Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation

Gerold Thölking,Hermann Pavenstädt,Stefan Reuter,Raphael Koch,Dirk Kuypers,Christine Kurschat,Brigitte Filensky,Barbara Suwelack,Katharina Schütte-Nütgen,Ulrich Jehn

doi:10.1038/s41598-021-95201-5

Gerold Thölking, Hermann Pavenstädt + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-95201-5

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Abstract

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.

Highlights

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers
ER- and IR-Tac have a narrow therapeutic window and high intra- and interindividual variability, transplant recipients are at risk of underexposure leading to rejection or overexposure causing e.g. calcineurin inhibitor (CNI)-related toxicity[8, 9]
Because IR-Tac and extended-release tacrolimus (ER-Tac) have comparable safety and efficacy, we hypothesized that a C/D ratio-guided analysis would be able to stratify patients treated with ER-Tac analogously to patients treated with IR-Tac with respect to their Tac metabolism

Summary

Introduction

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. ER- and IR-Tac have a narrow therapeutic window and high intra- and interindividual variability, transplant recipients are at risk of underexposure leading to rejection or overexposure causing e.g. CNI-related toxicity[8, 9]. With this in mind, sequential therapeutic drug monitoring is standard of care, Cmin-based dose titration is limited in predicting individual efficacy[9, 10]. A low C/D ratio is associated with higher C2 Tac levels and higher rejection rates despite comparable trough levels[21,22,23]

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