title: Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants.
abstract: BACKGROUND
  Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality.
  
  
  OBJECTIVE
  To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients.
  
  
  METHODS
  Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months).
  
  
  METHODS
  The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection.
  
  
  RESULTS
  Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03).
  
  
  CONCLUSIONS
  In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.
authors.affiliation: Division of Transplantation, Department of Surgery, University of California, San Francisco, CA 94143, USA. sandy.feng@ucsfmedctr.org
authors.forename: Sandy
authors.initials: S
authors.lastname: Feng
authors.forename: Udeme D
authors.initials: UD
authors.lastname: Ekong
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lobritto
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: John P
authors.initials: JP
authors.lastname: Roberts
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Estella M
authors.initials: EM
authors.lastname: Alonso
authors.forename: Mary C
authors.initials: MC
authors.lastname: Philogene
authors.forename: David
authors.initials: D
authors.lastname: Ikle
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Poole
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Bridges
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Nadia K
authors.initials: NK
authors.lastname: Tchao
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D008099:Liver / Q000502:physiology; D008103:Liver Cirrhosis; D016031:Liver Transplantation / Q000379:methods*; D019520:Living Donors; D008297:Male; D010290:Parents; D018579:Patient Selection; D011446:Prospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome