The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Patients
2.2. Biomarker Measurement
2.3. Histological Analysis
2.4. Immunosuppression and Tacrolimus Monitoring
2.5. Statistical Analysis
3. Results
3.1. Characteristics of the Study Population
3.2. Graft Biopsy Group Analysis
3.3. Association between Tacrolimus Monitoring and Biomarkers
3.4. Association between Tacrolimus Monitoring and Rejection
3.5. Tacrolimus Measurements and Graft Function
4. Discussion
5. Conclusions
- -
- The data in this study do not show an association between TAC exposure/metabolism and IF/TA progression during the first year after kidney transplantation. However, a higher TAC CV tertile was associated with a higher chronicity score at a one-year biopsy.
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- Faster TAC metabolism was associated with reduced kidney graft function and an increased risk of rejection. Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk for acute rejection and deterioration of graft function and be a simple and inexpensive tool that is useful for physicians in their daily clinical practice. Based on this finding, we recommend considering more frequently monitoring fast tacrolimus metabolizers and a more cautious tapering of other immunosuppressive medicaments.
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- Measuring tacrolimus blood level variability over six months to one year may help to identify patients at a greater risk of progression for chronic graft lesions and reduced long-term graft function. It may also point to potential non-adherence to immunosuppressive treatment.
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- uNGAL, a possible marker of CNI-induced renal injury, negatively correlated with TAC C0 and C/D ratio at three months and one year and with IF/TA and chronicity scores at three-month biopsies.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BMI | body mass index |
C/D | concentration doses ratio |
CI | confidence interval |
DGF | delayed graft function |
ECD | expanded-criteria donor |
eGFR | estimated glomerular filtration rate |
HD | hemodialysis |
IF/TA | interstitial fibrosis and tubular atrophy |
KIM-1 | kidney injury molecule-1 |
KRT | kidney replacement therapy |
NGAL | neutrophil gelatinase-associated lipocalin |
MMF | mycophenolate mofetil |
OR | odds ratio |
TAC CV | tacrolimus coefficient of variation |
TAC C0 | tacrolimus trough concentration. |
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Characteristics | Values |
---|---|
Donor age, years | 51.39 ± 15.92 |
Donor type, SCD/ECD, (%) | 87 (50.0)/87 (50.0) |
Donor gender, male/female, (%) | 97 (55.7)/77 (44.3) |
Donor hypertension, % | 52.9 |
Donor creatinine, µmol/L | 81 (32–332) |
Cold ischemia time, hours * | 15.3 (9.0–34.3) |
Recipient age, years | 49.09 ± 12.88 |
Recipient gender male/female, (%) | 104 (59.8)/70 (40.2) |
Recipient hypertension, % | 82.8 |
Diabetes mellitus, % | 10.9 |
Recipient BMI, kg/m2 | 25.48 (18.2–38.9) |
HLA mismatch * | 3 (1–6) |
Immunological risk, low/medium/high, (%) | 7.0/80.2/12.8 |
DGF, % | 26.4 |
Rejection during first year, % | 13.8 |
Variable | No IF/TA Progression n = 59 | IF/TA Progression n = 72 | p Value |
---|---|---|---|
TAC dose/weight at 3 months (mg/kg) | 0.121 ± 0.044 | 0.129 ± 0.48 | 0.453 |
TAC dose/weight at 1 year (mg/kg) | 0.079 ± 0.046 | 0.085 ± 0.052 | 0.507 |
