Treatment of Hepatic Failure with ex Vivo Pig-Liver Perfusion Followed by Liver Transplantation

Chari, Ravi S.; Collins, Bradley H.; Magee, John C.; DiMaio, J. Michael; Kirk, Allan D.; Harland, Robert C.; McCann, Richard L.; Platt, Jeffrey L.; Meyers, William C.

doi:10.1056/nejm199407283310404

Cited by 275 publications

(130 citation statements)

References 7 publications

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“…4 The invasion of recipient leukocytes in the absence of such a membrane is likely to be responsible for hepatocyte injury and shortening the duration of ex vivo pig liver therapy. 5 Less is known about the influence of subcellular (i.e., molecular) components of the recipient's immune system on hepatocyte function in a porcine BAL or the potentially harmful effects of porcine antigen leakage from the BAL into the patient's circulation. Titers of xenoreactive antibodies in patients increase after exposure to a porcine BAL, 6 and the ability of these antibodies to enter the BAL is influenced by pore size of the semipermeable membrane.…”

mentioning

confidence: 99%

Membrane barrier of a porcine hepatocyte bioartificial liver

Nyberg

Yagi

Matsushita

et al. 2003

Liver Transplantation

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Pores in the membrane of a bioartificial liver (BAL) allow it to function as a semipermeable barrier between its contents (i.e., liver cells) and components of the recipient's immune system. This study is designed to assess the influence of pore size on immune response to a BAL containing porcine hepatocytes. Sixteen healthy dogs were divided into four groups (four dogs per group) based on pore size of the BAL membrane and level of exposure to porcine hepatocytes. Group 1 dogs were administered porcine hepatocytes by intraperitoneal injection and served as positive controls. Group 2 dogs were exposed to porcine hepatocytes in a large-pore (200-nm) BAL, and group 3 dogs were exposed to porcine hepatocytes in a small-pore (10-nm) BAL. Group 4 dogs were exposed to a no-cell (unloaded) BAL and served as negative controls. Intraperitoneal injection of hepatocytes or 3 hours of BAL hemoperfusion was performed day 0 and 3 weeks later on day 21. Biochemical, humoral, and cellular measures of immune response were collected until day 44. The initiation of BAL hemoperfusion was associated with a rapid decline in CH 50 levels of complement and transient neutropenia and thrombocytopenia during all BAL exposures. Xenoreactive antibody response to BAL was increased by use of membranes with large pores and secondary exposures. Skin testing on day 42 showed a delayed-type hypersensitivity response to porcine hepatocytes that also correlated with level of previous antigen exposure. BAL

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confidence: 99%

Membrane barrier of a porcine hepatocyte bioartificial liver

Nyberg

Yagi

Matsushita

et al. 2003

Liver Transplantation

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“…The vector v u represents the best global fit to the linear system given by equation [6], but individual vector elements may not exactly satisfy local constraints, i.e., a flux balance around a particular metabolite may not close completely, similar to the way individual points may not lie on the linearly regressed line found by minimizing the sum of the least-square distances between all of the points and the line. Solutions to equation [5] were obtained with a program written in MATLAB RN (Mathworks, Inc., Natick, MA) and routinely took less than 1 minute for each measurement set on an IBM ThinkPad laptop computer with a Celeron 466-mHz processor. The fluxes obtained by equation [6] for each liver were reported as averages for each group (FHF and control) in Table 2.…”

Section: Appendixmentioning

confidence: 99%

“…[1][2][3][4] Because of the severe shortage in donor organs, various alternatives aimed at providing a "substitute" liver, such as xenogeneic whole liver perfusion 5 and extracorporeal bioartificial liver devices, 6,7 are being developed. Such systems, which can be used as a bridge to transplantation or provide temporary relief during the most acute phase of hepatic failure, are promising, although technically complex and expensive.…”

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confidence: 99%

Intrahepatic amino acid and glucose metabolism in a ?-galactosamine–induced rat liver failure model

