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Kahn J, Matzhold EM, Schlenke P, Schemmer P. Use of Nuclear Factor of Activated T Cell-Regulated Gene Expression for Monitoring Immunosuppression with Extended-Release Tacrolimus after Liver Transplantation-A Proof of Concept. Pharmaceutics 2024; 16:1317. [PMID: 39458646 PMCID: PMC11511070 DOI: 10.3390/pharmaceutics16101317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/04/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND There is a narrow therapeutic window for immunosuppression using calcineurin inhibitors. Drug trough levels do not reflect immunosuppression and should be replaced by pharmacodynamic monitoring. This prospective cohort study was designed to evaluate the effect of an extended-release formulation of tacrolimus (LCP Tac) on the nuclear factor of activated T cell-regulated gene expression (NFAT-RGE). METHODS The expression of interleukin-2, interferon-γ, granulocyte-macrophage colony-stimulating factor, and three reference genes was measured. Samples from 23 patients at defined time points in the first year after liver transplantation were analyzed using a droplet digital polymerase chain reaction. RESULTS All samples were within the targeted trough levels of LCP Tac, and their LCP Tac peak levels and residual NFAT-RGE showed a strong inverse correlation (r = -0.8). Most importantly, there was an individual immunosuppressive response to the LCP Tac. The mean individual trough effect of LCP Tac on the three target genes when all time points were pooled was 33% (26-56%) in patients without infection and 81% (53-95%) in those with infection (p < 0.011). The mean individual peak effect was 48% (44-64%) in patients without infection and 91% (90-94%) in those with infection (p < 0.001). CONCLUSIONS Thus, tailored immunosuppression based on residual NFAT-RGE could prevent infections associated with over-immunosuppression early after liver transplantation.
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Affiliation(s)
- Judith Kahn
- Division of General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
| | - Eva Maria Matzhold
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, 8036 Graz, Austria; (E.M.M.); (P.S.)
| | - Peter Schlenke
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, 8036 Graz, Austria; (E.M.M.); (P.S.)
| | - Peter Schemmer
- Division of General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
- Bern Visceral Surgery & Pancreas Clinic Switzerland, Hirslanden Hospital Beau-Site, 3013 Bern, Switzerland
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Boada-Pérez M, Ruiz de Miguel V, Erro M, Ussetti P, Aguilar M, Castejón R, Rosado S, Escobar-Fornieles R, Revilla-López E, Bravo C, Sáez-Giménez B, Zapata-Ortega M, Villena-Ortiz Y, Vima-Bofarull J, Monforte V, Gómez-Ollés S. Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels. Front Immunol 2024; 15:1382459. [PMID: 38799459 PMCID: PMC11116644 DOI: 10.3389/fimmu.2024.1382459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.
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Affiliation(s)
- Meritxell Boada-Pérez
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Pulmonology, Vall d’Hebron Institut de Recerca, Barcelona, Spain
| | | | - Marta Erro
- Department of Pulmonary Medicine, University Hospital Puerta de Hierro, Madrid, Spain
| | - Piedad Ussetti
- Department of Pulmonary Medicine, University Hospital Puerta de Hierro, Madrid, Spain
| | - Myriam Aguilar
- Department of Pulmonary Medicine, University Hospital Puerta de Hierro, Madrid, Spain
| | - Raquel Castejón
- Internal Medicine Laboratory, Instituto de Investigación Puerta de Hierro Segovia de Arana, Madrid, Spain
| | - Silvia Rosado
- Internal Medicine Laboratory, Instituto de Investigación Puerta de Hierro Segovia de Arana, Madrid, Spain
| | - Roser Escobar-Fornieles
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Eva Revilla-López
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Carlos Bravo
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Berta Sáez-Giménez
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marta Zapata-Ortega
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Yolanda Villena-Ortiz
- Central Laboratory Services, Pharmacology Section, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Jaume Vima-Bofarull
- Central Laboratory Services, Pharmacology Section, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Víctor Monforte
- Department of Pulmonology, Lung Transplant Program, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Susana Gómez-Ollés
- Department of Pulmonology, Vall d’Hebron Institut de Recerca, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
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Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell-Regulated Gene Expression in Healthy Volunteers. Ther Drug Monit 2023; 45:87-94. [PMID: 36191295 DOI: 10.1097/ftd.0000000000001046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/26/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Although therapeutic drug monitoring of calcineurin inhibitor (CNI) concentrations is performed routinely in clinical practice, an identical concentration may lead to different effects in different patients. Although the quantification of nuclear factor of activated T-cell-regulated gene expression (NFAT-RGE) is a promising method for measuring individual CNI effects, CNI pharmacodynamics are as of yet incompletely understood. METHODS CNI concentrations and NFAT-RGEs were quantified in 24 healthy volunteers receiving either ciclosporin or tacrolimus in 2 clinical trials. NFAT-RGE