title: Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine.
abstract: BACKGROUND
  The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored.
  
  
  METHODS
  In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations.
  
  
  RESULTS
  The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3 ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ≥ 12 ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8 ng/mL and CsA <100 ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations.
  
  
  CONCLUSIONS
  These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.
authors.affiliation: Division of Nephrology, University of Utah School of Medicine, Salt Lake City, UT, USA. Fuad.Shihab@hsc.utah.edu
authors.forename: Fuad S
authors.initials: FS
authors.lastname: Shihab
authors.forename: Diane
authors.initials: D
authors.lastname: Cibrik
authors.forename: Laurence
authors.initials: L
authors.lastname: Chan
authors.forename: Yu Seun
authors.initials: YS
authors.lastname: Kim
authors.forename: Mario
authors.initials: M
authors.lastname: Carmellini
authors.forename: Rowan
authors.initials: R
authors.lastname: Walker
authors.forename: Gazi
authors.initials: G
authors.lastname: Zibari
authors.forename: James
authors.initials: J
authors.lastname: Pattison
authors.forename: Catherine
authors.initials: C
authors.lastname: Cornu-Artis
authors.forename: Zailong
authors.initials: Z
authors.lastname: Wang
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco-Silva
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000453:epidemiology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus