Fast tacrolimus (Tac) metabolism is associated with a more rapid decline of renal function after renal transplantation (RTx). Because the pharmacokinetics of LCP-Tac (LCPT) and immediate-release Tac (IR-Tac) differ, we hypothesized that switching from IR-Tac to LCPT in kidney transplant recipients would improve the estimated glomerular filtration rate (eGFR), particularly in fast metabolizers. For proof of concept, we performed a pilot study including RTx patients who received de novo immunosuppression with IR-Tac. A Tac concentration-to-dose ratio (C/D ratio) < 1.05 ng/mL·1/mg defined fast metabolizers and ≥1.05 ng/mL·1/mg slow metabolizers one month after RTx. Patients were switched to LCPT ≥ 1 month after transplantation and followed for 3 years. Fast metabolizers (n = 58) were switched to LCPT earlier than slow metabolizers (n = 22) after RTx (2.0 (1.0–253.1) vs. 13.2 (1.2–172.8) months, p = 0.005). Twelve months after the conversion to LCPT, Tac doses were reduced by about 65% in both groups. The C/D ratios at 12 months had increased from 0.66 (0.24–2.10) to 1.74 (0.42–5.43) in fast and from 1.15 (0.32–3.60) to 2.75 (1.08–5.90) in slow metabolizers. Fast metabolizers showed noticeable recovery of mean eGFR already one month after the conversion (48.5 ± 17.6 vs. 41.5 ± 17.0 mL/min/1.73 m², p = 0.032) and at all subsequent time points, whereas the eGFR in slow metabolizers remained stable. Switching to LCPT increased Tac bioavailability, C/D ratio, and was associated with a noticeable recovery of renal function in fast metabolizers. Conversion to LCPT is safe and beneficial early after RTx.
Keywords: kidney transplantation; renal; LCPT; tacrolimus; metabolism; C/D ratio; conversion; switch
During the last decades, tacrolimus (Tac) has become the most commonly prescribed calcineurin inhibitor (CNI) after solid organ transplantation [[
Several studies have reported that the treatment of fast metabolizers after RTx with IR- or ER-Tac is associated with adverse outcomes [[
As bioavailability, and Tac peak levels in the blood especially, differ significantly between LCPT and IR-Tac treated patients, we hypothesize that the conversion of fast IR-Tac metabolizers to LCPT results in an improvement in kidney function.
We retrospectively analyzed RTx recipients who underwent transplantation at the University Hospital of Münster between 2005 and 2019. All patients started immunosuppression with IR-Tac and remained on the medication for at least one month after RTx. Included patients were switched to LCPT one month after RTx or later and then followed up for three years. Target Tac trough level was 6–10 ng/mL for the first month. LCPT was introduced with a 30% reduction of preconversion daily IR-Tac [[
The C/D ratio was calculated as described before [[
General demographic data on recipients and information on transplantation were obtained from electronic health records, and data on donors were taken from Eurotransplant. The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (Ethik Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität, No. 2014-381-f-N). Written informed consent with regard to recording their clinical data was given by all participants at the time of transplantation or inclusion into the study. Data were anonymized before analysis. RTx recipients younger than 18 years of age and pregnant women were excluded.
Statistical analyses were performed using IBM SPSS
In descriptive analysis, normally distributed continuous variables are reported as mean ± standard deviation and non-normally distributed continuous variables as median (25% quantile–75% quantile, IQR). Absolute and relative frequencies are given for categorical variables. Metabolism groups were compared using Welch's t-tests for normally distributed data, Mann–Whitney U tests for skewed-distributed data, and Fisher's exact or chi-squared tests for categorical variables. A comparison of the eGFR changes within each metabolism group was performed using Wilcoxon's signed-rank tests. Boxplots were used for graphical representation.
In order to model renal function (eGFR) over time adjusted for dropouts, a multivariable linear mixed model was fitted. The main effects of the factors, which were time since switch (Day 10, month 1, 3, 6, 9, 12, 24, and 36 after switch), metabolizer group (fast/slow), and the interaction between time and group were included as influencing variables. Repeated measurements of each patient were modeled using SAS PROC MIXED by fitting a marginal linear mixed model with an unstructured variance–covariance matrix for the residuals with patient as subject and the order given by time. The empirical sandwich covariance estimator was applied. Missing values were treated as missing at random. Results are reported as least square estimates with the corresponding 95% confidence interval (CI) and p-values from the Wald test.
In total, we followed up 80 RTx recipients who started on IR-Tac and were switched to LCPT one month after RTx or later. A total of 58 patients were characterized as fast and 22 as slow metabolizers according to their corresponding Tac C/D ratio at one month after RTx (Figure 1). Baseline characteristics at RTx did not differ noticeably between the groups (Table 1). There were no noticeable differences between the groups in terms of underlying diseases leading to end-stage renal disease. Most of the patients had arterial hypertension at the time of RTx. In average, fast Tac metabolizers were converted earlier to LCPT compared to slow metabolizers (0.2 (1.0–253.1) vs. 13.2 (1.2–172.8) months after RTx; p = 0.005). The main reasons for a switch in both groups were large trough level variations and avoidance of adverse effects (Table 2).
The immunosuppression is shown in Table 3. Prednisolone and mycophenolate doses did not differ between the metabolizer groups one month after RTx.
IR-Tac and LCPT doses of fast metabolizers were higher at all time points compared to slow metabolizers (all p < 0.016). After the recommended dose reduction of 30% at the day of conversion in both groups, the dose reduction in fast metabolizers was 31.7% on D10, 64.6% on M12, and 70.7% on M36. In slow metabolizers, the median Tac dose was reduced by 48.2% at D10, by 66.7% at M12, and by 70.4% at M36.
IR-Tac trough levels at month 1 and LCPT trough levels at time points D10, M1 and M6 were lower in fast metabolizers. Tac trough levels of fast metabolizers increased slightly after the conversion and achieved the level of the trough concentration "before conversion" approximately at the 12 months mark after conversion (M12). In the group of slow metabolizers, trough concentrations were reduced considerably during the 36-month follow-up.
The C/D ratios of fast metabolizers were lower compared to the C/D ratios of slow metabolizers at all time points. After conversion to LCPT, the median C/D ratio in fast metabolizers increased by 38.9% at D10, 163.6% at M12 and 180.3% after M36. The C/D ratios of slow metabolizers rose by 66.1% at D10 days, 139.1% at M12 and 130.4% after 36 months.
Compared with slow metabolizers, fast IR-Tac metabolizers showed a slightly but not noticeably reduced renal function one month after RTx (47.6 ± 20.8 vs. 44.4 ± 19.0 mL/min/1.73 m², respectively, p = 0.539, Figure 2). After conversion to LCPT, we observed similar eGFR values in both groups. In fast metabolizers, the mean eGFR increased from 41.5 ± 17.0 (before switch) to 48.5 ± 17.6 at M1, to 47.8 ± 15.4 at M12, and to 48.9 ± 19.0 mL/min/1.73 m² at M36 after the conversion. The mean eGFR values of slow metabolizers were 42.2 ± 17.5 before the switch and 43.2 ± 17.7 at M1, 43.7 ± 17.9 at M12, and 43.8 ± 19.2 mL/min/1.73 m² at M36 after the conversion.
In addition, the differences in eGFR between the "before switch" time point and all other time points (ΔeGFR) were analyzed (Figure 3). In fast metabolizers, the ΔeGFR between "M1 before switch" and the date "before switch" differed noticeably (Figure 3A). Additionally, all ΔeGFR values following the conversion also showed a noticeable increase compared with the value "before switch". In slow metabolizers, eGFR values did not differ noticeably between "before switch" and all other time points (Figure 3B).
In the multivariate analysis, a noticeable change of the eGFR over time pooled over both metabolism groups was observed (p = 0.003, Table S1). In this analysis, there was a noticeable eGFR increase in fast metabolizers at all time points compared to before the conversion. No noticeable changes in eGFR values (ΔeGFR) in slow metabolizers compared to before the conversion were found. When comparing the changes in eGFR (ΔeGFR) between fast and slow metabolizers (combination of main and interaction effects of tacrolimus metabolism group and time points), the fast group diverged the most from slow metabolizers within the first 10 days after the switch (4.15 (95% CI 0.54–7.76), p = 0.025). A further slight increase in the difference between the groups was found between D10 and M1 (1.84 (95% CI −1.39–5.07, p = 0.259).
In a further examination, ΔeGFR values were compared between fast and slow metabolizers when a lower C/D ratio cut-off of 0.6 ng/mL·1/mg was chosen (<0.6 = fast metabolizers; ≥0.6 = slow metabolizers (Figure 4)). In this analysis, the increase in ΔeGFR was even more pronounced in fast metabolizers (Figure 4A). Interestingly, slow metabolizers were also found to have higher ΔeGFR at "M1 before switch" and "M1 to M9 after switch" (Figure 4B).
