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      Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation

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          Abstract

          Background

          About 50% of the patients 5–7 years after kidney transplantation show impairment of memory, attention and executive function. Tacrolimus frequently induces neurological complications in the first few weeks after transplantation. Furthermore, tacrolimus treatment is associated with impaired cognitive function in the long-term in patients after liver transplantation. We hypothesize that long-term tacrolimus therapy is associated with cognitive dysfunction and alterations of brain structure and metabolism in patients after kidney transplantation.

          Methods

          Twenty-one patients 10 years after kidney transplantation underwent cognitive testing, magnetic resonance imaging and whole brain 31-phosphor magnetic resonance spectroscopy for the assessment of brain function, structure and energy metabolism. Using a cross-sectional study design the results were compared to those of patients 1 (n = 11) and 5 years (n = 10) after kidney transplantation, and healthy controls (n = 17). To further analyze the share of transplantation, tacrolimus therapy and kidney dysfunction on the results patients after liver transplantation (n = 9) were selected as a patient control group.

          Results

          Patients 1 and 10 years after kidney transplantation (p = 0.02) similar to patients 10 years after liver transplantation (p<0.01) showed significantly worse cognitive function than healthy controls. In contrast to patients after liver transplantation patients after kidney transplantation showed significantly reduced adenosine triphosphate levels in the brain compared to healthy controls (p≤0.01). Patients 1 and 5 years after kidney transplantation had significantly increased periventricular hyperintensities compared to healthy controls (p<0.05).

          Conclusions

          Our data indicate that cognitive impairment in the long-term after liver and kidney transplantation cannot exclusively be explained by CNI neurotoxicity.

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          Most cited references24

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          Long-term renal allograft survival in the United States: a critical reappraisal.

          Renal allograft survival has increased tremendously over past decades; this has been mostly attributed to improvements in first-year survival. This report describes the evolution of renal allograft survival in the United States where a total of 252 910 patients received a single-organ kidney transplant between 1989 and 2009. Half-lives were obtained from the Kaplan-Meier and Cox models. Graft half-life for deceased-donor transplants was 6.6 years in 1989, increased to 8 years in 1995, then after the year 2000 further increased to 8.8 years by 2005. More significant improvements were made in higher risk transplants like ECD recipients where the half-lives increased from 3 years in 1989 to 6.4 years in 2005. In low-risk populations like living-donor-recipients half-life did not change with 11.4 years in 1989 and 11.9 years in 2005. First-year attrition rates show dramatic improvements across all subgroups; however, attrition rates beyond the first year show only small improvements and are somewhat more evident in black recipients. The significant progress that has occurred over the last two decades in renal transplantation is mostly driven by improvements in short-term graft survival but long-term attrition is slowly improving and could lead to bigger advances in the future. ©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.
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            A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging.

            Differences in grading signal hyperintensities on magnetic resonance imaging may explain earlier reported conflicting results in studies of normal aging and dementia. We designed a new rating scale in which periventricular and white matter signal hyperintensities as well as basal ganglia and infratentorial signal hyperintensities are rated separately in a semiquantative way. In this study we compared the inter- and intra-observer agreements of this scale to the widely used rating scale of Fazekas. We confirmed the poor to reasonable intra- and inter-observer agreements of the Fazekas scale. The new scale, although more elaborate, provided good agreements with respect to the white matter, basal ganglia and infratentorial signal hyperintensities. In rating periventricular hyperintensities this scale yielded no advantage. It is concluded that this scale may be of use in studies especially focussing on deep white matter pathology on MRI, because it provides more detailed information, with good intra- and inter-observer reliability.
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              ATP and brain function.

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: ResourcesRole: Validation
                Role: ConceptualizationRole: Data curationRole: Methodology
                Role: ResourcesRole: Software
                Role: ConceptualizationRole: Resources
                Role: Resources
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 March 2020
                2020
                : 15
                : 3
                : e0229759
                Affiliations
                [1 ] Department of Neurology, Hannover Medical School, Hannover, Germany
                [2 ] Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
                [3 ] Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
                [4 ] Clinic for Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
                [5 ] Clinic for Nephrology, Hannover Medical School, Hannover, Germany
                University at Buffalo, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                [¤]

                Current address: Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

                ‡ MS and KW contributed equally and are Joint Senior Authors.

                Author information
                http://orcid.org/0000-0001-9570-9730
                Article
                PONE-D-19-27390
                10.1371/journal.pone.0229759
                7064204
                32155172
                3658f029-f442-4675-80eb-60b4c589c531
                © 2020 Pflugrad et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 September 2019
                : 13 February 2020
                Page count
                Figures: 6, Tables: 4, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: 01EO1302
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005624, Medizinischen Hochschule Hannover;
                Award Recipient :
                This study was supported partly by the German Research Foundation (XD) and by a grant from the German Federal Ministry of Education and Research (HP, reference number: 01EO1302). We acknowledge support by the German Research Foundation (DFG) and the Open Access Publication Fund of Hannover Medical School (MHH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Digestive System Procedures
                Liver Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Liver Transplantation
                Biology and Life Sciences
                Neuroscience
                Cognitive Science
                Cognitive Neuroscience
                Cognitive Neurology
                Cognitive Impairment
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                Neuroscience
                Cognitive Neuroscience
                Cognitive Neurology
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                Medicine and Health Sciences
                Neurology
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                Transplantation
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                Renal Transplantation
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                Urinary System Procedures
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                Diagnostic Medicine
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                Renal System
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                Physiology
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