Severe Calcineurin Inhibitor-Induced Parkinsonism After Kidney Transplantation

Most kidney transplant recipients need to adhere to strict immunosuppressive regimens, which generally includes calcineurin inhibitors (CNIs), to prevent graft rejection.¹ The CNI tacrolimus is considered superior to the alternative CNI cyclosporine because tacrolimus is associated with fewer acute rejections, better graft function, and higher graft survival rates.¹ However, tacrolimus use more often results in neurologic side effects.²

Postural tremor and polyneuropathy are increasingly recognized as side effects of tacrolimus. We describe a case of debilitating tacrolimus-induced parkinsonism. This case is particularly noteworthy because of its clinical severity, effect on daily life, and rapid improvement after replacement of tacrolimus therapy with cyclosporine. After 8 months of cyclosporine use, the parkinsonism recurred, but ultimately resolved after discontinuation of cyclosporine and switching to a different class of immunosuppressants.

Case Presentation

BN, age mid-60s, had a history of diabetic polyneuropathy and renal cell carcinoma as primary kidney diseases. BN had received a deceased donor kidney graft and had poor graft function at discharge (estimated glomerular filtration rate, 8 mL/min/1.73 m², with adequate diuresis). Immunosuppressive maintenance therapy was a CNI-based triple regimen with tacrolimus (target trough levels, 5–7 μg/L), everolimus (target trough levels, 3–6 μg/L), and prednisolone. Immediately after transplantation, there were difficulties in reaching target tacrolimus trough concentrations, with trough concentrations ranging from 1.2 to 5.1 μg/L in the first weeks.

Six weeks after transplantation, during a regular outpatient visit, the treating nephrologist noticed tremor and gait disturbance, which BN reported were progressive and had led to multiple falls, resulting in trauma to the face. The symptoms had arisen 4 weeks after transplantation and progressively worsened since that time. A detailed timeline of events, including symptoms and laboratory values, is shown in the Figure. BN was referred to the emergency department (ED) for a neurologic consultation.

At the ED, BN reported “shuffling” gait as well as reduced walking stamina with inability to walk the same distances as before the symptoms began. BN experienced leg weakness and had started to descend stairs facing backward as a precautionary measure against falling. Furthermore, BN reported trembling in the hands during typing and began to experience muscle cramping in the hands, particularly in the evening.

Neurologic examination revealed bilateral rest and postural tremor in the hands and bradykinesia on the left side, revealed by slow finger tapping with progressive halts. BN’s gait was shuffling and broad-based, with a stooped posture. BN had a striatal toe on the right and retropulsion upon testing of postural stability. There was no rigidity in the arms. No muscle weakness or ataxia were present. Romberg test results were unremarkable. However, BN was unable to walk on the heels or toes due to loss of balance. Medical history and medication use are summarized in the Table.

The dominant symptomatology met the parkinsonism criteria of the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson disease (PD). Most causes of parkinsonism (eg, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy) were deemed unlikely in this patient because of the rapid development of symptoms. The progressive and bilateral symptoms did not suggest a strategic infarction. Postural tremor has been well described with CNI use,³ but BN also had rest tremor, which has not been described before with CNI use and is a hallmark of parkinsonism. There was no concomitant medication use such as antidopaminergic agents which would help to explain the parkinsonism. BN had mild hypomagnesemia (0.58 mmol/L), which could contribute to the development of tremor and muscle cramps, but not parkinsonism. Further laboratory testing showed no metabolic disorders, electrolyte disturbances, or infectious diseases that could explain the clinical syndrome. Considering the clear temporal relationship with tacrolimus use and the absence of parkinsonism beforehand, we attributed the parkinsonism to tacrolimus usage.

Immunosuppressive therapy could not be stopped because of the kidney graft. Therefore, the treating neurologists and nephrologists decided to switch to the alternative CNI cyclosporine. The symptoms improved rapidly after the switch. In the first week after conversion, BN’s gait improved markedly, the tremor diminished, and the finger cramps resolved. After the second week of cyclosporine, the shuffling gait and stooped posture were still improving, and BN could walk unsupported and without risk of falling. Laboratory values also improved during the weeks after conversion: estimated glomerular filtration rate increased from 21 to 42 mL/min/1.73 m² and urea level decreased from 25.6 to 17.0 mmol/L.

After 8 months of cyclosporine use, BN was admitted to the ED with acute onset of parkinsonism demonstrated by symmetric bradykinesia and rigidity in all limbs. The course of this episode was similar to the first one, but with later onset of symptoms. The CNI cyclosporine was replaced by sirolimus, a mammalian target of rapamycin inhibitor. Again, the symptoms improved markedly in 2 weeks, and after 3 months, no signs of parkinsonism remained.

Discussion

This is the first case report to describe CNI-induced parkinsonism in a kidney transplant recipient. Our case report highlights the potential debilitating neurotoxicity of CNIs which was reversible after cessation of these drugs. This highlights the importance of tailored immunosuppression in kidney transplant recipients.

The neurotoxic effects of tacrolimus, which resulted in inability to type on a keyboard or eat soup with a spoon as well as postural instability and frequent falls, were severely debilitating, and had a substantial effect on BN’s psychological well-being (see Box).

In general, when side effects of tacrolimus are severe, conversion to cyclosporine is recommended.¹ Conversion from tacrolimus to cyclosporine is safe, and previous studies showed improvements in neurologic symptoms in liver and kidney transplant recipients with this therapy.^4–6 Initially, we were hesitant to replace tacrolimus with cyclosporine, because both may induce neurotoxicity.⁶ Our case report illustrates that cyclosporine may be a temporary solution. In contrast to tacrolimus, cyclosporine may not be able to cross the blood–brain barrier initially.⁷ This may explain why switching to cyclosporine was temporarily beneficial for BN, and why the onset of parkinsonism took longer after the initiation of cyclosporine compared with tacrolimus. Silva et al⁸ recently found that CNI use may be associated with a lower prevalence of PD. Therefore, whereas CNI use may cause parkinsonism, future studies are needed to investigate the role of CNI therapy in the development of PD.

We found similar case reports of tacrolimus-induced parkinsonism in liver transplant recipients, but they differed from our case in terms of treatment and transplant type.^9,10 In 1 case report, the parkinsonism was treated by switching to sirolimus.⁹ In the other case report, amantadine monotherapy was initiated 6 days after tacrolimus was discontinued.¹⁰ Because 6 days elapsed between the treatments, it is possible that cessation of tacrolimus alone could have contributed largely to the reduction of symptoms observed after initiating amantadine monotherapy. Furthermore, these reports describe liver transplant recipients, whereas our report describes a kidney transplant recipient. Previous underlying liver and kidney failures could have played important roles in the different disease progressions.

After successful reduction of neurotoxicity, reconversion to the original drug may be a beneficial option. One study reported 6 patients who were reconverted to tacrolimus because of ongoing rejection (n=3), retransplantation (n=2), or persistent nausea and vomiting (n=1), without recurrence of the original neurologic complication.⁶ Because tacrolimus is the superior immunosuppressant, we recommend future studies to investigate the effect of reconversion to tacrolimus on neurotoxicity in a larger cohort.

A strength of our case report is the documentation of BN’s frequent hospital visits and continuity in monitoring of symptomatology. Furthermore, BN participated in writing this report. A limitation of this case report is that MRI was not performed at the ED to assess the presence of possible brain lesions.

Key Points

• CNIs are important in transplantation medicine, but may be neurotoxic.
• CNI–induced parkinsonism can be severely debilitating and dangerous.
• CNI–induced parkinsonism may be reversible after discontinuation of the drug.