Is it time to give up with calcineurin inhibitors in kidney transplantation?

Abstract

Calcineurin inhibitors (CNIs) represent today a cornerstone for the maintenance immunosuppressive treatment in solid organ transplantation. Nevertheless, several attempts have been made either to minimize their dosage or to avoid CNIs at all because these drugs have the severe side effect of chronic nephrotoxicity. This issue represents a frontier for renal transplantation. The principal problem is to understanding whether the poor outcome over the long-term may be ascribed to CNIs nephrotoxicity or to the inability of these drugs to control the acute and chronic rejection B cells mediated. The authors analyze extensively all the international trials attempting to withdraw, minimize or avoid the use of CNIs. Few trials undertaken in low risk patients with an early conversion from CNIs to proliferation signal inhibitors were successful, but the vast majority of trials failed to improve CNIs side effects. To date the use of a new drug, a co-stimulation blocker, seems promising in avoiding CNIs with similar efficacy, better glomerular filtration rate and an improved metabolic profile. Moreover the use of this drug is not associated with the development of donor-specific anti-human leukocyte antigen antibodies. This point has a particular relevance, because the failure of CNIs to realize good outcomes in renal transplantation has recently ascribed to their inability to control the acute and chronic rejections B-cell mediated. This paper analyzes all the recent studies that have been done on this issue that represents the real frontier that should be overcome to realize better results over the long-term after transplantation.

Keywords: Calcineurin inhibitors nephrotoxicity; Calcineurin inhibitors withdrawal; Calcineurin inhibitors minimization; Calcineurin inhibitors avoidance; Donor specific antibodies; Antibody mediated rejection; New drugs in renal transplantation

Core tip: Calcineurin inhibitors (CNIs) based therapy is still a cornerstone in renal transplantation. Nevertheless, with the use of such drugs the long-term graft survival did not improve. Causes may be nephrotoxicity, underimmunesuppression or both. All the trials attempting to CNIs sparing have been examined, but nephrotoxicity doesn’t seem to be responsible for the lack of long-term improvement. In recent years emerged the problem of anti-human leukocyte antigen antibodies not adequately suppressed by the CNIs based therapy. New drugs are necessary, but the pipeline seems to be almost empty now. To date the only promising drug strategy is the co-stimulation blockade, whose four-year results are reported.