was measured using quantitative reverse transcription polymerase chain reaction tests of whole-blood samples. Pharmacokinetics and pharmacodynamics were analyzed using compartmental modeling and simulation. In addition, NFAT-RGE data from renal transplant patients were analyzed. RESULTS The average NFAT-RGE during a dose interval was reduced to approximately 50% with ciclosporin, considering circadian changes. The different effect-time course with ciclosporin and tacrolimus could be explained by differences in potency (IC 50 204 ± 41 versus 15.1 ± 3.2 mcg/L, P < 0.001) and pharmacokinetics. Residual NFAT-RGE at the time of maximum concentration (RGE tmax ) of 15% when using ciclosporin and of 30% when using tacrolimus was associated with similar average NFAT-RGEs during a dose interval. Renal transplant patients had similar but slightly stronger effects compared with healthy volunteers. CONCLUSIONS Ciclosporin and tacrolimus led to similar average suppression of NFAT-RGE in a dose interval, despite considerably different RGE tmax . Pharmacodynamic monitoring of average NFAT-RGE should be considered. When using NFAT-RGE at specific time points, the different effect-time courses and circadian changes of NFAT-RGEs should be considered.
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Brunet M, Millán O. Getting immunosuppression just right: the role of clinical biomarkers in predicting patient response post solid organ transplantation. Expert Rev Clin Pharmacol 2021; 14:1467-1479. [PMID: 34607521 DOI: 10.1080/17512433.2021.1987882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Actually, immunosuppression selection isn't based on individual immune alloreactivity, and immunosuppressive drug dosing is mainly based on the development of toxicity and the achievement of specific target concentrations. Since a successful outcome requires optimal patient risk stratification and treatment, several groups have evaluated candidate biomarkers that have shown promise in the assessment of individual immune responses, the prediction of personal pharmacodynamic effects of immunosuppressive drugs and the prognosis and diagnosis of graft outcomes.. AREAS COVERED This review includes biomarkers that the Scientific Community in Solid Organ Transplantation currently considers to have potential as diagnostic and prognostic biomarkers of graft evolution. We have focused on recent scientific advances and expert recommendations regarding the role of specific and non-specific pharmacodynamic biomarkers that are mainly involved in the T-cell-mediated response. EXPERT OPINION Integral pharmacologic monitoring that combines pharmacokinetics, pharmacogenetics and predictive pharmacodynamic biomarkers may provide crucial information and allow personal adjustment of immunosuppressive drugs at an early stage before severe adverse events ensue. Multicentre, randomized, prospective and interventional trials are needed to fine tune the established cut-off values for each biomarker and the optimal monitoring frequency for each biomarker and to accurately evaluate possible clinical confounding factors to enable correct clinical qualification.
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Affiliation(s)
- Mercè Brunet
- Pharmacology and Toxicology Section, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.,Biomedical Research Center in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Olga Millán
- Pharmacology and Toxicology Section, CDB, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.,Biomedical Research Center in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Sommerer C, Brunet M, Budde K, Millán O, Guirado Perich L, Glander P, Meuer S, Zeier M, Giese T. Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study. Br J Clin Pharmacol 2021; 87:3851-3862. [PMID: 33620734 DOI: 10.1111/bcp.14794] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/06/2021] [Accepted: 02/13/2021] [Indexed: 12/25/2022] Open
Abstract
AIMS Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections. METHODS NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colony-stimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids. RESULTS Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs. 10%, P = .01). CONCLUSIONS NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients. Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.
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Affiliation(s)
- Claudia Sommerer
- Department of Nephrology, University of Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, CDB, CIBERehd, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Klemens Budde
- Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany
| | - Olga Millán
- Pharmacology and Toxicology Laboratory, CDB, CIBERehd, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Spain
| | - Lluis Guirado Perich
- Renal Transplant Unit, Nephrology Department, Fundació Puigvert, Barcelona, Spain
| | - Petra Glander
- Department of Nephrology, Charité University Hospital Berlin, Berlin, Germany
| | - Stefan Meuer
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, University of Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Giese
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
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Leino AD, Pai MP. Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection. Clin Pharmacokinet 2020; 59:1317-1334. [PMID: 32720300 DOI: 10.1007/s40262-020-00923-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Calcineurin inhibitors, the primary immunosuppressive therapy used to prevent alloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.
