title: Mammalian Target of Rapamycin Inhibitors and Clinical Outcomes in Adult Kidney Transplant Recipients.
abstract: Emerging evidence from recently published observational studies and an individual patient data meta-analysis shows that mammalian target of rapamycin inhibitor use in kidney transplantation is associated with increased mortality. Therefore, all-cause mortality and allograft loss were compared between use and nonuse of mammalian target of rapamycin inhibitors in patients from Australia and New Zealand, where mammalian target of rapamycin inhibitor use has been greater because of heightened skin cancer risk.
  
  
  
  Our longitudinal cohort study included 9353 adult patients who underwent 9558 kidney transplants between January 1, 1996 and December 31, 2012 and had allograft survival ≥1 year. Risk factors for all-cause death and all-cause and death-censored allograft loss were analyzed by multivariable Cox regression using mammalian target of rapamycin inhibitor as a time-varying covariate. Additional analyses evaluated mammalian target of rapamycin inhibitor use at fixed time points of baseline and 1 year.
  
  
  
  Patients using mammalian target of rapamycin inhibitors were more likely to be white and have a history of pretransplant cancer. Over a median follow-up of 7 years, 1416 (15%) patients died, and 2268 (24%) allografts were lost. There was a higher risk of all-cause mortality with time-varying mammalian target of rapamycin inhibitor use (hazard ratio, 1.47; 95% confidence interval, 1.23 to 1.76) as well as in the fixed time model analyses comparing mammalian target of rapamycin inhibitor use at baseline (hazard ratio, 1.54; 95% confidence interval, 1.22 to 1.93) and 1 year (hazard ratio, 1.63; 95% confidence interval, 1.32 to 2.01). Time-varying mammalian target of rapamycin inhibitor use was associated with higher risk of death because of malignancy (hazard ratio, 1.37; 95% confidence interval, 1.09 to 1.71). There were no statistically significant differences in the risk of all-cause (hazard ratio, 0.98; 95% confidence interval, 0.85 to 1.12) and death-censored (hazard ratio, 0.85; 95% confidence interval, 0.69 to 1.03) allograft loss between the mammalian target of rapamycin inhibitor use and nonuse groups in the time-varying model as well as the fixed time models.
  
  
  
  Mammalian target of rapamycin inhibitor use was associated with a higher risk of all-cause mortality but not allograft loss.
authors.affiliation: Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia.|Department of Nephrology, St. George Hospital, Sydney, Australia.|Renal and Metabolic Division, The George Institute for Global Health, Sydney, Australia.
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Badve
authors.affiliation: Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Pascoe
authors.affiliation: Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Burke
authors.affiliation: The Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Service, School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Clayton
authors.affiliation: Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Campbell
authors.affiliation: Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia.|Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Hawley
authors.affiliation: Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia; and.
authors.forename: Wai H
authors.initials: WH
authors.lastname: Lim
authors.affiliation: The Australia and New Zealand Dialysis and Transplant Registry, Adelaide, Australia.|Central Northern Adelaide Renal and Transplantation Service, School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: McDonald
authors.affiliation: Center for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Germaine
authors.initials: G
authors.lastname: Wong
authors.affiliation: Australasian Kidney Trials Network, School of Medicine, University of Queensland, Brisbane, Australia.|Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
mesh_terms: D000328:Adult; D001315:Australia / Q000453:epidemiology; D002423:Cause of Death; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007239:Infections / Q000401:mortality; D007676:Kidney Failure, Chronic / Q000601:surgery; D016030:Kidney Transplantation / Q000401:mortality*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology* / Q000401:mortality; D009520:New Zealand / Q000453:epidemiology; D057234:Preoperative Period; D016016:Proportional Hazards Models; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013997:Time Factors; D066027:Transplant Recipients / Q000706:statistics & numerical data; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Allografts; Longitudinal Studies; Skin Neoplasms; Transplant Recipients; Transplantation, Homologous; cohort studies; graft survival; humans; immunosuppression; kidney transplantation; mortality; risk factors