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SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.
Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.
الموضوعات
Animals , Mice , Piperidones/administration & dosage , Pyrimidines/administration & dosage , Tea , Plant Extracts/administration & dosage , Tacrolimus/toxicity , Kidney Diseases/drug therapy , Piperidones/pharmacology , Pyrimidines/pharmacology , Plant Extracts/pharmacology , Protective Agents , Drug Synergism , Immunosuppressive Agents/toxicity , Kidney/drug effects , Kidney Diseases/chemically inducedالملخص
Introducción. El tacrolimus es un medicamento inmunosupresor ampliamente usado en trasplante hepático, que presenta una gran variabilidad interindividual la cual se considera asociada a la frecuencia de polimorfismos de CYP3A5 y MDR-1. El objetivo de este estudio fue evaluar la frecuencia de los polimorfismos rs776746, rs2032582 y rs1045642 y su asociación con rechazo clínico y toxicidad farmacológica. Métodos. Se incluyeron pacientes inmunosuprimidos con tacrolimus a quienes se les realizó trasplante hepático en el Hospital San Vicente Fundación Rionegro entre 2020 y 2022, con supervivencia mayor a un mes. Se evaluaron las variables clínicas, rechazo agudo y toxicidad farmacológica. Se secuenciaron los genes de estudio mediante PCR, comparando la expresión o no en cada uno de los pacientes. Resultados. Se identificaron 17 pacientes. El 43 % de los pacientes se clasificaron como CYP3A5*1/*1 y CYP3A5*1/*3, entre los cuales se encontró asociación con aumento en la tasa de rechazo agudo clínico, al comparar con los pacientes no expresivos (100 % vs. 44 %, p=0,05); no hubo diferencias en cuanto a la toxicidad farmacológica u otros desenlaces. Se encontró el polimorfismo rs2032582 en un 50 % y el rs1045642 en un 23,5 % de los pacientes, sin embargo, no se identificó asociación con rechazo u otros eventos clínicos. Conclusiones. Se encontró una asociación entre el genotipo CYP3A5*1/*1 y CYP3A5*1/*3 y la tasa de rechazo clínico. Sin embargo, se requiere una muestra más amplia para validar estos datos y plantear modelos de medicina personalizada.
Introduction. Tacrolimus is an immunosuppressive drug widely used in liver transplantation, which presents great interindividual variability which is considered associated with the frequency of CYP3A5 and MDR-1 polymorphisms. The objective of this study was to evaluate the frequency of the rs776746, rs2032582 and rs1045642 polymorphisms and their association with clinical rejection and drug toxicity. Methods. Immunosuppressed patients with tacrolimus who underwent a liver transplant at the Hospital San Vicente Fundación Rionegro between 2020 and 2022 were included, with survival of more than one month. Clinical variables, acute rejection and pharmacological toxicity were evaluated. The study genes were sequenced by PCR, comparing their expression or not in each of the patients. Results. Seventeen patients were identified. 43% of the patients were classified as CYP3A5*1/*1 and CYP3A5*1/*3, among which an association was found with increased rates of clinical acute rejection when compared with non-expressive patients (100% vs. 44%, p=0.05). There were no differences in drug toxicity or other outcomes. The rs2032582 polymorphism was found in 50% and rs1045642 in 23.5% of patients; however, no association with rejection or other clinical events was identified. Conclusions. An association was found between the CYP3A5*1/*1 and CYP3A5*1/*3 genotype and the clinical rejection rate. However, a larger sample is required to validate these data and propose models of personalized medicine.
الموضوعات
Humans , Pharmacogenetics , Liver Transplantation , Polymorphism, Single Nucleotide , Organ Transplantation , Tacrolimus , Graft Rejectionالملخص
Objective To establish a quality control method for monitoring the blood concentrations of cyclosporin A and tacrolimus by HPLC-MS/MS,and to evaluate the quality control samples using the Westgard multi-rule theory.Methods HPLC-MS/MS was used to determine the concentration of cyclosporin A and tacrolimus in human whole blood.The quality control samples of low,medium and high concentration levels in the therapeutic drug monitoring process were statistically analyzed,Levery-Jennings and Z-score quality control charts were drawn,and the Westgard multi-rule theory was applied for in-house quality control evaluation.Results The established method was fully validated with linear ranges of 10.40-1 040.00 ng·mL-1 and 0.50-49.50 ng·mL-1,the quantification limits were 10.40 and 0.50 ng·mL-1,respectively.The extraction recoveries were 108.61％-113.24％and 101.99％-109.37％,respectively.The matrix factors normalized by internal standard were 106.68％-111.27％and 95.70％-97.81％for cyclosporin A and tacrolimus,respectively.The intra-day and inter-day accuracy and precision were less than 15.0％.Other parameters were also validated and met the acceptance criteria.Levery-Jennings and Z-score quality control charts showed that there were 4 warnings(violation of the 12s rule)in the results of the 26 groups of quality control samples in the third quarter of 2022,and no phenomenon was observed to be out of control.Conclusion The established in-house quality control system for therapeutic drug monitoring of cyclosporin A and tacrolimus can effectively ensure the accuracy of blood drug concentration detection.
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Objective To present a pharmaceutical care case of a pediatric patient with nephrotic syndrome developing tacrolimus-inducedposterior reversible encephalopathy syndrome(PRES)during tacrolimus treatment,and to accumulate experience for the treatment and pharmaceutical services of related diseases.Methods Clinical pharmacists conduct an analysis and evaluation of the correlation of drug-induced PRES caused by tacrolimus in a pediatric patient.Simultaneously,regarding the latest evidence-based information,they propose optimized drug therapy recommendations and provide personalized pharmaceutical services.Results After treatment with antispasmodics,blood pressure control,intracranial pressure reduction,and tapering of tacrolimus,the clinical symptoms of the child improved.Follow-up cranial MRI demonstrated partial absorption of abnormal signals in the brain,and the lesions were significantly smaller than before.Conclusion For tacrolimus-related PRES,clinical pharmacists can enhance the long-term safety and effectiveness of patient medication through aspects such as choosing antihypertensive drugs,adjusting treatment plans based on drug concentration monitoring,and implementing targeted pharmaceutical monitoring and educatio.
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Tacrolimus is a commonly used medication for the treatment of nephrotic syndrome. Due to its narrow therapeutic window and significant pharmacokinetic differences among individuals, therapeutic drug monitoring is required during its clinical use. In the process of therapeutic drug monitoring, machine learning-based personalized dosing prediction models for tacrolimus can excavate medication patterns from a large amount of clinical data, assist in clinical decision-making, and achieve individualized precise medication. Machine learning models, the application progress of machine learning in personalized administration of tacrolimus for patients with nephrotic syndrome, modeling points of machine learning prediction models, and the limitations of current prediction models were reviewed in this paper, which could provide references for future research in this field.
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Objective To investigate the characteristics of adverse drug event (ADE) related to tacrolimus (Tac) in pediatric solid organ transplant recipients. Methods The data were retrieved from the US Food and Drug Administration Adverse Event Reporting System database from the first quarter of 2004 to the second quarter of 2023. The ADE data of pediatric organ transplant recipients with Tac as the primary suspected drug were extracted. The relationship between Tac and ADE was quantitatively analyzed by proportional imbalance method. Basic characteristics and signal strength of ADE related to Tac were analyzed. ADE related to Tac in children of different ages and different types of organ transplantation were analyzed. Results A total of 1 443 children's ADE reports involving Tac were screened, including 188 cases (13.0%) of heart transplantation, 668 cases (46.3%) of liver transplantation, 531 cases (36.8%) of kidney transplantation and 56 cases (3.9%) of lung transplantation. The median age of children was 10 years old. The top three countries with ADE reporting were the United States, France and the United Kingdom. China reported 26 cases, accounting for 1.8%. Infection and infectious diseases accounted for the highest proportion (20.96%) in ADE related to Tac, including EB virus and cytomegalovirus infection, etc. Infection and infectious diseases occupied the largest proportion of ADE related to Tac in children of different ages, whereas the pathogen types were different. Rejection, unstable immunosuppression level and renal function damage were also common ADE related to Tac in children of all ages. Nervous system disease was the main ADE in heart transplant recipients, while infection and infectious diseases were more common in liver and kidney transplant recipients. Rejection was the most common ADE in lung transplant recipients. Conclusions ADE related to Tac possess different distribution characteristics in different types of organ transplantation. Extensive attention should be paid to individualized drug monitoring and risk assessment in pediatric organ transplant recipients, thereby optimizing Tac treatment and reducing the risk of ADE.