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Affiliation(s)
- Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA.
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Lemaitre F, Monchaud C, Woillard JB, Picard N, Marquet P. [Summary of the recommendations of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) on the therapeutic drug monitoring of tacrolimus]. Therapie 2020; 75:681-685. [PMID: 32653093 DOI: 10.1016/j.therap.2020.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/20/2020] [Accepted: 06/15/2020] [Indexed: 11/18/2022]
Abstract
Recently, the International Association of Therapeutic Drug Monitoring (IATDMCT), that is the learning society for biological pharmacology and toxicology, issued recommendations on the therapeutic drug monitoring (TDM) of tacrolimus. This is the second consensus after the one issued in 2009. In this document, the role of tacrolimus TDM for the four principal transplanted organs is discussed. The analytical aspects, pharmacogenetics, TDM alternative approaches and the positioning of biomarkers are also presented. Stronger recommendations are about trough concentration targets in kidney and liver transplantation and for other indication of tacrolimus use. For the first time, an area under the curve of tacrolimus concentrations target is recommended for recipients management. Eventually, another set of recommendations are proposed for pharmacodynamic biomarkers used in patients' follow-up.
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Affiliation(s)
- Florian Lemaitre
- Inserm, EHESP, institut de recherche en santé, environnement et travail (Irset) - UMRS 1085, université Rennes, CHU Rennes, 35000 Rennes, France; Inserm, centre d'investigation clinique 1414, 35000 Rennes, France.
| | - Caroline Monchaud
- Service de pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, 87000 Limoges, France; Inserm, UMR-1248, 87000 Limoges, France
| | - Jean-Baptiste Woillard
- Service de pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, 87000 Limoges, France; Inserm, UMR-1248, 87000 Limoges, France; Faculté de médicine, univeristé Limoges, 87000 Limoges, France
| | - Nicolas Picard
- Service de pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, 87000 Limoges, France; Inserm, UMR-1248, 87000 Limoges, France; Faculté de médicine, univeristé Limoges, 87000 Limoges, France
| | - Pierre Marquet
- Service de pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, 87000 Limoges, France; Inserm, UMR-1248, 87000 Limoges, France; Faculté de médicine, univeristé Limoges, 87000 Limoges, France
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Millán O, Ruiz P, Fortuna V, Navasa M, Brunet M. Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients. Liver Int 2020; 40:931-946. [PMID: 31883422 DOI: 10.1111/liv.14339] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/10/2019] [Accepted: 12/21/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Nuclear factor of activated T cell-regulated gene expression (NFAT-RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to evaluate the role of NFAT-RGE in modulating intralymphocytary IL-2 and IFN-γ expression and its clinical utility as an early non-invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients. METHODS Fifty-six LT recipients treated with Tac or CsA [with and without mycophenolate mofetil (MMF)] were included: 30 free of rejection or infection, 11 rejectors (T cell-mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT-RGE of IL-2, IFN-γ and GM-CSF and intralymphocytary synthesis of IL-2 and IFN-γ were evaluated by real-time PCR and flow cytometry respectively. RESULTS A significant increase in NFAT-RGE was observed in patients who experienced TCMAR (75% [42-100%]) or SCR (41% [18-78%]) compared with patients without rejection or infection (14% [2-23%]). Positive correlations between the %NFAT-RGE-IFN and both the %CD8CD69IFN-γ and %CD4CD69IFN-γ and between the %NFAT-RGE-IL2 and the %CD8CD69IL2 were observed. NFAT-RGE was significantly lower in CMV+ patients than in non-infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT-RGE were observed. CONCLUSIONS Sequential post-transplantation NFAT-RGE monitoring combined with intralymphocytary IL-2 and IFN-γ before transplantation and at the first and third month post-transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.
