The New Challenge in Pediatric Liver Transplantation: Chronic Antibody-Mediated Rejection

Abstract

Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.

Molecular signatures of chronic antibody-mediated rejection in human liver transplants

“…Nonetheless, these findings have to be validated externally by future multicenter efforts. However, a reasonable amount of cABMR may be missed in such studies if svLBx and DSA testing were not performed routinely as up to 81% of cABMR in our cohort had liver enzymes below two xULN and would not be eligible for liver biopsy in studies that do not incorporate svLBx 47,48 .…”

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance

“…However, long-term improvements in LTx procedures and patient outcomes have been hampered by the cumulative toxicity of maintenance IS therapy ( 57 ). FK506, for instance, was confirmed to be an IS in early studies and is currently the most commonly used drug in the clinic for acute tolerance induction after LTx ( 58 ); however, it can cause infection, nephrotoxicity, and incomplete preservation of graft function during tolerance induction ( 59 ). Therefore, novel immunosuppressive strategies for active liver tolerance induction and long-term good prognosis are urgently needed.…”

Design and evaluation of an educational mobile program for liver transplant patients

“…Lack of adherence to medications in transplanted patients, reflexes a serious problem leading to an increase in the rates of graft rejection and transplanted organ rejection [ 12 ]. Estimates indicate that half of the organ rejections and 15% of the transplant rejections are due to the lack of acceptance and continued use of immunosuppressive medicine [ 13 , 14 ].…”