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Objective To analyze the co-expressed genes in blood lipid metabolism, hyperlipidemia and tacrolimus metabolism and their correlation with blood lipid levels in kidney transplant recipients. Methods Co-expressed genes were screened from Comparative Toxicogenomic Database (CTD). Baseline data of 25 kidney transplant recipients were collected. The expression levels of ATP binding cassette subfamily A member 1(ABCA1), peroxisome proliferator activated receptor γ (PPAR-γ) and glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) were measured. All recipients were followed up. The concentrations of fasting blood glucose, glycosylated hemoglobin, triglyceride, total protein, albumin, globulin, cholesterol, high-density lipoprotein, low-density lipoprotein and tacrolimus blood concentration were collected at postoperative 1, 3, 6 and 12 months, and the incidence of hyperlipidemia in the recipients was analyzed. The correlation between ABCA1, GPIHBP1, PPAR-γ and clinical indexes was assessed. The diagnostic efficiency of related indexes for hyperlipidemia after kidney transplantation was evaluated. Results Three co-expressed genes including ABCA1, PPAR-γ and GPIHBP1 were screened. ABCA1 was positively correlated with cholesterol level at postoperative 6 months and tacrolimus blood concentration at postoperative 3 months, whereas negatively correlated with fasting blood glucose level at postoperative 3 months (all P<0.05). GPIHBP1 was negatively correlated with preoperative cholesterol and triglyceride levels, whereas positively correlated with tacrolimus blood concentration at postoperative 3 months (all P<0.05). PPAR-γ was negatively correlated with preoperative globulin and low-density lipoprotein levels (both P<0.05). ABCA1, GPIHBP1 and PPAR-γ combined with preoperative globulin and blood glucose level at postoperative 1 and 6 months after operation yielded high diagnostic efficiency for hypertriglyceridemia after kidney transplantation (AUC=0.900). ABCA1, GPIHBP1 and PPAR-γ combined with tacrolimus blood concentrations at postoperative 1 and 6 months and blood glucose level at postoperative 6 months had high diagnostic efficiency for hypercholesterolemia after kidney transplantation (AUC=0.931). Conclusions ABCA1, GPIHBP1 and PPAR-γ are correlated with blood lipid level and tacrolimus blood concentration after kidney transplantation to different degrees. No definite evidence has been supported for predicting hyperlipidemia after kidney transplantation. Immunity improvement and rational blood glucose management may be beneficial factors for hyperlipidemia control.
