To the Editor, Tacrolimus, a calcineurin inhibitor (CNI), is the mainstay of maintenance immunosuppression after kidney transplantation. It acts by inhibiting calcineurin and suppressing T-lymphocyte activation. It enhances graft survival and dramatically lowers the chance of graft rejection, but because of its limited therapeutic index, even a small dose modification may result in toxicities.1 A 56 year-old man with End stage kidney disease due to diabetic kidney disease underwent ABO compatible living donor kidney transplantation with wife as donor. Methylprednisolone pulses (1.5 g total) and anti-thymocyte globulin (200 mg) were used for induction immunosuppression, and tacrolimus (1.25 mg twice daily), mycophenolate mofetil (1000 mg twice daily), and prednisolone (20 mg once daily) were used for maintenance therapy. He had an uncomplicated postoperative course and was discharged on postoperative day (POD) 11 with a tacrolimus trough of 9.1 ng/mL and blood creatinine of 0.9 mg/dL. On POD 16, he developed sudden-onset lightheadedness and transient loss of consciousness lasting 2 min, followed by spontaneous recovery and no residual deficits. Neurological examination was normal. Noncontrast computed tomography of the brain showed ill-defined hypodensity in the left deep white matter. Laboratory analysis revealed serum potassium 6.5 mEq/L, creatinine 1.4 mg/dL, and tacrolimus trough 21 ng/mL. A diagnosis of CNI neurotoxicity secondary to tacrolimus toxicity was considered. The next day, he experienced a recurrent brief episode of unresponsiveness. Electrolytes, electrocardiogram, and echocardiogram were normal. Magnetic resonance imaging (MRI) brain (diffusion-weighted imaging) revealed a small-to-medium-sized hyperintense lesion in the left deep white matter without any features suggestive of posterior reversible encephalopathy syndrome (PRES) or cerebral edema Figure 1. Magnetic resonance angiography of the brain and neck vessels revealed no vasospasm or atherosclerotic changes Figure 2. Genetic analysis revealed a CYP3A5-3/3 genotype, indicative of a poor metabolizer phenotype for tacrolimus. This finding correlates with the supratherapeutic tacrolimus levels and neurotoxicity despite the standard dose. Tacrolimus dose was reduced to 1 mg once daily, after which trough levels declined to 7 ng/mL. Potassium normalized (4.8 mEq/L) and serum creatinine returned to baseline (0.9 mg/dL). The patient remained asymptomatic and was discharged in stable condition.Figure 1: Magnetic resonance imaging of the brain (diffusion-weighted imaging) revealing a small-to-medium-sized hyperintense lesion in the left deep white matter without any features suggestive of posterior reversible encephalopathy syndrome or cerebral edemaFigure 2: Magnetic resonance angiography of the brain and neck vessels revealing no vasospasm or atherosclerotic changesTacrolimus is metabolized by cytochrome P450 enzymes, mainly CYP3A4 and CYP3A5. Genetic polymorphisms, particularly in CYP3A5, result in marked inter-individual variability in drug metabolism and exposure. Individuals carrying the CYP3A5-3/3 genotype are poor metabolizers and therefore at increased risk of supratherapeutic tacrolimus levels and toxicity even with standard dosing.1 Our case highlights tacrolimus-related neurotoxicity in a CYP3A5-3/3 poor metabolizer who presented with transient loss of consciousness, and MRI of the brain showed a left deep white matter lesion. This patient despite standard dosing developed supratherapeutic trough levels (21 ng/mL) and neurological symptoms that resolved with dose reduction. A number of symptoms, including headache (9%–64%), tremor (15%–54%), seizure (15%), sleeplessness (9%–64%), and paresthesia (17%–40%), can indicate tacrolimus-related neurotoxicity.2 Chronic inflammatory demyelinating polyradiculoneuropathy and PRES are two examples of broader syndromes that might show similar symptoms. Neurotoxicity signs commonly show up in the 1st month after a transplant.3 Vasospasm, endothelial dysfunction, and disruption of the blood–brain barrier are all part of the pathophysiology of CNI neurotoxicity.4 Tacrolimus levels in poor metabolizers can be up to twice as high at the same dose; hence, genetic factors may influence an individual’s susceptibility to the adverse effects.1 Studies of different transplant groups show that CYP3A5 genotyping can help determine the initial dose of tacrolimus, thus reducing the chances of underexposure and toxicity.5 It is therefore important to look for clinical signs of neurotoxicity that can happen before radiologic findings or look like metabolic and vascular events. Early neuroimaging, pharmacogenetic profiling, and therapeutic medication monitoring are crucial for safer and more individualized immunosuppressive treatments.1,5 In conclusion, tacrolimus-related neurotoxicity may present in highly atypical forms, including isolated lacunar-type infarcts without the classic radiological features of PRES. This case underscores the importance of maintaining a high index of suspicion for CNI neurotoxicity, particularly in CYP3A5 3/3 poor metabolizers who are inherently predisposed to supratherapeutic drug exposure despite standard dosing. Early recognition through vigilant neurological assessment, timely neuroimaging, therapeutic drug monitoring, and consideration of pharmacogenetic profiling can enable prompt intervention, prevent irreversible complications, and support safer, individualized immunosuppression in kidney transplant recipients. Declaration of patient consent The authors certify that patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Yadav et al. (Thu,) studied this question.