Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management

被引：65

作者：

Feng, Sandy ^{[1
]}

Bucuvalas, John C. ^{[2
,3
]}

Mazariegos, George, V ^{[4
]}

Magee, John C. ^{[5
]}

Sanchez-Fueyo, Alberto ^{[6
]}

Spain, Katharine M. ^{[7
]}

Lesniak, Andrew ^{[8
]}

Kanaparthi, Sai ^{[9
]}

Perito, Emily ^{[10
]}

Venkat, Veena L. ^{[11
]}

Burrell, Bryna E. ^{[9
]}

Alonso, Estella M. ^{[12
]}

Bridges, Nancy D. ^{[13
]}

Doo, Edward ^{[14
]}

Gupta, Nitika A. ^{[15
]}

Himes, Ryan W. ^{[16
]}

Ikle, David ^{[7
]}

Jackson, Annette M. ^{[17
]}

Lobritto, Steven J. ^{[18
]}

Lozano, Juan Jose ^{[19
]}

Martinez, Mercedes ^{[18
]}

Ng, Vicky L. ^{[20
]}

Rand, Elizabeth B. ^{[21
]}

Sherker, Averell H. ^{[14
]}

Sundaram, Shikha S. ^{[22
]}

Turmelle, Yumirle P. ^{[23
]}

Wood-Trageser, Michele ^{[8
]}

Demetris, Anthony J. ^{[8
]}

机构：

[1] Univ Calif San Francisco, Dept Surg, Div Transplantat, 505 Parnassus Ave, San Francisco, CA 94143 USA

[2] Mt Sinai Kravis Childrens Hosp, New York, NY USA

[3] Mt Sinai Hlth Syst, Recanati Miller Transplantat Inst, New York, NY USA

[4] Childrens Hosp Pittsburgh, Hillman Ctr Pediat Transplantat, Pittsburgh, PA 15213 USA

[5] Univ Michigan, Dept Surg, Sect Transplant Surg, Ann Arbor, MI 48109 USA

[6] Kings Coll London, Inst Liver Studies, London, England

[7] Rho Inc, Chapel Hill, NC USA

[8] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[9] Immune Tolerance Network, Bethesda, MD USA

[10] Univ Calif San Francisco, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, San Francisco, CA 94143 USA

[11] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Div Gastroenterol Hepatol & Nutr,Med Ctr, Pittsburgh, PA 15213 USA

[12] Ann & Robert H Lurie Childrens Hosp Chicago, Siragusa Transplantat Ctr, Chicago, IL 60611 USA

[13] NIAID, Transplantat Branch, Div Allergy Immunol & Transplantat, Rockville, MD USA

[14] NIDDK, Div Digest Dis & Nutr, Bethesda, MD 20892 USA

[15] Emory Univ, Div Pediat Gastroenterol Hepatol & Nutr, Dept Pediat, Sch Med, Atlanta, GA 30322 USA

[16] Texas Childrens Hosp, Sect Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA

[17] Duke Univ, Dept Surg, Durham, NC USA

[18] Columbia Univ x, Ctr Liver Dis & Transplantat, Dept Surg, Med Ctr Med Ctr, New York, NY USA

[19] Inst Salud Carlos III, Biomed Res Ctr Hepat & Digest Dis, Bioinformat Platform, Barcelona, Spain

[20] Univ Toronto, Hosp Sick Children, Transplant & Regenerat Med Ctr, Div Pediat Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[21] Childrens Hosp Penn, Liver Transplant Program, Philadelphia, PA USA

[22] Univ Colorado, Childrens Hosp Colorado, Div Gastroenterol Hepatokigy & Nutr, Sch Med, Aurora, CO USA

[23] Washington Univ, Sch Med, Div Gastroenterol Hepatol & Nutr, St Louis, MO USA

来源：

HEPATOLOGY | 2021年 / 73卷 / 05期

基金：

英国医学研究理事会;

关键词：

GRAFT FIBROSIS; OPERATIONAL TOLERANCE; CELLULAR REJECTION; T-CELLS; ANTIBODIES; OUTCOMES; FAILURE; GENES; DEATH; RISK;

D O I：

10.1002/hep.31520

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and Aims Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. Approach and Results We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at <= 32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. Conclusions Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

引用

页码：1985 / 2004

页数：20

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