Insight Into the Potential Influence of Inter- And Intra-Individual Variability of Tacrolimus Exposure on Graft Function Decline in Three-Year Period Following Kidney Transplantation

Abstract

The main goal of the present study was to evaluate the association of tacrolimus (Tac) exposure parameters (trough concentration (TTC), dose-adjusted TTC (C0/D)), Tac intra-individual variability (IPV), and Tac-related gene polymorphisms (CYP3A5 and ABCB1) with kidney function in three-year period after kidney transplantation (Tx). The study enrolled 103 Caucasian patients who were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T polymorphism. High IPV, lower average C0/D, kidney function at 6 months post-transplantation, and acute rejection were independent predictors of worse eGFR values between 13 and 36 months after Tx. Significant eGFR decline was observed in the low C0/D (p = 0.010) and high IPV patients' group (p = 0.018) between 13-24 and 25-36 months. The carriers of CYP3A5*1 allele had lower C0/D values compared to the CYP3A5*3/*3 carriers during entire observation period, while ABCB1 3435 gene polymorphism did not affect C0/D. Tailoring Tac treatment based on IPV, C0/D and CYP3A5 genotype in clinical practice may identify patients at risk for graft function decline. Rezumat Scopul principal al prezentului studiu a fost de a evalua asocierea parametrilor de expunere la tacrolimus (Tac) (concentrați e minimă (TTC), TTC ajustată la doză (C0/D)), variabilitatea intra-individuală a Tac (IPV) și polimorfismul genetic determinat de Tac (CYP3A5 și ABCB1), cu funcția renală pe o perioadă de trei ani după transplantul renal (Tx). Studiul a înrolat 103 pacienți caucazieni care au fost genotipați (polimorfismul CYP3A5 6986A>G și ABCB1 3435C>T). IPV ridicat, C0/D mediu mai scăzut, funcția renală la 6 luni după transplant și respingerea acută au fost predictori independenți ai valorilor eGFR mai slabi între 13 și 36 de luni după Tx. Scăderea semnificativă a eGFR a fost observată în grupul de pacienți cu C0/D scăzut (p = 0,010) și în grupul de pacienți cu IPV ridicat (p = 0,018) între 13-24 și 25-36 de luni. Purtătorii alelei CYP3A5*1 au avut valori C0/D mai mici comparativ cu purtătorii CYP3A5*3/*3 pe întreaga perioadă de observație, în timp ce polimorfismul genei ABCB1 3435 nu a afectat C0/D. Adaptarea tratamentului Tac bazat pe genotipul IPV, C0/D și CYP3A5 în practică poate identifica pacienții cu risc de rejectare a grefei.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

“…The present study is the continuation of the research published by Stefanović et al [8], whereby the proposed linear regression model revealed the significant and independent predictors of estimated glomerular filtration rate (eGFR) values up to three years after Tx: established eGFR at 6th month (eGFR6), occurrence of acute rejection episodes within the first-year post-transplantation (AR), Tac IPV, and mean C 0 /D during 6-12 months after Tx.…”

“…After obtaining statistically significant predictors in multivariate regression analysis (Table 3), i.e., eGFR6, Tac IPV, Tac C0/D, sex, and AR, a regression equation was constructed based on the coefficients and causal relationship between the dependent variable and independent predictors, which represents a basis for the MC simulation (Model*). The covariate coefficients in Model* slightly differ from the published model [8] due to different presentations of Tac IPV covariate, but this change was not significant for further analysis. Since the performed regression analysis and MC stimulation included mea values at 6-12 months as predictor and input variable, respectively, an accomp analysis demonstrates a high positive correlation between Tac C0/D at the 3rd (indicative of poor post-transplantation outcomes) and mean C0/D values at 6-12 after Tx (Figure 3).…”

“…After obtaining statistically significant predictors in multivariate regression analysis (Table 3), i.e., eGFR6, Tac IPV, Tac C 0 /D, sex, and AR, a regression equation was constructed based on the coefficients and causal relationship between the dependent variable and independent predictors, which represents a basis for the MC simulation (Model*). The covariate coefficients in Model* slightly differ from the published model [8] due to different presentations of Tac IPV covariate, but this change was not significant for further analysis.…”

“…Multivariable linear regression analysis was conducted in order to estimate factors influencing eGFR values from 13 to 36 months after Tx. With reference to the performed experimental study [8], where 103 patients were included, a regression equation was created, which served as a basis for MC simulation. All of the significant parameters from the regression analysis were assigned input values, defined by upper and lower limits for each of the measured parameters.…”

“…All patients had proton pump inhibitor (PPI) in their treatment protocol. Detailed information regarding biochemical monitoring can be found in Stefanović et al [8]. The Modification of Diet in Renal Disease (MDRD) equation was used for the calculation of eGFR [12].…”