CONTEXT: 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. DESIGN, SETTING, AND PATIENTS: 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). MAIN OUTCOME MEASURES: 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). CONCLUSION: 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.
CONTEXT: 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. DESIGN, SETTING, AND PATIENTS: 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). MAIN OUTCOME MEASURES: 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). CONCLUSION: 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: Abraham Shaked; Michele R DesMarais; Heather Kopetskie; Sandy Feng; Jeffrey D Punch; Josh Levitsky; Jorge Reyes; Goran B Klintmalm; Anthony J Demetris; Bryna E Burrell; Allison Priore; Nancy D Bridges; Peter H Sayre Journal: Am J Transplant Date: 2018-12-31 Impact factor: 8.086
Authors: J G O'Leary; A J Demetris; L S Friedman; H M Gebel; P F Halloran; A D Kirk; S J Knechtle; S V McDiarmid; A Shaked; P I Terasaki; K J Tinckam; S J Tomlanovich; K J Wood; E S Woodle; A A Zachary; G B Klintmalm Journal: Am J Transplant Date: 2014-03-01 Impact factor: 8.086
Authors: Joseph Leventhal; Michael Abecassis; Joshua Miller; Lorenzo Gallon; David Tollerud; Mary Jane Elliott; Larry D Bozulic; Christopher Houston; Nedjema Sustento-Reodica; Suzanne T Ildstad Journal: Transplantation Date: 2013-01-15 Impact factor: 4.939
Authors: Sandy Feng; John C Bucuvalas; Anthony J Demetris; Bryna E Burrell; Katherine M Spain; Sai Kanaparthi; John C Magee; David Ikle; Andrew Lesniak; Juan J Lozano; Estella M Alonso; Robert A Bray; Nancy E Bridges; Edward Doo; Howard M Gebel; Nitika A Gupta; Ryan W Himes; Annette M Jackson; Steven J Lobritto; George V Mazariegos; Vicky L Ng; Elizabeth B Rand; Averell H Sherker; Shikha Sundaram; Yumirle P Turmelle; Alberto Sanchez-Fueyo Journal: Gastroenterology Date: 2018-08-23 Impact factor: 22.682
Authors: Matthew James Vitalone; Liang Wei; Masato Fujiki; Audrey H Lau; Erik Littau; Carlos Esquivel; Olivia M Martinez; Sheri M Krams Journal: Transplantation Date: 2016-04 Impact factor: 4.939
Authors: E R Perito; S Mohammad; P Rosenthal; E M Alonso; U D Ekong; S J Lobritto; S Feng Journal: Am J Transplant Date: 2015-02-03 Impact factor: 8.086