No differences were observed in infection rates (CMV, BKV), BKVN, de novo development of post-transplant diabetes mellitus, CNIT, AR, or death between the groups at any time during the study (Table 4).
In this study, we observed that the marked decline in renal function frequently observed in fast Tac metabolizers treated with IR- or ER-Tac after transplantation was prevented after switching to LCPT (Figure 3) [[
Previously, we found that fast Tac metabolism in IR-treated RTx patients is associated with higher Tac peak levels and higher rejection and BKVN rates, leading to worse renal function compared with IR-treated slow metabolizers [[
A major reason for switching from IR-Tac to LCPT was the variability in intra-patient trough levels (IPV, Table 2). IPV is associated with worse outcomes for several reasons [[
LCPT was shown to be non-inferior to IR-Tac in RTx recipients and demonstrated lower efficacy failure rates in blacks [[
An important difference in the Tac-pharmacokinetics (PK) of patients with a low and a high C/D ratio is the peak concentration, which is thought to play a role in the development of Tac-associated nephrotoxicity [[
As previously shown by us and others, eGFR was lower in fast IR- and ER-Tac metabolizers than in slow metabolizers already at M1 after RTx [[
Our study has several limitations. Because it is a single-center study with a limited number of patients, its power is limited. Further, due to the retrospective nature of our pilot study (first proof of concept), it can only be hypothesis-generating and encourage further prospective studies. Moreover, we did not determine the PK, peak, or IPV in our patients. Therefore, we can only make assumptions about the effects of LCPT on renal values. Fast metabolizers were mostly switched earlier to LCPT than slow metabolizers. This is not surprising, as the main reasons for switching were the side effects and IPV. Side effects and IPV are partly related to Tac dosage which are usually higher early after transplantation than later, due to different reasons, such as the intended trough level or decreasing steroid dosage [[
Our study revealed that switching from IR-Tac to LCPT increased the bioavailability of Tac, saved doses (and costs), and increased the C/D ratio. This may have mitigated the pronounced deterioration of renal function, particularly in fast metabolizers, which are more vulnerable in this respect. Because patients with a low C/D ratio are at risk for a worse outcome after RTx, we suggest calculating the C/D ratio early after RTx in patients treated with IR-Tac. Switching to LCPT was safe and could be beneficial early after RTx.
Graph: Figure 1 Study design and patient enrolment. A total of 80 renal transplant recipients met the inclusion criteria. RTx recipients were defined as fast and slow Tac metabolizers one month after transplantation. All patients were switched to LCPT and observed in a 3-year follow-up. Abbreviations: RTx, renal transplantation; IR-Tac, immediate-release tacrolimus; C/D ratio, concentration-to-dose ratio.
Graph: Figure 2 Boxplots of the renal function at different time points (eGFR, estimated glomerular filtration rate) within 3 years after kidney transplantation. p-values are from Mann–Whitney U tests comparing fast vs. slow metabolizers at each time point. There were no noticeable differences between the groups after conversion.
Graph: Figure 3 Boxplots of the differences in estimated glomerular filtration rates (ΔeGFR) of fast and slow Tac metabolizers (all time points—date of the switch). p-values are from Wilcoxon-signed rank tests for the dependent comparisons of eGFR values at each time point with the eGRF values at the time of the switch. The C/D ratio cut-off to characterize the metabolizer group was 1.05 ng/mL·1/mg. Fast metabolizers developed a noticeable increase in ΔeGFR at D10 after conversion and all following time points (A). ΔeGFR values of slow metabolizers remained stable during the 3 years after the switch (B).
Graph: Figure 4 Boxplots of the differences in estimated glomerular filtration rates (ΔeGFR) of fast and slow Tac metabolizers (all time points—date of the switch). p-values are from Wilcoxon-signed rank tests for the dependent comparisons of eGFR values at each time point with the eGRF values at the time of the switch. The C/D ratio cut-off that characterized the metabolizer groups was changed to 0.6 ng/mL·1/mg. In this case, fast metabolizers developed an even more pronounced increase in ΔeGFR at D10 after conversion and all following time points compared with fast metabolizers defined by a C/D ratio cut-off of 1.05 ng/mL·1/mg (A). ΔeGFR of slow metabolizers also increased at M1–M9 after conversion to LCPT (B).
