Tacrolimus Neurotoxicity and the Role of the Renin–Angiotensin System

A 77-year-old woman was admitted to a psychiatry service for a 4-week history of depressed mood, anxiety, insomnia, agitation, and fluctuating confusion. Medications included tacrolimus ER, mycophenolate mofetil, and sertraline (sertraline was initiated 4 weeks previously). Medical history included renal transplantation (10 years earlier) and multiple admissions for recurrent delirium of unspecified etiology (Mini-Mental State Examination between 0/30 and 27/30) during the previous 12 months, in which time immunosuppressants were continued at the same dosages, with tacrolimus trough levels <5.0 ng/mL (reference range, 5.0–15.0 ng/mL).

Examination revealed diplopia on lateral gaze (without oculoparesis or papilledema), truncal ataxia, extremity and head tremor, and normal blood pressure. Mental status examination revealed dysphoric affect, memory and attention deficits, temporal disorientation, and psychomotor agitation. On day 3, worsening confusion and tremor, with new dysarthria, headache, nausea, and vomiting occurred. Incidentally, her blood pressure had acutely increased to 220/98 mm Hg, for which ramipril was started with subsequent good blood pressure control. Laboratory values, electrocardiogram, chest X-rays, and blood culture were unremarkable. Tacrolimus trough level was 3.7 ng/mL. A brain MRI scan revealed deep white matter changes. An EEG showed slowing of background rhythm. After 2 weeks, her depressed mood, insomnia, anxiety, confusion, headache, ataxia, and visual changes all remitted without further medication changes. After 2 months, she remained well.

Emergence of neurotoxicity in a stable immunosuppressed renal transplant patient was striking in the context of subtherapeutic tacrolimus levels. As there was no hyperthermia, diaphoresis, or myoclonus, a serotonin syndrome was ruled out. Resolution of neurotoxicity followed therapy with ramipril, an angiotensin-converting enzyme inhibitor.

Tacrolimus has been associated with neurotoxicity, with various neuropsychiatric symptoms and signs¹ and with a less frequent clinico-radiological syndrome termed posterior reversible encephalopathy syndrome, characterized by mental status changes and focal neurological and characteristic neuroimaging findings.¹ Our patient’s neuropsychiatric symptoms were compelling in the context of hypertensive emergency, suggesting a tacrolimus-related posterior reversible encephalopathy syndrome. Although unstable blood pressure frequently accompanies neurotoxicity, significant hypertension may be absent or the blood pressure may be normal despite associated-neuroimaging changes,^1,2 thus making its clinical recognition challenging.

Posterior reversible encephalopathy syndrome can remit with discontinuation/switch of tacrolimus; however, this may worsen the course by increasing the risk of organ rejection,³ and controlling blood pressure while continuing tacrolimus with monitoring of serum levels may be necessary. Failure to promptly recognize posterior reversible encephalopathy syndrome may cause death due to cardiovascular toxicity.^1,4 Pathophysiology of neurotoxicity remains unclear, but vasculopathy has been suggested.¹ As renin–angiotensin system inhibitors, particularly angiotensin-converting enzyme inhibitors, have proven to be nephroprotective and improved cardiovascular dysfunction in renal transplantation,⁵ some analogy between cellular responses in tacrolimus neurotoxicity, perhaps through cerebrovascular dysfunction, may be inferred, thus hypothetically explaining our patient’s clinical improvement. Solely relying on tacrolimus levels to attribute suspect neurotoxicity can be misleading because trough tacrolimus levels have poor correlation with clinical manifestations.¹

Psychiatrists should actively consider neurotoxicity in any patient on tacrolimus who presents with mental status changes. Full evaluation of cognitive status and prompt recognition and intervention is needed. Prompt management of hypertension may reverse neuropsychiatric signs, even with continued use of tacrolimus. Further elucidation of the CNS benefits in application of angiotensin-converting enzyme inhibitors as end-organ protection agents, independent of blood pressure lowering, and their most effective doses in continued tacrolimus administration is warranted.