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

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.

Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

“…reported in a large US-based single-center study that the tacrolimus metabolism rate, defined as the concentration-to-dose ratio (CDR), does not have an impact on biopsy-proven acute rejection as previously shown in kidney transplant recipients. [1][2][3] In contrast to our results, they observed a higher mortality rate in nonrapid metabolizers (NRM) compared to rapid metabolizers (RM). 2 Although estimated glomerular filtration rate values were lower at several time points in RMs compared to NRM, they vote against CDR-based tailoring of the tacrolimus therapy.…”

Early postoperative calculation of the tacrolimus concentration‐to‐dose ratio does not predict outcomes after kidney transplantation

“…Recently, Jouve et al [3] showed in a large retrospective singlecenter study that the C/D ratio was in contrast to the CYP3A5 genotype strongly associated with outcomes after renal transplantation (RTx). They used a C/D ratio cutoff of 1.05 µg/l 9 1/mg, which we used to guide risk stratification of RTx patients, as a low C/D ratio (fast Tac metabolism) is associated with, for example, an increased calcineurin inhibitor nephrotoxicity rate, a lower estimated glomerular filtration rate (eGFR), and five-year patient and overall graft survival [5,9].…”

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There is an emerging interest in the tacrolimus metabolism rate as it is linked to outcomes after transplantation [1][2][3][4][5][6][7]. We and others propose the concentration-to-dose (C/D) ratio as a simple surrogate for the individual tacrolimus (Tac) metabolism rate [5,8,9]. Recently, Jouve et al [3] showed in a large retrospective singlecenter study that the C/D ratio was in contrast to the CYP3A5 genotype strongly associated with outcomes after renal transplantation (RTx).

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“…Recently, Jouve et al [3] showed in a large retrospective singlecenter study that the C/D ratio was in contrast to the CYP3A5 genotype strongly associated with outcomes after renal transplantation (RTx). They used a C/D ratio cutoff of 1.05 µg/l 9 1/mg, which we used to guide risk stratification of RTx patients, as a low C/D ratio (fast Tac metabolism) is associated with, for example, an increased calcineurin inhibitor nephrotoxicity rate, a lower estimated glomerular filtration rate (eGFR), and five-year patient and overall graft survival [5,9].Initially, we proposed a classification of patient's Tac metabolism rate based on the C/D ratio expressed as the Tac trough level concentration normalized by the dose (mean C/D ratios at one, three, and six months after RTx) [5]. Notably, even a single C/D ratio calculated in stable patients three months after RTx predicted outcomes, as it is relatively stable over time after the third postoperative months [3,9].Since the negative effect of fast Tac metabolism becomes apparent within a month after RTx and the C/ D ratio is a simple but valuable tool to identify patients who might profit from modification of the immunosuppressive regime, we and others asked whether it can be reliable calculated within the first days after RTx to identify high-risk patients very early [5]?To this end, we retrospectively analyzed the data of 882 patients who received a donor kidney at the University Hospital of M€ unster between January 2007 and December 2017.…”

“…Initially, we proposed a classification of patient's Tac metabolism rate based on the C/D ratio expressed as the Tac trough level concentration normalized by the dose (mean C/D ratios at one, three, and six months after RTx) [5]. Notably, even a single C/D ratio calculated in stable patients three months after RTx predicted outcomes, as it is relatively stable over time after the third postoperative months [3,9].…”