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Affiliation(s)
- Olga Millán
- Biomedical Research Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Centre (CDB), IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Pablo Ruiz
- Liver Transplant Unit, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Virginia Fortuna
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Centre (CDB), IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Miquel Navasa
- Biomedical Research Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Liver Transplant Unit, IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
| | - Mercè Brunet
- Biomedical Research Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Centre (CDB), IDIBAPS, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
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Zarrinpar A, Kim UB, Boominathan V. Phenotypic Response and Personalized Medicine in Liver Cancer and Transplantation: Approaches to Complex Systems. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.201900167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Ali Zarrinpar
- Department of Surgery, College of MedicineUniversity of Florida Gainesville FL 32610 USA
- Department of Biochemistry and Molecular Biology, College of MedicineUniversity of Florida Gainesville FL 32610 USA
- Department of Bioengineering, Herbert Wertheim College of EngineeringUniversity of Florida Gainesville FL 32610 USA
| | - Un Bi Kim
- Department of Surgery, College of MedicineUniversity of Florida Gainesville FL 32610 USA
| | - Vijay Boominathan
- Department of Surgery, College of MedicineUniversity of Florida Gainesville FL 32610 USA
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Wang Z, Zhang H, Yang H, Zheng M, Guo M, Chen H, Sun L, Han Z, Tao J, Ju X, Tan R, Wei JF, Gu M. An intronic polymorphism of NFATC1 gene shows a risk association with biopsy-proven acute rejection in renal transplant recipients. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:211. [PMID: 32309358 PMCID: PMC7154465 DOI: 10.21037/atm.2020.01.61] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background We aimed to explore the influence of single nucleotide polymorphisms (SNPs) in NFATC1 gene on the occurrence of biopsy-proven acute rejection (BPAR) in renal transplant recipients. Methods Blood samples from 131 subjects with stable allograft function (STA) and 69 with BPAR episodes were collected and analyzed using target sequencing (TS) with an established panel. Odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated for logistic regression models adjusted for confounding factors. Pathological changes were extracted and the relationship with tagger SNPs was calculated. Moreover, the CCK-8 assay was performed to explore the proliferation of T lymphocytes, and PCR, Western blotting and enzyme-linked immunosorbent assay were applied to identify the effect of mutant on the activation of T cells. Results High-quality readouts were obtained for 55 NFATC1 SNPs and 14 tagger SNPs were remained for further analysis. After adjusting for clinical confounding factors, the distribution of four NFATC1 SNPs, including rs2290154, rs2304738, rs754093 and rs754096, were statistically significant between STA and BPAR groups. Pathological association analysis indicated one SNP, rs2290154, was significantly related with the Banff score and renal tubulitis. Our in vitro study suggested that NFATC1 rs2290154 mutant could remarkably promote the T cell proliferation, increase the transcription of NFATC1 mRNA and expression of NFATC1 protein, as well as the interleukin-2 (IL-2) secretion. Conclusions We reported the crucial association of NFATC1 gene with the occurrence of acute rejection (AR) episodes. Moreover, in vitro NFATC1 rs2290154 was significantly involved in the T lymphocytes activation and proliferation through increasing the translation of NFATC1 mRNA and expression of NFATC1 protein, along with the secretion of IL-2.
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Affiliation(s)
- Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hengcheng Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ming Zheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Miao Guo
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Xiaobing Ju
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit 2019; 41:261-307. [DOI: 10.1097/ftd.0000000000000640] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Brunet M, van Gelder T, Åsberg A, Haufroid V, Hesselink DA, Langman L, Lemaitre F, Marquet P, Seger C, Shipkova M, Vinks A, Wallemacq P, Wieland E, Woillard JB, Barten MJ, Budde K, Colom H, Dieterlen MT, Elens L, Johnson-Davis KL, Kunicki PK, MacPhee I, Masuda S, Mathew BS, Millán O, Mizuno T, Moes DJAR, Monchaud C, Noceti O, Pawinski T, Picard N, van Schaik R, Sommerer C, Vethe NT, de Winter B, Christians U, Bergan S. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit 2019. [DOI: 10.1097/ftd.0000000000000640
expr 845143713 + 809233716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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Improved Pulse Wave Velocity and Renal Function in Individualized Calcineurin Inhibitor Treatment by Immunomonitoring: The Randomized Controlled Calcineurin Inhibitor-Sparing Trial. Transplantation 2018; 102:510-520. [PMID: 29077654 DOI: 10.1097/tp.0000000000001973] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE). METHODS Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months. RESULTS In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P < 0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009). CONCLUSIONS NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.
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Greenland JR, Chong T, Wang AS, Martinez E, Shrestha P, Kukreja J, Hays SR, Golden JA, Singer JP, Tang Q. Suppressed calcineurin-dependent gene expression identifies lung allograft recipients at increased risk of infection. Am J Transplant 2018; 18:2043-2049. [PMID: 29673076 PMCID: PMC6699504 DOI: 10.1111/ajt.14886] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 03/21/2018] [Accepted: 04/08/2018] [Indexed: 01/25/2023]
Abstract
Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC50 ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%-29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.
