Impact of Immunosuppression On Executive Functioning After Pediatric Liver Transplantation: An Observational Cohort Study

Objectives: Children after liver transplantation (LTx) show increased rates of impaired cognitive functioning. We aimed to assess the potential effects of immunosuppressive therapy on executive functioning measured by the Children's Colour Trail Test (CCTT) and the cognitive functioning module of the PedsQL (cogPedsQL) in liver transplanted children in order to explore potential targets for intervention to improve executive functioning. Methods: We performed a cross-sectional study in 155 children (78 female) aged 10.4 (2–18) years at 5.0 (0.1–17) years after LTx, with follow-up at 6 months in n = 114. Executive functioning was assessed by CCTT (ages 8–16) and by patients & parent-proxy cogPedsQL. (ages 5–18/2–18 respectively). Results were correlated with clinical parameters. Stability of results over time was compared between n = 23 patients who for clinical reasons switched from twice daily calcineurin inhibitor (CNI) to once-daily slow-release tacrolimus during the study period, and patients with unchanged CNI. Results: Worse executive functioning was associated with longer stay in the ICU and longer time elapsed since transplantation. No difference was found between users of cyclosporin and tacrolimus. Children on once-daily slow-release tacrolimus performed better than children on twice-daily tacrolimus. In children who switched from twice-daily CNI to once-daily tacrolimus, parent-proxy cogPedsQL improved significantly compared to stable results in the non-switch group. Conclusions: Besides a strong impact of disease burden around transplantation, executive functioning appears to deteriorate over time. While there is no clear-cut advantage of any CNI, once-daily tacrolimus appears to be advantageous compared to twice-daily tacrolimus. Address correspondence and reprint requests to Imeke Goldschmidt, Hannover Medical School, Paediatric Gastroenterology and Hepatology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany (e-mail: goldschmidt.imeke@mh-hannover.de). Received 12 June, 2018 Accepted 22 December, 2018 Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). Authorship contributions: Imeke Goldschmidt: participated in research design, organised and performed data acquisition, performed data analysis and wrote the first draft of the manuscript Rolf van Dick: contributed to research design, data analysis and interpretation, and participated in writing the manuscript Ulrich Baumann: initiated and participated in research design, and participated in data interpretation and in writing the manuscript Christoph Jacobi: participated in translation of the PedsQL cognitive functioning module, participated in data acquisition and made important contributions to the manuscript Norman Junge: supported patient acquisition and made important contributions to the manuscript Eva Doreen Pfister: supported patient acquisition and made important contributions to the manuscript Nico Richter: supported patient acquisition and made important contributions to the manuscript Conflicts of interests and sources of funding: This study was supported by an unrestricted grant by Astellas Pharma. Since an analysis of effect of immunosuppression on cognitive functioning is included in the study, this may be perceived as a conflict of interest. Astellas pharma did not participate in or influence data analysis or interpretation. The original PedsQL modul on cognitive functioning was provided by MAPI research trust for a structured translation. No funds were received for the translation. MAPI research trust did not participate in or influence data analysis or interpretation. © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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