17 The first Denver successes were bolstered

by the opening in 1968 of a second clinical liver program by Roy Calne in Cambridge, England,133 following preclinical studies in outbred pigs.21,134 The early trials were described in my 1969 book titled, “Experience Selleck Raf inhibitor in Hepatic Transplantation”,22 based on our first 25 human liver replacements and eight performed elsewhere (four by Calne). Collateral support was provided with the use of the same immunosuppression regimen for the first successful human heart, lung, and pancreas transplantations (Table 5).135-137 However, the promise of the nonrenal procedures, and even of deceased donor kidney transplantation, was unfulfilled for the next 12 years because of immunosuppression-related

morbidity and mortality. Half or more of the liver recipients treated during this time died within the first Depsipeptide post-transplant year. The most encouraging observation was that many patients who survived to this milestone were quietly compiling years of good health thereafter (Fig. 7).64,155 Despite deepening suspicion that progress in the whole field of organ transplantation had permanently stalled, the new French and German liver teams of Henri Bismuth and Rudolf Pichlmayr joined the Denver-Cambridge (England) alliance in the early 1970s, followed later in the decade by the Dutch group of Rudi Krom. Much of the medical-scientific, logistic, and administrative framework of hepatic transplantation that exists today was developed by the five mutually supportive liver centers during the frustrating period between 1969

and 1979. Most of the indications for liver transplant candidacy see more were obvious, including inheritable disorders with a definitive biochemical explanation (e.g., Wilson’s disease23). The acid test of liver transplantation ultimately would help elucidate the mechanisms or pathophysiology of less well-understood inborn errors: e.g., the three diseases that were palliated by portacaval shunt (see above). Four patients with alpha-1-antitrypsin deficiency underwent liver transplantation between 1973-1977.138,139 Liver replacement for treatment of glycogen storage disorders,140,141 hyperlipoproteinemia,44, 45 and a growing panoply of other metabolic diseases awaited better immunosuppression. Improvements in therapy were heralded in 1979 by Roy Calne’s report of cyclosporine-based immunosuppression in 34 patients, including two liver recipients.33 The side effects of cyclosporine precluded its use as a single agent. However, when it was substituted for azathioprine in our two-drug or three-drug therapeutic algorithm that included dose-maneuverable prednisone,34 cyclosporine’s full potential was realized. Kidney recipients were the first to be treated, with liver recipients close behind. Eleven of our first 12 liver recipients treated in Colorado with cyclosporine-based immunosuppression during 1979-1980 survived for >1 year.