Proliferation signal inhibitor toxicities after thoracic transplantation

Thoracic transplantation represents the definitive therapy for end-stage lung and heart diseases. Over the life of the allograft, upregulation of profibroproliferative mechanisms result in the advancement of chronic rejection. These take the form of bronchiolitis obliterans syndrome (BOS) in a lung recipient and cardiac allograft vasculopathy (CAV) in a heart recipient. The proliferation signal inhibitors (PSI), sirolimus and everolimus, represent a therapeutic option to downregulate this fibroproliferative effect. Additionally, these drugs may result in renal sparing and express potent anti-viral activity. However, they are fraught with substantial and complex toxicities that limit their use.

In this review, the authors first describe the mechanism of immunosuppression and pharmacokinetics of the PSIs. Subsequently, their use in thoracic transplant recipients for the purposes of renal sparing, anti-cytomegalovirus effect, and antifibroproliferative effects to prolong the onset or arrest progression of BOS and CAV are reviewed. The toxicities associated with PSI use are described, and three areas are focused on in detail: nephrotoxicities, wound healing impairment, and pulmonary toxicities. Finally, the authors summarize the patients in whom PSI use may be advantageous while minimizing potential toxicities.

The potential benefits of PSI use in thoracic transplantation make their use attractive. Relative to alternative antiproliferatives, such as mycophenolate or azathioprine, PSI-treated patients experience significantly more serious adverse effects and discontinue treatment significantly more often. It is critical that patients be wisely selected for PSI use in an effort to minimize toxicities.