Kidney Transplantation Under FK 506

Starzl, Thomas E.; Fung, John J.; Jordan, Mark L.; Shapiro, Ron; Tzakis, Andreas G.; McCauley, Jerry; Johnston, James R.; Iwaki, Yuichi; Jain, Ashok; Alessiani, M.; Todo, Satoru

doi:10.1001/jama.1990.03450010067032

Cited by 176 publications

(84 citation statements)

References 21 publications

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“…[1][2][3][4] The use of this agent in the pediatric population is less well described. We and others have previously reported that its use in pediatric patients is associated with excellent patient and graft survival results in a relatively small number of patients.…”

mentioning

confidence: 99%

Tacrolimus-based immunosuppression in pediatric renal transplantation

Jordan

Shapiro

Scantlebury

et al. 1999

Transplantation Proceedings

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Tacrolimus has been shown to be a safe and effective immunosuppressive agent in adult renal transplantation with significant advantages, including the ability to taper corticosteroids in up to 65% of recipients. [1][2][3][4] The use of this agent in the pediatric population is less well described. We and others have previously reported that its use in pediatric patients is associated with excellent patient and graft survival results in a relatively small number of patients. 5-9 Here we report our expanded experience on the use of tacrolimus in pediatric renal transplantation. PATIENTS AND METHODSBetween December 1989 and December 1996, 82 pediatric renal transplants were performed using tacrolimus-based immunosuppression without antilymphocyte antibody induction therapy. The mean age of the recipients was 10.6 ± 5.2 years (range 0.7 to 17.9 years). More than one-quarter of patients could be categorized as 'high-risk' with 18 (22%) cases being retransplantations and 6 (7%) patients having panel reactive antibody (PRA) levels ≥40%. A total of 34 (41%) cases were with living donors and 48 (59%) were with cadaveric donors, with a mean donor age of 27.3 ± 14.6 years (range 0.7 to 50 years), and a mean cold ischemia time in the cadaveric cases of 26.5 ± 8.8 hours. The mean number of HLA matches and mismatches was 2.8 ± 1.2 and 2.9 ± 1.3. respectively, and there were five (6%) O-antigen mismatches. The mean duration of follow-up was 4.0 ± 0.2 years (range 0.6 to 7.5 years). Immunosuppression consisted of a 0.15 mg/kg oral dose of tacrolimus preoperatively, with postoperative administration at 0.05 to 0.10 mg/kg as a continuous intravenous infusion. Patients were subsequently converted to oral administration of tacrolimus at a dose of 0.15 mg/ kg twice daily. The dose of tacrolimus was adjusted according to target whole blood trough levels. The levels aimed for were 20 to 25 ng/mL during the first 2 weeks, 15 to 20 ng/mL at 1 month, 10 to 15 ng/mL at 3 months, and <5 to 8 to 9 ng/mL over the long term. Patients also received tapered corticosteroid therapy, the aim being to withdraw corticosteroids completely by month 6. RESULTSOne-and 4-year actuarial patient survival was 99% and 94%, and actuarial graft survival was 98% and 84%, respectively (Table 1). There was no significant difference in patient and graft survival between the living donor and cadaveric donor recipients. However, 4-year graft survival was significantly higher in patients receiving a primary transplant compared with retransplant patients (P < .02). PRA levels were also a prognostic indicator of graft survival, with 87% 4-year survival in those with levels <40% and 57% in patients with levels ≥40%

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confidence: 99%

Tacrolimus-based immunosuppression in pediatric renal transplantation

Jordan

Shapiro

Scantlebury

et al. 1999

Transplantation Proceedings

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“…[10][11][12] It had been learned that the three major side effects of the drug (nephrotoxicity, neurotoxicity, and diabetogenicity) were comparable to cyclosporine. Hypertension and hyperlipidemia were less than in historical cyclosporine controls, and the cosmetic effects of cyclosporine (hirsutism, gingival hyperplasia, and facial brutalization) had not been seen.…”