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Objective To evaluate the predictive ability and influencing factors of individualized drug administration adjuvant decision-making system Java PK® for Desktop (JPKD) for tacrolimus blood concentration in kidney transplant recipients. Methods The monitoring data of tacrolimus blood concentration from 149 recipients early after kidney transplantation were collected. The trough blood concentration of tacrolimus was predicted by JPKD. The absolute weighted deviation and relative prediction deviation between the actual and predicted concentration were calculated. The influencing factors of the absolute weighted deviation were analyzed by univariate and multivariate logistic regression analyses, and the predictive values of these influencing factors on the accuracy of software prediction were assessed by delineating the receiver operating characteristic (ROC) curve. Results Two hundred and sixty-six samples of tacrolimus blood concentration data were collected from 149 patients. The measured blood concentration of tacrolimus was (6.5±3.0) ng/mL (1.1-16.6 ng/mL), and the predicted value calculated by JPKD was (5.6±2.5) ng/mL (1.4-14.4 ng/mL). The absolute weighted deviation of the calculated data was 28.38%, and the relative prediction deviation was −13.55%. Univariate analysis showed that gender, albumin, changes in hematocrit, cytochrome P450 (CYP)3A5*3 genotype and C3435T genotype were associated with the inaccurate prediction results. Multivariate logistic regression analysis found that CYP3A5*3 genotype of AA and the changes in hematocrit were the independent risk factors affecting the accuracy of tacrolimus blood concentration predicted by JPKD. ROC curve analysis showed that when the changes in hematocrit exceeded 2.25%, the risk of inaccurate software prediction was increased. Conclusions JPKD possesses certain accuracy in predicting the blood concentration of tacrolimus in kidney transplant recipients, which may improve the qualified rate of tacrolimus blood concentration. Nevertheless, CYP3A5*3 genotype and the changes of hematocrit may affect the accuracy of predictions.
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Objective To study the effect of Bailing capsule on renal function and other organ systems in 60 patients after renal transplantation in No. 910 Hospital of Joint Logistics Support Force. Methods 60 patients with renal allograft in 2018−2020 were divided into 2 groups according to different immunosuppressive regimens. In the control group, 35 cases were treated with MMF + CsA or FK506; in the treatment group, 25 cases were treated with MMF + CsA or FK506 + Bailing capsule. Blood and urine routine, liver and renal function and uric acid were measured after operation. The dosage of immunosuppressive drugs was recorded in stages at 48 weeks. Results The urinary red and white blood cell counts, blood aspartate transaminase and alanine transaminase, serum uric acid, total bilirubin and direct bilirubin in the treatment group were significantly less than those in the control group, while the serum total protein and albumin were significantly higher than those in the control group. The number of red blood cells and white blood cells in the treatment group was significantly higher than that in the control group at 12-48 weeks after kidney transplantation, and that in the lymphocyte group was significantly higher than that in the control group at 24-48 weeks after kidney transplantation. The dosage of CsA and FK506 in the treatment group was significantly lower than that in the control group after 48 weeks. Conclusion Bailing capsule could protect liver and kidney, stimulate hematopoiesis, improve hypoalbuminemia and reduce the dosage of immunosuppressant, which could be an ideal immunomodulator.
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OBJECTIVE To investigate the monitoring of tacrolimus blood concentration in patients with nephrotic syndrome （NS），and to establish a prediction model for tacrolimus blood concentration. METHODS Data from 509 concentration monitoring sessions of 166 NS patients using tacrolimus were collected from January 1， 2020 to August 31， 2023 in Zhongshan Hospital Affiliated to Xiamen University. The relationship of efficacy and adverse drug reaction（ADR） with blood concentration was analyzed. A multilayer perceptron （MLP） prediction model was established by using the blood concentration monitoring data of 302 times from 109 NS patients with genetic information， and then verified. RESULTS In terms of efficacy， the median blood concentration of tacrolimus in the non-remission group was 2.20 ng/mL， which was significantly lower than that in the partial remission group （4.00 ng/mL， P＜0.001） and the complete remission group （3.60 ng/mL， P＝0.002）. In terms of ADR， the median blood concentration of tacrolimus in the ADR group was 5.01 ng/mL， which was significantly higher than that in the non-ADR group （3.37 ng/mL） （P＝0.001）. According to the subgroup analysis of the receiver operating characteristic curve， when the blood concentration of tacrolimus was ≥6.65 ng/mL， patients were more likely to develop elevated blood creatinine [area under the curve （AUC） was 0.764， P＜0.001）； when the blood concentration of tacrolimus was ≥6.55 ng/mL， patients were more likely to develop blood glucose （AUC＝0.615， P＝ 0.005）. The established MLP prediction model has a loss function of 0.9， with an average absolute error of 0.279 5 ng/mL between the predicted and measured values. The determination coefficient of the validation scatter plot was 0.984， indicating an excellent predictive performance of the model. CONCLUSION Tacrolimus blood concentration has an impact on both efficacy and ADR in NS patients. The use of the MLP model for predicting blood concentration exhibits high accuracy with minimal error between predicted and measured values. The model can be used as an important tool in clinical individualized medication regimens.
