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Patient variability in clinical response to the calcineurin inhibitors (CNIs) cyclosporine A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure....
Citations
... Therapeutic drug monitoring (TDM) is routinely performed to maintain Tac trough concentration (TTC) within an optimal range with a view to reduce toxicity and improve the efficacy of immunosuppressive treatment [8,23]. Still, some patients will experience adverse effects or lack of efficacy with the TTC within the optimal range, which suggests that further investigation of factors that contribute to these disadvantages is required [1,16]. Studies showed that genetics along with demographic factors and drug-drug interactions are the main contributors to Tac inter-individual pharmacokinetic variability [22,23,31]. ...
... TDM involves the measurement of drug blood concentrations in terms of area-under-the-blood concentration versus time curve (AUC) or trough levels. 61 Analytical measures to determine blood concentrations may differ in sensitivity and specificity and subsequently have variable performance. This variability can potentially lead to clinically relevant differences in dose adjustments. ...
Transplantation medicine is a rapidly evolving field and over the last years there has been substantial progress in organ exchange strategies. Organ exchange helps improve transplantation opportunities for patients in special groups, such as highly immunized or high urgent (HU) patients. It also ensures that organs that have no suitable recipient in the country of donation can be made available for transplantation elsewhere.
The goal of transplantation is to not only ensure patient survival but also offer improved health and a good balance between the functional efficacy of the graft and their physical and psychological well-being to patients. Encouraging higher levels of patient engagement and personalizing communications may enhance long-term posttransplant care. The meeting thus encompassed a range of topics around a patient-centered approach in transplantation with consideration of the following issues: quality of life (QoL) beliefs and behaviors; medication adherence; optimization of follow-up; and personalized medicine.
... Hence, therapeutic drug monitoring of Tac is a necessary tool with a view to reduce the toxicity and improve efficacy. Still, there are patients who will experience adverse effects or lack in efficacy with the Tac concentration in the optimal range, which suggests that additional investigation of the factors that may contribute to these effects is needed (3,4). It is showed that genetics was one of the main determinants, along with demographic factors and drug-drug interactions that affects interindividual variability in Tac pharmacokinetics (4,5). ...
... Cyclosporine A (CsA), a fungus-derived immunosuppressant, has been clinically used to prevent organ graft rejection by inhibiting the proliferation of lymphocytes in transplant patients [21]. However, sustained CsA-immunosuppression causes endothelial dysfunction, hypertension, dyslipidemia, and nephrotoxicity. ...
Background
Vascular calcification (VC) progresses substantially even after kidney transplantation, and is a predictor of morbidity and mortality. However, the effect of cyclosporin A (CsA) on VC has not been reported in diabetic kidney transplant patients. In this study, we evaluated the effect of CsA on the VC of mouse vascular smooth muscle cells (VSMCs) under high glucose (HG).
Material/Methods
To demonstrate the effect of CsA (1.0 μmol/L) and HG (30 mM) in the induction of the VC of the VSMCs, we determined alkaline phosphatase (ALP) activity, microscopic morphology of calcification, the expressions of the calcification and inflammation-related genes, and the intracellular calcium concentrations in VSMCs.
Results
Calcification was observed 14 days after exposure to a calcifying medium (sodium phosphate monobasic and dibasic mixture). On microscopic morphology, CsA alone did not induce calcification under HG conditions, but clearly increased calcification under HG with a calcifying medium. ALP activity increased under HG with CsA or a calcifying medium compared to HG conditions alone. CsA increased ALP activity under low glucose (LG, 5.5 mM) with a calcifying medium, but markedly increased under HG with a calcifying medium. CsA significantly increased the mRNA expressions of the calcification markers (core binding factor-alpha 1, bone morphologic proteins 2) as well as those of the inflammatory marker (interleukin 6), under HG with a calcifying medium. Intracellular calcium concentrations were unchanged in CsA alone but significantly increased with the presence of a calcifying medium under both LG and HG conditions.
Conclusions
Considering the effect of CsA on VC, the vascular adverse effects of CsA need to be verified in diabetic transplant patients in the future.
