Dataset Information

Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients

ABSTRACT:

Background

Tacrolimus is a key drug in kidney transplantation with a narrow therapeutic index. However, whether tacrolimus exposure variability affects clinical outcomes and adverse reactions remains unknown.

Objective

Our study investigated the factors that influence tacrolimus exposure in kidney transplantation recipients and the relationship between tacrolimus concentration and clinical outcomes and adverse reactions.

Settings and Methods

We examined the effect of tacrolimus concentration on clinical outcomes and adverse reactions in 201 kidney transplantation recipients, and identified clinical and pharmacogenetic factors that explain tacrolimus exposure.

Results

The CYP3A5 genotype was clearly associated with dose-adjusted trough blood tacrolimus concentrations (C0/D), whereas no significant difference was observed in patients with the CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. Clinical factors such as red blood cell count, hemoglobin, and albumin were the most useful influence factors affecting tacrolimus C0/D. Besides, Wuzhi capsule increased tacrolimus C0/D in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and post-transplant diabetes mellitus (PTDM) risk but not with acute rejection and chronic allograft kidney dysfunction.

Conclusion

Clinical factors, medication, and CYP-enzyme polymorphisms accounted for tacrolimus concentration variability in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and PTDM risk.

SUBMITTER: Cheng F

PROVIDER: S-EPMC8610755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCalcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients.MethodSingle-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations.ResultsIn total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible.ConclusionMeasuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.