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BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.
INTRODUCCIÓN: La ototoxicidad corresponde a un efecto secundario a agentes terapéuticos que se manifiesta como hipoacusia sensorioneural bilateral simétrica de frecuencias agudas. Se postulan posibles efectos ototóxicos de los inmunosupresores inhibidores de la calcineurina, pero hasta la fecha es aún incierto. El objetivo de este estudio fue evaluar los cambios audiológicos en pacientes trasplantados en tratamiento inmunosupresor con inhibidores de calcineurina. MATERIAL Y MÉTODO: Cohorte prospectiva. Se incluyeron pacientes adultos sometidos a trasplante hepático o renal tratados con inhibidores de calcineurina. Se realizó una evaluación otorrinolaringo-lógica pre-trasplante con audiometría tonal, emisiones otoacústicas por producto de distorsión y cuestionario Tinnitus Handicap Inventory. Se realizó una evaluación audiológica de seguimiento uno, tres y seis meses después del trasplante. Se compararon los umbrales auditivos antes y después del inicio del tratamiento inmunosupresor y se correlacionaron con las concentraciones plasmáticas de IC. RESULTADOS: Se incluyeron 17 pacientes, 59% hombres, con una mediana de edad de 54,7 años. La mediana de seguimiento fue 5,8 meses. Se observaron cambios en el promedio tonal puro en dos pacientes, los cuales no seguían un patrón audiométrico sugerente de ototoxicidad. Todos los pacientes recibieron Tacrolimus dentro del rango terapéutico durante el seguimiento. Tres pacientes diferentes excedieron el rango esperado una vez sin embargo, se corrigieron rápidamente y no se correlacionaron con cambios auditivos, puntaje de tinnitus o emisiones otoacústicas. DISCUSIÓN: Impresiona que Tacrolimus no se asocia a hipoacusia cuando los niveles están en rango terapéutico durante un período de seguimiento de seis meses post trasplante.
الموضوعات
Humans , Male , Female , Adult , Middle Aged , Aged , Audiometry, Pure-Tone , Kidney Transplantation , Liver Transplantation , Calcineurin Inhibitors/adverse effects , Ototoxicity , Immunosuppressive Agents/adverse effects , Time Factors , Prospective Studies , Follow-Up Studies , Tacrolimus/adverse effects , Hearing Loss, Sensorineural/chemically inducedالملخص
Objective:To compare ocular surface dry eye-related indexes and tear cytokine level changes in chronic ocular graft-versus-host disease (oGVHD) patients after receiving topical treatment of 0.05% cyclosporine or 0.1% tacrolimus eye drops.Methods:A randomized controlled study was conducted.A total of 60 chronic oGVHD patients (60 eyes) were recruited at Beijing University Third Hospital from April 2020 to April 2021.The patients were divided into tacrolimus group and cyclosporine group by a random number table, with 30 patients (30 eyes) in each group.Patients in tacrolimus group used 0.1% tacrolimus eye drops (twice a day) and patients in cyclosporine group used 0.05% cyclosporine eye drops (4 times a day).Additionally, 0.1% flumetholon (twice a day), deproteinized calf blood extract (3 times a day), and 0.1% sodium hyaluronate eye drops (8 times a day) were applied for anti-inflammation and lubrication in both groups.Patients were screened according to exclusion criteria after 1-month treatment.Eventually, 21 patients (21 eyes) in tacrolimus group and 12 patients (12 eyes) in cyclosporine group were included for further study.Patients were examined before and 1 month after treatment.The primary evaluation indexes included Ocular Surface Disease Index (OSDI), corneal fluorescein staining scores and tear film break-up time (BUT).Expressions of interleukin (IL)-6, IL-8, IL-17, epidermal growth factor (EGF), and tumor necrosis factor-α (TNF-α) in tears were detected before and after treatment using Luminex chip.