Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation

Riva, Natalia; Dip, Marcelo; Halac, Esteban; Guido, Paulo Cáceres; Woillard, Jean‐Baptiste; Licciardone, Nieves; Chan, Débora; Buendía, Jefferson Antonio; Borgnia, Daniela; Bosaleh, Andrea; Davila, María Teresa de; Imventarza, Oscar; Schaiquevich, Paula

doi:10.1097/ftd.0000000000000517

Cited by 12 publications

(18 citation statements)

References 64 publications

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“…The CYP3A5 polymorphism distribution in both donors and recipients included in this study is reported in Supporting Table . The genotype frequencies of the CYP3A5 polymorphism did not deviate from the Hardy‐Weinberg equilibrium ( P > 0.5) . According to the report of the Clinical Pharmacogenetics Implementation Consortium, the estimated allele frequency of CYP3A5*1 and *3 in our population was similar to that reported for the Latin American cohort of patients analyzed in the mentioned guideline.…”

Section: Resultssupporting

confidence: 83%

“…The genotype frequencies of the CYP3A5 polymorphism did not deviate from the Hardy-Weinberg equilibrium (P > 0.5). (6) According to the report of the Clinical Pharmacogenetics Implementation Consortium, (34) the estimated allele frequency of CYP3A5*1 and *3 in our population was similar to that reported for the Latin American cohort of patients analyzed in the mentioned guideline. Specifically, our population showed an allele frequency of 25.4% and 74.6% for the CYP3A5*1 and *3 allele, respectively.…”

Section: Resultssupporting

confidence: 82%

“…Peritransplant and posttransplant variables were studied including the following: CYP3A5 genotyping procedure was previously described. (6) In addition, we registered concomitant immunosuppressive agents, such as steroids (at least 30 consecutive days), azathioprine, mycophenolate mofetil, and sirolimus.…”

Section: Biochemical Clinical and Genetic Factorsmentioning

confidence: 99%

“…Although the optimization of immunosuppressive therapies and the improvements in surgical procedures have contributed to longer overall survival and graft survival rates in pediatric liver transplantation patients, clinical issues, such as acute rejection and adverse drug reactions to tacrolimus, confer morbidity and mortality . Previous reports have described a significant association between variability in tacrolimus C0 and the development of acute rejection and adverse drug reactions . Furthermore, other factors, including time after transplant, body weight, hematocrit, age, liver function parameters, and type of graft, contribute to the pharmacokinetic variability in pediatric liver transplant patients …”

mentioning

confidence: 99%

“…(1,4) Previous reports have described a significant association between variability in tacrolimus C0 and the development of acute rejection and adverse drug reactions. (1,(5)(6)(7) Furthermore, other factors, including time after transplant, body weight, hematocrit, age, liver function parameters, and type of graft, contribute to the pharmacokinetic variability in pediatric liver transplant patients. (1,(8)(9)(10)(11)(12)(13)(14)(15)(16) Different polymorphisms of cytochrome P450 enzymes, especially for cytochrome P450 3A5 (CYP3A5), affect tacrolimus clearance.…”

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confidence: 99%

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Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

et al. 2019

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Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady‐state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log‐transformed tacrolimus dose‐normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β = 0.019, 95% confidence interval [CI], 0.010‐0.028) and ALT values (β = 0.00030, 95% CI, 0.00002‐0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β = −0.349, 95% CI, −0.631 to −0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out‐of‐range therapeutic window that may lead to adverse drug reactions or acute rejection.

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Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 82%

Section: Biochemical Clinical and Genetic Factorsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

et al. 2019

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Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

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Hypertension in Pediatric Solid Organ Transplant Recipients

Hamdani

Mitsnefes

2023

Curr Hypertens Rep

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Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation

Abstract: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.

Cited by 12 publications

References 64 publications

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Hypertension in Pediatric Solid Organ Transplant Recipients

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