et al. 2001

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A better understanding of the hepatic metabolic pathways affected by fulminant hepatic failure (FHF) would help develop nutritional support and other nonsurgical medical therapies for FHF. We used an isolated perfused liver system in combination with a mass-balance model of hepatic intermediary metabolism to generate a comprehensive map of metabolic alterations in the liver in FHF. To induce FHF, rats were fasted for 36 hours, during which they received 2 D-galactosamine injections. The livers were then perfused for 60 minutes via the portal vein with amino acid-supplemented Eagle minimal essential medium containing 3% wt/ vol bovine serum albumin and oxygenated with 95% O 2 /5% CO 2 . Control rats were fasted for 36 hours with no other treatment before perfusion. FHF rat livers exhibited reduced amino acid uptake, a switch from gluconeogenesis to glycolysis, and a decrease in urea synthesis, but no change in ammonia consumption compared with normal fasted rat livers. Mass-balance analysis showed that hepatic glucose synthesis was inhibited as a result of a reduction in amino acid entry into the tricarboxylic acid cycle by anaplerosis. Furthermore, FHF inhibited intrahepatic aspartate synthesis, which resulted in a 50% reduction in urea cycle flux. Urea synthesis by conversion of exogenous arginine to ornithine was unchanged. Ammonia removal was quantitatively maintained by glutamine synthesis from glutamate and a decrease in the conversion of glutamate to ␣-ketoglutarate. Mass-balance analysis of hepatic metabolism will be useful in characterizing changes during FHF, and in elucidating the effects of nutritional supplements and other treatments on hepatic function. (HEPATOLOGY 2001;34:360-371.)Since the late 1980s, orthotopic liver transplantation has become the only widely accepted treatment for fulminant hepatic failure (FHF). [1][2][3][4] Because of the severe shortage in donor organs, various alternatives aimed at providing a "substitute" liver, such as xenogeneic whole liver perfusion 5 and extracorporeal bioartificial liver devices, 6,7 are being developed. Such systems, which can be used as a bridge to transplantation or provide temporary relief during the most acute phase of hepatic failure, are promising, although technically complex and expensive. It has been hypothesized that hepatic encephalopathy may result from the elevation of circulating levels of putative toxins such as ammonia, mercaptans, short-chain fatty acids, [8][9][10] and an abnormal amino acid profile. [11][12][13] In FHF patients, alterations in amino acid concentrations in systemic plasma have been characterized by several investigators, 14,15 which led to the use of solutions rich in branchedchain amino acids (BCAA) for the treatment of hepatic encephalopathy. 16,17 These approaches, which were largely unsuccessful, aimed at counteracting the observed shifts in metabolite levels in the systemic circulation; however, systemic changes in metabolite levels do not solely reflect alterations in liver function, but also changes in whole-b...

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“…PERV particles are spontaneously released in cultures of porcine peripheral blood lymphocytes (PBLs) and cell lines from a variety of porcine tissues including kidneys (PK15 MPK, PORC), lymph nodes (Shimozuma-1, 38A-1, Testes, ST-MO) and fallopian tubes (PFT). PERV from PK-15 cells can infect a variety of human cell lines in vitro such as kidney, lung, muscle and lymphoid cells, suggesting that these retroviruses may also be able to infect a spectrum of human tissues in vivo [8]. Therefore in this study porcine tissues to be used as xenografts were analyzed using PCR and RT-PCR for the molecular detection of PERV sequences.…”

Section: Introductionmentioning

confidence: 99%

Polymerase chain reaction in detection of porcine endogenous retrovirus (PERV) from porcine tissues

Prabha

Verghese

2009

Indian J Microbiol

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Pigs offer an unlimited source of xenografts for humans. The use of transplants from animal origin offers a potential solution to the limited supply of human organs and tissues. However, like many other mammalian species, pigs harbor porcine endogenous retrovirus (PERV), which are encoded in their genomic DNA and are assumed to have been integrated into the porcine germline. The ability of PERV to infect human cells in vitro has heightened safety concerns regarding the transmission of PERV to pig xenograft recipients. Porcine tissues were analyzed using validated assays specifi c for PERV: polymerase chain reaction (PCR) (for PERV DNA) and reverse transcriptase (RT)-PCR (for PERV RNA). PERV-specifi c gag sequences were found in the porcine heart tissue samples using DNA-PCR and RT-PCR. PCR is a rapid and specifi c test for the detection of PERV from xenografts. These fi ndings have demonstrated that the presence of both DNA and RNA forms of PERV in porcine tissues needs to be carefully considered when the infectious disease potential of xenotransplantation is being assessed.

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Treatment of Hepatic Failure with ex Vivo Pig-Liver Perfusion Followed by Liver Transplantation

Cited by 275 publications

References 7 publications

Membrane barrier of a porcine hepatocyte bioartificial liver

Membrane barrier of a porcine hepatocyte bioartificial liver

Intrahepatic amino acid and glucose metabolism in a ?-galactosamine–induced rat liver failure model

Polymerase chain reaction in detection of porcine endogenous retrovirus (PERV) from porcine tissues

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