Cadaveric domino liver transplantation: the first case in Japan.

The first case of domino liver transplantation from a brain-dead donor in Japan is described. A 49-year-old man with familial amyloidotic polyneuropathy received a cadaver liver, and his native liver was transplanted into a 53-year-old man with polycystic liver and kidney disease. The cadaveric liver allograft was transplanted by the conventional technique. The graft taken from the first recipient had four outflow orifices (the left, middle, and right hepatic veins, and upper vena cava), for which a single orifice was created at the back table. This graft was transplanted in piggy-back fashion. The first recipient developed acute rejection on day 13 and hepatic artery stenosis on day 36. These were treated by steroid recycle therapy and percutaneous transarterial angioplasty. He was discharged on day 57 with normal liver function. The second recipient underwent re-operation for bleeding from the right adrenal gland and left thoracic cavity. He was diagnosed with acute rejection on day 7, which was treated by steroid pulse therapy. He was discharged uneventfully on day 39 with normal liver function.

A new immunosuppressant, FTY720, in canine kidney transplantation: effect of single-drug, induction and combination treatments.

Three different types of treatment were conducted to clarify the properties of a novel immunomodulator, FTY720, in canine kidney allograft models. Survival, biochemical and hematological tests, pharmacokinetics, and histopathology of grafts and extra-renal organs were analyzed. Accompanying a remarkable reduction in circulating lymphocytes, single-drug treatment of FTY720, ranging from 0.05 to 10 mg/kg, exhibited significant prolongation of graft survival without a dose-dependent effect. Short-course induction with FTY720 at 5 mg/kg per day exhibited similar anti-rejection effects as did single-drug treatment but no advantage in rescuing ongoing rejection. In combination with cyclosporine (CsA; 5 mg/kg) or tacrolimus (FK; 0.5 mg/kg), FTY720 had an additive effect. Trough blood concentrations of FTY720 were linearly correlated with dose. No animal showed critical adverse effects at any point. FTY720 holds promise as a candidate in a new category of drugs that can be combined with conventional agents for induction and maintenance immunosuppression in clinical organ transplantation.

[Liver regeneration in living-donor liver transplantation].

Liver regeneration in living-donor liver transplantation is summarized from the authors' data. In donors, liver function tests recovered to within the normal range 2 weeks after surgery regardless of graft type. At 2 weeks, the volumetric recovery of the remnant liver was 65% and 80% of the original volume in right and left lobe donors, respectively. These results suggest that functional recovery occurs earlier than morphologic restoration in donors. In recipients, the factor that affected the regeneration rate in size 4 weeks after transplantation was only implanted graft size; the rate was greater in patients in whom smaller grafts were implanted. In recipients with a rate of two or more, however, high portal vein pressure and flow were observed. Further, persistent low platelet counts and hyperbilirubinemia were seen in those patients. These results indicate that size enlargement may be caused by engorgement, and functional recovery is not achieved concurrently with morphologic restoration, especially in patients with smaller grafts. In patients with fulminant hepatic failure who receive auxiliary partial orthotopic liver transplantation, sequential histopathologic observations of the diseased liver revealed that liver regeneration initiates from cytokeratin 17-positive ductules and at least 1 year is necessary for complete recovery.

Dipyridamole protects the liver against warm ischemia and reperfusion injury.

BACKGROUND: Adenosine, a metabolite of adenosine triphosphate degradation during ischemia, is reported to attenuate ischemia and reperfusion injury in several tissues. Dipyridamole is a nucleoside transport inhibitor that augments endogenous adenosine. In this study, we tested whether dipyridamole would attenuate hepatic I/R injury. For this purpose, dipyridamole was applied to a 2-hour total hepatic vascular exclusion model in dogs. STUDY DESIGN: Dipyridamole (DYP) was given by continuous intravenous infusion for 1 hour before ischemia at a dose of 0.25 mg/kg (high-DYP, n = 6), 0.1 mg/kg (medium-DYP, n = 6), or 0.05 mg/kg (low-DYP, n = 6). Nontreated animals were used as ischemic controls (CT, n = 12). Two-week survival, systemic and hepatic hemodynamics, liver function tests, energy metabolism, adenosine 3', 5'-cyclic monophosphate (cyclic AMP) levels, platelet numbers, arachidonic acid metabolites, and histopathology were analyzed. RESULTS: Two-week animal survival was 25% in CT, 17% in high-DYP, 100% in medium-DYP, and 17% in low-DYP. Dipyridamole significantly improved postreperfusion hepatic blood flow and energy metabolism, attenuated liver enzyme release and purine catabolite production, and augmented cyclic AMP levels. The medium dose of dipyridamole lessened platelet aggregation, thromboxane B2 production, and polymorphonuclear neutrophil infiltration, and improved survival. CONCLUSIONS: We demonstrated marked hepatoprotective effects of dipyridamole against severe ischemia and reperfusion injury in canine livers. Dipyridamole is a promising agent for liver surgery and transplantation.

A novel inhibitor of Rho-associated protein kinase, Y-27632, ameliorates hepatic ischemia and reperfusion injury in rats.

