Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients

doi:10.1016/S1053-2498(99)00016-9

The Journal of Heart and Lung Transplantation

Volume 18, Issue 5, May 1999, Pages 448-455

https://doi.org/10.1016/S1053-2498(99)00016-9 Get rights and content

Abstract

Background

Refractory acute cellular rejection may occur despite triple-drug immunosuppression (cyclosporine A, steroids, azathioprine/mycophenolate mofetil). The purpose of this study was to determine the efficacy of tacrolimus rescue therapy in patients maintained on cyclosporine-based immunosuppression (CBI).

Methods

Between December 1993 and October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. One hundred forty-nine patients underwent heart replacement; 59 underwent lung transplantation. One hundred thirty-nine of the heart transplant cohort received CBI preceded by induction therapy with OKT3. Forty-six of the lung transplant cohort received CBI without induction cytolytic therapy. Refractory rejection was defined as failure to respond to high-dose steroids (500 mg to 1 g IV methylprednisolone for 3 days) and/or monoclonal antibody therapy (OKT3, 5 to 10 mg IV/day for 7 to 14 days). In patients with refractory rejection, cyclosporine was replaced with tacrolimus.

Results

Overall, 16% (30/185) of patients receiving CBI experienced refractory rejection. Thirty-one episodes of grade IIIa or greater rejection occurred in 11% (15/139) of heart transplant recipients. Twenty episodes of grade II to IV rejection occurred in 33% (15/46) of lung transplant recipients. After tacrolimus rescue therapy, 93% (14/15) of patients in the heart transplant group converted to grade II or less rejection. Refractory rejection was reversed in 73% (11/15) of the lung transplant group. Reversal was documented at biopsy in all (8/8) lung recipients in whom it had been histologically identified. FEV₁ values of 3 additional patients stabilized.

Conclusions

The incidence of refractory rejection in thoracic organ transplant recipients on CBI is significant. Reversal of refractory rejection follows rescue immunotherapy with tacrolimus.

Section snippets

Patients and methods

During the period from December 1993 until October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. There were 149 heart transplant recipients. Fifty-nine patients underwent lung transplantation. Most heart (139) and lung (46) transplant recipients underwent cyclosporine-based immunosuppression (cyclosporine A, steroids, azathioprine).

Immunosuppression was initiated at the time of transplantation. Methylprednisolone, 500 mg

Results

The overall incidence of refractory rejection in our thoracic organ transplant recipients maintained on cyclosporine-based immunosuppression was 16% (30/185). Eleven percent (15/139) of heart transplant recipients and 33% (15/46) of lung transplant recipients experienced refractory rejection. The primary diagnoses of patients who experienced refractory rejection were similar to those of the entire group of patients who underwent heart and lung transplantation during the same period (Figure 1).

Discussion

Although cyclosporine-based immunosuppression (CBI) has improved survival after thoracic organ transplantation,1, 2 some recipients continue to experience refractory acute cellular rejection. Refractory rejection has been described in 15% of heart transplant recipients.9 In addition, reports of recurrent acute rejection in lung transplant recipients are consistent with an incidence of refractory rejection of 13 to 36%.10, 11 In our series, 11% of heart transplant recipients and 33% of lung

Acknowledgements

We gratefully acknowledge the help of Dennis M. Heisey, PhD, with the statistical analysis.

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It has also been used to treat graft-vs-host disease, rheumatologic disorders (lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis), inflammatory bowel disease, various skin conditions other than atopic dermatitis, and uveitis. Table 13 summarizes the 16 clinical trials reporting on the use of tacrolimus for various lung diseases.151,152,179–192 The FDA has issued a black box warning for increased susceptibility to infection and the possible development of lymphoma.193
Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents.
Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline.
It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease.
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Success in cardiac transplantation has been achieved by the development of improved immunosuppressive therapies, which have led to a concomitant decrease in cardiac allograft rejection and infection. Rejection however continues to be the cause of significant morbidity and mortality particularly in the first year after cardiac transplantation. The endomyocardial biopsy remains an essential tool for its diagnosis. Acute cellular rejection has been a well recognized phenomenon although more recently, the diagnosis of antibody-mediated rejection has gained acceptance, a condition associated with greater graft dysfunction, subsequent development of cardiac allograft vasculopathy and mortality. In this article we review the current status of the diagnosis of cardiac allograft rejection as determined by the traditional endomyocardial biopsy, the more recent advances in the non-invasive evaluation of rejection, detection of circulating antibodies and the treatment of rejection.
The international society of heart and lung transplantation guidelines for the care of heart transplant recipients
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Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA
Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesù, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK
Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria.
Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruña, La Coruña, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA
Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.
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Citation Excerpt :
During scheduled myocardial biopsies, 30 patients (41%) showed acute cellular rejection, which was treated successfully with optimization of immunosuppression (additional steroids or ATG). In six patients it was deemed necessary to replace cyclosporine with tacrolimus for persistent cellular rejection.32 The five patients (9.4%) who developed acute renal failure after transplantation were placed temporarily on hemodialysis.
Heart transplantation is the “gold standard” for treating patients in end-stage heart failure who satisfy strict selection criteria. However, infrequent transplant performance, eg, less than nine per year, may be associated with suboptimal results.
We reviewed our 13-year clinical experience (1996–2008) with 73 orthotopic heart transplants performed under strict selection criteria and followed closely thereafter at the only accredited center in Greece, a country with an annual rate of only seven donors per million population.
Low perioperative (5.47%) and long-term (7.5%) mortality rates were responsible for a 94% survival rate in the first year, 92% at five years, and 70% at ten years—similar to those reported worldwide—along with excellent functional recovery.
Strict recipient and donor selection criteria, combined with a rigorous multidisciplinary follow-up, yield excellent results despite the existing shortage of available grafts.

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²: Current address: Department of Surgery, University of Kentucky, Lexington, Kentucky.

¹: Reprint requests: Robert B. Love, MD, Division of Cardiothoracic Surgery, Clinical Science Center, H4/358, 600 Highland Avenue, Madison, Wisconsin 53792.

View full text

Immunosuppression—Clinical and Animal StudiesEfficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients

Abstract

Background

Methods

Results

Conclusions

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

J Thorac Cardiovasc Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

Transpl Immunol

Human Immunol

Cyclosporine A in cardiac allograftinga preliminary experience

Transplant Proc

Lung transplantation

A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection. Heart Rejection Study Group

J Heart Transplant

A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection. Lung Rejection Study Group

J Heart Transplant

Pulmonary transplantation

Ann Surg

A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts

J Heart Lung Transplant

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation

N Engl J Med

A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation

Transplantation

FK506historical perspectives

Transplant Proc

In vivo immunopharmacology of the macrolides FK506 and rapamycintoward the era of rational immunosuppressive drug discovery, development and use

Transplant Proc

Immunosuppression—Clinical and Animal Studies
Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients