisper

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.

Technology Insight: artificial extracorporeal liver support—how does Prometheus ® compare with MARS ® ?

Artificial extracorporeal liver support or liver dialysis has been used in patients with severe liver failure with increasing frequency since the Molecular Adsorbents Recirculating System (MARS®), a variant of albumin dialysis, was introduced in 1999. Nevertheless, liver dialysis must still be thought of as experimental because its contribution to improved patient survival has not been proven in large randomized trials. Prometheus® is a novel device for fractionated plasma separation via an albumin-permeable filter that was developed to improve removal of albumin-bound toxins. Initial studies have proven clinical use of Prometheus® to be feasible and safe. Head-to-head comparisons of Prometheus® and MARS® have shown treatment with the former to be more efficient with respect to removal of most albumin-bound and water-solved markers. As controlled studies with clinical end points are lacking, it is not known whether the observed greater detoxification capacity of Prometheus® will translate into clinical benefit; two small studies indicate that there might be a beneficial effect in hepatic encephalopathy and pruritus. In a recent randomized comparison of MARS® and Prometheus®, however, hemodynamic improvement was observed in response to MARS®, but not Prometheus®, treatment. A large randomized controlled trial investigating the effect of Prometheus® on survival—the HELIOS study—has been initiated. First results are expected in 2008 and will be crucial to establishing a role for Prometheus® in the field of extracorporeal liver support.

Oxidative albumin damage in chronic liver failure: Relation to albumin binding capacity, liver dysfunction and survival

BACKGROUND & AIMSnImpaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis.nnnMETHODSnPatients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand.nnnRESULTSnBoth in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort.nnnCONCLUSIONSnOur results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure.

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.

Clearing of toxic substances: are there differences between the available liver support devices?

Toxins accumulating in liver failure split into water solved (e.g. ammonia) and albumin bound substances (e.g. bilirubin). Because the latter cannot be removed by conventional haemodialysis, special liver support systems have been developed. The majority of data concerning elimination efficiency exist for the cell‐free devices Molecular Adsorbent Recirculating System (MARS) and Prometheus, as they have been commercially available in Europe since many years. Overall, Prometheus provides higher clearances for most liver toxins, especially if they are tightly albumin bound. However, for bile acids and cytokines no such differences could be found. Single pass albumin dialysis (SPAD) can be assumed to be equally effective as MARS. None of the bioartificial liver support systems being developed is on the market today and published clearance data are scarce. In general, clearance efficiency for albumin bound substances is relatively low in all systems currently available. Besides optimizing biocompatibility and selectivity, future technologies should also focus on improved detoxification efficiency of liver support devices.

Effect of Extracorporeal Liver Support by Molecular Adsorbents Recirculating System and Prometheus on Redox State of Albumin in Acute-on-Chronic Liver Failure

Oxidative stress is believed to play an important role in acute‐on‐chronic liver failure (AoCLF). Albumin, an important transport vehicle, was found to be severely oxidized in AoCLF patients. Extracorporeal liver support systems may exert beneficial effects in AoCLF via removal of albumin‐bound toxins. At present, two systems are commercially available, the molecular adsorbents recirculating system (MARS) and fractionated plasma separation, adsorption and dialysis (FPAD, also known as Prometheus). The aim of this study was to compare the effect of MARS and Prometheus treatments on the redox state of human serum albumin. Eight patients with AoCLF underwent alternating treatments with either MARS or Prometheus in a randomized cross‐over design. Sixteen treatments (eight MARS and eight Prometheus) were available for analysis. The fraction of human mercaptalbumin (HMA), human nonmercaptalbumin‐1 (HNA1), and human nonmercaptalbumin‐2 (HNA2) were measured before and after single MARS and Prometheus treatments and during follow‐up. In AoCLF patients the oxidized fractions of albumin, HNA1, and HNA2 were markedly increased. Both MARS and Prometheus treatments resulted in a shift of HNA1 to HMA, while HNA2 was not significantly affected. This shift in albumin fractions was transient and disappeared within 24u2003h after treatment. There were no significant differences between MARS and Prometheus treatments with respect to the redox state of albumin. Both MARS and Prometheus treatments lead to transient improvements of the redox state of albumin, which could be beneficial in the treatment of AoCLF.

