Neurotoxic Side Effects of Calcineurin Inhibitors in Patients After Liver Transplantation: Preliminary Results of a Quantitative MRI Study of the Brain

Background: Calcineurin inhibitors (CNI) are the most often used immunosuppressive drugs for the prevention of graft rejection after liver transplantation (LT). Long-term CNI treatment, however, is associated with cardiovascular disease and renal dysfunction. Considering the high frequency of neurotoxic side effects during the first weeks after treatment onset, long-term effects upon brain tissue structure and brain function must be expected. Aiming to estimate the long-term influence of CNI on cerebral microstructure and function after LT we carried out this quantitative MR study. Methods: Ninety patients (mean age: 58 ± 8) with a history of at least 3 years after liver transplantation were studied. They were divided into three groups according to their medication of the last two years: 23 patients without CNI, 36 patients with reduced dose of CNI (stable tacrolimus blood trough levels below 5 μg/l or stable cyclosporine A blood trough levels below 50 μg/l) and 31 patients with standard dose of CNI. Four patients were excluded due to incomplete examinations or artefacts. Thirty-two healthy gender- and age-adjusted volunteers served as reference group. All subjects underwent neuropsychological testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and MR examinations at 3 T (Verio, Siemens, Erlangen). The MR protocol included a T1 weighted GRE with 2 flip angles, a T2 weighted TSE with three echoes, a T2* weighted GRE with triple TE. Quantitative T1, relative proton density (PD, in ratio to water phantom), T2 and T2* maps were obtained on-the-fly on the MR system with an extended image reconstruction provided by the manufacturer, using monoexponential fitting to the signal intensity decay curves of the T1 GRE, T2 TSE and T2 GRE sequences, respectively, for region of interest (ROI) measurements, which were made in 18 ROIs located in cerebellum, brainstem, and cerebral gray and white matter. One-way ANOVA with Bonferroni corrected post hoc tests (α = 0.05) were used to compare the qMRI data and Kruskal–Wallis test to compare the RBANS scores between groups. Results: RBANS scores revealed that patients receiving CNI owned a significantly worse visuospatial/constructional ability, and patients with low dose CNI an overall impaired cognitive function compared to controls. qMRI revealed significant microstructural changes, especially in frontal white matter, with higher PD and T2 (CNI free) and higher T2* (CNI free and low dose), indicating increased free water (PD and T2) and reduced metabolism (T2*) within brain tissue of these patients compared to controls. Interestingly, little change has been found in patients with standard CNI dose, indicating probably different phenotypes between patients, by considering that the CNI dose was applied depending on patients’ tolerability to CNI medication. Conclusion: These preliminary results showed that long term medication with CNI affects tissue microstructure in human brain and the brain function after liver transplantation (Figure 1). The authors have none to declare.