BACKGROUND: A Rho-ROCK signal system induces vascular contraction and neutrophil migration, both of which are characteristic features found with ischemia and reperfusion injury of the liver. We tested our hypothesis that a novel ROCK I inhibitor, Y-27632, attenuates hepatic ischemia and reperfusion injury. METHODS: Rats underwent 70% partial hepatic ischemia for 120 minutes and subsequent reperfusion. Y-27632 of 10mg/kg was given orally 1 hour before ischemia, while distilled water was given to the control animals. One week animal survival, systemic hemodynamics, hepatic tissue blood flow, liver function tests, plasma endothelin-1, serum hyaluronic acid levels, myeloperoxidase activity and malondialdehyde level in liver tissue, membrane attack complex-1 and intracellular adhesion molecule-1 staining, and histological architecture were analyzed. RESULTS: Y-27632 prolonged 1-week animal survival from 25% of untreated animals to 75% accompanied with significant amelioration of hepatic tissue blood flow, liver function tests and histological architecture without any adverse effects on systemic hemodynamics. In addition, plasma endothelin-1 and serum hyaluronic acid levels decreased markedly compared to the control, concomitant with remarkable suppression of membrane attack complex-1 stain positive neutrophils infiltration, myeloperoxidase activity and malondialdehyde level. CONCLUSION: Present study suggests that activation of a Rho-ROCK signal system is associated with ischemia and reperfusion injury of the liver, and that Y-27632 may be an attractive agent for application in major liver resection using temporary inflow occlusion and hepatic preservation.

A novel leflunomide derivative, FK778, for immunosuppression after kidney transplantation in dogs.

BACKGROUND: Leflunomide and its metabolite, A77 1726, interfere with pyrimidine metabolism and exert potent immunosuppression in experimental organ transplantation. However, clinical use of the agents has been restrained because of an extended half-life. FK778, one synthetic malononitrilamide derived from A77 1726, is synthesized to overcome this problem while maintaining similar therapeutic efficacy. METHODS: Immunosuppressive effect, pharmacokinetics, and adverse events of FK778, as a single drug treatment or combination with tacrolimus or cyclosporine, were determined in a canine kidney transplantation model. The agents were daily administered orally to the animals for 90 days after surgery. Animal survival, pharmacokinetics, biochemistry, hematology, and histopathology were evaluated. RESULTS: FK778 at 4 mg/kg prolonged median survival of the control animals from 10 days to 30.5 days. Administration of 4 mg/kg FK778 with 0.3 mg/kg tacrolimus or 10 mg/kg cyclosporine increased median survival to 75.5 days and 50.5 days, respectively. In combined treatments, trough levels of FK778 at 4 mg/kg ranged between 40 microg/mL and 100 microg/mL after 1 month. Vomiting and diarrhea were common in animals given FK778. Bone marrow suppression was seen at higher doses. CONCLUSIONS: FK778 is a promising new immunosuppressant that may be used in combination with current standard drugs in organ transplantation.

Role of cyclic nucleotides in ischemia and reperfusion injury of canine livers.

BACKGROUND: In a series of canine liver ischemia experiments, we have shown that amelioration of hepatic injury is achievable by the inhibition of vasoconstriction, cytokine production, platelet aggregation, and neutrophil infiltration. Cyclic adenosine diphosphate (cAMP) was considered to be involved in most of these events. In our study, we tested our hypothesis that augmentation of endogenous cAMP by phosphodiesterase (PDE) 3 inhibitor, amrinone (AM), or adenylate cyclase stimulator, NKH477 (NKH), could attenuate ischemia and reperfusion injury of the liver. METHODS: Thirty-six beagle dogs were used. They were divided into group CT (untreated control), group AM, group NKH, and group CB (treated by both agents). AM or NKH were administered i.v. 1 hr before ischemia (group preAM and group preNKH) or 15 min before reperfusion (pos-AM and postNKH). Combination group animals were treated only before ischemia. Animal survival, hepatic tissue blood flow, liver enzymes, platelet counts, energy metabolism, hepatic cAMP and cyclic guanosine 3',5'-cyclic monophosphate levels, and histopathology were analyzed. RESULTS: Two-week animal survival was significantly improved by pre- or posttreatment with either agent. After reperfusion, hepatic tissue blood flow, liver enzyme release, platelet counts, energy metabolism, tissue cAMP levels, and histological architecture were also ameliorated markedly. Combination of both agents induced severe liver damage and lethal hypotension. AM treatment exhibited more protective effects than NKH, particularly when it was given before ischemia. Interestingly, not only cyclic guanosine 3',5'-cyclic monophosphate, were also restored at higher levels after reperfusion by preischemia treatment. CONCLUSIONS: Administration of amrinone or NKH477 maintained hepatic tissue concentrations of cyclic nucleotides, and attenuated ischemia and reperfusion injury of the liver. Thus, regulation of hepatic tissue cyclic nucleotides is an important alternative for prevention of hepatic damage in liver preservation and surgery.