Renal transplantation, past, present and future.

In the absence of immunosuppression, renal transplantation was sporadically and unsuccessfully performed during the first half of this century. Over the past 40 years, immunosuppressive drug regimens have evolved greatly and transformed solid-organ transplantation into a routine clinical procedure with a 1-year graft survival between 80% and 90%. The original immunosuppressive scheme was based on the administration of glucocorticoids and azathioprine. However, many patients developed acute rejection which required very high dose of prednisone. As a consequence, a high mortality rate due to opportunistic infections was frequently observed, since this immunosuppressive regimen nonselectively inhibited elements of host resistance such as monocytes, granulocytes, and macrophages. In the early Eighties, the introduction of monoclonal antibodies directed against the CD3 molecule and of cyclosporine, a lymphokine synthesis inhibitor, allowed a more effective control of acute allograft rejection and a more specific target with maintenance immunosuppression. Furtherly, with the knowledge of molecular immunology the better understanding of the cellular and molecular mechanisms that underlie the immunological response to transplanted organs, led to the discovery of new immunosuppressive agents, such as tacrolimus, rapamycin, interleukin-2 monoclonal antibodies, and mycophenolate mofetil. All these drugs showed a more selective mechanism for T- and B-cell alloimmune responses. The results of recent clinical trials based on the combination of these drugs with steroids and cyclosporine reduced the incidence of acute rejection episodes to less than 10% and permitted a steroid-sparing policy in kidney transplantation. Today, the main problem is related to the side-effects of vigorous and prolonged immunosuppression, mainly infections and malignancies. If it were possible to obtain permanent immunological tolerance, immunosuppressive therapy could be minimized. In this respect, the new generation of drugs, FTY 20, antisense oligonucleotides and agents capable of blocking the costimulatory pathway of allorecognition, might have the potential of favoring tolerance in the host against alloantigens.