TAC C0 at 3 months (ng/mL) | 9.14 ± 2.89 | 9.49 ± 2.96 | 0.49 |
TAC C0 at 6 months (ng/mL) | 8.03 ± 2.4 | 7.59 ± 2.5 | 0.33 |
TAC C0 at 12 months (ng/mL) | 7.53 ± 2.32 | 7.56 ± 2.48 | 0.945 |
C/D at 3 months (ng/mL/mg) | 1.18 (0.32–5.73) | 1.09 (0.28–5) | 0.963 |
C/D at 6 months (ng/mL/mg) | 1.28 (0.45–5.7) | 1.33 (0.3–7.5) | 0.235 |
C/D at 12 months (ng/mL/mg) | 1.3 (0.52–4.7) | 1.24 (0.19–5.95) | 0.454 |
Fast metabolizer percentage at 6 months | 46.3 | 39.7 | 0.457 |
Fast metabolizer percentage at 1 year | 40.9 | 30.2 | 0.266 |
TAC-C0 CV, % | 26.27 ± 11.49 | 27.88 ± 10.44 | 0.423 |
Third TAC-C0 tertile CV | 40.07 ± 8.5 | 38.8 ± 6.6 | 0.678 |
Univariate | Multivariate | |||||
---|---|---|---|---|---|---|
OR | 95% CI | p Value | OR | 95% CI | p Value | |
DGF | 4.19 | 1.719–10.214 | 0.002 | 3.935 | 1.329–11.646 | 0.013 |
Recipient age, years | 0.974 | 0.942–1.007 | 0.122 | |||
Diabetes | 3.513 | 1.187–10.396 | 0.023 | 3.882 | 1.150–13.112 | 0.029 |
Donor age, years | 1.025 | 0.993–1.058 | 0.125 | |||
Donor creatinine, µmol/L | 1.007 | 0.999–1.014 | 0.083 | |||
Cold ischemia time, hours | 1.049 | 0.955–1.142 | 0.34 | |||
TAC C0 at 6 months, ng/mL | 0.78 | 0.622–0.977 | 0.031 | 0.752 | 0.570–0.991 | 0.043 |
Fast metabolizer at 3 months | 3.017 | 1.214–7.497 | 0.017 | |||
Fast metabolizer at 6 months | 2.736 | 1.077–6.951 | 0.034 | |||
Fast metabolizer at 1 year | 2.30 | 0.888–5.958 | 0.081 | |||
C/D at 3 months, ng/mL/mg | 0.301 | 0.12–0.752 | 0.01 | 0.301 | 0.110–0.821 | 0.019 |
C/D at 6 months, ng/mL/mg | 0.44 | 0.188–1.049 | 0.064 | |||
C/D at 1 year, ng/mL/mg | 0.444 | 0.205–0.962 | 0.04 |
Univariate | Multivariate | |||||
---|---|---|---|---|---|---|
OR | 95% CI | p Value | OR | 95% CI | p Value | |
Recipient age, years | 1.001 | 0.974–1.029 | 0.933 | |||
Donor age, years | 1.033 | 1.009–1.056 | 0.006 | 1.043 | 1.001–1.086 | 0.045 |
Donor evaluation | 3.175 | 1.484–6.790 | 0.003 | |||
Donor hypertension | 2.498 | 1.199–5.208 | 0.015 | |||
Cold ischemia time, hours | 1.117 | 1.013–1.232 | 0.027 | |||
KRT time before transplantation, months | 0.986 | 0.973–1.00 | 0.050 | |||
TAC C0 at 6 months, ng/mL | 0.832 | 0.707–0.979 | 0.027 | |||
Fast metabolizer at 6 months | 2.437 | 1.107–5.365 | 0.027 | 4.654 | 1.197–18.097 | 0.026 |
Rejection during first year | 4.648 | 1.014–21.306 | 0.048 | |||
IF/TA score at 1 year | 2.185 | 1.212–3.939 | 0.009 | |||
Chronicity score at 1 year | 1.788 | 1.179–2.711 | 0.006 | 1.575 | 1.002–2.473 | 0.049 |
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Maslauskiene, R.; Vaiciuniene, R.; Radzeviciene, A.; Tretjakovs, P.; Gersone, G.; Stankevicius, E.; Bumblyte, I.A. The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants. Biomedicines 2024, 12, 1125. https://doi.org/10.3390/biomedicines12051125
Maslauskiene R, Vaiciuniene R, Radzeviciene A, Tretjakovs P, Gersone G, Stankevicius E, Bumblyte IA. The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants. Biomedicines. 2024; 12(5):1125. https://doi.org/10.3390/biomedicines12051125
Chicago/Turabian StyleMaslauskiene, Rima, Ruta Vaiciuniene, Aurelija Radzeviciene, Peteris Tretjakovs, Gita Gersone, Edgaras Stankevicius, and Inga Arune Bumblyte. 2024. "The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants" Biomedicines 12, no. 5: 1125. https://doi.org/10.3390/biomedicines12051125