Abstract
Fast tacrolimus (TAC) metabolism (concentration/dose (C/D) ratio <1.05 ng/mL/mg) is a risk factor for inferior outcomes after renal transplantation (RTx) as it fosters, e.g., TAC-related nephrotoxicity. TAC minimization or conversion to calcineurin-inhibitor free immunosuppression are strategies to improve graft function. Hence, we hypothesized that especially patients with a low C/D ratio profit from a switch to everolimus (EVR). We analyzed data of 34 RTx recipients (17 patients with a C/D ratio <1.05 ng/mL/mg vs. 17 patients with a C/D ratio ≥1.05 ng/mL/mg) who were converted to EVR within 24 months after RTx. The initial immunosuppression consisted of TAC, mycophenolate, prednisolone, and basiliximab induction. During an observation time of 36 months after changing immunosuppression from TAC to EVR, renal function, laboratory values, and adverse effects were compared between the groups. Fast TAC metabolizers were switched to EVR 4.6 (1.5–21.9) months and slow metabolizers 3.3 (1.8–23.0) months after RTx (p = 0.838). Estimated glomerular filtration rate (eGFR) did not differ between the groups at the time of conversion (baseline). Thereafter, the eGFR in all patients increased noticeably (fast metabolizers eGFR 36 months: + 11.0 ± 11.7 (p = 0.005); and slow metabolizers eGFR 36 months: + 9.4 ± 15.9 mL/min/1.73 m2 (p = 0.049)) vs. baseline. Adverse events were not different between the groups. After the switch, eGFR values of all patients increased statistically noticeably with a tendency towards a higher increase in fast TAC metabolizers. Since conversion to EVR was safe in a three-year follow-up for slow and fast TAC metabolizers, this could be an option to protect fast metabolizers from TAC-related issues.
Highlights
Tarolimus (TAC)-based therapy is the recommended immunosuppressive standard therapy after renal transplantation (RTx), its numerous adverse effects include the development of acute and chronic nephrotoxicity [1]
Despite similar TAC trough levels after the first month (M1), TAC doses were noticeably higher and C/D ratio values were lower for fast metabolizers than for slow metabolizers, due to group classification
This finding was confirmed by others, even when higher C/D ratios were used for group definitions or when including patients receiving extended-release TAC [7,16]
Summary
Tarolimus (TAC)-based therapy is the recommended immunosuppressive standard therapy after renal transplantation (RTx), its numerous adverse effects include the development of acute and chronic nephrotoxicity [1]. Using this C/D ratio cut off, we and others showed that the renal function of fast metabolizers is inferior to that of slow metabolizers after RTx and liver transplantation (cut off 1.09 ng/mL/mg), which is due to, e.g., higher incidences of TAC-related nephrotoxicity and rejections [4,5,6,7,8,9,10] This resulted in decreased graft and patient survival [5,7]. In view of the data, modifications of the immunosuppressive regime of patients with a C/D ratio < 1.05 ng/mL/mg should be considered
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