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Affiliation(s)
- John R Greenland
- Medical Service, Veterans Affairs Health Care System, San Francisco CA, 94121,Department of Medicine, University of California, San Francisco CA, 94143,Corresponding author:
| | - Tiffany Chong
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Angelia S Wang
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Emily Martinez
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Pavan Shrestha
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Jasleen Kukreja
- Department of Surgery, University of California, San Francisco CA, 94143
| | - Steven R. Hays
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Jeffrey A Golden
- Department of Medicine, University of California, San Francisco CA, 94143,Department of Surgery, University of California, San Francisco CA, 94143
| | - Jonathan P Singer
- Department of Medicine, University of California, San Francisco CA, 94143
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco CA, 94143
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Nuclear Factor of Activated T Cell-regulated Cytokine Gene Expression for Adjustment of Tacrolimus in Kidney Transplant Recipients: A Randomized Controlled Pilot Trial. Transplant Direct 2018; 4:e369. [PMID: 30046659 PMCID: PMC6056278 DOI: 10.1097/txd.0000000000000810] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 05/22/2018] [Accepted: 05/23/2018] [Indexed: 01/05/2023] Open
Abstract
Background The aim of this pilot study was to assess the feasibility of a pharmacodynamics assay that measures Nuclear Factor of Activated T Cell-dependent cytokines expressed as % mean residual expression (MRE) to adjust tacrolimus (tac) dose (intervention [INT] arm) in comparison with the standard of care of tac trough levels (control [CTL] arm). Methods We conducted a single-center randomized controlled trial involving 40 stable kidney transplant recipients over 1 year. In the INT arm, the dose of tac was reduced by 15% if the MRE was less than 20% and was increased by 15% if the MRE was greater than 60%. Controls were adjusted based on tac trough levels. Results There was a median of 2 tac dose changes per arm. Ten subjects had 1 or more infections in the INT arm and 6 subjects had 1 or more infection in the CTL arm. Rates for hospitalizations, rejections, malignancies and death were similar in both arms. In subjects whose tac dose was not adjusted in the first 6 months, those with infections had a lower MRE at enrollment compared with those without infections (P = 0.049). This was not true for tac trough levels (P = 0.80). There was no correlation between MRE and rejection. Conclusions Our study suggests that adjusting tac based on this pharmacodynamics assay is feasible. Quantitative analysis of nuclear factor of activated T-regulated gene expression may serve as a reliable assay to lower tac dosing. Further studies with larger populations are needed.
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17
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Lea-Henry T, Chacko B. Management considerations in the failing renal allograft. Nephrology (Carlton) 2017; 23:12-19. [DOI: 10.1111/nep.13165] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Tom Lea-Henry
- Nephrology and Transplantation Unit; John Hunter Hospital; Newcastle New South Wales Australia
| | - Bobby Chacko
- Nephrology and Transplantation Unit; John Hunter Hospital; Newcastle New South Wales Australia
- School of Medicine and Public Health; University of Newcastle; Newcastle New South Wales Australia
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18
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Andrews LM, Li Y, De Winter BCM, Shi YY, Baan CC, Van Gelder T, Hesselink DA. Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients. Expert Opin Drug Metab Toxicol 2017; 13:1225-1236. [PMID: 29084469 DOI: 10.1080/17425255.2017.1395413] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure - research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.
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Affiliation(s)
- Louise M Andrews
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Yi Li
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.,b Department of Laboratory Medicine , West China Hospital of Sichuan University , Chengdu , China
| | - Brenda C M De Winter
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Yun-Ying Shi
- c Department of Nephrology , West China Hospital of Sichuan University , Chengdu , China
| | - Carla C Baan
- d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Teun Van Gelder
- a Department of Hospital Pharmacy , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands.,d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
| | - Dennis A Hesselink
- d Department of Internal Medicine , Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
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Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model. Transpl Immunol 2017; 46:14-20. [PMID: 28988984 DOI: 10.1016/j.trim.2017.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 10/02/2017] [Accepted: 10/04/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. METHODS Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated. RESULTS AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts. CONCLUSIONS These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.
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20
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Bremer S, Vethe NT, Skauby M, Kasbo M, Johansson ED, Midtvedt K, Bergan S. NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. Br J Clin Pharmacol 2017; 83:2494-2502. [PMID: 28686294 DOI: 10.1111/bcp.13367] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/08/2017] [Accepted: 07/04/2017] [Indexed: 11/28/2022] Open
Abstract
AIMS Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of the present study was to characterize nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. METHODS In 29 renal allograft recipients, samples were drawn once pre-Tx, and before and 1.5 h after Tac dosing at approximately 1 week, 6 weeks and 1 year post-Tx. Tac concentrations were measured by immunoassay, while the expression of genes encoding NFAT-regulated cytokines [interleukin 2 (IL2), interferon gamma (IFNG), colony stimulating factor 2 (CSF2)] and cytochrome P450 3A5 (CYP3A5) genotyping were determined by real-time polymerase chain reaction. RESULTS The cytokine response after Tac dosing varied up to 46-fold between patients and changed significantly with time post-engraftment. Tac concentrations 1.5 h postdose (C1.5 ) >15 μg l-1 were associated with strong cytokine inhibition and residual gene expression (RGE) ≤10%, while lower Tac C1.5 resulted in more variable responses (RGE 2.5-68.7%). Patients with ongoing subclinical acute rejection (n = 5) demonstrated limited cytokine inhibition (RGE 39.7-72.6%), while patients with polyoma virus viraemia (n = 3) had relatively strong inhibition of cytokines (RGE 2.5-32.5%). By contrast, there was no association between Tac exposure and rejection or viraemia. CONCLUSIONS The findings of our study support the potential of NFAT-regulated gene expression measurements as a pharmacodynamic tool for additional monitoring of Tac therapy, especially in the context of overimmunosuppression and viraemia.
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Affiliation(s)
- Sara Bremer
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Nils T Vethe
- Deptartment of Pharmacology, Oslo University Hospital, Oslo, Norway
| | - Morten Skauby
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Margrete Kasbo
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.,Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Elisabet D Johansson
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.,Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Karsten Midtvedt
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Stein Bergan
- Deptartment of Pharmacology, Oslo University Hospital, Oslo, Norway.,Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
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21
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Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S1-20. [PMID: 26977997 DOI: 10.1097/ftd.0000000000000287] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.
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22
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Nuclear Factor of Activated T Cells-Regulated Gene Expression as Predictive Biomarker of Personal Response to Calcineurin Inhibitors. Ther Drug Monit 2016; 38 Suppl 1:S50-6. [PMID: 26418701 DOI: 10.1097/ftd.0000000000000234] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs) represent the most widely used immunosuppressive agents in kidney transplantation. Both CNIs show a narrow therapeutic window; thus, monitoring is necessary to balance efficacy and toxicity. Several approaches have been undertaken to measure the biological effects of CNI-based immunosuppression. METHODS A quantitative analysis of gene expression was established to calculate the functional effects of calcineurin inhibition, the assessment of nuclear factor of activated T cells (NFAT)-regulated gene expression. This assay is based on the quantitative analysis of interleukin-2, interferon-γ, and granulocyte macrophage colony-stimulating factor gene expression in whole blood samples collected at the time cyclosporine A/tacrolimus troughs (C0) and 2 hours after oral uptake (C2). RESULTS In this comprehensive review, analytical aspects of the assay and also clinical benefits and limitations are presented and discussed. Several observational studies underline the beneficial effect of NFAT-regulated gene expression as biomarker of personal response on CNI therapy, especially in infectious complications, malignancies, and acute rejection episodes. Data are more comprehensive in cyclosporine A compared with tacrolimus therapy. However, results on prospective interventional studies are sparse. A randomized controlled study evaluating the opportunity for NFAT-guided immunosuppression is ongoing. CONCLUSIONS NFAT-regulated gene expression is a promising biomarker in CNI therapy concerning infectious complications, malignancies, and acute rejection. Prospective interventional studies and randomized controlled studies are ongoing to confirm the encouraging results.
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23
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Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S80-92. [PMID: 26418704 DOI: 10.1097/ftd.0000000000000230] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In response to the urgent need for new reliable biomarkers to complement the guidance of the immunosuppressive therapy, a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors, and levels of similarity to other molecules, etc. In addition, a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes, a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of "fitness for purpose" is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between laboratories and between methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions. This overview focuses on preanalytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation, and commercialization.
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24
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Analytical Validation and Cross-Validation of an NFAT-Regulated Gene Expression Assay for Pharmacodynamic Monitoring of Therapy With Calcineurin Inhibitors. Ther Drug Monit 2016; 38:711-716. [DOI: 10.1097/ftd.0000000000000340] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Shao K, Lu Y, Wang J, Chen X, Zhang Z, Wang X, Wang X, Yang H, Liu G. Different Effects of Tacrolimus on Innate and Adaptive Immune Cells in the Allograft Transplantation. Scand J Immunol 2016; 83:119-27. [PMID: 26524694 DOI: 10.1111/sji.12398] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 10/22/2015] [Indexed: 01/14/2023]
Abstract
While tacrolimus (FK506) is currently used as immunosuppression therapy in transplant recipient, the immunological mechanism remains unknown. Herein, the immunoregulatory effects of FK506 were investigated in the physiological status and allogeneic skin transplantation. FK506 cannot significantly alter the functions of innate immune cells (macrophages and neutrophils) and adaptive immune cells (T cells) in the physiological status. However, it can effectively delay allogeneic skin-graft rejection through ameliorating the T cell responses, but not myeloid-derived innate immune cell responses. Importantly, it did not affect the allograft recipient macrophage innate immune defence capacity to bacteria. In clinics, FK506 treatment can significantly control the cytokine production in T cells, but not non-T cells. This study shows targeting calcineurin signalling, FK506, to be essential in inducing allograft tolerance, but not to damage the innate defence capacity, validating the immune cell phenotypes as a potential marker in transplantation following FK506 treatment.
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Affiliation(s)
- K Shao
- Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China.,Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China
| | - Y Lu
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.,Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - J Wang
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.,Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - X Chen
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.,Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - Z Zhang
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.,Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
| | - X Wang
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China
| | - X Wang
- Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China
| | - H Yang
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China
| | - G Liu
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.,Biotherapy Research Center, Institute of Immunobiology, Fudan University, Shanghai, China.,Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
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26
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O.Millán, Brunet M. Cytokine-based immune monitoring. Clin Biochem 2016; 49:338-46. [DOI: 10.1016/j.clinbiochem.2016.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 01/04/2016] [Accepted: 01/05/2016] [Indexed: 12/13/2022]
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27
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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28
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Bergan S, Bremer S, Vethe NT. Drug target molecules to guide immunosuppression. Clin Biochem 2015; 49:411-8. [PMID: 26453533 DOI: 10.1016/j.clinbiochem.2015.10.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 09/25/2015] [Accepted: 10/03/2015] [Indexed: 10/22/2022]
Abstract
The individual and interindividual variability of response to immunosuppressants combined with the prevailing concept of lifelong immunosuppression following any organ transplantation motivates the search for methods to further individualize such therapy. Traditional therapeutic drug monitoring, adapting dose according to concentrations in blood, targets the pharmacokinetic variability. It has been increasingly recognized, however, that there is also a considerable variability in the response to a given concentration. Attempts to overcome this variability in response include the efforts to identify relevant targets and methods for pharmacodynamic monitoring. For several of the currently used immunosuppressants there is experimental data suggesting markers that are relevant as indicators for individual monitoring of the effects of these drugs. There are also some clinical data to support these approaches; however what is generally missing, are studies that in a prospective manner demonstrates the benefits and effects on outcome. The monitoring of antithymocyte globulin by lymphocyte subset counts is actually the only well established example of pharmacodynamic monitoring. For drugs such as MPA and mTOR inhibitors, there are candidates such as IMPDH activity expression and p70SK6 phosphorylation status, respectively. The monitoring of CNIs using assays for NFAT RGE, either alone or combined with concentration measurements, is already well documented. Even here, some further investigations relating to the categories of organ transplant, combination of immunosuppressants etc. will be requested. Although some further standardization of the assay is warranted and there is a need for specific recommendations of target levels and how to adjust dose, the NFAT RGE approach to pharmacodynamic monitoring of CNIs may be close to implementation in clinical routine.
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Affiliation(s)
- Stein Bergan
- Oslo University Hospital, Department of Pharmacology, Oslo, Norway; University of Oslo, School of Pharmacy, Oslo, Norway.
| | - Sara Bremer
- Oslo University Hospital, Department of Medical Biochemistry, Oslo, Norway
| | - Nils Tore Vethe
- Oslo University Hospital, Department of Pharmacology, Oslo, Norway
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29
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Shi YY, Hesselink DA, van Gelder T. Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients. Transplant Rev (Orlando) 2015; 29:224-30. [PMID: 26048322 DOI: 10.1016/j.trre.2015.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 04/29/2015] [Accepted: 04/30/2015] [Indexed: 02/05/2023]
Abstract
Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients.
