Tacrolimus-induced Neurotoxicity Research Articles

Tacrolimus-Induced Neurotoxicity After Transplant: A Literature Review.

Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used globally to prevent rejection after organ transplantation. Although it significantly improves outcomes for solid organ transplant patients, it is associated with various side effects such as nephrotoxicity and neurotoxicity. Tacrolimus-induced neurotoxicity is frequently encountered in clinical practice and can present with a variety of symptoms that may occur even at therapeutic levels. Although tacrolimus-induced neurotoxicity is well documented, there is limited literature available on pharmacologic management. Twenty-eight case reports of tacrolimus-induced neurotoxicity were identified and analyzed in addition to other literature including reviews, retrospective studies, and animal model studies. The severity of cases of tacrolimus-induced neurotoxicity reported ranged from mild symptoms that could be managed with symptomatic treatment to conditions such as posterior reversible encephalopathy syndrome and chronic inflammatory demyelinating polyradiculoneuropathy that may require more immediate intervention. This information was utilized in addition to clinical experience to compile potential management options for prevention and treatment of neurotoxic adverse events. This review is limited by the utilization of primarily retrospective studies and case reports. The available literature on the subject is largely narrative and there are no guidelines on treatment of tacrolimus-induced neurotoxicity at the time of this research. This comprehensive review may guide further studies to investigate the pathophysiology of tacrolimus-induced neurotoxicity and to define patient-specific strategies for mitigation or minimization of neurotoxicity. This is especially important given that management of tacrolimus-induced neurotoxicity can include changes to immunosuppression that can result in an increased risk of rejection.

Neuroprotective effects of ibudilast against tacrolimus induced neurotoxicity

Neurotoxicity is one of the major side effects caused by calcineurin inhibitors such as tacrolimus in clinical practice. The underlying mechanisms remain unclear, and no potential protective agents have been identified yet. Here, we aimed to investigate tacrolimus-induced neurotoxicity and assess the protective effects of ibudilast, a nonselective phosphodiesterase inhibitor with neuroprotective effects, against tacrolimus-induced neurotoxicity. An in vitro assay of human neuroblastoma SH-SY5Y cells showed that ibudilast reduced tacrolimus-induced cell death. Subsequently, using in vivo studies, we assessed the pathological mechanism of neurotoxicity and evaluated the protective effect of ibudilast. Wistar rats were subcutaneously administered tacrolimus (2.5 or 5.0 mg/kg/day) for 14 d, and ibudilast (7.5 mg/kg/day) was intraperitoneally administered once a day beginning 2 d prior to tacrolimus (5 mg/kg/day) administration. We observed that ibudilast significantly reduced the tacrolimus-induced neurotoxic events. From the assessment of excised brains, we found that tacrolimus was penetrated to brain and the brain concentration was correlated with the neurotoxicity-score, although ibudilast had no effect on this pharmacokinetics. Tacrolimus-induced neuronal damage was histopathologically evaluated using Nissl and TUNEL staining, where only the cerebral cortex and CA1 region in hippocampus exhibited neuronal death, but not the CA3 region, dendrite gyrus, and cerebellum. Co-administration of ibudilast significantly attenuated these histopathological changes. In conclusion, these results suggest that tacrolimus translocation into the brain and neuronal damage in the cerebral cortex and CA1 are the underlying mechanisms of tacrolimus-induced neurotoxicity and that ibudilast could be a protective agent against this adverse event.

Tacrolimus-Induced Neurotoxicity in Early Post-Liver Transplant Saudi Patients: Incidence and Risk Factors.

