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Ann Thorac Surg 1995;60:495-496
© 1995 The Society of Thoracic Surgeons
Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, MN
Cyclosporine has been the mainstay of immunosuppressive regimens for solid-organ transplantation since its introduction in 1981. This agent is largely responsible for the explosive growth in solid-organ transplantation that has occurred in the ensuing 15 years. The initial success of transplantation of the liver, pancreas, heart/lung, and lung has been attributed to cyclosporine. In addition, cyclosporine is credited with markedly improving outcomes in kidney and heart transplantation. We have learned much about this agent with respect to toxicity, dosing, and combination therapies of cyclosporine and other immunosuppressive agents. Because the lung is the most recent organ to be successfully transplanted, cyclosporine-based immunosuppressive regimens established for other organs, most commonly the heart, have been applied with some modifications to lung transplantation [1, 2]. As in all fields of medicine, progress continues and, in transplantation, the golden grail remains the agent(s) that will induce tolerance to the transplanted organ without impairing host defenses.
Although cyclosporine-based immunosuppression has clearly enhanced both patient and graft survival in all solid-organ transplants compared with the era of azathioprine and steroids, many centers still report a high incidence of rejection in cyclosporine-treated patients. The enhanced immunosuppressive therapy necessary to control such rejection, primarily in the form of steroids and antilymphocyte preparations, conspire to increase the risk of infectious complications. Therefore, any agent that may lead to a lower incidence of graft rejection would be very beneficial from the standpoint of both graft survival and patient survival and infectious morbidity.
Tacrolimus (FK 506) is a macrolide immunosuppressant with similar, but more potent, immunosuppressive properties to cyclosporine. The drug inhibits cell-mediated and humoral immune responses. Tacrolimus inhibits calcium-dependent signal transduction pathways in T cells, thereby preventing transcription of a discrete set of lymphokine genes. In vivo, tacrolimus is approximately ten times more potent than cyclosporine in suppressing T cell–dependent antibody production, delayed type hypersensitivity, and graft-versus-host reactivity. Review of in vivo studies in a number of animal models has demonstrated a marked ability to prevent rejection after various types of organ transplantations. Interestingly, tacrolimus has also shown the ability to reverse ongoing rejection in animal models [3]. Based on these properties, initial studies of clinical efficacy of tacrolimus were performed. The primary site of testing for this agent has been the University of Pittsburgh, where tacrolimus was employed first in recipients of liver allografts [4]. Its success in liver and kidney transplantation, both as rescue therapy for acute rejection and as a primary agent of immunosuppression, led rapidly to its application to thoracic organ recipients at Pittsburgh [4–6]. Initially as a rescue agent and later as primary therapy, tacrolimus again demonstrated its potency and its efficacy as a primary immunosuppressive agent in heart transplantation [7–10].
In the excellent article in the current issue, Keenan and associates [11] report long-term results of a randomized trial of tacrolimus versus cyclosporine in lung transplantation. Clearly a head-to-head trial of these two agents is the only way to adequately assess their relative efficacy and toxicity. Over a 2
-year period, 133 recipients of lung transplants were randomized, with equal numbers receiving cyclosporine and tacrolimus. The patient groups were similar in age, sex, and underlying pulmonary disease. The outcomes in these patients were carefully analyzed and revealed some very interesting findings. Survival at 1 and 2 years after transplantation was similar in both groups, although there was a trend toward increased survival with tacrolimus. Acute rejection episodes per 100 patient-days were fewer in the group receiving tacrolimus (0.85) than in the group receiving cyclosporine (1.09), although this trend did not achieve statistical significance (p = 0.07). Of most note, fewer patients in the tacrolimus group had development of obliterative bronchiolitis (OB) (21.7%) compared with the cyclosporine group (35.8%; p = 0.025). Over time patients receiving tacrolimus had greater freedom from OB (p < 0.03).
Thirteen patients in the cyclosporine group required cross-over to tacrolimus (19.4%), and only 2 patients required cross-over in the reverse direction (3%; p = 0.02). Of 9 patients requiring the switch from cyclosporine to tacrolimus for refractory rejection, 6 had their rejection successfully controlled. The overall prevalence of infectious complications was similar in the two groups. However, bacterial infections were significantly more frequent with cyclosporine, and fungal infections with tacrolimus. From the standpoint of systemic toxicity, both groups experienced transient renal dysfunction in the postoperative period. At 1-year follow-up, the extent of renal impairment was similar in the two groups. In contrast to earlier reports, the frequency of systemic hypertension requiring medication to control was also similar between the two groups. A significant point that emerges from this and other studies of the clinical use of tacrolimus is that patients accept this agent with a greater degree of frequency than cyclosporine because of the noted absence of gingival hyperplasia and hirsutism, two side effects of cyclosporine that have proved particularly troublesome, the latter especially in women.
Obliterative bronchiolitis is the Achilles' heel of modern lung transplantation. Although current surgical techniques and improved immunologic management have in large measure solved the problem of airway healing, the greater early success of lung transplantation has yielded to a discouraging incidence of chronic rejection in the form of OB. This insidious disease can occur anywhere from several months to several years after transplantation. Obliterative bronchiolitis afflicts 30% to 50% or more of patients in most series and is the eventual vehicle of the patient's demise in most cases. Attempts to interdict this process have been singularly unrewarding. More than any other transplanted solid organ, the transplanted lung is subject to destruction of its functional unit, the respiratory bronchiole, by the ravages of injury caused by infection or rejection and eventuating in obliteration of the terminal airways by an exuberant fibroproliferative response. Heretofore, no therapy has emerged that has had a demonstrable impact on the incidence of OB after lung transplantation. Thus, the data reported by Keenan and associates represent the first evidence that the incidence of this dreaded complication can be affected by medical therapy. The reduced incidence of OB in patients receiving tacrolimus as primary immunosuppressive therapy is highly provocative information indeed. To be sure, this represents an evolutionary, as opposed to a revolutionary, change in therapy for lung transplant recipients. The data are relatively short term and the numbers of patients studied is small. Nonetheless, if these data can be reproduced by other investigators this may represent a very important incremental first step to improving long-term outcomes after lung transplantation. Clearly, for lung transplantation to begin to assume its proper position as a long-term therapy for organ failure alongside the other solid-organ procedures, the incidence of OB must be decreased substantially.
At the very least, it seems evident from the present report and previous studies by these authors and others that tacrolimus-based immunosuppression is at least as safe and effective as that provided by cyclosporine-based regimens. It is well tolerated by patients and, if it can be further shown to possess steroid-sparing properties, may prove to be even more attractive in the future. Tacrolimus, although not the next miracle drug of transplantation, may, in fact, be a significant advance in the care of recipients of pulmonary allografts.
Footnotes
Address reprint requests to Dr Bolman, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Box 207 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.
References
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