Individualized Dosage of Tacrolimus for Renal Transplantation Patients Based on Pharmacometabonomics
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Sample Collection
2.3. Metabolomics Analysis
2.4. Pharmacodynamic Analysis
2.5. Statistical Analysis
3. Results
3.1. Basic Characteristics of the Study Cohorts
3.2. Correlation of T Lymphocytes with Renal Function Indexes and Outcome of Renal Transplantation
3.3. Metabolic Profiling of Plasma Samples
3.4. Identification of Metabolites Significantly Associated with the Percentage of T Lymphocytes
3.5. Prediction of the Percentage of T Lymphocytes Based on Key Metabolites and Clinical Characteristics
3.6. OPLS-DA Models to Characterize Pharmacodynamic Responses
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Clinical Characteristics | Normal Group (n = 73) | Low-Response Group (n = 16) | High-Response Group (n = 20) | p |
---|---|---|---|---|
Ages (years) | 40.73 ± 11.29 | 40.44 ± 11.14 | 48.8 ± 8.03 | 0.093 |
Female (%) | 24 (32.9%) | 4 (25%) | 5 (25%) | 0.741 |
Tacrolimus dose | 3.03 ± 0.75 | 3.19 ± 0.66 | 2.83 ± 0.90 | 0.369 |
BMI (kg/m2) | 21.46 ± 3.14 | 21.70 ± 3.18 | 22.60 ± 3.04 | 0.254 |
Cr (μmol/L) | 156.43 ± 110.56 | 154.06 ± 79.36 | 484.1 ± 338.47 | <0.001 |
CYC (mg/mL) | 2.43 ± 0.81 | 2.38 ± 0.75 | 5.58 ± 2.71 | <0.001 |
Ccr (ml/min) | 57.03 ± 22.62 | 56.66 ± 23.72 | 24.13 ± 25.62 | <0.001 |
Albumin (g/L) | 36.05 ± 3.04 | 35.83 ± 3.60 | 34.99 ± 2.78 | 0.405 |
Hemoglobin (g/L) | 751.81 ± 538.32 | 97.35 ± 87.39 | 1017.98 ± 619.39 | <0.001 |
Hematocrit (%) | 30.70 ± 5.77 | 27.96 ± 5.76 | 29.53 ± 6.32 | 0.233 |
ALT (U/L) | 30.23 ± 37.84 | 35.81 ± 22.31 | 31.15 ± 26.94 | 0.843 |
AST (U/L) | 19.22 ± 13.47 | 18.25 ± 6.23 | 22.70 ± 16.40 | 0.532 |
Total bilirubin (μmol/L) | 7.29 ± 3.49 | 6.73 ± 2.05 | 8.33 ± 4.94 | 0.398 |
Subgroups | Delayed Graft Function (%) | Acute Rejection (%) |
---|---|---|
Normal group a (n = 73) | 3 (4.11%) | 7 (9.59%) |
Low-response group b (n = 16) | 0 | 4 (25%) |
High-response group c (n = 20) | 11 (68.75%) | 0 |
p | <0.0001 | 0.105 |
Metabolites | ID | Adduct (Observed) | Retention Time | m/z (Observed) | VIP | Correlation Coefficient | p-Value |
---|---|---|---|---|---|---|---|
Mesobilirubinogen | HMDB01898 | [M + H]+ | 4.69 | 593.33 | 1.25 | −0.337 | <0.001 |
Cinnamoside | HMDB38923 | [M + NH4]+ | 4.78 | 536.27 | 1.23 | −0.455 | <0.001 |
L-Isoleucine | HMDB00172 | [M + H]+ | 1.05 | 132.10 | 1.22 | −0.271 | 0.003 |
5-Methoxyindoleacetate | HMDB04096 | [M − H]− | 1.04 | 204.07 | 1.20 | −0.413 | <0.001 |
DG(18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)/0:0) | HMDB07179 | [M − H]− | 11.13 | 667.53 | 1.19 | −0.337 | <0.001 |
PI(16:1(9Z)/0:0) | LMGP06050009 | [M + H − H2O]+ | 4.71 | 553.28 | 1.17 | −0.483 | <0.001 |
Isoleucyl-Proline | HMDB03141 | [M + H]+ | 1.05 | 229.15 | 1.16 | −0.500 | <0.001 |