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Peking University Third Hospital (No.M2020489).Written informed consent was obtained from each subject before any medical examination.Results:The OSDI differences between before and after treatment were 0.4(-5.6, 2.5) in tacrolimus group and 27.2(4.6, 45.0) in cyclosporine group, and the OSDI improvement was significantly greater in cyclosporine group than in tacrolimus group ( Z=-2.547, P=0.009).The differences of corneal fluorescein staining scores and BUT between before and after treatment were 5.0(2.5, 10.0) scores and 3.5(-0.5, 13.8) seconds in tacrolimus group, 0.0(-3.0, 0.0) scores and -1.5(-3.0, 0.0) seconds in cyclosporine group, respectively, with no significantly difference between both groups ( Z=-0.526, -0.804; both at P>0.05).The differences of IL-6, IL-8, IL-17, EGF and TNF-α expressions between before and after treatment in tacrolimus group and cyclosporine group were not significantly different ( Z=-0.487, -0.112, -0.412, -1.085, -1.198; all at P>0.05). Conclusions:Altered levels of all tested cytokines in oGVHD tears are of no significant differences between tacrolimus and cyclos porine treatment.In addition, 0.05% cyclosporine eye drops may be more comfortable than 1% tacrolimus for chronic oGVHD patients.
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This report describs 2 domestic cases of tacrolimus poisoning in kidney transplant recipients due to overexposure of tacrolimus caused by nirmatrelvir/ritonavir for SARS-CoV-2 infection.Phenytoin sodium is prescribed for inducing CYP3A enzyme.It is intended for providing references for formulating and adjusting treatment protocols for tacrolimus overexposure and related toxicity in kidney transplant recipients caused by nirmatrelvir/ritonavir.
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OBJECTIVE To compare the efficacy， safety and economy of tacrolimus （TAC）， cyclosporin A （CsA）， cyclophosphamide （CTX） and rituximab （RTX） in the treatment of membranous nephropathy （MN）. METHODS Retrieved from Pubmed， the Cochrane Library， Wanfang data， CNKI and health technology assessment （HTA） official website， HTA reports， systematic reviews/meta-analysis and pharmacoeconomic studies about TAC， CsA， CTX and RTX combined with glucocorticoid in the treatment of MN were collected during the inception and Mar. 2022. After data extraction and quality evaluation， descriptive analysis was performed on the results of the included studies. RESULTS A total of 15 articles were included， involving 13 systematic reviews/meta-analysis and 2 pharmacoeconomic studies. In terms of efficacy， TAC and CsA showed significant advantages in increasing the response rate， and could improve the levels of urine protein， serum albumin， serum creatinine and serum total cholesterol. In terms of safety， the incidence of adverse reaction induced by TAC， CsA and RTX was low and the symptoms were mild. In terms of economics， CTX cost lower but caused severe adverse reaction； TAC cost higher but showed higher remission rate and good safety. CONCLUSIONS TAC combined with glucocorticoid may be the recommended scheme for MN.
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AIM: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4 / 5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration / dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. RESULTS: Out of 42 patients (CYP3A5 expressers, n=56, and non-expressers, n= 83), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers. Factors affecting the elevation of tacrolimus C/ D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers and increased HbA1c levels and CYP3A5 non-expressers, respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y=54.6x+194.6, R=0.63, P=0.004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y=54.5x + 20.2, R=0.41, P=0.036, Bonferroni correction). CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.
