Conversion of liver allograft recipients with cyclosporine related complications from cyclosporine to FK 506

Abstract

W ITH the use of Cy A for clinical liver transplantation, I-year survival rates have approached 70%.Nevertheless, allograft rejection continues to be the most common cause of retransplantation and death.Clinical rejection occurs in 70% ofliver allograft recipients on CyA and steroid therapy. 1 In addition, nephrotoxicity is the principal and dose-limiting side effect of Cy A. Chronic renal damage and functional impairment have been shown to occur in 87.4% of liver transplant patients, 2 and hypertension is an almost universal complication.Antihypertensive therapy is required in the majority of these patients.Alterations in clinical immunosuppression to prevent or reverse these and other side effects have included (1) reduction of Cy A dose or (2) addition of azathioprine, antilymphocyte antibodies (ALG), or other agents with concomitant reductions in the Cy A dose.These methodologies have their inherent dangers: increasing susceptibility to rejection and increased susceptibility to infection, respectively.FK 506 is a potent and novel immunosuppressive agent, discovered in Japan less than 4 years ago.3 -5 Much is known about FK 506: in vivo studies of the effectiveness of FK 506 in several allograft models in rats, dogs, and baboons;6-16 as well as in vitro studies of the properties of FK 506, its mechanisms of action, and its intrinsic cytotoxicity have been documented.3-6,17,18 Both in vitro and in vivo synergism of FK 506 with other immunosuppressive drugs has been demonstrated and, for this reason, it was planned to give the first human patients a combination of FK 506 and CyA.A phase IIII trial of FK 506 was conducted with the approval of the University of Pittsburgh Institutional Review Board and the FDA in 1989.The plan was to give FK 506 to patients who were rejecting their liver grafts, in spite of conventional immunosuppression.19 The protocol was to initially combine low doses of FK 506 with CyA.This was attempted in the first 11 patients.As will be described, this combination was accompanied by a number of adverse reactions.Eventually, a simple switch (clean conversion) was made from CyA to FK 506.The following is an account of the first 40 liver transplant recipients entered into this pilot study. PATIENTS AND METHODS Patient ProfilesNineteen patients were females and 21 were males, ranging from 5 to 74 years of age.The original liver diseases and dates of liver transplants are noted in Table J.