Retinoyl b-glucuronide | HMDB28915 | [M + H − H2O]+ | 4.64 | 459.24 | 1.16 | −0.462 | <0.001 |
Tryptophyl-Arginine | HMDB29077 | [2M + H]+ | 4.65 | 721.39 | 1.15 | −0.489 | <0.001 |
Butyric acid | HMDB00039 | [2M + H]+ | 4.65 | 177.11 | 1.13 | −0.480 | <0.001 |
Norepinephrine | HMDB00216 | [M + H]+ | 1.05 | 170.08 | 1.12 | −0.452 | <0.001 |
Eicosapentaenoic acid | HMDB01999 | [M − H]− | 9.72 | 301.22 | 1.08 | −0.303 | 0.001 |
Gamma glutamyl ornithine | HMDB02248 | [2M + H]+ | 4.47 | 523.27 | 1.05 | −0.446 | <0.001 |
Methionyl-Methionine | HMDB28979 | [M − H2O − H]- | 3.19 | 261.07 | 1.05 | −0.309 | 0.001 |
Hydroxybutyrylcarnitine | HMDB13127 | [M + NH4]+ | 4.94 | 265.18 | 1.05 | −0.359 | <0.001 |
N2-Succinoylarginine | HMDB32764 | [2M + H]+ | 4.84 | 549.26 | 1.05 | −0.299 | 0.001 |
L-Aspartyl-L-phenylalanine | HMDB00706 | [M - H]- | 0.98 | 279.10 | 1.04 | −0.301 | 0.001 |
24-Keto-25dehydrocholesterol | LMST01010299 | [M + H − H2O]+ | 4.93 | 381.31 | 1.03 | −0.287 | 0.002 |
7-Methylhypoxanthine | HMDB03162 | [M + H]+ | 1.05 | 151.06 | 1.00 | −0.373 | <0.001 |
Variables | Low-Response Group | High-Response Group | ||||||
---|---|---|---|---|---|---|---|---|
95% CI | 95% CI | |||||||
p-Value | OR | Lower | Upper | p-Value | OR | Lower | Upper | |
Dosages | 0.783 | 0.888 | 0.383 | 2.060 | 0.376 | 0.555 | 0.151 | 2.040 |
Serum creatinine | 0.693 | 0.471 | 0.011 | 19.876 | 0.104 | 86.550 | 0.401 | 18,686.260 |
Mesobilirubinogen | 0.179 | 1.135 | 0.944 | 1.364 | 0.010 | 1.351 | 1.074 | 1.699 |
L-Isoleucine | 0.062 | 0.649 | 0.412 | 1.022 | 0.001 | 0.256 | 0.114 | 0.574 |
5-Methoxyindoleacetate | 0.836 | 0.934 | 0.490 | 1.782 | 0.040 | 3.176 | 1.054 | 9.568 |
Eicosapentaenoic acid | 0.638 | 1.082 | 0.778 | 1.505 | 0.019 | 1.686 | 1.089 | 2.608 |
N2-succinoylarginine | 0.114 | 1.014 | 0.997 | 1.031 | 0.108 | 1.014 | 0.997 | 1.031 |
Tryptophyl-arginine | 0.038 | 1.158 | 1.008 | 1.329 | 0.009 | 1.357 | 1.079 | 1.707 |
Butyric acid | 0.022 | 0.896 | 0.816 | 0.984 | 0.111 | 0.889 | 0.770 | 1.027 |
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He, X.; Yang, X.; Yan, X.; Huang, M.; Xiang, Z.; Lou, Y. Individualized Dosage of Tacrolimus for Renal Transplantation Patients Based on Pharmacometabonomics. Molecules 2022, 27, 3517. https://doi.org/10.3390/molecules27113517
He X, Yang X, Yan X, Huang M, Xiang Z, Lou Y. Individualized Dosage of Tacrolimus for Renal Transplantation Patients Based on Pharmacometabonomics. Molecules. 2022; 27(11):3517. https://doi.org/10.3390/molecules27113517
Chicago/Turabian StyleHe, Xiaoying, Xi Yang, Xiaoting Yan, Mingzhu Huang, Zheng Xiang, and Yan Lou. 2022. "Individualized Dosage of Tacrolimus for Renal Transplantation Patients Based on Pharmacometabonomics" Molecules 27, no. 11: 3517. https://doi.org/10.3390/molecules27113517