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Objective To identify the risk factors of new-onset hypertriglyceridemia (HTG) in kidney transplant recipients. Methods Clinical data of 149 kidney transplant recipients were retrospectively analyzed. According to serum triglyceride (TG) level after operation, they were divided into the non-HTG group (TG≤1.7 mmol/L, n=60) and new-onset HTG group (TG>1.7 mmol/L, n=89). Baseline data of all recipients were compared between two groups. The risk factors of HTG in kidney transplant recipients were analyzed by generalized estimating equation (GEE), and validated by multiple regression equations. Results No significant differences were observed in baseline data between two groups (all P>0.05). Multivariate analysis showed that the incidence of HTG in the middle and high tacrolimus (Tac) concentration groups was higher than that in the low Tac concentration group [odds ratio (OR) 3.11, 95% confidence interval (CI) 1.22-7.93, P=0.018 in the middle Tac concentration group; OR 5.11, 95%CI 1.31-19.98, P=0.019 in the high Tac concentration group]. Compared with type-A blood recipients, the risk of new-onset HTG was significantly increased in type-O blood counterparts (OR 2.77, 95%CI 1.14-6.71, P=0.024). The risk of new-onset HTG was decreased along with the increase of preoperative globulin level (OR 0.93, 95%CI 0.87-0.99, P=0.043). At postoperative 3 months, Tac blood concentration in the new-onset HTG group was significantly higher compared with that in the non-HTG group, and significant difference was observed (P<0.05). Multiple regression equations confirmed that the risk of new-onset HTG in type-O blood kidney transplant recipients was higher than that in type-A blood counterparts, and the risk of new-onset HTG in the middle and high Tac concentration groups was higher than that in the low Tac concentration group (all P<0.05). Conclusions Type-O blood kidney transplant recipients are more prone to HTG. It is necessary to strengthen postoperative monitoring and control of blood lipids. The blood concentration of Tac probably affects the new-onset HTG in kidney transplant recipients. Maintaining an appropriate blood concentration of Tac may be beneficial to lowering the risk of HTG.
الملخص
Objective To investigate the intra-patient variability (IPV) of tacrolimus trough concentrations and its effect on serum creatinine (Scr) level in kidney transplant recipients treated with nematvir/ritonavir. Methods Clinical data of 41 kidney transplant recipients infected by SARS-CoV-2 and treated with nematvir/ritonavir were collected. The usage of nematvir/ritonavir and tacrolimus was summarized. The distribution of tacrolimus trough concentrations and the attainment rate of target concentration were analyzed. The correlation between the IPV distribution of tacrolimus trough concentrations and the changes of Scr level was determined. Results Among 41 kidney transplant recipients, 46%(19/41) were given with full- and low-dose nematvir/ritonavir, and 7%(3/41) were given with high-dose nematvir/ritonavir. Use of tacrolimus was discontinued at 24 h before nematvir/ritonavir treatment in 95%(39/41) patients, and at 24 h after use of nematvir/ritonavir in 5%(2/41) patients. Tacrolimus was given at least 3 d after the 5-d course of nematvir/ritonavir in all patients. The attainment rate of tacrolimus trough concentration was 73%(30/41), 30%(3/10), 48%(15/31), 35%(11/31) and 53%(16/30) before, during, 1 week, 2 weeks and 1 month after use of nematvir/ritonavir, respectively. The median IPV was 35%(23%, 51%). Spearman correlation analysis showed that the increase of Scr level was positively correlated with IPV (rs=0.400 7, P=0.028 2). Conclusions The attainment rate of tacrolimus trough concentration is declined in kidney transplant recipients treated with nematvir/ritonavir. The IPV of tacrolimus trough concentrations is elevated. The recipients with higher IPV are prone to an elevation in Scr level.