Table 1 Patients' characteristics.
Fast Metabolizers Slow Metabolizers age (years) 50.0 ± 16.1 49.8 ± 14.7 0.957 a sex (m/f), 37 (63.8%)/21 (36.2%) 13 (59.1%)/9 (40.9%) 0.797 b weight (kg) 80.8 ± 18.3 76.4 ± 15.1 0.274 a height (m) 1.77 ± 0.09 1.75 ± 0.09 0.267 a BMI (kg/m²) 25.5 ± 5.3 24.9 ± 4.3 0.570 a living donor transplantation 37 (63.8%) 16 (72.7%) 0.598 b ABO-i 13 (22.4%) 7 (31.8%) 0.399 b ESP transplantation 4 (6.9%) 1 (4.5%) 1 b DGF 6 (10.3%) 3 (13.6%) 0.700 b cold ischemic time (h) 7.4 ± 5.0 6.7 ± 4.3 0.539 a warm ischemic time (min) 35.9 ± 8.3 35.9 ± 9.2 0.968 a Number of Transplantations 1 51 (87.9%) 19 (86.4%) 0.785 b 2 6 (10.3%) 3 (13.6%) 3 1 (1.7%) 0 HLA MM 0 13 (22.4%) 8 (36.4%) 0.462 b 1–3 23 (39.7%) 7 (31.8%) 4–6 22 (37.9%) 7 (31.8%) PRA > 20% 5 (8.6%) 2 (9.1%) 1 b CMV risk status low 13 (22.4%) 2 (9.1%) 0.105 b intermediate 34 (58.6%) 11(50.0%) high 11 (19.0%) 9 (40.9%) Donor Characteristics donor age (years) 52.7 ± 12.2 55.8 ± 9.7 0.246 a donor sex (m/f), n (%) 24 (41.4%)/34 (58.6%) 7 (31.8%)/15 (68.2%) 0.608 b Diagnosis of ESRD benign nephrosclerosis 4 (6.9%) 1 (4.5%) 0.345 b diabetic nephropathy 3 (5.2%) 1 (4.5%) glomerulonephritis 31 (53.4%) 14 (63.6%) chronic pyelonephritis 0 1 (4.5%) cystic nephropathy 14 (24.1%) 2 (9.1%) Alport syndrome 1 (1.7%) 0 Mediterranean fever 0 1 (4.5%) congenital renal dysgenesis 4 (6.9%) 1 (4.5%) interstitial nephritis 1 (1.7%) 1 (4.5%) Comorbidities Before Transplantation arterial hypertension 56 (96.6%) 21 (95.5%) 1 b diabetes mellitus 8 (13.8%) 1 (4.5%) 0.432 b
Table 2 Reasons for the switch from IR-Tac to LCPT.
Fast Metabolizers Slow Metabolizers infection 1 (1.7%) 1 (4.5%) 0.778 neurological disorder 2 (3.4%) 0 acute rejection 1 (1.7%) 0 CNIT 2 (3.4%) 2 (9.1%) DGF 2 (3.4%) 1 (4.5%) diabetes mellitus 1 (1.7%) 0 trough level variation/avoidance of adverse effects 49 (84.5%) 18 (81.8%)
Table 3 Immunosuppression.
