Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study

Karla C L Lee, Luisa A Baker, Giacomo Stanzani, Hatim Alibhai, Yu Mei Chang, Carolina Jimenez Palacios, Pamela J Leckie, Paola Giordano, Simon L Priestnall, Daniel J Antoine, Rosalind E Jenkins, Christopher E Goldring, B Kevin Park, Fausto Andreola, Banwari Agarwal, Rajeshwar P Mookerjee, Nathan A Davies, Rajiv Jalan, Karla C L Lee, Luisa A Baker, Giacomo Stanzani, Hatim Alibhai, Yu Mei Chang, Carolina Jimenez Palacios, Pamela J Leckie, Paola Giordano, Simon L Priestnall, Daniel J Antoine, Rosalind E Jenkins, Christopher E Goldring, B Kevin Park, Fausto Andreola, Banwari Agarwal, Rajeshwar P Mookerjee, Nathan A Davies, Rajiv Jalan

Abstract

Background & aims: In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure.

Methods: Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure.

Results: The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen.

Conclusions: The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients.

Keywords: Acetaminophen; Acute liver failure; Albumin; Endotoxin; Extracorporeal liver assist device; Toll-like receptor 4; UCL-LDD.

Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
UCL-LDD reduces risk of death in ALF. Effect of UCL-LDD (solid black line) on survival compared to CD (broken black line).
Fig. 2
Fig. 2
UCL-LDD improves cardiovascular function in ALF. UCL-LDD delayed vasoplegia/high output cardiac failure and reduced severity of cardiovascular failure during the first 8 h of treatment i.e. 2–10 h after ALF (blue shading) in the APAP-UCL-LDD group (solid black line) compared to APAP-CD Group (broken black line) [Control-CD Group (grey line)]. (ALF, time INR exceeded 3; MAP, mean arterial pressure; HR, heart rate; SVRI, systemic vascular resistance index; CI, cardiac index; SVI, stroke volume index; LVSWI, left ventricular stroke work index; RVSWI, right ventricular stroke work index; Voluven, colloid therapy; ∗, significant (p <0.0500) difference between APAP-UCL-LDD and APAP-CD).
Fig. 3
Fig. 3
UCL-LDD delays onset of acute lung injury in ALF. UCL-LDD resulted in a delay in respiratory failure during the first 8 h of treatment i.e. 2–10 h after ALF (blue shading) in the APAP-UCL-LDD group (solid black line) compared to APAP-CD Group (broken black line) [Control-CD Group (grey line)]. (ALF, time INR exceeded 3; PaO2/FiO2, ratio of partial pressure of oxygen in arterial blood to percentage of oxygen in inspired gases; Compl, lung compliance; RR, respiratory rate; PEEP, positive end expiratory pressure; Pinsp, inspiratory pressure; *, significant (p <0.0500) difference between APAP-UCL-LDD and APAP-CD).
Fig. 4
Fig. 4
UCL-LDD reduces endotoxaemia in ALF. Endotoxin concentrations measured in plasma samples from APAP-CD, APAP-UCL-LDD and Control-CD pigs at time zero (0 h), ALF, ALF + 4 h, ALF + 8 h and the last blood sampling point prior to death (‘Terminal’). All plasma samples were diluted 1 in 10 and spiked with 5EU endotoxin. Endotoxin concentrations at ALF + 8 h (*p = 0.018) and ‘Terminal’ (**p = 0.002) were significantly lower in the APAP-UCL-LDD group compared to the APAP-CD group.
Fig. 5
Fig. 5
UCL-LDD delays activation of the TLR-4 signalling pathway in ALF. Response ratios (relative to negative control) for TLR4 reporter cell assay. Response ratio for positive control was 3.196 ± 0.369. Response ratio for APAP-CD was only significantly increased compared to Control-CD at ALF + 12 h (*p = 0.040). Response ratio for APAP-UCL-LDD was only significantly increased compared to Control-CD at ALF + 20 h (**p = 0.030), representing a delay in TLR4 activation by UCL-LDD treatment.
Fig. 6
Fig. 6
UCL-LDD has no effect on total HMGB1 plasma concentrations in ALF. Total HMGB1 concentrations measured in plasma samples from APAP-CD, APAP-UCL-LDD and Control-CD pigs at 0 h, ALF, ALF + 4 h, ALF + 8 h and the last blood sampling point prior to death (‘Terminal’). Data was log transformed for statistical analysis. There was a significant increase in total HMGB1 in APAP-CD and APAP-UCL-LDD groups with time (p <0.001) but not in the Control-CD group. After onset of ALF, UCL-LDD treatment did not significantly affect further increase in HMGB1 compared to CD treatment.

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