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Immunosuppression in heart transplantation: shooting ourselves in the foot!

Background
Kidney transplantation began during a time when immunosuppression was not well understood, and achieved a modicum of success utilizing steroids and 6-mercaptopurine, later replaced by azathioprine. When heart transplantation began in 1967 [1], this two-drug combination was also employed [2, 3], with dismal results. Indeed by the early 1970s, many centers had abandoned heart transplantation, and were it not for the advent of cyclosporine A (CYA), heart transplantation would be a historical footnote in the literature about failed therapies for end-stage heart disease [4]. Instead, CYA was combined with steroids and azathioprine and triple therapy was born. The fact that 2 drugs did not produce acceptable protection from rejection has led to steadfast adherence to triple drug therapy for many years, and the logic of this approach has stifled efforts to examine less intense regimens. The purpose of this paper is to examine the changes that have occurred in heart transplant immunosuppression over the last 20 years, and consider the provocative question of whether immunosuppression prevents the development of partial tolerance.
Immunosuppressive regimens for heart transplantation
A triple combination of CYA, an anti-proliferative drug such as azathioprine, and corticosteroids has been the typical post-transplant regimen for more than 25 years. Over time, a variety of medications have been substituted for azathioprine and even CYA is less commonly used, with tacrolimus being substituted [5-7]. Newer elements of the immunosuppressive armamentarium include mycophenolate mofetil, which was shown to be superior to azathioprine in a randomized, controlled trial [8]. Other alternative cell cycle inhibitors include rapamycin, and everolimus, which are also substituted for azathioprine or mycophenolate in some patients. Tacrolimus has been increasingly used in heart transplants instead of cyclosporine [9], and has proven to be efficacious even in cases of refractory rejection [10-13]. Steroids are commonly maintained at some minimum dosage long-term, despite literature suggesting that withdrawal is safe and may carry significant benefits [14-17]. Long-term corticosteroid therapy is associated with numerous morbidities including hyperlipidemia, hypertension, obesity, cataract formation, osteoporosis, diabetes mellitus, and the development of Cushingoid facial features, just to name a few. Given these problems, it is...


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