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. 2019 Apr 28;8(5):587.
doi: 10.3390/jcm8050587.

Fast Tac Metabolizers at Risk ⁻ It is Time for a C/D Ratio Calculation

Katharina Schütte-Nütgen  1 , Gerold Thölking  2 , Julia Steinke  3 , Hermann Pavenstädt  4 , René Schmidt  5 , Barbara Suwelack  6 , Stefan Reuter  7
Affiliations

Fast Tac Metabolizers at Risk ⁻ It is Time for a C/D Ratio Calculation

Katharina Schütte-Nütgen et al. J Clin Med. .

Erratum in

Abstract

Tacrolimus (Tac) is a part of the standard immunosuppressive regimen after renal transplantation (RTx). However, its metabolism rate is highly variable. A fast Tac metabolism rate, defined by the Tac blood trough concentration (C) divided by the daily dose (D), is associated with inferior renal function after RTx. Therefore, we hypothesize that the Tac metabolism rate impacts patient and graft survival after RTx. We analyzed all patients who received a RTx between January 2007 and December 2012 and were initially treated with an immunosuppressive regimen containing Tac (Prograf®), mycophenolate mofetil, prednisolone and induction therapy. Patients with a Tac C/D ratio <1.05 ng/mL × 1/mg at three months after RTx were characterized as fast metabolizers and those with a C/D ratio ≥1.05 ng/mL×1/mg as slow metabolizers. Five-year patient and overall graft survival were noticeably reduced in fast metabolizers. Further, fast metabolizers showed a faster decline of eGFR (estimated glomerular filtration rate) within five years after RTx and a higher rejection rate compared to slow metabolizers. Calculation of the Tac C/D ratio three months after RTx may assist physicians in their daily clinical routine to identify Tac-treated patients at risk for the development of inferior graft function, acute rejections, or even higher mortality.

Keywords: C/D-ratio; kidney transplantation; pharmacokinetics; tacrolimus.

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Conflict of interest statement

SR received travel support from Astellas, Chiesi, and Pfizer and lecture fees from Chiesi.

Figures

Figure 1
Figure 1
Enrollment flow chart for the study population. RTx = Renal transplantation; N/A: not available.
Figure 2
Figure 2
(A) Kaplan-Meier curves for patient survival and (B) overall graft survival. Survival rates of slow (red lines) and fast metabolizers (blue lines) were analyzed by the Kaplan–Meier method and compared using the log-rank test. Fast metabolizers showed a noticeably reduced patient and overall graft survival.
Figure 3
Figure 3
Time course of the eGFR within five years after renal transplantation. Fast metabolizers show a faster decline in the eGFR as compared to slow metabolizers over the first five years.
Figure 4
Figure 4
(A) Kaplan-Meier curves for rejection-free survival of slow (red lines) and fast metabolizers (blue lines), analyzed by the Kaplan–Meier method and compared using the log-rank test. Fast metabolizers showed a noticeably reduced rejection-free survival. (B) Subtype analysis of the first rejection episode within the first five years after transplantation. Fast metabolizers experienced increased frequencies of humoral and mixed acute rejection, whereas slow metabolizers were mainly affected by borderline rejections.
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