Randomized trial of FK 506/prednisone vs FK 506/azathioprine/prednisone after renal transplantation: preliminary report.

FK 506 was used as a primary immunosuppressive agent in 125 cases of renal transplantation in a randomized trial comparing FK 506/prednisone with FK 506/azathioprine/prednisone. With a mean follow-up of 5.5 +/- 2.5 months, there has been a 6-month actuarial patient survival of 99% and graft survival of 88%. There is no difference thus far between the two-drug and three-drug groups, although there may be less rejection and diabetes in the three-drug group. These results suggest that FK 506 is a useful immunosuppressive agent in kidney transplantation

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

Improving results of pediatric renal transplantation

BACKGROUND: Outcome after renal transplantation in children has been variable. We undertook a retrospective study of our experience over the past five years. STUDY DESIGN: From January 1, 1988, to October 15, 1992, 60 renal transplantations were performed upon 59 children at the Children's Hospital of Pittsburgh. Twenty-eight (47 percent) of the kidneys were from cadaveric donors, and 32 (53 percent) were from living donors. The recipients ranged in age from 0.8 to 17.4 years, with a mean of 9.8 ± 4.8 years. Forty-six (77 percent) recipients were undergoing a first transplant, while 14 (23 percent) received a second or third transplant. Eight (13 percent) of the patients were sensitized, with a panel reactive antibody of more than 40 percent. Eleven of the 14 patients undergoing retransplantation and seven of the eight patients who were sensitized received kidneys from cadaveric donors. Thirty- three (55 percent) patients received cyclosporine-based immunosuppression, and 27 (45 percent) received FK506 as the primary immunosuppressive agent. RESULTS: The median follow-up period was 36 months, with a range of six to 63 months. The one- and four-year actuarial patient survival rate was 100 and 98 percent. The one- and four-year actuarial graft survival rate was 98 and 83 percent. For living donor recipients, the one- and four-year actuarial patient survival rate was 100 and 100 percent; for cadaveric recipients, it was 100 and 96 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 95 percent for the living donor recipients and 96 and 69 percent for the cadaveric recipients. Patients on cyclosporine had a one- and four-year patient survival rate of 100 and 97 percent, and patients on FK506 had a one- and three-year patient survival rate of 100 and 100 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 85 percent in the cyclosporine group, while one- and three-year actuarial graft survival rates were 96 and 84 percent in the FK506 group. The mean serum creatinine level was 1.24 ± 0.64 mg per dL; the blood urea nitrogen level was 26 ± 13 mg per dL. The incidence of rejection was 47 percent; 75 percent of the rejections were steroid-responsive. The incidence of cytomegalovirus was 10 percent. The incidence of post-transplant lymphoproliferative disorder was 8 percent. None of the patients on cyclosporine were able to be taken off prednisone; 56 percent of the patients receiving FK506 were taken off prednisone successfully. Early growth and development data suggest that the patients receiving FK506 off prednisone had significant gains in growth. CONCLUSIONS: These results support the idea that renal transplantation is a successful therapy for end-stage renal disease in children. They also illustrate the potential benefits of a new immunosuppressive agent, FK506

In vitro immunosuppressive effects of FR 900506 on human T lymphocyte alloactivation

FR 900506 (FR) is a new immunosuppressive drug which prolongs allograft survival. Our studies have compared the in vitro inhibitory effects of FR and cyclosporine (CsA) on human lymphocyte proliferation. Considerably lower doses of FR were required to induce inhibition of lymphocyte proliferation induced by concanavalin A (Con A) stimulation or in primary mixed lymphocyte reactions (MLR). Similar differences between FR and CsA were observed with the secondary stimulation of alloactivated T cells generated in MLR or propagated from liver transplant biopsies. These observations provide further evidence that FR is about 500 fold more potent than CsA and may be a useful immunosuppressive agent in organ transplantation