Fast Metabolizers Slow Metabolizers 17.5 (5–25) 15 (5–50) 0.680 a mycophenolate mofetil, 30 (51.7%) 13 (59.1%) 0.621 b mycophenolate sodium, 28 (48.3%) 9 (40.9%) mycophenolate mofetil dose (mg) 1000 (500–2000) 1000 (500–2000) 0.932 a mycophenolate sodium dose (mg) 1440 (720–1440) 1080 (720–1440) 0.213 a IR-Tac M1 12 (5–20) 7 (4–12) <0.001 a before switch (IR-Tac) 10.25 (3–18) 6.75 (1.5–17) <0.001 a D10 LCPT 7 (1.5–14) 3.5 (1.8 11) <0.001 a M1 LCPT 6 (1.5–13.5) 3 (1.5–11) <0.001 a M3 LCPT 4.75 (1.5–12) 3 (1–8) 0.002 a M6 LCPT 4 (1.5–12) 2.5 (0.75–5) 0.001 a M9 LCPT 4 (1.5–11) 2.5 (1–6) 0.001 a M12 LCPT 3.63 (1.5–11) 2.25 (1–5) 0.001 a M24 LCPT 3.38 (1–9) 2.13 (0.75–5.5) 0.008 a M36 LCPT 3 (1–8.5) 2 (0.75–3.5) 0.016 a IR-Tac M1 6.8 (2.4–15.9) 8.7 (6.8–13.5) <0.001 a before switch (IR-Tac) 6.3 (2.4–12.3) 7.5 (3.9–13.5) 0.065 a D10 LCPT 7.2 (1.6–14.7) 6.3 (4.1–9.9) 0.026 a M1 LCPT 7.6 (1.5–19.5) 6.2 (3.7–12.9) 0.041 a M3 LCPT 7.3 (3.8–18.1) 6.7 (4.9–9.9) 0.311 a M6 LCPT 7.0 (2.7–11.4) 6.2 (4.0–10.4) 0.043 a M9 LCPT 6.5 (3.4–10.7) 6.3 (4.2–9.2) 0.992 a M12 LCPTT 6.2 (3.5–10.3) 6.05 (3.8–8.3) 0.224 a M24 LCPT 6.2 (4.0–10.7) 6.2 (2.1–9.4) 0.254 a M36 LCPT 5.5 (4.1–8.9) 5.40 (4.0–8.7) 0.698 a IR-Tac M1 0.64 (0.24–1.01) 1.25 (1.08–3.38) <0.001 a before switch (IR-Tac) 0.66 (0.24–2.10) 1.15 (0.32–3.60) 0.001 a D10 LCPT 1.08 (0.33–4.90) 1.91 (0.40–4.06) 0.002 a M1 LCPT 1.24 (0.21–6.93) 2.23 (0.55–3.47) 0.010 a M3 LCPT 1.52 (0.55–4.93) 2.33 (0.94–6.60) 0.004 a M6 LCPT 1.58 (0.39–5.93) 2.65 (1.06–7.07) 0.007 a M9 LCPT 1.63 (0.40–5.07) 3.23 (1.23–6.30) <0.001 a M12 LCPTT 1.74 (0.42–5.43) 2.75 (1.08–5.90) 0.007 a M24 LCPT 1.81 (0.64–5.40) 2.58 (0.96–6.27) 0.083 a M36 LCPT 1.85 (0.69–5.80) 2.65 (1.32–5.73) 0.026 a
Table 4 Complications before and after switch.
Fast Metabolizers Slow Metabolizers CMV infection before switch to LCPT 8 (13.8%) 2 (9.1%) 0.719 after switch to LCPT (3 y-follow up) 3 (5.2%) 2 (9.1%) 0.612 BKV infection before switch to LCPT 3 (5.2%) 3 (13.6%) 0.338 after switch to LCPT (3 y-follow up) 1 (1.7%) 0 1 BKV nephropathy before switch to LCPT 1 (1.7%) 2 (9.1%) 0.182 after switch to LCPT (3 y-follow up) 0 0 - CNIT before switch to LCPT 3 (5.2%) 2 (9.1%) 0.612 after switch to LCPT (3 y-follow up) 1 (1.7%) 0 1 acute rejection before switch to LCPT 12 (20.7%) 9 (40.9%) 0.089 after switch to LCPT (3 y-follow up) 8 (13.8%) 2 (9.1%) 0.719 death within 3 years after switch 2 (3.4%) 0 1 diabetes mellitus before switch to LCPT 1 (1.7%) 1 (4.5%) 0.477 after switch to LCPT (3 y-follow up) 0 0 -
Conceptualization, G.T. and S.R.; Data curation, F.T.-K.; Formal analysis, F.T.-K., R.K., U.J. and G.T.; Methodology, G.T., S.R.; Resources, H.P. and B.S.; Supervision, G.T.; Writing—original draft, G.T., R.K. and S.R.; Writing—review and editing, H.P. and B.S. All authors have read and agreed to the published version of the manuscript.
This research did not receive external funding.
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethik Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität (No. 2014-381-f-N).
Informed consent was obtained from all subjects involved in the study.
G.T. and S.R. received lecture fees and an unrestricted research grant from Chiesi GmbH, Hamburg, Germany. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
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By Gerold Thölking; Filiz Tosun-Koç; Ulrich Jehn; Raphael Koch; Hermann Pavenstädt; Barbara Suwelack and Stefan Reuter
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