The tacrolimus metabolism rate influences renal function after kidney transplantation

Abstract

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient's risk management strategies.

Figure 1. Histogram of the distribution of the Tac C/D ratio (ng/mL*1/mg).

The patients showed a symmetric distribution relating to their C/D ratio and were categorized in three groups: slow, intermediate and fast metabolizers. Intermediate metabolizers were grouped around the mean C/D ratio value (1.05–1.54). Patients showing a C/D ratio <1.05 were defined as fast metabolizers, ≥1.55 as slow metabolizers.

Figure 2. eGFR value comparison between the three metabolism groups (a).

Fast and intermediate Tac metabolizers showed statistically noticeable lower eGFR values compared to slow metabolizers one month after RTx. P-values refer to the linear mixed model. Renal function in a 24 months follow-up (b). The differences between the follow-up eGFR values (month 2, 3, 6, 12, 24) and the eGFR value and the eGFR value at month 1 are shown for every metabolism group.