Targeting High Calcineurin Inhibitor Levels After Acute Rejection With Less Tremor: A New Strategy

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Excerpt

Tremor is one of the most common tacrolimus induced side effect that may affect medication adherence and quality of life in kidney transplant recipients.1,2 The highest amplitude of tremor is typically associated with the peak serum concentration of tacrolimus. Tacrolimus dose reduction is often performed to decrease peak drug levels and therefore tremor severity. However, this approach may increase the risk of rejection in certain patients. In addition, this approach is not reasonable for patients treated for acute rejection as higher drug exposure is needed but the higher drug exposure may be associated with more side effects such as tremor.
Tacrolimus-LCP (Tac-LCP) (Envarsus XR) is an extended-release once-daily tacrolimus preparation that has lower peak concentration, less fluctuation, similar trough levels, and similar exposure measured by area under the curve as twice daily immediate release tacrolimus (Tac-IR).3 Langone et al4 reported a statistical and clinical improvement in tremor as measured by the Fahan-Tolosa-Marin scale by independent blinded neurologists and tremor amplitude measured by Tremor-Meter in 40 kidney transplant recipients converted from Tac-IR to Tac-LCP. However, this study excluded patients who had a rejection episode within 3 months of screening. The use of Tac-LCP after rejection has not been examined, where higher drug exposure is needed and more tremors are expected.
We report a 38-year-old, white man with end stage kidney disease secondary to Henoch-Schonlein purpura who received a deceased donor kidney transplant with a 1A, 2B, 1DR mismatch, panel-reactive antibody of 0% for class 1 and 2, cytomegalovirus donor negative into recipient negative (D-/R-), and induction with thymoglobulin 5 mg/kg. Maintenance immunosuppression was Tac-IR, mycophenolic acid, and prednisone. During the first month, the patient developed tremor with a tacrolimus trough levels ranging from 8 to 10 ng/mL. Tac-IR dose was reduced to a tough level of 5 to 7 ng/mL in the second month (per our protocol). At 3 months posttransplant, the serum creatinine level increased from 1.7 to 3.3 mg/dL (Figure 1). The tacrolimus trough level on admission was 5.8 ng/mL. A kidney allograft biopsy showed a mixed acute cellular rejection (Banff 2A) and antibody mediated rejection. After treatment with plasmapheresis, intravenous immunoglobulin, thymoglobulin 6 mg/kg, and rituximab 200 mg once, Tac-IR was increased to achieve a higher trough of 10 to 12 ng/mL. Upon this increase, the patient developed a severe tremor that was like the immediate time after transplant. Tac-IR was converted to Tac-LCP at 80% of his total daily Tac-IR dose. Follow-up in a week after conversion showed that despite a tacrolimus trough level of 11 ng/mL, his tremor had almost completely resolved. Tacrolimus trough levels were maintained at 10 to 12 ng/mL for 3 months postrejection and then at 5 to 7 ng/mL. 1-year postrejection, the patient continues to have stable kidney function with a creatinine level of 1.4 ng/mL.
Tac-LCP may be a good alternative for patients requiring high levels of tacrolimus in the setting of recent rejection and suffering from severe tremor as in this patient.
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