FK506 IN PEDIATRIC KIDNEY-TRANSPLANTATION - PRIMARY AND RESCUE EXPERIENCE

Between December 14, 1989, and December 17, 1993,43 patients undergoing kidney transplantation alone at the Children’s Hospital of Pittsburgh received FK506 as the primary immunosuppressive agent. The mean recipient age was 10.2 ± 4.8 years (range 0.7–17.4), with 7 (16%) children under 5 years of age and 2 (5%) under 2 years of age. Fifteen (35%) children underwent retransplantation, and 5 (12%) had a panel reactive antibody level greater than 40%. Twenty-two (51%) cases were with cadaveric donors, and 21 (49%) were with living donors. The mean follow-up is 25 ± 14 months. There were no deaths. One and three year actuarial graft survival was 98% and 85%. The mean serum creatinine and BUN were 1.2 ± 0.6 mg/dl and 26 ± 11 mg/dl; the calculated creatinine clearance was 75 ± 23 ml/min/1.73 m(2). Twenty-four (62%) patients have been successfully withdrawn from steroids, and 24 (62%) require no anti-hypertensive medication. Improved growth was seen, particularly in pre-adolescent children off steroids. Between July 28, 1990, and December 2, 1993, 24 children were referred for rescue therapy with FK506, 14.6 ± 16.4 months (range 1.1–53.2) after transplantation. Nineteen (79%) were referred because of resistant rejection; 4 (17%) were referred because of proteinuria; 1 (4%) was switched because of steroid-related obesity. There were no deaths. One and two year graft survival was 75% and 68%. Seventeen (71%) patients were successfully rescued, including 1 of 2 patients who arrived on dialysis. Four (24%) of the successfully rescued patients were weaned off steroids. While not without side effects, which include nephrotoxicity, neurotoxicity, diabetogenicity, and viral complications, FK506 appears to be an effective immunosuppressive agent for both primary and rescue therapy after kidney transplantation. Its steroid-sparing qualities may be of particular importance in the pediatric population

Suppression of allograft rejection with FK506: I. prolonged cardiac and liver survival in rats following short-course therapy

Heterotopic heart and orthotopic liver grafts from ACI donors were transplanted to Lewis rat recipients that were treated with a 3 (or 4) day course of FK506 IM that was started on postoperative day 0, 2, 3, 4, 5, or 6. Hearts, which rejected after a median of 6 days in untreated controls, always had prolonged survival (median 91 days) when treatment was started on postoperative day 4. The results were inferior when treatment was started earlier or later than this, but even when the first dose of FK506 was on postoperative day 5, one day before rejection was imminent in controls, the median survival was 50 days. The poorest results with a median graft survival of only 36 days were obtained when injections were on days 0–3. Results were similar with liver grafts that rejected after a median time of 10 days in nontreated controls but that usually survived permanently after a 3 (or 4) day FK506 course starting on day 0, 2, 3, or 4. Therapy started on day 6 was too late. © 1990 by Williams & Wilkins

Cytomegalovirus infection of the upper gastrointestinal tract following liver transplantation—incidence, location, and severity in cyclosporine- and FK506-treated patients

One hundred and forty randomly selected liver transplant recipients were studied before and after primary orthotopic liver transplantation for the presence or absence of CMV enteritis. Following OLTx, 65 patients were treated with cyclosporine A and 75 were treated with FK506. The two groups were similar with regard to the incidence, location, and outcome of their upper gastrointestinal CMV infection. Prior to OLTx, only one patient had evidence of enteric CMV infection. The incidence of CMV enteritis post-OLTx was 27.7% in the CsA-treated group and 20% in the FK-treated group. During the first posttransplant month, no patient in the FK-treated group developed CMV enteritis, compared with 11.5% of the patients who were treated with CsA (P<0.05). Gastric CMV was found in over 80% of those positive for any organ in either group. In addition to CMV infection of the upper gastrointestinal tract, clinically evident CMV disease involved more nonenteric organs in the CsA-treated group than in the FK-treated group. In the CsA-treated group, CMV-negative patients had a statistically higher 1-year survival rate (100%) than CMV-positive patients (77.8%) (P<0.05). In the FK-treated group, no difference in survival was observed between CMV-positive or CMV-negative cases at 1 year. Of the patients on CsA, 20% received OKT3 for persistent rejection, as compared with 13% in the FK-treated group. The patients receiving both CsA and OKT3 had a higher rate of upper gastrointestinal CMV infection than did FK-treated patients who also received OKT3 therapy (38.5% versus 20%, respectively). Based upon these data, it can be concluded that (1) patients receiving FK have a lower incidence of enteric CMV infection; (2) following OLTx, upper gastrointestinal CMV infection presents later in FK-treated patients; (3) the stomach is the most frequently involved organ in the UGIT; (4) FK-treated liver recipients have less severe enteric CMV infection than do CsA-treated patients; (5) enteric CMV is not a major cause of mortality in liver trans lant recipients; and (6) in patients receiving FK, those who require OKT3 therapy do not appear to be at a greater risk for the development of CMV enteritis than those who do not. © 1992 by Williams & Wilkins