... It suggested that the nuclear factor of activated T-cells (NFAT) reduce after Calcineurin inhibition; genetic polymorphisms in the encoding NFAT genes could also be reasons for variation in CsA efficacy and toxicity. Also, CsA metabolites and their different organ delivery may possibly be another reasons (92). Additionally, enzymes are responsible; the most important enzyme in CsA hepatic metabolism is cytochrome P450 3A4 (93). ...
Context: An immunosuppressive drug, Cyclosporine (CsA), has been commonly used in kidney transplants. A safe dosing of CsA often causes nephrotoxity, bone marrow toxicity, and infection. Pharmacokinetic characteristics of CsA and CsA marker relation to the immune suppression have not been completely described in clinical practices yet. Objectives: This review summarizes our achievements on pharmacokinetic and CsA level Marker in kidney transplant patients. Search methods and Selection criteria: A literature review was done using the National Center for Biotechnology Information’s Pubmed Medline, Ovid Medline and Embase, and Iranian registries (Iranmedex, SID, MagIran, and IranDoc). Titles and abstracts were then reviewed to select studies based upon the predefined inclusion criteria. Our study defined a population of adult solid organ transplant recipients receiving the cyclosporine that Cyclosporine monitoring was done. Data Collection and Analysis: Two reviewers independently appraised the quality of each trial and extracted the data from the included trials. Results: CsA pharmacokinetics is very different between kidney transplant recipients, in order to CsA profiling, no pharmacodynamic tools has been confirmed yet in clinical practices and the best way to individualize calcineurin inhibitor therapy is still a controversial issue. C0 levels do not exactly predict the CsA level or rejection risk, patient monitored by C2 levels have upper doses of CsA and have a lower frequency of early acute allograft rejection than patients profiled with C0 and although CA is highly heterogeneous closely post-transplant and seems to be unhelpful early after post-transplant it is more favorable after first months after. Conclusions: Establishing a biological CsA marker may be helpful in clinical decisions on the dose. It seemed to be logical that we should re-inspect the possibility of usingthemas a supplementary tool towards better therapeutic drug monitoring of cyclosporine or it needs to be reevaluated and needs to find a new target for a therapeutic plan in kidney transplant patients.
... In this context variability in the genes coding for the metabolic cytochrome enzymes (CYP3A4&CYP3A5), transporter proteins (ABCB1), and the nuclear factor pregnane-X-receptor (NR1I2) are of interest. While there are no clear relationships between single nucleotide polymorphisms (SNPs) in ABCB1 and CsA exposure (17), associations between genetic variants in ABCB1 and graft function and graft survival have been described (18)(19)(20)(21). Furthermore, graft survival was not altered in renal transplant recipients on CsA therapy, when either these recipients or their donors were carriers of the CYP3A5*1 allele (22), but these recipients were found to have a survival benefit (23).CYP3A4*22 has previously been associated with DGF but has never been replicated (24). ...
... Genetic variability in genes coding for calcineurin, could alter the susceptibility for CsA as has been shown for tacrolimus (26). Polymorphisms in these genes could potentially be related to acute rejection and/or subclinical rejection (17).. Acute rejection is caused by a complex interplay of time varying and time constant pharmacological, transplant related, genetic and non-genetic factors. In the present study a systematic analysis is performed using a parametric survival model to describe the time to acute rejection in renal transplant recipients to explore potential risk factors. ...
... PPP3CB could be primarily of relevance since this gene principally encodes the calcineurin present in cells of the immune system, whereas PPP3CA is thought to be more relevant in other tissues including renal tubular epithelial cells. The selected haplotype may not bespecific for the actual calmodulin and calcineurin binding parts (17) and expression of this protein may be regulated by other (nuclear) factors. ...
Aims:
This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR).
Methods:
Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model.
Results:
Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%).
Conclusions:
Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.
... This variability may lead to under-immunosuppression and acute rejection episodes or over-immunosuppression, which can be potentially severe due to adverse effects and toxicity. Hence, therapeutic drug monitoring (TDM) of Tac is a required tool for reducing its toxicity and improving efficacy (1,2). However, there are patients who will experience adverse effects or a lack in efficacy with a Tac concentration within the optimal range, which suggests that additional investigation of the factors that may contribute these effects is required (3). ...
