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Introduction Multivisceral transplantation includes the simultaneous transplantation of multiple abdominal viscera including the stomach, duodenum, pancreas, and small intestine, with (multivisceral transplant, MVT) or without the liver (modified MVT, MMVT). This study reviews the changing indications and outcomes for this procedure over a 7-year period at a university medical center. Methods This study is a retrospective case review of MVTs performed between 2004 and 2010 at a single center. All cases were either MVT or MMVT and included a simultaneous kidney transplant, if indicated. Graft failure was defined as loss of the graft or complete loss of function. Graft function was monitored by clinical function, laboratory values, and serial endoscopy with biopsy. Results During the study period, 95 patients received 100 transplants including 84 MVT and 16 MMVT. There were 19 patients who received a simultaneous kidney graft. There were 24 pediatric and 76 adult recipients (range 7 months to 66 years). Indications included intestinal failure alone, intestinal failure with cirrhosis, complete portal mesenteric thrombosis, slow-growing central abdominal tumors, intestinal pseudoobstruction, and frozen abdomen. All patients received antibody-based induction immunosuppression with calcineurin inhibitor-based maintenance immunosuppression. At a median mortality adjusted follow-up of 25 months, 1- and 3-year patient survival is 72 % and 57 %. There was a learning curve with this complex procedure resulting in a 48 % patient survival during the period from 2004 to 2007, followed by a 70 % patient survival during the period from 2008 to 2010. Post-transplant complications included rejection (50 % MMVT and 17 % MVT), infection (>90 % first year), graft versus host disease (13 %), and post-transplant lymphoproliferative disorder (5 %). Conclusion Indications for MVT and MMVT have broadened to include patients with terminal conditions not amenable to other medical therapies such as slow-growing tumors of the mesenteric root, complete portomesenteric thrombosis, and abdominal catastrophes/frozen abdomen. Outcomes have improved over time with many patients returning to full functional status and enjoying long-term survival.

The future of solid organ transplantation is challenged by an increasing shortage of available allografts. Xenotransplantation of genetically modified porcine organs offers an answer to this problem. Strategies of genetic modification have ‘humanized’ the porcine model towards clinical relevance. Most notably, these approaches have aimed at either antigen reduction or human transgene expression. The object of this study was to evaluate the relative effects of both antigen reduction and direct complement regulation on the human-anti-porcine complement dependent cytotoxicity response. Genetically modified animals were created through CRISPR/Cas9-directed mutation and human transgene delivery. Pigs doubly deficient in GGTA1 and CMAH genes were compared to pigs of the same background that expressed a human complement regulatory protein (hCRP). A third animal was made deficient in GGTA1, CMAH and B4GalNT2 gene expression. Cells from these animals were subjected to measures of human antibody binding and antibody-mediated complement-dependent cytotoxicity by flow cytometry. Human IgG and IgM antibody binding was unchanged between the double knockout and the transgenic hCRP double knockout pig. IgG and IgM binding was reduced by 49.1 and 43.2 % respectively by silencing the B4GalNT2 gene. Compared to the double knockout, human anti-porcine cytotoxicity was reduced by 8 % with the addition of a hCRP ( p  = .032); It was reduced by 21 % with silencing the B4GalNT2 gene ( p  = .012). Conclusions: Silencing the GGTA1, CMAH and B4GalNT2 genes in pigs achieved a significant antigen reduction. Changing the porcine carbohydrate profile effectively mediates human antibody-mediated complement dependent cytoxicity.

Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.

Acute liver failure (ALF) is an uncommon disorder that leads to jaundice, coagulopathy, and multisystem organ failure. Its definition is based on the timing from onset of jaundice to encephalopathy. In 2005, ALF accounted for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the United States. Several classification systems have been developed for ALF, with the King's College criteria most widely used for prediction of OLT. Specific diagnostic tests should be implemented to identify the cause of ALF, which will help to determine its treatment and prognosis. Viral hepatitis was previously reported to be the most common cause of ALF in the United States, but acetaminophen overdose and idiosyncratic drug reactions have emerged as the most frequent causes in recent studies. Malignancy is an uncommon cause of ALF, and thus imaging studies may not be useful in this setting, but liver biopsy may be beneficial in selected cases. An overall strategy for ALF should start with identifying the cause, assessing the prognosis, and early transfer to a transplantation center for suitable candidates. OLT has emerged as a life-saving procedure leading to marked improvement in survival rates. Improved surgical techniques, immunosuppression, and comprehensive care have led to an overall survival rate of approximately 65% with OLT. N-acetylcysteine is effective in ALF caused by acetaminophen overdose, with results strongly related to how soon it is given rather than the route of administration. Liver support systems show potential for the treatment of ALF, but their role needs validation in large multicenter randomized trials.

Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/- transgenic for human CD46, is associated with survival of approximately 7-9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a 'bridge' to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application.

Liver xenotransplantation could eliminate the liver donor shortage, but currently it is not possible because of a lack of understanding of liver xenograft rejection. Hyperacute xenograft rejection is initiated by the binding of preformed naturally occurring xenoreactive antibodies (XNA) to the xenograft endothelium. The XNA bind to the xenograft endothelium, leading to complement-mediated endothelial injury. Liver xenotransplantation will be initially offered to patients with severe liver failure as a bridge to a human liver transplantation. The hypothesis tested in this thesis is that hyperacute rejection of liver xenografts placed into recipients with liver failure will be diminished because of the complement deficiency that accompanies liver failure. The experiments described in this thesis detail the development of an in vitro pig-to-human liver xenotransplant model incubating cultured pig hepatic endothelial cells (PHEC) and human serum in culture. We showed that either classical or alternative complement pathways could initiate endothelial injury. Next we developed the dog-to-pig liver xenograft model and characterized the lethal coagulopathy that results from hyperacute rejection. The coagulopathy results from the lack of function of platelets as well as their disappearance from the circulation. We then used the galactosamine induced liver injury model in porcine recipients of canine liver xenografts to demonstrate that hyperacute rejection in the setting of liver failure is diminished. We showed that; tissue injury, coagulopathy and platelet defect, and endothelial injury were diminished. Our experiments suggested that the cause of the decreased injury was the lack of complement in the pigs with galactosamine induced liver injury since the XNA levels were no different than in control animals. Our final experiments evaluated serum from patients with liver failure and compared the injury caused by incubation with PHEC. Serum from the liver failure patients had similar levels of XNA when compared with normal subjects, but had less complement activity, and less C3 and C4. Incubation of liver failure serum with PHEC caused much less injury and complement activation than serum from control subjects. The results in this thesis suggest that liver failure will have a significant impact on liver xenograft rejection, helping to diminish hyperacute rejection.