Effect of FK506 in experimental organ transplantation.

FK506 is the most potent immunosuppressive agent known. Its toxicity is substantial in dogs, minor in rats, and unknown in subhuman primates. In small doses that are nontoxic even in dogs, it can be used in synergistic combination with cyclosporine, steroids, and presumably in other drugs

Orthotopic liver transplantation in dogs receiving FK-506.

Ten dogs that survived the perioperative events of liver transplantation were treated with 1 mg/kg/d oral FK. Eight of the recipients lived for at least 1 month postoperatively, and seven are still alive with normal hepatic function after 35 to 65 days. The consistency and good quality of results with this difficult transplant preparation using FK, in spite of its rumored great toxicity in dogs, have highlighted the importance of further developing the drug

Immunosuppression of canine, monkey, and baboon allografts by FK 506: With special reference to synergism with other drugs and to tolerance induction

In dogs the most effective oral dose of FK 506 for prevention of renal homograft rejection was 1.5 mg/kg/day. With maximum credit allowed at 90 days, survival was increased to 61.0 ± 33.6 (SD) days compared with 13.0 ± 4.1 in untreated control animals. Higher doses were toxic. The smallest dose that was used (0.5 mg/kg/day) prolonged survival after renal transplantation to 33.7 ± 23.9 (SD) days. When the small dose of FK 506 was combined with 5 mg/kg/day of cyclosporine and 5 mg of prednisone, five of six canine kidney recipients lived for 90 days. These results were degraded by omission of any of the constituent drugs or reduction by half of the triple drug doses. Thirteen of the dogs treated with various drug regimens lived for 90 days, after which time treatment was stopped; 10 of the dogs eventually rejected the grafts, but three had continued graft junction for 6 months or longer and may be permanently tolerant. Moreover, in dogs when 1 mg/kg of intramuscular FK was given to 19 kidney and seven liver recipients for 3 days on postoperative days 1 to 3, 4 to 6, or 7 to 9, the animals survived subsequently for 11 to more than 160 days. All but four of the grafts were eventually rejected, but the prolonged effect of a short course of delayed therapy suggests the possibility of tolerance induction. In cynomolgus monkeys and baboons, FK as a single drug was found to be immunosuppressive after kidney transplantation. Correlation in the dogs and primates between immunosuppression, toxicity and FK blood levels was not possible because of presently imperfect standardization of assay and monitoring techniques. FK had serious side effects in dogs, but not so obviously in monkeys and not at all in baboons

Liver transplantation before 1 year of age

Since 1981, 20 infants younger than 1 year of age received 26 orthotopic liver transplants. Immunosuppression was with cyclosporine and corticosteroids. Thirteen (65%) of the reciplents were discharged from the hospital. To date, 12 (60%) of the 20 reciplents are surviving, with follow-up of 1 to 56 months (average 14 months). The 5-year acluarial survival is 53.8%. The allograft liver function in the majority of surviving infants is excellent. The predominant causes of mortality were primary nonfunction of the allograft (three patients) and sepsis (three). Major morbidity was caused by hepatic artery thrombosis (five patients), gastrointestinal complications (six), biliary tract complications (five), and bacterial and viral infections (13). Six patients underwent retransplantation; three of these six survived. Results could be improved by prevention of hepatic artery thrombosis, by decreasing the incidence of sepsis, and by procurement of more and better suited pediatric donors. © 1987 The C. V. Mosby Company

Indications for pediatric liver transplantation

Two hundred fifty pediatric (<18 years of age) patients underwent orthotopic liver transplantation because of end-stage liver disease and were given combination therapy with cyclosporine and prednisone. The most common indications for transplantation in decreasing order of frequency were biliary atresia, inborn errors of metabolism, and postnecrotic cirrhosis. The 5-year actuarial survival for the entire group was 69.2%. Age and diagnosis did not influence survival. Infections were the most common cause of death, followed by liver failure and cerebrovascular accident. The impact of retransplantation on survival depends on the indication. The survival is better when retransplantation is carried out after rejection than because of technical complications, and the latter has a better survival than does primary graft nonfunction. The difference in survival among these groups is statistically significant. The quality of life for 164 of 173 survivors is good to excellent; only nine children are currently experiencing medical problems. A persistent problem in pediatric transplantation is the scarcity of small donors. © 1987 The C. V. Mosby Company

A new liver perfusion and preservation system for transplantation Research in large animals

A kidney perfusion machine, model MOX-100 (Waters Instruments, Ltd, Rochester, MN) was modified to allow continuous perfusion of the portal vein and pulsatile perfusion of the hepatic artery of the liver. Additional apparatus consists of a cooling system, a membrane oxygenator, a filter for foreign bodies, and bubble traps. This system not only allows hypothermic perfusion preservation of the liver graft, but furthermore enables investigation of ex vivo simulation of various circulatory circumstances in which physiological perfusion of the liver is studied. We have used this system to evaluate the viability of liver allografts preserved by cold storage. The liver was placed on the perfusion system and perfused with blood with a hematocrit of approximately 20% and maintained at 37°C for 3 h. The flows of the hepatic artery and portal vein were adjusted to 0.33 mL and 0.67 mL/g of liver tissue, respectively. Parameters of viability consisted of hourly bile output, oxygen consumption, liver enzymes, electrolytes, vascular resistance, and liver histology. This method of liver assessment in large animals will allow the objective evaluation of organ viability for transplantation and thereby improve the outcome of organ transplantation. Furthermore, this pump enables investigation into the pathophysiology of liver ischemia and preservation. © 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Canine kidney transplantation with FK-506 alone or in combination with cyclosporine and steroids.

The immunosuppressive agent FK permitted increased kidney transplant survival in dogs over a wide dose range, but with weight loss and manifold evidence of toxicity. The best use of FK at low doses was in combination with CyA and Pred

Isolation and primary cultures of human intrahepatic bile ductular epithelium

A technique for the isolation of human intrahepatic bile ductular epithelium, and the establishment of primary cultures using a serum- and growth-factor-supplemented medium combined with a connective tissue substrata is described. Initial cell isolates and monolayer cultures display phenotypic characteristics of biliary epithelial cells (low molecular weight prekeratin positive; albumin, alphafetoprotein, and Factor VIII-related antigen negative). Ultrastructural features of the cultured cells show cell polarization with surface microvilli, numerous interepithelial junctional complexes and cytoplasmic intermediate prekeratin filaments. © 1988 Tissue Culture Association, Inc

Liver transplantation today

In summary, liver transplantation has truly come of age. To put things in perspective, the recipient waiting list at the University of Pittsburgh never includes fewer than 200 suitable candidates, and it continues to grow in spite of the fact that we are now doing essentially one transplant per day. There are many excellent transplant centers throughout the United States and Europe, the only limiting factor being the supply of donors. Orthotopic liver transplantation is now covered by most major health insurance carriers, and some form of government coverage is anticipated for the indigent. As the supply of donors increases with aggressive education programs, the need for transplantation centers will also increase. However, this should not be uncontrolled growth. Mandatory training in transplantation surgery will surely be required as a prerequisite to the establishment of transplant centers in the future. The field of organ transplantation is the newest and most dynamic in medicine today. The results are encouraging and acceptable and offer the only hope to many persons dying of end-stage organ failure. With improvements in immune modulation at hand, organ transplantation will soon become a commonplace procedure offering a completely normal life expectancy