**3. Results**

### *3.1. Descriptive Statistics*

Patient characteristics, transplantation data, and immunosuppression after the first month are given in Table 1. Slow metabolizers tended to be older and had a lighter body weight, but all characteristics did not differ noticeably between groups. Fast metabolizers were converted from TAC to EVR after a median of 4.6 (1.5–21.9) months, slow metabolizers 3.3 (1.8–23.0) months after RTx (*p* = 0.832). Despite similar TAC trough levels after the first month (M1), TAC doses were noticeably higher and C/D ratio values were lower for fast metabolizers than for slow metabolizers (both *p* < 0.001), due to group classification.


**Table 1.** Patient characteristics and immunosuppression.


**Table 1.** *Cont.*

BMI, body mass index; RTx, renal transplantation; ABOi, ABO incompatible transplantation; ESP, European senior program; CIT, cold ischemia time; WIT, warm ischemia time; CMV, cytomegalovirus; TAC, tacrolimus; C/D, concentration/dose. Statistics: Variables are reported as absolute and relative frequencies, mean ± standard deviation or median (minimum–maximum). a Fisher's exact test; b Welch's t-test; c Mann–Whitney U-test.

The main reason for a conversion from TAC to EVR was CNI-nephrotoxicity in both metabolism groups (Table 2).


**Table 2.** Reasons for the conversion to everolimus.

CNI, calcineurin inhibitor; DGF, delayed graft function; NODAT, new onset diabetes mellitus after transplantation; BKV, BK virus. Statistics: Fisher's exact test.

#### *3.2. Renal Function*

The renal function of fast and slow metabolizers was similar ten days after RTx (39.2 ± 19.7 vs. 33.7 ± 22.5 mL/min/1.73 m2, *p* = 0.456), one month after RTx (39.4 ± 18.8 vs. 34.2 ± 13.5 mL/min/1.73 m2, *p* = 0.367), and at the time of conversion of TAC to EVR (35.1 ± 15.2 vs. 34.2 ± 13.2 mL/min/1.73 m2, *p* = 0.850, Figure 1A). Figure 1B provides the renal function at different time points minus the baseline eGFR (eGFR at the time of conversion, Month 0 (M0)). At the end of the follow-up, the eGFR of the fast TAC metabolizers increased considerably by 11.0 ± 11.7 mL/min/1.73 m<sup>2</sup> (*p* = 0.005, Figure 1B) compared to 9.4 ± 15.9 mL/min/1.73 m<sup>2</sup> in slow metabolizers (*p* = 0.049). These changes were not statistically noticeably different between both groups (*p* = 0.691), but more homogenous in fast metabolizers.

**Figure 1.** Comparison of renal function (eGFR values) of fast and slow TAC metabolizers. Both groups showed a considerable increase in renal function from Day 10 after kidney transplantation to 36 months after conversion from TAC to EVR (no differences between the groups) (**A**). Comparison of eGFR values to baseline eGFR (time of conversion from TAC to EVR) (**B**). Thirty-six months after transplantation, renal function of slow metabolizers showed a noticeable increase (*p* = 0.049), while fast metabolizers a highly noticeable increase (*p* = 0.005).

#### *3.3. Adverse Events*

The median proteinuria value of fast metabolizers was 193 (19–665) mg/g creatinine at M1 after RTx and 361 (97–831) mg/g creatinine at M6 (maximum values) after conversion (Figure 2). The proteinuria in slow metabolizers was 218 (137–664) mg/g creatinine at M1 after RTx and 344 (167–665) mg/g creatinine at M6 (maximum values). At M36, proteinuria had declined to the baseline values without difference between the groups at all time points.

**Figure 2.** Proteinuria. There was a slight increase in proteinuria in both groups from M1 after RTx to M1 after conversion. At a follow-up of 36 months post-conversion, proteinuria recovered to values measured at M1 after RTx.

Table 3 shows the adverse events before and after conversion to EVR. There was no graft loss and no di fferences in outcomes such as delayed graft function (DGF) or overall survival between the groups. The DSA number in all patient groups before and after conversion was low and did not change noticeably. Although it was 9 vs. 6 biopsy-proven acute rejection (BPAR) cases in fast vs. slow metabolizers before conversion to EVR, BPAR rates were considerably lower during follow-up (two episodes (12%) in fast metabolizers and one episode (6%) in slow metabolizer) than before conversion. Cytomegalovirus (CMV) and BK virus (BKV) infections did not occur at di fferent frequencies in fast or slow TAC metabolizers and were uncommon after conversion to EVR.


DGF, delayed graft function; DSA, donor-specific antibody; BPAR, biopsy-proven acute rejection; AMR, antibody-mediated rejection; TCMR, T-cell mediated rejection; EVR, everolimus. Statistics: Adverse events are reported as absolute and relative frequencies. a Fisher's exact test.

Cholesterol and triglycerides tended to be higher in fast than slow metabolizers (no noticeable di fferences, Figure 3A,B) and increased to a similar extent (approximately 20 mg/dL) in both groups after conversion to EVR. Platelets slightly increased after RTx but without di fferences between fast and slow metabolizers (Figure 3C). Hemoglobin levels decreased by 1 g/dL on average in both groups one month after RTx, but increased from 10.8 ± 1.7 g/dL (M1) to 12.5 ± 1.4 g/dL (M36 after conversion) in fast metabolizers and from 10.6 ± 1.6 g/dL (M1) to 13.9 ± 1.1 g/dL (M36 after conversion) in slow metabolizers (Figure 3D). Three years after conversion, hemoglobin levels were noticeably higher in slow metabolizers (*p* = 0.019). None of the RTx recipients needed erythropoiesis-stimulating agents. HbA1c levels increased slightly from 5.3% (4.5–6.4%) at RTx to 6.3% (5.3–9.1%) at M6 after conversion in fast metabolizers and from 5.3% (4.6–6.0%) at RTx to 5.5% (5.0–7.1%) at M6 in slow metabolizers (Figure 3E). HbA1c values decreased only slightly in both groups to a comparable extent until M36.

**Figure 3.** Courses of laboratory values. Cholesterol (**A**) and triglyceride (**B**) levels showed an increase after transplantation, but in a 36-month follow-up values decreased close to values measured at RTx (no noticeable differences between fast and slow metabolizers at any time). Mean platelets (**C**) and hemoglobin (**D**) remained in the normal range at all times without noticeable differences between the groups. Hemoglobin values dropped more than 1 g/dL at M1 after RTx, but had recovered already at the time of conversion from TAC to EVR (no noticeable differences between fast and slow metabolizers at all times). HbA1c levels (**E**) showed an increase one month after RTx without a relevant recovery during a 36-month follow-up after conversion. There were no noticeable differences in HbA1c values between the groups.
