title: The effect of everolimus versus mycophenolate upon proteinuria following kidney transplant and relationship to graft outcomes.
abstract: Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.
authors.affiliation: University of Colorado, Denver, CO, USA. alexander.wiseman@ucdenver.edu
authors.forename: A C
authors.initials: AC
authors.lastname: Wiseman
authors.forename: K
authors.initials: K
authors.lastname: McCague
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.forename: F
authors.initials: F
authors.lastname: Geissler
authors.forename: M
authors.initials: M
authors.lastname: Cooper
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009173:Mycophenolic Acid / Q000627:therapeutic use*; D011507:Proteinuria / Q000097:blood / Q000188:drug therapy*; D012307:Risk Factors; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus