Chronic Neurotoxicity Of Calcineurin Inhibitors In Patients After Liver Transplantation

Background and Aims: Orthotopic liver transplantation (OLT) usually requires lifelong calcineurin inhibitor (CNI) therapy to achieve immunosuppression. Due to extended survival of OLT patients, long-term side effects of this drug regime receive increasing attention. Renal dysfunction, malignancy and cardiovascular disease, each affecting about 25% of the patients 10 years after OLT, are predominantly considered. Although calcineurin inhibitors are known to induce neurotoxicity in the first weeks after OLT, long-term data is scarce. The few existing studies indicated memory impairment and brain atrophy. We hypothesize that long-term CNI therapy after OLT causes a dose-dependent cognitive dysfunction and alteration of brain structure. Methods: 20 patients with CNI free immunosuppression, 35 patients on CNI low dose (stable tacrolimus blood trough levels below 5 μg/l or stable cyclosporine A blood trough levels below 50 μg/l) and 30 patients on standard dose (stable tacrolimus blood trough levels above 5 μg/l or stable cyclosporine A blood trough levels above 50 μg/l) CNI immunosuppression matched for age, gender and time since transplantation were included. They underwent neurological examination, psychometric testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Magnetic resonance imaging (MRI) for a semi-quantitative assessment of structural brain alterations such as white matter lesions, ventricular width and periventricular hyperintensities. CNI doses had been adjusted in the low dose and CNI free groups in the past predominantly due to CNI induced kidney damage (n = 50 of n = 55 patients; 91%). 33 healthy controls matched for age, gender and education served as control group. Results: Patients receiving CNI therapy showed significantly worse visuospatial/constructional ability than controls (P ≤ 0.01). Furthermore, patients on low dose CNI therapy showed an overall impaired cognitive function compared to controls (P = 0.03). Patients treated with CNI both showed significantly more parietal white matter lesions than controls (P ≤ 0.03) and more occipital white matter lesions than patients with CNI-free immunosuppression (P ≤ 0.01). The cumulative tacrolimus dosage was significantly associated with the RBANS domain score Language (r = −0.363; P = 0.02). The total WMH were an independent prognostic factor for the RBANS sum score (P = 0.04) and the mean tacrolimus blood trough level was an independent prognostic factor for the ventricular width at the level of the caudate nucleus (P = 0.03). Conclusions: Long-term CNI therapy is associated with cognitive dysfunction and white matter lesions with Tacrolimus seeming to be more neurotoxic than Ciclosporin. After the occurrence of nephrotoxic side effects, continuation of CNI therapy—even in a low dose—carries the risk for cognitive alterations in the long-term, indicating an increased susceptibility against toxic CNI effects in this subgroup of patients. Patients showing CNI toxicity early after OLT might benefit from a change to CNI free immunosuppression in the long-term. The authors have none to declare.