Efficacy and Safety of Anticoagulation With Heparin Versus Heparin Plus Epoprostenol in Patients Undergoing Extracorporeal Liver Support With Prometheus

Anticoagulation for extracorporeal liver support is delicate due to underlying coagulation disorders in patients with liver failure and to the associated elevated bleeding risk. To date, there has been no detailed report on anticoagulation issues in patients treated with Prometheus, a device based on the principle of fractionated plasma separation and adsorption. We studied 17 patients from two centers treated with Prometheus, comparing standard anticoagulation with heparin (15 treatments) and a combination of heparin and the synthetic prostacyclin epoprostenol (22 treatments). Standard coagulation tests, proteins C and S, and thrombin-antithrombin (TAT) complex were determined, and adverse events were recorded. All but two treatments could be completed as scheduled, although filter exchange due to filter clotting was required in 24% of the treatments. Three out of 17 patients developed severe bleeding complications within 24 h of treatment. There were no overt thrombotic events. Addition of epoprostenol neither reduced coagulation-related adverse events nor improved standard coagulation parameters. Protein C, but not protein S, showed a significant reduction (23 +/- 18%) after Prometheus treatments, but levels rebounded to baseline within 18 h. TAT levels--a measure for activation of coagulation--were only altered by Prometheus in patients where TAT was already elevated before treatment. In conclusion, anticoagulation of Prometheus with heparin is feasible but still associated with a relatively high frequency of filter clotting and a considerable risk of severe bleeding in this high-risk patient population. As addition of epoprostenol did not prove beneficial, other strategies, such as regional anticoagulation with citrate, should be further evaluated.

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.

On-line dialysate infusion to estimate absolute blood volume in dialysis patients.

It was the aim to measure the distribution volume and the elimination of ultra-pure dialysate in stable hemodialysis patients during on-line hemodiafiltration (HDF). Dialysate was automatically infused as a volume indicator using standard on-line HDF equipment. Indicator concentration was noninvasively measured in the arterial blood-line (using the blood volume monitor, Fresenius Medical Care, Bad Homburg vor der Höhe, Germany), and its time course was analyzed to obtain the elimination rate and the distribution volume Vt at the time of dilution. Blood volume at treatment start (V0) was calculated accounting for the degree of intradialytic hemoconcentration. Five patients (two females) were studied during 15 treatments. Two to six measurements using indicator volumes ranging from 60 to 210 ml were done in each treatment. V0 was 4.59 ± 1.15 L and larger than the volume of 4.08 ± 0.48 L estimated from anthropometric relationships. The mean half-life of infused volume was 17.2 ± 29.7 min. Given predialysis volume expansion V0 was consistent with blood volume determined from anthropometric measurements. Information on blood volume could substantially improve volume management in hemodialysis patients and fluid therapy in intensive care patients undergoing extracorporeal blood treatment. The system has the potential for complete automation using proper control inputs for BVM and HDF modules of the dialysis machine.

Access recirculation in a native fistula in spite of a seemingly adequate access flow

True access recirculation (AR) measured by ultrasound dilution technique is usually absent in well-working shunts. It occurs with low access flows (Qa). High access flow rates are assumed to prevent AR. Two major exceptions to these rules are known: presence of intra-access strictures and inadvertently reversed blood lines. We present an additional exception in which true access recirculation occurred in a native arteriovenous (AV) fistula with correct placement of bloodlines. Surprisingly, access blood flow exceeded pump blood flow (Qb) almost threefold. The situation was clarified by a magnetic resonance angiogram showing a collateral forming a functional loop. This loop led to true access recirculation in one branch, although overall blood flow through both branches appeared to be adequate. The different findings in this shunt over time give insight into the often complex pathophysiology of native fistulae. This case proves that seemingly adequate access flow does not necessarily prevent access recirculation in native AV fistulae. We suggest monitoring both access flow and recirculation in hemodialysis accesses on a regular basis.