BackgroundTacrolimus is a calcineurin inhibitor (CNI) commonly used as an immunosuppressant to prevent the rejection of organ transplants. After liver transplantation, it can cause early neurological complications, known as early calcineurin inhibitor-induced neurotoxicity (ECIIN). Its management requires CNI withdrawal, a measure that can affect post-transplant outcomes, primarily allograft rejection. In addition, it can negatively impact the quality of life. The incidence and risk factor of ECIIN has not been reported in the Saudi population. We investigated the incidence and risk factors of ECIIN after liver transplant in Saudi patients. We also looked at the length of stay in the Intensive Care Unit, hospital, and 30-day mortality as secondary endpoints.Material/MethodsThis was a retrospective cohort study of adult patients on tacrolimus with mild, moderate, or severe neurological events within the first month after liver transplantation at a single center of patients who meet the inclusion criteria and were over age 14 years. A total of 338 patients were included in the analysis, and the sample size was calculated based on a pilot study.ResultsAmong 338 liver transplantation patients, 63 patients (19%) developed ECIIN. Forty-eight percent of patients had seizures, 23% had agitation, 21% had psychosis, 10% had severe tremors, 13% had confusion, and 6% developed coma. The median time of the incident to develop ECIIN was 9 (IQR: 5–13.5) days after transplant. Thirty-eight patients were managed by switching to cyclosporine, 12 required a reduction in the dose, and 3 were managed temporarily by discontinuing therapy. Autoimmune hepatitis as an underlying liver disease was one of the statistically significant risk factors (P=0.0311). The median length of hospital stay was 31 (IQR: 21–75.5) days, ICU length of stay was 10 (IQR: 5–20.5) days, and 8 patients died within 30 days after transplant.ConclusionsThe incidence of ECIIN in Saud Arabia was similar to that reported in other populations with similar risk factors. Electrolyte imbalance, mainly hyponatremia, was significantly associated with developing ECIIN. Therefore, ECIIN may potentially increase hospital and ICU length of stay.

Tacrolimus-induced neurotoxicity from bipolar disorder to status epilepticus under the therapeutic serum level: a case report

BackgroundTacrolimus is a macrolide immunosuppressant widely used to prevent rejection after solid organ transplantation. In general, adverse events of tacrolimus occur more often as the concentration of tacrolimus in the blood increases. We report the case of a 39-year-old man who developed a variety of adverse events despite in the therapeutic level of tacrolimus in the blood.Case presentationA 39-year-old man underwent liver transplantation for liver cirrhosis due to alcoholic liver disease. The postoperative immunosuppressant consisted of tacrolimus (5 mg) and mycophenolate (500 mg) twice daily. Five months after taking tacrolimus, he presented with talkativeness, which gradually worsened. Brain magnetic resonance imaging performed 10 months after tacrolimus administration revealed a hyperintense lesion affecting the middle of the pontine tegmentum on T2WI. The blood concentration of tacrolimus was 7.2 ng/mL (therapeutic range 5–20 ng/mL). After 21 months, he exhibited postural tremor in both the hands. Twenty-four months after taking tacrolimus, he showed drowsy mentality, intention tremor, and dysdiadochokinesia. Electroencephalography presented generalized high-voltage rhythmic delta waves; therefore, tacrolimus was discontinued in suspicion of tacrolimus-induced neurotoxicity, and anticonvulsive treatment was started. The level of consciousness gradually improved, and the patient was able to walk independently with mild ataxia.ConclusionThis case shows that tacrolimus-induced neurotoxicity can occur even at normal concentrations. Therefore, if a patient taking tacrolimus exhibits psychiatric or neurologic symptoms, neurotoxicity should be considered even when the blood tacrolimus is within the therapeutic range.

Tuberculum sellae meningioma with possible tacrolimus neurotoxicity manifesting as manic-like psychosis after kidney transplantation

