Clinical extracorporeal hybrid liver support – phase I study with primary porcine liver cells

Abstract

The objective of this study was to evaluate the feasibility and safety of a hybrid liver support system with extracorporeal plasma separation and bioreactor perfusion in patients with acute liver failure (ALF) who had already fulfilled the criteria for high urgency liver transplantation (LTx). Eight patients (one male, seven female) were treated in terms of bridging to transplantation. The mean age was 36.5 yr (range 20 to 58). Etiology of liver failure was drug-related in two patients, hepatitis B infection in three patients, and unknown for three patients. The bioreactors were charged with primary liver cells from specific pathogen-free pigs. Cell viability varied between 91 and 98%. Continuous liver support treatment over a period of 8 to 46 h (mean 27.3 h) was safely performed and well-tolerated by all patients. No complications associated with the therapy were observed during the follow-up period. Thrombocytopenia was considered to be an effect of the plasma separation. Subsequently, all patients were transplanted successfully and were observed over at least 3 yr with an organ and patient survival rate of 100%. Screening of patient's sera for antibodies specific for porcine endogenous retroviruses (PERVs) showed no reactivity--either prior to application of the system, or after extracorporeal treatment. The results encourage us to continue the development of the technology, and further studies appear to be justified. The bioreactor technology has been integrated into a modular extracorporeal liver support (MELS) system, combining biologic liver support with artificial detoxification technology.

Pig-to-Baboon Liver Xenoperfusion Utilizing GalTKO.hCD46 Pigs and Glycoprotein Ib Blockade.

“…These studies have been in pre-clinical large animal models utilizing both hepatocyte-based devices [12,13] and whole-organ liver perfusion [14], as well as in limited clinical applications using porcine hepatocytes or whole livers [2,[15][16][17][18]. In our present report, we utilize a genetically modified GalTKO.hCD46 porcine liver designed to eliminate hyperacute rejection while simultaneously attempting to interfere with the constitutive activation between VWF and the GPIb receptor by administering D-arginine vasopressin (DDAVP) and αGPIb antibody.…”

Evidence and Consequence of Porcine Endogenous Retrovirus Recombination

“…While barrier derivation technologies allow the breeding of pigs free of exogenous pathogens, porcine endogenous retroviruses (PERV) are not eliminated due to their presence in germ line DNA. Moreover, certain PERV have been shown to infect human cells in vitro (25,34,54) although no in vivo transmission to human xenograft recipients has been observed as yet (5,7,8,13,22,30,32,37,52). Three replication-competent, gammaretrovirus subgroups of PERV (PERV-A, -B, and -C) have been identified in the genomic DNA of pigs (21,33,34,48).…”

Monitoring for Presence of Potentially Xenotic Viruses in Recipients of Pig Islet Xenotransplantation

“…Whether PERV truly poses an infection risk will ultimately be determined by in vivo monitoring of patients and experimental animals receiving xenografts. To date, more than 200 patients exposed to pig cells have been tested for evidence of PERV infection (3,5,14,15,16,17,21,24,26,27,33,34). Additionally, some 50 nonhuman primates have also been tested for PERV infection (20,32).…”