Introduction:
Renal transplantation stands as a pivotal treatment for end-stage kidney disease, offering a lifeline to patients in need. The administration of tacrolimus, a leading calcineurin inhibitor (CNI), is the preferred choice for kidney transplant recipients. When combined with mycophenolate mofetil and prednisolone, the Tacrolimus regimen has proven to deliver superior graft function, effective acute rejection prevention, and enhanced graft survival. However, the clinical utility of Tacrolimus is constrained by its narrow therapeutic window. Its metabolism relies on the activity of CYP3A4 and CYP3A5 enzymes, where the presence of CYP3A5 introduces a significant challenge. Patients expressing CYP3A5 are fast metabolizers and consequently require approximately 50% higher doses to achieve target concentrations. The Tacrolimus trough concentration/dose (C0/D) ratio has recently emerged as a promising prognostic marker for unfavourable outcomes post kidney transplantation, especially for those necessitating high Tacrolimus doses, leading to elevated peak concentrations and a subsequent higher risk of graft loss.
AIM:
This study endeavors to investigate whether patients with a high Tacrolimus metabolism rate, as denoted by the C0/D ratio, exhibit poorer graft function. The primary goal is to compare the genotype-based metabolizer status of Tacrolimus with the phenotype status derived from the C0/D ratio. Additionally, the research aims to scrutinize how metabolizer status influences graft outcomes in patients undergoing Tacrolimus-based immunosuppressive therapy post kidney transplantation.
Methods:
This retrospective observational study analyzed 90 patients who underwent kidney transplantation between 2019 and 2021, with Tacrolimus serving as the primary CNI for their maintenance immunosuppression. Patient data was sourced from transplant databases and included demographics, transplant dates, Tacrolimus dosing, CYP3A5 genotypic information, and C0/D ratio measurements at 3 months, 6 months, and 1 year post-transplant. Patients were categorized as fast, intermediate, or slow metabolizers based on their CYP3A5 genotypic classification. The C0/D ratio was calculated for each time point, and patients were classified as fast, intermediate, or slow metabolizers based on the mean C0/D value (C0/D < 1.05 for fast, 1.05 ≥ C0/D ≤ 1.54 for intermediate, and C0/D ≥ 1.5 for slow metabolizers). Patient genotypes and phenotypic statuses were compared, and graft outcomes, such as graft survival, graft rejection episodes, graft function, and any adverse events, were collected and analyzed. Descriptive statistics were used to summarize patient demographics, CYP3A5 genotypic classification, and C0/D ratio-based phenotypic classification. Associations between CYP3A5 genotype, C0/D ratio, and graft outcomes were assessed using appropriate statistical tests (e.g., chi-square, ANOVA).
Results:
The study encompassed 90 renal transplant recipients, of which 10% underwent deceased donor transplant (DDRT) and 90% had live related renal transplant (LRRT). The gender distribution was 23.86% female and 76.14% male. Genotypically, 13.33% were extensive metabolizers, 48.9% were intermediate metabolizers, and 37.78% were poor metabolizers. Phenotypically, based on the mean C0/D ratio, 33.3% were classified as extensive metabolizers,26.7 % as intermediate metabolizers, and 40% as poor metabolizers. There was a statistically significant correlation between genotype and phenotype distribution in the study population. Additionally, among the phenotypes, extensive metabolizers exhibited a lower mean estimated glomerular filtration rate (eGFR) of 66.18mL/min, compared to 80.54 mL/min for intermediate metabolizers and 70.25mL/min for poor metabolizers, with the differences being statistically significant. Biopsy proven CNI toxicity was found in 46% of the study population, but there was no statistical significance between the groups. Also prevalence of PTDM was found in 24% and post-transplant erythrocytosis in 12% of the study population, they did not show statistical difference among the study groups. Infection rates were equal among the three groups except BKV infection which was more in patients who were extensive metabolizer phenotypically and the difference was statistically significant.
Conclusions:
This study delves into the connection between Tacrolimus metabolism, as determined by the C/D ratio, and graft outcomes. It sheds light on the potential of the C0/D ratio to identify a subset of patients at an increased risk of unfavourable outcomes following kidney transplantation. The findings underscore the importance of personalized pharmacogenomic strategies in organ transplantation, considering both genotypic and phenotypic classifications of Tacrolimus metabolizers. Tailoring immunosuppressive therapies based on metabolizer status has the potential to enhance graft outcomes and optimize patient care in renal transplantation.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.