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.
Highlights
Tacrolimus (Tac) is recommended by The Kidney Disease: Improving Global Outcomes (KDIGO) guideline as the immunosuppressant of choice after renal transplantation (RTx) [1]
Kidney function was lower in fast than in slow metabolizers [8,9,15,16]. Based on these findings, suggesting an influence of fast Tac metabolism on adverse events and inferior renal function after renal transplantation, the aim of this study was to analyze whether Tac metabolism type might even impact on definite outcomes such as patient and graft survival and to identify whether fast Tac metabolism constitutes an independent risk factor that physicians should consider besides already known determinants of kidney transplant patients’ long-term outcome
The following parameters were examined: Patient and donor demographics, recipient body mass index (BMI), recipient history of hypertension or diabetes mellitus, cause of end-stage renal disease (ESRD), number of prior kidney transplants, time on dialysis, donor type of transplantation, degree of human leukocyte antigen (HLA)-mismatching, current panel-reactive antibodies (PRA), cold and warm ischemia time and incidence of new-onset diabetes after transplantation (NODAT) and cytomegalovirus (CMV) DNAaemia (a number of >600 copies/mL was considered as relevant corresponding to the threshold value given by the manufacturer (TaqMan-PCR, QIAamp DNA Blood Kit, Qiagen, Hilden, Germany))
Summary
Tacrolimus (Tac) is recommended by The Kidney Disease: Improving Global Outcomes (KDIGO) guideline as the immunosuppressant of choice after renal transplantation (RTx) [1] It is very effective in terms of preventing organ rejection, its highly inter-individual variable metabolism rate can be a challenging factor for physicians as many factors can impact on Tac metabolism [2]. Kidney function (three to 24 months after RTx and 36 months after liver transplantation, respectively) was lower in fast than in slow metabolizers [8,9,15,16] Based on these findings, suggesting an influence of fast Tac metabolism on adverse events and inferior renal function after renal transplantation, the aim of this study was to analyze whether Tac metabolism type might even impact on definite outcomes such as patient and graft survival and to identify whether fast Tac metabolism constitutes an independent risk factor that physicians should consider besides already known determinants of kidney transplant patients’ long-term outcome. Hypothesizing that Tac metabolism-dependent effects on mortality might become discernable in the long-term, the present study was performed in a patient cohort with a complete five-year follow-up
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