Progress of Immunosuppressive regimen after kidney transplantation

抄録

Transplantation is the treatment of choice for patients with end-stage renal, cardiac, liver and lung disease. The remarkable success of solid organ transplantation can in large part be attributed to the development of potent immunosuppressive therapy which has reduced the incidence of acute allograft rejection and allograft loss.

In kidney transplantation, tacrolimus-based immunosuppression is the standard in most centers worldwide. Most kidney transplant recipients are treated with induction therapy (consisting of T lymphocyte-depleting antibodies or an interleukin-2 receptor blocker) followed by maintenance therapy consisting of tacrolimus combined with mycophenolate and glucocorticoids.

The (nephro)toxicity of tacrolimus has prompted extensive research into alternative immunosuppressive strategies. Many of these alternative immunosuppressive regimens however, have failed to replace tacrolimus-based immunosuppression because of either unacceptably higher acute rejection rates or because of unanticipated toxicity.

Two immunosuppressive therapies have shown promise as realistic alternatives for tacrolimus-mycophenolate combination maintenance therapy. The first of these is belatacept-based immunosuppression. Belatacept is a co-stimulatory signal blocking agent that is not nephrotoxic. Long-term follow-up data has demonstrated that belatacept-based immunosuppression improves kidney allograft and patient survival as compared with ciclosporin-based immunosuppression. However, the increased acute rejection rates seen during belatacept treatment, the comparison with ciclosporin rather than tacrolimus in the registration studies, and manufacturing problems may limit widespread adoption of belatacept as the primary immunosuppressant. The second alternative is everolimus plus low-exposure calcineurin inhibitor (either tacrolimus or ciclosporin) combination therapy. In the TRANSFORM study, the largest trial ever performed in kidney transplantation with n = 2037 patients, this regimen was compared with standard-exposure calcineurin inhibitor plus mycophenolate therapy. In TRANSFORM, low-exposure calcineurin inhibitor plus everolimus therapy was shown to be non-inferior in terms of the primary end-point consisting of biopsy-proven acute rejection or an eGFR <50 ml/min per 1.73 m2. Cytomegalovirus and BK virus infections were less frequent in the everolimus arm than in the mycophenolate arm.

It is imagined that the benefits of these two alternative immunosuppressive regimens will be further explored in the next decade. In addition, novel compounds, specifically targeting B lymphocyte responses will likely be developed and tested clinically.