Longterm calcineurin inhibitor therapy and brain function in patients after liver transplantation

Abstract

Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P £ 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P 5 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low-dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression.Liver Transplantation 24 56-66 2018 AASLD.Received August 9, 2017; accepted October 19, 2017. Orthotopic liver transplantation (OLT) requires lifelong immunosuppression, which is usually composed of calcineurin inhibitors (CNIs; cyclosporine or tacrolimus), mycophenolate mofetil, and steroids. (1) The development of immunosuppressive therapy regimens based on CNI led to significantly increased survival rates after OLT. (2) In consequence, longterm adverse effects of CNI therapy gained increased importance. Renal dysfunction, malignancy, and cardiovascular disease are predominantly considered, each affecting approximately 25% of the patients 10 years after OLT. (3) Interestingly, data about the longterm effects of CNI on the central nervous system are sparse although neurotoxic side effects of CNI are known especially for the first weeks after OLT. (4,5) Within the first weeks after OLT, approximately 30% of the patients present with neurological symptoms like disorientation, hallucinations, cognitive dysfunction, alterations of consciousness, and seizures, which are generally considered as being caused by CNI therapy. (6) So far, those few studies that addressed the longterm effect of CNI on the central nervous system

Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation

“…To analyse the discussed underlying mechanism of CNI‐induced neurotoxicity we performed a single centre observational study in patients who had undergone liver transplantation 10 years before to investigate CNI‐related alterations in cognitive function, brain structure and metabolism, by using combined psychometric testing, magnetic resonance imaging and magnetic resonance spectroscopy (MRS). The results concerning cognitive dysfunction and alterations of brain structure in CNI‐treated patients have been reported previously . This sub‐study concentrates on the question whether the observed cognitive alterations are related to or accompanied by metabolic alterations of the brain measured with phosphorus and proton MRS.…”

“…The subjects were recruited as previously described in detail . To sum up, all patients treated at the liver transplantation outpatient clinic at Hannover Medical School, who had had liver transplantation more than 2 years before and had the inclusion criteria of age ≥18 years at the time of transplantation and who also had a stable immunosuppressive therapy for at least 2 years, were asked to participate.…”

“…Exclusion criteria were re‐transplantation (>3 months after the first liver transplantation), additional transplantation of another organ, neurological or psychiatric diseases, regular medication with brain affecting drugs, regular daily alcohol consumption or drug addiction, contraindications for magnetic resonance imaging, acute transplant‐rejection at study assessment, acute infection or decompensated heart, liver or kidney function. Of the 85 patients described in Pflugrad et al, three patients had to be excluded due to incomplete MRS measurements. Finally, 82 patients (age 58.3 ± 9.7 years, n = 53 (64.6%) male) were considered in the present analysis.…”

“…The few studies available for liver patients describe cognitive impairment and brain atrophy in patients who underwent liver transplantation about 6‐10 years before. These studies also suggest a negative effect of long‐term CNI therapy upon brain structure and function . Currently several possible mechanisms of CNI‐induced alteration of the brain are discussed: premature CNI induced atherosclerosis and microangiopathy with consecutive structural brain alterations, impairment of the cerebral immune system, impairment of the mitochondrial energy metabolism and alteration of mitochondrial function …”

“…Proton MRS allows the quantification of metabolites such as N‐acetylaspartate (NAA), total choline (tCh), total creatine (tCr), glutamate and glutamine (Glx) and myo‐Inositol (mI) and thereby provides information about neuronal density and integrity (→NAA), turnover of cell membrane (→tCh) or energy metabolism (→tCr). Therefore, for this sub‐study a nonlocalised brain phosphorus MRS was used to measure global concentrations of phosphorous metabolites and a single voxel proton MRS was used to measure regional proton metabolites with the purpose to evaluate neurometabolic alterations in patients treated with different CNI doses after liver transplantation, which may contribute to the reported cognitive dysfunction . We hypothesised that alterations of brain metabolite concentrations are associated with the administered dose of long‐term CNI therapy and that they are linked to cognitive impairment.…”