الملخص
Objective To evaluate the efficacy and safety of tacrolimus extended-release (Tac-ER) in the early stage after kidney transplantation. Methods Clinical data of 68 recipients undergoing kidney transplantation from 34 pairs of renal allografts were retrospectively analyzed. Two recipients who received bilateral kidneys from the same donor were treated with Tac-ER (Tac-ER group) and tacrolimus immediate-release (Tac-IR) (Tac-IR group) as one of the basic immunosuppressant. The changes of tacrolimus dosage and blood concentration, intra-patient variability (IPV), renal function, incidence of acute rejection, recipient and allograft survival rates and adverse events were statistically compared between two groups. Results The average daily dose of tacrolimus in the Tac-ER group was significantly higher than that in the Tac-IR group (F=8.386, P=0.005). In the Tac-ER group, the mean trough concentration at postoperative 4 d was (6.14±4.04) ng/mL, did not reach the target concentration, significantly lower than (9.41±5.47) ng/mL in the Tac-IR group (F=7.854, P=0.007). In the Tac-ER group, the IPV of trough concentration of tacrolimus within postoperative 1 month was significantly higher than that in the Tac-IR group (0.44±0.15 vs. 0.36±0.12, P=0.032). At postoperative 6 months, there was no significant difference in the renal function between two groups [serum creatinine level was (126±26) μmol/L vs. (120±28) μmol/L, and the estimated glomerular filtration rate was (56±13) mL/(min·1.73 m2) vs. (60±15) mL/(min·1.73 m2), both P > 0.05]. The allograft and recipient survival rates were 100% in both groups. The incidence of acute rejection within postoperative 1 month was 18% in the Tac-ER group and 3% in the Tac-IR group, with no significant difference (P > 0.05). The overall incidence of adverse events was 94% in the Tac-ER group and 97% in the Tac-IR group, with no significant difference (P > 0.05). Conclusions The efficacy and safety of Tac-ER are equivalent to those of Tac-IR, whereas a higher dose of Tac-ER should be orally given to reach the blood concentration similar to that of Tac-IR. During early-stage drug treatment, Tac-ER should be orally given before kidney transplantation or inittally with loading dose, aiming to increase the systemic exposure to tacrolimus early after kidney transplantation and prevent acute rejection caused by insufficient exposure.
الملخص
OBJECTIVE To provide a reference for the dose adjustment of tacrolimus in patients who underwent lung transplantation after combined use of voriconazole. METHODS The clinical data of lung transplantation patients who used voriconazole and tacrolimus in our hospital from January 2020 to December 2022 were collected retrospectively. The effects of voriconazole on the valley concentration， daily dose and standardized blood concentration of tacrolimus were analyzed by using SPSS 21.0 software； multiple linear regression analysis was conducted for the factors that may affect the standardized blood concentration of tacrolimus. RESULTS A total of 153 lung transplantation patients were included. After the combination of voriconazole， the average daily dose of tacrolimus decreased from 3.37 mg to 0.76 mg， and valley concentration and standardized blood concentration were increased significantly （P＜0.000 1）. The average daily dose of voriconazole was negatively correlated with the standardized blood drug concentration of tacrolimus （P＝0.000 1，r＝－0.224）. The valley concentration of voriconazole was positively correlated with valley concentration （P＜0.000 1，r＝0.316） and standardized blood concentration （P＜0.000 1，r＝ 0.249） of tacrolimus. After combination with voriconazole， the standardized blood drug concentration of patients who underwent single lung transplantation was significantly higher than those who underwent double lung transplantation， and the standardized blood concentration of tacrolimus after oral administration of voriconazole was significantly higher than after intravenous drip of voriconazole （P＜0.05）. Most liver and kidney function indicators showed no significant changes. The results of multiple factor regression analysis showed that the valley concentration of voriconazole had a significant impact on the standardized blood concentration of tacrolimus （P＜0.001）. CONCLUSIONS The valley concentration of voriconazole has greatest influence on the blood concentration and dose adjustment of tacrolimus， which is an independent influencing factor. In clinical practice， the dose of tacrolimus should be reduced in combination with voriconazole， and therapeutic drug monitoring should be conducted for both drugs.