Section: Pilot Primary Treatment Experiencementioning

confidence: 99%

“…12,35,36 A randomized renal transplantation trial of tacrolimus versus cyclosporine was carried out in Pittsburgh in 1990 and 1991 37 but was suspended less than a year after its inception at the recommendation of the same Patients' Rights Committee that had taken similar action with the liver trial (see earlier).…”

Section: Kidney and Other Organ Transplantationmentioning

confidence: 99%

“…Hypertension and hyperlipidemia were less than in historical cyclosporine controls, and the cosmetic effects of cyclosporine (hirsutism, gingival hyperplasia, and facial brutalization) had not been seen. [10][11][12][13][14] Although it was recognized that these first patients had been started on too much tacrolimus, complications of overdosage had been minimized by using the characteristic side effects cited above to determine dose ceilings from the first day of treatment onward. Rejection established the dose floor.…”

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confidence: 99%

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Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet

Starzl

Todo

Demetris

et al. 1998

American Journal of Kidney Diseases

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The pivotal issue of transplant rejection diagnosis and management is design, conduct, and analysis of clinical trials. The historical experience with clinical trials of major immunosuppressive drugs (cyclosporine and especially tacrolimus) is examined in this article. Cyclosporine was a turning point in transplantation, providing an extraordinary improvement over previous therapies. Additionally, early investigational experience with tacrolimus was shown to be important in rescue from cyclosporine failure. Experience with tacrolimus in liver recipients for primary therapy led to understanding that the side effect profile was similar to cyclosporine and that the important side effects of tacrolimus (toxicity and diabetes) could be lessened by altering the drug dose. Early dosing regimens were determined by attempts to balance the toxicities (representing a dose ceiling) against rejection (for minimum dosing). Drug levels became understandable and trough levels could be used to guide therapy. However, when the multicenter liver trial was implemented, high starting doses were included in the protocol design, ignoring information obtained with drug level monitoring. Disregard for this information led to a distortion of the potential value of tacrolimus. Historical controls from the Pittsburgh experience suggested that tacrolimus was a critical immunosuppressant, and the randomized trial against cyclosporine confirmed the drug's ability to compete. The multicenter liver trial, however, was not balanced across treatment arms for other immunosuppressive agents (ie, higher doses of prednisone from center to center, additional induction protocols at various centers). Additionally, analysis of study results differed across continents, and the role of tacrolimus in cyclosporine rescue was not examined thoroughly. When tacrolimus was proposed for use in extrahepatic organ transplantation, again the Pittsburgh experience, as well as experience from other single centers, was determined inadequate evidence of efficacy, and randomized trials were required by the FDA. The fact that multicenter trials in transplantation have historically been poorly designed or analyzed weighed against the dramatic improvements shown from historically controlled studies or single-center trials should lead to question of the regulatory requirement for multicenter randomized trials for all organ types. INDEX WORDSKidney; liver; transplantation; tacrolimus; cyclosporine; regulatory; clinical trials Much of the discussion at this consensus symposium on immunosuppressive drag testing has concerned the clinical and/or histopathological diagnosis of rejection. As important as this may be, it is not the core issue that we should be examining. Most errors in the evaluation of new immunosuppressants can be traced to the design, conduct, and analysis of clinical trials. In NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript turn, the scientific considerations that go into what is indisputably a human experiment are inseparabl...

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“…It has well described in vitro and experimental in vivo immunosuppressive properties 1 , and has been used in clinical heart 2 , lungs 3 , liver 4 , kidney [5][6][7][8][9] , intestinal 10 , and islet 11 transplantation. The initial experiences in pediatric kidney transplantation have been previously described.…”

Section: Introductionmentioning

confidence: 99%

FK506 in pediatric kidney transplantation—Primary and rescue experience

et al. 1995

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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.

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Kidney Transplantation Under FK 506

Cited by 176 publications

References 21 publications

Tacrolimus-based immunosuppression in pediatric renal transplantation

Tacrolimus-based immunosuppression in pediatric renal transplantation

Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet

FK506 in pediatric kidney transplantation—Primary and rescue experience

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