BackgroundAlthough kidney transplantation is the best treatment option for chronic kidney disease, the accompanying immunosuppressive treatment can induce severe neurotoxicity presenting, on rare occasions, as psychosis. However, a brain tumor synchronous with immunosuppressant neurotoxicity has never been reported in a kidney transplant recipient. Herein, we report the first case of possible tacrolimus neurotoxicity with a meningioma manifesting as manic-like psychosis after kidney transplantation.Case presentationA 63-year-old male presenting with acute psychotic mania was admitted to a psychiatric ward approximately 2 years after kidney transplantation. On brain magnetic resonance imaging, a tuberculum sellae meningioma was found, and hyperintense white matter lesions with possible tacrolimus-induced neurotoxicity were seen on fluid-attenuated inversion recovery images. Interestingly, the patient showed no visual field defects, and his blood tacrolimus concentration was within therapeutic ranges. After 3 weeks of adjunctive treatment with blonanserin, most of the symptoms had abated.ConclusionsThe present case highlights the fact that neuroimaging studies are necessary to investigate underlying causes, as well as immunosuppressant neurotoxicity, which should all be considered when atypical psychiatric symptoms develop after organ transplantation. Further, this case suggests that the additional use of atypical antipsychotics while maintaining immunosuppressants may be effective for manic-like psychotic symptoms secondary to possible immunosuppressant neurotoxicity synchronous with a meningioma.

Tacrolimus-induced severe headache associated with diffuse leukoencephalopathy: Evidence for an immune-mediated pathogenesis

Tacrolimus-induced encephalopathy presents with acute neurological symptoms such as headache, seizures, visual disturbances, hemiplegia, and altered mental status. A 60-year-old woman, presented to our clinic with a 4-month history of severe headache. She recently underwent kidney transplantation and was taking tacrolimus. MRI scan showed diffuse and symmetric alterations involving both supratentorial and infratentorial white matter. Cerebral spinal fluid assessment for infectious diseases were negative but elevated total protein level and oligoclonal bands positivity were reported. Treatment with steroid bolus, along with tacrolimus tapering, provided clinico-radiological improvement. This is the first case of tacrolimus-induced neurotoxicity strongly suggestive of an immune-mediated pathogenesis.

The association between tacrolimus blood levels and possible neurotoxicity following liver transplantation

Aim: Tacrolimus is an immunosuppressive agent used for prophylaxis of organ rejection after solid organ transplantations. Neuropsychiatric adverse effects that occur in the first 4 weeks following initiation of tacrolimus defined as early tacrolimus-induced neurotoxicity (TIN). In our study, we aimed to determine the incidence of possible TIN and to examine its association with tacrolimus blood levels and establish other medical and clinical factors to predict in patients with liver transplantation.Material and Methods: This retrospective, single-center study was conducted at a transplantation unit of tertiary level university hospital. All the patients were enrolled, who undergone liver transplantation between January 2013 and December 2018. Tacrolimus blood levels were obtained the day after the initiation of tacrolimus and for consecutive 10 days. All the patients z-scores calculated for tacrolimus mean blood levels until index day. Index day is defined as ‘the day of diagnosis of possible TIN’. Age, gender, previous encephalopathy, cadaveric/live donor transplantation, pre-transplantation MELD score, CRP levels and tacrolimus blood levels were investigated as predictors of possible neuropsychiatric events following liver transplantation in two weeks.Results: Tacrolimus z-scores were detected to be significantly different between groups; found to be lower in the possible tacrolimus-induced neurotoxicity group compared to the control group (t=2.607, p=0.01). Pre-transplantation model significantly predicts neuropsychiatric adverse events(χ²(7)=16.049, p=0.035). Conclusion: To our knowledge, this is the first study that shows an inverse association with tacrolimus blood levels and possible TIN; which requires consideration. It is obvious that further well designed, prospective studies are needed to clearly establish risk factors for TIN.

Catatonia as a manifestation of tacrolimus-induced neurotoxicity in organ transplant patients: a case series

Tacrolimus has been associated with severe neurotoxicity in organ transplant patients. Catatonia can be a rare manifestation of tacrolimus-induced neurotoxicity as we report two cases of catatonia in solid organ transplant patients on tacrolimus. Catatonic symptoms completely resolved in these patients after reducing the tacrolimus dosage or switching it to alternative immunosuppressants. Catatonia symptoms in organ transplant patients should alert clinicians to look for tacrolimus-induced neurotoxicity despite normal serum tacrolimus levels and neuroimaging findings.

Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Piątkowska M, Wysocki M, Styczyński J. Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation. Contemporary Oncology/Współczesna Onkologia. 2011;15(3):159-163. doi:10.5114/wo.2011.23006. APA Piątkowska, M., Wysocki, M., & Styczyński, J. (2011). Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation. Contemporary Oncology/Współczesna Onkologia, 15(3), 159-163. https://doi.org/10.5114/wo.2011.23006 Chicago Piątkowska, Magdalena, Mariusz Wysocki, and Jan Styczyński. 2011. "Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation". Contemporary Oncology/Współczesna Onkologia 15 (3): 159-163. doi:10.5114/wo.2011.23006. Harvard Piątkowska, M., Wysocki, M., and Styczyński, J. (2011). Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation. Contemporary Oncology/Współczesna Onkologia, 15(3), pp.159-163. https://doi.org/10.5114/wo.2011.23006 MLA Piątkowska, Magdalena et al. "Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation." Contemporary Oncology/Współczesna Onkologia, vol. 15, no. 3, 2011, pp. 159-163. doi:10.5114/wo.2011.23006. Vancouver Piątkowska M, Wysocki M, Styczyński J. Cerebral complications induced by calcineurin inhibitors in children after haematopoietic stem cell transplantation. Contemporary Oncology/Współczesna Onkologia. 2011;15(3):159-163. doi:10.5114/wo.2011.23006.

09 Tacrolimus-induced neurotoxicity

09 Tacrolimus-induced neurotoxicity

Tacrolimus-induced neurotoxicity and nephrotoxicity is ameliorated by administration in the dark phase in rats.

1. Tacrolimus, a potent immunosuppressant, induces impaired renal function and neurological complications. We investigated the influence of dosing time on the neurotoxicity, nephrotoxicity, and immunosuppressive effect of tacrolimus in rats. 2. The repeated injection of tacrolimus in the light phase (8:00) produced a significantly greater increase than that in the dark phase (20:00) in the duration of harmine-induced tremors and in the blood urea nitrogen (BUN) concentration in rats. An immunosuppressive effect of tacrolimus on the xenotransplantation of mouse-to-rat skin grafts was apparent in the dark phase but not in the light phase. 3. The dosing time-dependent pharmacokinetic results were not observed when tacrolimus concentrations in rat whole blood were measured after a single or repeated injection in the light or dark phase. 4. These findings suggest that treatment in the active phase of the diurnal cycle ameliorates neurotoxicity and nephrotoxicity while maintaining the immunosuppressive effect of tacrolimus. The present findings have important implications for therapeutic approaches to avoid tacrolimus-induced neurotoxicity and nephrotoxicity.

Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives.

The promise of pharmacogenetics is to elucidate the inherited basis of differences between individual responses to drugs, in order to identify the right drug and dose for each patient. Genetic polymorphisms are implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs. The first pharmacogenetic trait identified was monogenic, and concerned the prototypic example of thiopurine methyltransferase (TPMT) implicated in azathioprine metabolism. Individuals with low TPMT activity, inherited in an autosomal codominant fashion, are at risk of drug-induced myelosuppression. TPMT activity determination and DNA-based tests are now used in clinical practice. It has been also demonstrated that there is a link between the polymorphisms of the cytochrome P450 3A5, 3A4 and the multidrug resistance-1 (MDR1) genes, and the daily dose necessary to achieve adequate blood tacrolimus levels. Analysis of MDR1 haplotypes or using the association of the different genes might further improve predictions. Since genotyping methods improve rapidly, it will soon be easy to test for thousands of single nucleotide polymorphisms in one assay. Present challenges are to determine the genes of interest and to validate such determination prospectively in clinical practice.

Steroid-free immunosuppression during and after liver transplantation--a 3-yr follow-up report.

