Reduction of Nephro- and Neurotoxicity by Usage of Extended-Release Calcineurin Inhibition after Heart Transplantation

Objectives: Nephro- and Neurotoxicity as side effects of calcineurin inhibitors (CI) determine morbidity and mortality of patients after heart transplantation (HTX). Potential mechanisms of toxicity include high peak plasma concentrations of CIs with intrarenal vasoconstriction. Tacrolimus as common CI is available as standard-release tacrolimus (Tac) as well as an extended-release tacrolimus (Tac-ER). It was our aim to analyze whether application of the CI tacrolimus with extended release has beneficial effects after HTX.

Methods: Retrospective analyses of 20 patients with regular follow-up after HTX. 10 patients received permanent therapy with Tac. In 10 patients therapy with the CI was switched from Tac to Tac-ER. Endpoints included renal function, variance of CI through level and variance of the prescribed CI doses 3 visits before and after conversion in comparison to patients with permanent Tac therapy, furthermore occurrence of neurologic complications such as tremor or somnolence.

Results: Patient groups were comparable regarding interval after transplantation and immunosuppressive regime. Renal function at conversion was comparable between study groups (GFR Tac: 54 ± 19; Tac-ER: 49 ± 13 mL/min; p = 0.51). After conversion from Tac to Tac-ER an increasing improvement of the glomerular filtration rate was observed (mean T1-T3: 46 ± 16 vs. T6: 55 ± 14 mL/min; p = 0.05). In the study group with permanent Tac medication GFR remained unchanged. Therapy in both study groups resulted in a stable immunosuppression as assessed by standard deviation of intraindividual CI through levels. Following conversion to Tac-ER, even somewhat lesser adaptions of the CI dose to obtain stable immunosuppression were noted (4 vs. 7 in response to 60 through level measurements; p = 0.26). Also, intraindividual deviation of the prescribed CI dose was not increased during the therapy with Tac-ER (0.2 ± 0.3 vs. 0.4 ± 0.5 mg). No case of transplant rejection was observed. Regarding neurologic outcome we observed by trend a reduction of episodes of tremor or somnolence in patients after switch to Tac-Er.

Conclusion: The results from this small retrospective analysis indicate a promising trend for reduced nephro- and neurotoxicity in patients after heart transplantation receiving the calcineurin inhibitor tacrolimus in extended-release form. A conversion to extended-release tacrolimus is safe and feasible requiring no more dose adaptions.