Tofacitinib in kidney transplantation

Introduction: This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase (JAK) 3 inhibitor tofacitinib, formerly known as CP-690,550 and tasocitinib. Areas covered: Successful kidney transplantation requires adequate immunosuppression. Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors. JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, particularly members of the cytokine receptor common gamma (c gamma) chain family. JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis. Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control. Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival. There was also a lower rate of new onset diabetes after transplant. However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis. Expert opinion: Tofacitinib may be a promising alternative to calcineurin inhibitors. The optimal therapeutic window is still being determined.