Steroids are traditionally used in liver transplantation as a part of a triple or quadruple immunosuppressive regimen. Steroids act non-specifically and cause multiple side-effects. Most liver transplantation centers reduce the dosage of steroids and eventually withdraw them after various time intervals. A few steroid-free trials have been recently conducted after liver transplantation but long-term data are not yet available. In addition, in these trials steroids were usually given during surgery. We report the long-term (median = 40 months) follow-up data of a prospective pilot study designed to determine whether liver transplantation could be performed with no steroids at all (neither during nor after surgery). Twenty-one consecutive liver transplantations in 20 adult patients between August 1998 and July 1999 were prospectively included in an ab initio steroid-free immunosuppressive protocol. Mean age was 54 yr (40-67 yr). Tacrolimus (through levels, 8-10 ng/mL) and azathioprine (1-2 mg/kg) were started after liver transplantation. Patients were not given steroids during or after liver transplantation except in the event of rejection or in case of tacrolimus or azathioprine toxicity requiring significant dose reduction and/or withdrawal. There has been no case of primary graft dysfunction or non-function. Eleven of 21 liver transplantations (52%) received no steroids throughout the whole study. Rejection developed in five of 21 liver transplantations (23.5%). These rejections responded to standard i.v. steroids (plus ATG in one patient), followed by an oral steroid taper stopped 3 months after rejection. Steroids were transiently given in six liver transplantations for non-immune reasons: two with tacrolimus-induced neurotoxicity, three cases where azathioprine was discontinued, and one for an allergic reaction; four of these six patients are off steroids at last follow-up. The 3-yr graft and patient survival is 95 and 100%, respectively. Steroids are not necessary in more than 50% of liver transplantations. Steroids were transiently needed to treat acute rejection in 23.5% liver transplantations and for toxicity of calcineurin inhibitors or azathioprine or other reason in 28%. Of the patients who received steroids, the majority (70%) was eventually taken off steroids. This prospective single-center pilot study shows that liver transplantation without steroids is feasible and yields no penalty in terms of acute and chronic rejection, immune graft loss, graft function, patient and graft survival.

Tacrolimus-induced neurotoxicity in kidney transplant recipients

Tacrolimus-induced neurotoxicity in kidney transplant recipients

Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene.

Tacrolimus is a substrate of P-glycoprotein (PGP) encoded by the multidrug resistant (MDR)1 gene (ABCB1). PGP, a multidrug efflux pump, restricts the distribution of tacrolimus in the brain. In this study, we investigate the correlation of ABCB1 gene polymorphism with tacrolimus-induced neurotoxicity in patients after liver transplantation. The genotype of 6 patients with neurotoxic events and 11 patients without neurotoxic events was analyzed by polymerase chain reaction (PCR), and 8 mutations were detected. In addition to laboratory findings and patient characteristics, the contribution of mutations in the ABCB1 gene was evaluated with stepwise discriminant function analysis. High tacrolimus concentration, liver dysfunction, and mutation at position 2677 in exon 21 were demonstrated as positive predictors of tacrolimus-induced neurotoxicity. It is indicated that blood concentrations, liver function, graft weight, and polymorphism in the ABCB1 gene are important factors in tacrolimus-induced neurotoxicity.

免疫抑制薬の中枢毒性モニタリング

Cyclosporine-or tacrolimus-induced neurotoxicity was retrospectively evaluated in five patients. Symptoms ranging from mild (tremor, insomnia, visual disturbance) to severe events (convulsion, leukoencephalopathy) were observed. The predisposing risk factors in these patients included hypomagnesemia, liver dysfunction and transient high blood concentrations of the immunosuppressants. Besed on our findings as well as those from other reports, the initial signs and symptoms of immunosuppressant-induced neurotoxicity were as follows ; tremor, headache, anorexia, nausea, vomiting, lethargy, insomnia, anxiety, amnesia, visual disturbance. However, not all of these events correlated with the blood concentrations of the immunosuppressants. The blood cyclosporine concentrations decreased by concomitant use of phenytoin. The blood tacrolimus concentrations varied markedly during the two-week-period after liver transplantation. To prevent patientsfrom developing serious events under immunosuppressant therapy, pharmacists should thus recognize the predisposing risk factors in patients, and carefully monitor the initial signs related to neurotoxicity and the blood concentrations of the patients receiving immunosuppressants.