The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters [creatinine (Cre) clearance and serum Cre level] were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.
... The preceding findings could be attributed to cytochrome P450 3A5 (CYP3A5), the main enzyme involved in drug metabolism. Current clinical data reveal that Itsumi Kokosu (the main component of a five-ester capsule), grapefruit juice (grapefruit), diltiazem, and imidazoles combined with tacrolimus can increase the blood concentration of tacrolimus to different degrees; the inhibitory mechanism of CYP3A5 activity on tacrolimus involves CYP3A substrate (Chang et al., 2010;Press et al., 2010;Page et al., 2011;Pavan et al., 2011). If patients are taking medications or other substances that interact with CYP3A5, blood tacrolimus concentrations may be maintained within the normal range by appropriately reducing the tacrolimus dose and determining its concentration in the blood. ...
This study aimed to 1) analyze the results of tacrolimus blood concentration monitored in patients after renal transplantation, 2) observe and establish an optimal therapeutic window for patients, and 3) provide evidence for the clinical and rational use of drugs. Tacrolimus blood concentration was determined by enzyme-linked immunosorbent assay. A total of 1824 cases were obtained from the monitoring of 74 patients after renal transplantation. These cases were then retrospectively analyzed. Over time, the mean whole blood tacrolimus trough concentration after transplantation gradually decreased. This result suggests that the optimal therapeutic windows for patients with renal transplants are as follows: 5 to 20 μg/L at 1 month after surgery; 5 to 15 μg/L at 1-3 months after surgery; 4 to 12 μg/L at 3-6 months after surgery; 4 to 10 μg/L at 6-12 months after surgery; and 3 to 8 μg/L at >12 months after surgery. The absorption of tacrolimus is highly variable. Therefore, tacrolimus concentration in the blood and the recommended clinical therapeutic window should be routinely monitored to adjust the treatment regimen and reduce adverse reactions. In this way, treatment can be optimized.
... Even though the evaluation of molecular profiles associated with AR was not the aim of this study, we observed differentially expressed genes and associated pathways in concordance with already described findings (36)(37)(38). Moreover, the individual analysis of IF/TA profiles was in concordance with our previous reports (39)(40)(41)(42)(43). ...
The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: (1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study) and (2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n = 14), acute rejection (n = 13) and CAD with IF/TA (n = 10) were evaluated. Normal allografts (n = 18) were used as controls. To test CNIT contribution to CAD progression, an independent set of biopsies (n = 122) from 61 KT patients collected at 3 and ∼12 months post-KT (range = 9–18) were evaluated. Patients were classified based on 2-year post-KT graft function and histological findings as progressors (n = 30) or nonprogressors to CAD (n = 31). Molecular signatures characterizing CNIT samples were identified. Patients classified as progressors showed an overlap of 7% and 22% with the CNIT signature at 3 and at ∼12 months post-KT, respectively, while the overlap was <1% and 1% in nonprogressor patients, showing CNIT at the molecular level as a nonimmunological factor involved in the progression to CAD.
... Likewise, the pharmacokinetics of mycophenolate mofetil is subject to polymorphic pharmacokinetics, whereas for cyclosporine no genetic variants have thus far been identified that are clearly associated with patients' plasma drug levels. 17 It can be concluded that for all three major immunosuppressants there is little evidence so far that the application of pharmacogenetics could improve clinical outcome by lowering nephrotoxicity and the risk of transplant rejection. ...
Genetic information is increasingly used to optimize clinical treatment of patients, but obstacles remain to practical implementation as well as challenges to our understanding of genetic variation in drug response. These areas that particularly require research attention include gene-environment interactions, the consequences of genetic variation, and the impact of epigenetics on gene expression and function. In this issue of Clinical Pharmacology & Therapeutics focused on pharmacogenetics, we discuss some of the recent advances in understanding from a variety of viewpoints.
