title: Targeting JAK/STAT Signaling to Prevent Rejection After Kidney Transplantation: A Reappraisal.
abstract: The profound involvement of cytokines in allograft rejection makes the molecules that control their actions, members of the Jak-Stat pathway, ideal targets for pharmacological intervention. Numerous studies have demonstrated that Jak3 is widely involved in the activation cascade and function of most immune cells. Tofacitinib, an oral Janus kinase inhibitor that targets Jak1/Jak3 dependent Stat activation, has been assessed as a substitute for calcineurin inhibitor therapy after low-to-moderate risk kidney transplantation in 3 randomized trials. Results using fixed-dose regimens showed a low incidence of rejection and better renal function with less interstitial fibrosis/tubular atrophy versus calcineurin inhibitor therapy. However, the safety profile of tofacitinib was poor, including increased incidences of cytomegalovirus disease, herpes zoster, BK virus, and nephropathy, which led to the discontinuation of its development for transplantation. High tofacitinib concentrations were independently associated with serious infection. Dosing according to exposure levels, coupled with pharmacodynamic monitoring based on phosphorylation of Stat5, could improve safety compared to the early fixed-dose regimens. Future studies could assess individualized dosing based on pharmacokinetic and pharmacodynamic monitoring. Additionally, because the increase of viral infections under tofacitinib may have been influenced by overlapping toxicity with concomitant mycophenolic acid, exploration of alternative adjunctive therapies (eg, a mammalian target of rapamycin inhibitor or belatacept) may demonstrate a better efficacy/safety profile. We believe that Jak inhibitors are a good and useful addition to the immunosuppressive armentarium for kidney transplant patients, and that new studies with personalized drug dosing, improved immune monitoring, and better patient selection should be performed.
authors.affiliation: 1 Department of Internal Medicine-Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands. 2 Division of Nephrology, Hospital do Rim-UNIFESP, Sao Paulo, Brazil.
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Nynke M
authors.initials: NM
authors.lastname: Kannegieter
authors.forename: Claudia Rosso
authors.initials: CR
authors.lastname: Felipe
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco Silva
mesh_terms: D000818:Animals; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects*; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012307:Risk Factors; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; C507933:JAK3 protein, human; D053616:Janus Kinase 3