FK 506 associated disorders in liver transplantation

Transplantation Proceedings

We recently reported our initial experience with FK 506 in 36 patients undergoing renal transplantation. 1 This series was characterized by a high average complexity, and included 10 patients who also were liver recipients either concomitantly or at an earlier time. Additionally, 2 of the 10 also were given a heart or pancreas.

Transplantation proceedings, 1991

FK 506 has established itself as a promising immunosuppressive drug in organ transplantation and in the treatment of autoimmune disease. Therapeutic monitoring of plasma concentrations of FK 506 is essential to ensure appropriate dosage for adequate immunosuppression and to minimize potential side effects. Routine monitoring of FK 506 plasma concentration is performed with an enzyme-linked immunoassay (ELISA) previously developed by Tamura et al 1 and modified by Cadoff et al.2 Plasma FK 506 levels also have been measured with an in vitro bioassay.3 This assay is based on the inhibition of the alloantigen driven proliferation of cloned alloreactive T cells. These activated lymphocytes show a narrow sensitivity range to FK 506 and the IC50 is 0.07 to 0.12 nmol/L. In liver allograft recipients. the FK 506 levels as determined by bioassay are consistently lower than those measured by ELISA (Fig 1). These results suggest that the plasma may contain biologically less active FK 506 metabolites, which can be detected by ELISA.

JAMA: The Journal of the American Medical Association, 1990

The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81 %) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation. Encouraging clinical trials in liver transplantation have been reported with the new immunosuppressive agent FK 506, 1-3 which is produced by the fungus Streptomyces tsukubaensis. 4,5 Although the molecular structure of FK 506 is unrelated to cyclosporine and has a different cytosolic binding site, 6,7 the two drugs have similar effects on the immune system. 8,9 We report here a trial of FK 506 in kidney recipients, of whom the majority had complex clinical problems or were at high risk because of adverse medical or immunologic factors. METHODS Recipient Case Material Complexity factors in the 36 patients included concomitant or prior liver transplantation (29%), previous kidney transplantation (29%), and causes of renal failure that increase the risk of transplantation (Table 1). The only child in the series (10 years old) had hemolytic uremic syndrome. Hemolytic uremic syndrome is a known complication of cyclosporine use 10 that has been treated successfully with FK 506.11 Five patients were older than 60 years.

Transplantation proceedings, 1991

No group of patients is likely to benefit more by improvements in immunosuppression than the pediatric transplant recipients who face lifelong treatment. The advent of cyclosporine (CyA) has transformed liver transplantation into the preferred treatment modality for chronic liver failure. 1 Its effect on pediatric liver transplantation was profound, allowing for acceptable patient and graft survival when used with steroids at a fraction of the dose necessary under previous immunosuppressive regimens. 2-8 Complications included renal toxicity, hypertension, gum hyperplasia, hirsutism, and an uncommon but very troubling syndrome of facial disfigurement. FK 506, a new immunosuppressive agent derived from Streptomyces tsukubaensis, was first shown to be efficacious in experimental 9 and clinical primary liver transplantation, 10-12 and also in reversing rejection in patients who failed CyA treatment. 13 Additional indications for use in pediatrics were its apparent simplicity of use, low toxicity, and independence from adjuvant steroid therapy. 9-14 This report summarizes our clinical experience with FK 506 from a prospective study of children who underwent primary liver transplantation at the Children's Hospital of

Organ Transplantation 1990, 1991

Transplantation, 1995

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/ prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8 ± 13.7 years (range 17.6-78). The mean donor age was 34.0 ± 20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 ± 8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22 ± 4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P = ns compared with double therapy), and a one-year actual graft survival of 82% (P < 0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P < . 07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8 ± 0.8 mg/dl. The mean BUN was 33 ± 21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192 ± 49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus-14%; new-onset diabetes-16% (half of which was reversible); and posttransplant lymphoproliferative disorder-1%. There was a high incidence of crossover between the two groups, 27% of the patients in the double therapy group requiring the addition of azathioprine, and 45% of the patients in the triple therapy group requiring its discontinuation (usually temporary). These results show that FK506 is an excellent immunosuppressive agent after renal transplantation and that azathioprine is not routinely effective 1

Transplantation proceedings, 1991

In the transplant populations and patients with autoimmune diseases, the quality of liver function significantly influences FK 506 doses, drug trough plasma levels, and kidney function. The interrelationship of these variables has been previously discussed in patients with different kinds of organ transplantation. 1 In this report, however, we will concentrate only on liver recipients with different degrees of graft dysfunction, particularly in the perioperative period. From this study, a better understanding has been achieved of FK 506 management strategy in patients with variable quality of liver function.

Transplantation proceedings, 1991

We have reported encouraging clinical trials with a new immunosuppressive agent called FK 506, 1-3 which is a macrolide antibiotic produced by the fungus Streptomyces tsukubaensis. 4 The molecular structure of FK 506 is unrelated to cyclosporine (CyA), and the two drugs have different cytosolic binding sites. 5, 6 However, both drugs inhibit T-lymphocyte activation, in part by suppressing the synthesis and expression of the cytokine interleukin 2.4 , 7 ,8 Both drugs appear to be potent suppressors of T-cell function, although FK 506 accomplishes equal immunosuppression at levels 100 times less than that of CyA. The first clinical use of FK 506 was preceded by extensive in vitro and in vivo studies.

Transplantation proceedings, 1991