FK 506 for Liver, Kidney, and Pancreas 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.

Clinical …, 1993

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

Early reports on the use of FK 506 after kidney transplantation emphasized the ability to stop prednisone in a significant percentage of successfully transplanted patients. 1,2 In addition, there was a relative freedom from antihypertensive agents and a tendency toward low serum cholesterol levels. This report will summarize our experience to date with FK 506 in renal transplantation and will compare the results with a nearly concurrent group of patients treated with cyclosporine (CyA)-based immunosuppression. MATERIALS AND METHODS Between March 27, 1989, the date of the first kidney transplant under FK 506 immunosuppression, and May 1, 1991, 464 kidney transplantations were performed at the University of Pittsburgh. Of these 28 were in patients who had received concomitant or previous liver transplants, and these were the only exclusions from the analysis. Of the 436 transplants in 425 patients, 196 received CyA-based immunosuppression; over 80% of this group received azathioprine as well (Table 1). Some 240 cases were treated with FK 506 and steroids. The mean recipient age was 39.5 ± 14.9 years; 44 (10.1%) of the cases were performed in patients over 60 years of age, and 31 (7.1%) of the transplants were to children. Sixty (13.7%) of the cases involved black recipients. There was a significantly higher incidence of retransplantation in the FK 506 group-over 30% of the FK 506 cases were to patients undergoing their second to fifth transplant, whereas just under 20% of the CyA cases were retransplants (P <.005). Over 25% of the transplants were to sensitized recipients. A higher percentage of living-donor cases were done under CyA-14.3% vs 5% of the FK 506 cases (P < .02). The mean donor age was 34.0 ± 16.6 years; 73 (18.4%) of the cadaver transplants were with pediatric en bloc kidneys. The mean cold ischemia time was 36.3 ± 10.6 hours. HLA matches and mismatches revealed a small number of good matches, with less than 2% of cases being 6-antigen matches and nearly two-thirds of cases having a 2-antigen match or less. There was thus no attempt to be particularly discriminating in either donor or recipient selection. The FK 506 cases were actually a higher-risk group than was the CyA groupmore retransplants, fewer living donor cases, slightly more sensitized patients, and en bloc kidneys. This had the effect of subjecting FK 506 to a rather stringent evaluation.

PubMed, 1990

Journal of Gastroenterology and Hepatology, 1992

Immunosuppressive regimens are usually required for patients receiving organ transplants. The development of a post-transplant lymphoproliferative disorder is an infrequent complication of such therapy. FK 506 is a new immunosuppressant agent that has recently been used in patients receiving organ transplantation. This report describes a 20 month old Saudi child who developed post-transplant lymphoproliferative disorder while receiving FK 506 following liver transplantation. Such a complication has been recognized with cyclosporine but has not been well addressed as yet with FK 506. The child also developed progressive renal complications. There was also a difficulty in interpreting the results for IgM antibodies to different viruses. The overall features of progressive renal toxicity and those of lymphadenopathy, hepatosplenomegaly, fever, neutropenia and thrombocytopenia reversed following discontinuation of FK 506 therapy. It is concluded that all the above complications, though reversible, may well be linked to the new immunosuppressant agent FK 506.

Transplantation proceedings, 1995

Transplantation proceedings, 1991

PubMed, 1994

Previous clinical evaluation of FK506 in renal transplantation has demonstrated equivalent patient and graft survival when compared with cyclosporine-based regimens. However, lower steroid and anti-hypertensive mediation requirements and lower serum cholesterol levels have been seen in patients receiving FK506. In August, 1991, a prospective, randomized trial was begun, comparing FK506/prednisone with FK506/azathioprine/prednisone. Two-hundred-and-four adults were entered into this trial between August 1, 1991, and October 11, 1992. The mean recipient age was 43.8 +/- 13.7 years, with a range of 17.6-78.0 years. Sixty-one (30%) recipients received a 2nd, 3rd or 4th transplant, while 35 (17%) had a PRA greater than 40% at the time of transplant. Thirty-three (16%) of the transplants were in recipients over 60 years of age, Thirteen percent of the kidneys were from living donors; 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 hours, and the mean donor age was 34 +/- 2.10 years, with a range from 4 months to 75 years. With a mean follow-up of 9 +/- 4 months, the 1-year actuarial patient survival is 93%; for the two-drug group it is 95%, and for the three-drug group it is 91% (p = NS). One-year actuarial graft survival is 86%; in the two-drug group it is 90%, while in the three-drug group it is 82% (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

PubMed, 1991

Formal studies have not been published on the nephrotoxicity of FK 506 when the drug was used from the outset. This kind of information was sought in 101 recipients of primary livers, 24 hearts, and 3 double lungs or heart-lung. Perioperative renal dysfunction was commonly seen, which appeared to be related to FK 506 doses and plasma levels, particularly when the drug was given IV. This was reversible. Late renal function has been generally satisfactory in all three cohorts of patients, and the incidence of hypertension has been low. The therapeutic index of FK 506 is a good one, as revealed by these observations in patients whose most notable achievement was a low mortality.

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.

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

Transplant International, 1994

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i. e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.