Fk506 “Rescue” for Resistant Rejection of Renal Allografts Under Primary Cyclosporine Immunosuppression1

Jordan, Mark L.; Shapiro, Ron; Vivas, Carlos; Scantlebury, Velma P.; Rhandhawa, Parmjeet; Carrieri, G.; McCauley, Jerry; Demetris, A. J.; Tzakis, Andreas G.; Fung, John J.; Simmons, Richard L.; Hakala, Thomas R.; Starzl, Thomas E.

doi:10.1097/00007890-199403270-00016

Cited by 145 publications

(55 citation statements)

References 11 publications

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“…The success rate of 71 % is the same as that reported in the larger series reported by Jordan et al 17,18 The success rate might conceivably have been higher but for a fairly broad willingness to accept patients for rescue therapy. Until the spring of 1994, FK506 remained investigational, and the ability to use it as a rescue agent for renal transplantation patients was limited, with few exceptions, to a single center.…”

Section: Discussionsupporting

confidence: 75%

“…15,16 FK506 has also been used in an attempt to salvage patients transplanted under cyclosporine immunosuppression. 17,18 The most common indication has been resistant acute rejection, and a success rate of 70-75% in unselected adults and children has been achieved. Most of these patients have received one or more courses of antilymphocyte therapy, and a smaller number of patients were on or had returned to dialysis prior to the initiation of rescue therapy.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

FK506 in pediatric kidney transplantation—Primary and rescue experience

et al. 1995

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“…One of the most exciting developments of the new age of immunosuppressive therapy in the 1990s is the emergence of novel agents that have the ability to reverse ongoing rejection episodes in renal allograft recipients receiving traditional baseline immunotherapy with CsA (4,(8)(9)(10)(11)(12). Tacrolimus (formerly known as FK506) has previously been shown to provide salvage of refractory allograft rejection in 74% of patients on baseline CsA therapy who have failed either high dose corticosteroid therapy and/or antilymphocyte therapy in short term follow-up (4).…”

Section: Discussionmentioning

confidence: 99%

“…Conversion performed before or after 2 or 3 months following transplantation did not appear to influence the outcome. Probably more important than the timing of conversion are the findings on preconversion biopsy, in which the presence of chronic rejection or ACR with primary allograft nonfunction portends a worse prognosis (4,13). One of the most striking observations in our early experience with tacrolimus rescue was the ability to taper and even stop prednisone therapy in approximately 20% of patients successfully salvaged (4), This trend was maintained in this expanded experience.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus Rescue Therapy for Renal Allograft Rejection-Five-Year Experience1

et al. 1997

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“…4,6,7,[31][32][33] This precedent was broken with the large-scale randomized liver transplant trials. The decision to go forward with the multicenter trials was made despite prima facie evidence of tacrolimus superiority from the increasingly well-documented rescue of liver allografts (see earlier) and shortly thereafter of intractably rejecting kidneys 34 and hearts. 35 Remarkably, this experience that was promptly confirmed in multiple other centers was dismissed as a basis for regulatory approval because of the difficulty (and ethical unacceptability) of obtaining "controls.…”

Section: Kidney and Other Organ Transplantationmentioning

confidence: 99%

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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Fk506 “Rescue” for Resistant Rejection of Renal Allografts Under Primary Cyclosporine Immunosuppression1

Cited by 145 publications

References 11 publications

FK506 in pediatric kidney transplantation—Primary and rescue experience

FK506 in pediatric kidney transplantation—Primary and rescue experience

Tacrolimus Rescue Therapy for Renal Allograft Rejection-Five-Year Experience1

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

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