title: A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.
abstract: BACKGROUND
  We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal.
  
  
  METHODS
  Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications.
  
  
  RESULTS
  Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups.
  
  
  CONCLUSIONS
  The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.
authors.affiliation: 1 Department of Surgery, Wright State University Boonshoft School of Medicine, Dayton, OH. 2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE. 3 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE. 4 Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK. 5 Sigma Analytics, Inc., Anthem, AZ. 6 Department of Surgery, Methodist Hospital, Houston, TX.
authors.forename: R Brian
authors.initials: RB
authors.lastname: Stevens
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Foster
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Miles
authors.forename: James T
authors.initials: JT
authors.lastname: Lane
authors.forename: Andre C
authors.initials: AC
authors.lastname: Kalil
authors.forename: Diana F
authors.initials: DF
authors.lastname: Florescu
authors.forename: John P
authors.initials: JP
authors.lastname: Sandoz
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Rigley
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Nielsen
authors.forename: Jill Y
authors.initials: JY
authors.lastname: Skorupa
authors.forename: Anna M
authors.initials: AM
authors.lastname: Kellogg
authors.forename: Tamer
authors.initials: T
authors.lastname: Malik
authors.forename: Lucile E
authors.initials: LE
authors.lastname: Wrenshall
mesh_terms: D000328:Adult; D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D016016:Proportional Hazards Models; D011817:Rabbits; D012307:Risk Factors; D020123:Sirolimus / Q000008:administration & dosage; D013256:Steroids / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D013256:Steroids; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus
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