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      Anti-thymocyte globulin induction with delayed introduction of tacrolimus preserves renal function in pediatric liver transplant recipients

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          Abstract

          Background:

          Tacrolimus (TAC)-mediated renal disease occurs in up to 70% of pediatric liver transplant (LT) recipients. The safety and efficacy of renal-sparing immunosuppression using anti-thymocyte globulin (ATG) induction and delayed TAC administration has not been studied in children. We evaluated the safety and efficacy of ATG induction on preserving renal function in children within the first year (Y1) post-LT in a single-center retrospective cohort study.

          Methods:

          Children under age 18 years of who received isolated LT from 2008 to 2020 with a GFR < 70 received renal-sparing (RS) protocol consisting of ATG with methylprednisolone (MP), delayed TAC administration, lower initial TAC trough goals, and mycophenolate mofetil (MMF). The RS group was matched 1:2 by age and LT indication with standard immunosuppression (SI) group. Changes in renal function as well as adverse events within Y1 post-LT were compared.

          Results:

          Forty-four pediatric patients were included in the analysis, of which 13 received RS. As expected, the RS group had significantly lower mean TAC trough levels at 30 days (10.3 vs. 13.2, p = .001) post-LT. Renal function was significantly preserved at 6 (−0.26 vs. 0.21, p = .004) and 12 months (−0.33 vs. 0.11, p = .003) post-LT in the RS versus SI group as measured by mean change in serum creatinine, with similar trends observed in eGFR and cystatin C. ACR, sepsis, viremia, graft loss and mortality occurred at similar rates in both RS and SI groups.

          Conclusion:

          Induction immunosuppression with ATG and delayed TAC administration in children with renal impairment is safe and effectively preserves renal function during Y1 post-LT.

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          Most cited references17

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          Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future.

          The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.
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            Immunosuppression in pediatric liver transplant recipients: Unique aspects

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              Society of pediatric liver transplantation: Current registry status 2011-2018.

              SPLIT was founded in 1995 in order to collect comprehensive prospective data on pediatric liver transplantation, including waiting list data, transplant, and early and late outcomes. Since 2011, data collection of the current registry has been refined to focus on prospective data and outcomes only after transplant to serve as a foundation for the future development of targeted clinical studies.
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                Author and article information

                Journal
                9802574
                21161
                Pediatr Transplant
                Pediatr Transplant
                Pediatric transplantation
                1397-3142
                1399-3046
                14 February 2024
                June 2023
                15 March 2023
                20 February 2024
                : 27
                : 4
                : e14509
                Affiliations
                [1 ]Department of Pediatric Gastroenterology Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
                [2 ]Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
                [3 ]Department of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
                Author notes

                AUTHOR CONTRIBUTION

                Rogers, M—First author. Developed the project and methods, analyzed the data, and wrote and edited the final manuscript. Ambrosino, T—Developed the project and methods. Hatcher, L—Developed the project and methods. Bondoc, A—Edited the final manuscript. Tiao, G—Edited the final manuscript. Peters, A—Senior author. Originated idea of project. Developed the project and methods, wrote and edited the final manuscript.

                Correspondence Anna L. Peters, Department of Pediatric Gastroenterology Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. anna.peters@ 123456cchmc.org
                Author information
                http://orcid.org/0000-0002-5533-1259
                http://orcid.org/0000-0003-0327-1378
                Article
                NIHMS1964403
                10.1111/petr.14509
                10877086
                36919408
                b6f1e1a7-cb80-4a2c-b02d-00343c6c8e5c

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Categories
                Article

                antilymphocyte antibodies,anti-thymocyte globulin,complications of liver transplantation,immunosuppression,pediatric liver transplantation,renal insufficiency,tacrolimus toxicity

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