**1. Introduction**

Tarolimus (TAC)-based therapy is the recommended immunosuppressive standard therapy after renal transplantation (RTx), although its numerous adverse e ffects include the development of acute and chronic nephrotoxicity [1]. Unfortunately, TAC has a narrow therapeutic window and a high inter- and intraindividual variable pharmacokinetics, which requires therapeutic drug monitoring (TDM). TAC metabolism is subject to several non-modifiable factors such as age, sex, and CYP3A4/5 genotype of the RTx recipient as well as parameters that may vary, e.g., hematocrit, serum albumin, and steroid doses [2]. In view of the variety of impacting factors, transplant physicians are waiting for a stratification method to identify individuals with a high risk to develop TAC-related adverse effects.

Recently, we and others described a simple and cost-effective tool, the TAC concentration/dose ratio (C/D ratio), to address this problem [3,4]. The C/D ratio is calculated by dividing the TAC trough level by the daily TAC dose. To keep the tool as simple and practical as possible for clinical application, we decided to use only two different C/D ratio categories, although our first approach involved three [4]. A TAC C/D ratio < 1.05 ng/mL/mg assessed three months after RTx indicates fast TAC metabolism, whereas a C/D ratio ≥ 1.05 ng/mL/mg is suggestive of individuals with slow Tac clearance [5]. Using this C/D ratio cut <sup>o</sup>ff, we and others showed that the renal function of fast metabolizers is inferior to that of slow metabolizers after RTx and liver transplantation (cut off 1.09 ng/mL/mg), which is due to, e.g., higher incidences of TAC-related nephrotoxicity and rejections [4–10]. This resulted in decreased graft and patient survival [5,7]. In view of the data, modifications of the immunosuppressive regime of patients with a C/D ratio < 1.05 ng/mL/mg should be considered.

The ZEUS study showed that conversion of RTx recipients from calcineurin inhibitor (CNI) to everolimus (EVR) 4.5 months posttransplant is associated with a significant improvement in renal function, which is maintained for at least five years after RTx [11]. Despite increased rates of early mild acute rejections, long-term graft function was not affected in patients who switched to EVR. A positive effect of conversion from CNI to EVR on renal function was even shown for late conversion after RTx (after a mean of 82.6 months) [12]. However, in none of these studies was a C/D ratio-based stratification investigated in this regard.

Due to the negative impact of TAC on the outcomes of fast metabolizers, we hypothesized that these patients, after conversion to EVR, might have greater benefits than slow metabolizers.

#### **2. Patients and Methods**