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Affiliation(s)
- Yun-Ying Shi
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Nephrology, West China Hospital of Sichuan University, Chengdu, China
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
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Maguire O, Tornatore KM, O'Loughlin KL, Venuto RC, Minderman H. Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus. Cytometry A 2013; 83:1096-104. [PMID: 24136923 DOI: 10.1002/cyto.a.22401] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 09/12/2013] [Accepted: 09/24/2013] [Indexed: 01/10/2023]
Abstract
Nuclear factor of activated T cells (NFAT) is a family of transcription factors involved in regulating the immune response. The canonical NFAT pathway is calcium-dependent and upon activation, NFAT is dephosphorylated by the phosphatase, calcineurin. This results in its translocation from the cytoplasm to the nucleus and transcription of downstream target genes that include the cytokines IL-2, IL-10, and IFNγ. Calcineurin inhibitors including tacrolimus inhibit the NFAT pathway and are used as immunosuppressants in transplant settings to prevent graft rejection. There is, as yet, no direct means to monitor tacrolimus pharmacodynamics. In this study, a rapid, quantitative, image cytometry-based measurement of nuclear translocation of NFAT1 is used to evaluate NFAT activation in T cells and its tacrolimus-induced inhibition. A strong dose-dependent correlation between NFAT1 inhibition and tacrolimus dose is demonstrated in vitro. Time kinetic analysis of NFAT1 inhibition in plasma from stable renal transplant recipients before and after an in vivo dose with tacrolimus correlated with the expected pharmacokinetic profile of tacrolimus. This was further corroborated by analysis of patients' autologous CD4 and CD8 T cells. This is the first report to show that the measurement of NFAT1 activation potential by nuclear translocation can be used as a direct, sensitive, reproducible and quantitative pharmacodynamic readout for tacrolimus action. These results, and the rapid turnaround time for this assay, warrant its evaluation in a larger clinical setting to assess its role in therapeutic drug monitoring of calcineurin inhibitors.
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Affiliation(s)
- Orla Maguire
- Department of Flow and Image Cytometry, Roswell Park Cancer Institute, University at Buffalo, New York
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DNA binding activity of nuclear factor of activated T cells in mononuclear cells from renal transplant patients with and without BK virus viruria. Tzu Chi Med J 2013. [DOI: 10.1016/j.tcmj.2013.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Rodrigo E, López-Hoyos M, Corral M, Fábrega E, Fernández-Fresnedo G, San Segundo D, Piñera C, Arias M. ImmuKnow as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 2012; 18:1245-53. [PMID: 22740321 DOI: 10.1002/lt.23497] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immune status monitoring of transplant recipients could identify patients at risk of acute rejection, infection, and cancer, which are important sources of morbidity and mortality in these patients. The ImmuKnow assay provides an objective assessment of the cellular immune function of immunosuppressed patients. Inconclusive results concerning the ability of the ImmuKnow test to predict acute rejection and infection have raised concerns about the predictive value of ImmuKnow in liver transplant recipients. We conducted a systematic literature review to identify studies published up to March 2012 that documented the use of ImmuKnow for monitoring immune function in liver transplant recipients. The study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 score. We identified 5 studies analyzing ImmuKnow performance for infection and 5 studies analyzing ImmuKnow performance for acute rejection. The pooled sensitivity, specificity, positive likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 83.8% [95% confidence interval (CI) = 78.5%-88.3%], 75.3% (95% CI = 70.9%-79.4%), 3.3 (95% CI = 2.8-4.0), 14.6 (95% CI = 9.6-22.3), and 0.824 ± 0.034, respectively, for infection and 65.6% (95% CI = 55.0%-75.1%), 80.4% (95% CI = 76.4%-83.9%), 3.4 (95% CI = 2.4-4.7), 8.8 (95% CI = 3.1-24.8), and 0.835 ± 0.060, respectively, for acute rejection. Heterogeneity was low for infection studies and high for acute rejection studies. In conclusion, the ImmuKnow test is a valid tool for determining the risk of further infection in adult liver transplant recipients. Significant heterogeneity across studies precludes the conclusion that ImmuKnow identifies liver transplant patients at risk for rejection.
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Affiliation(s)
- Emilio Rodrigo
- Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, Spain.
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Kim Y, Park KH, Chung BH, Choi BS, Yang CW, Kim JI, Moon IS, Park YJ, Han K, Oh EJ. Pretransplant IFN-γ ELISPOT assay as a potential screening test to select immunosuppression protocols for patients receiving basiliximab induction therapy. Transl Res 2012; 160:230-6. [PMID: 22683414 DOI: 10.1016/j.trsl.2012.02.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 02/10/2012] [Accepted: 02/14/2012] [Indexed: 11/29/2022]
Abstract
The use of basiliximab induction therapy has increased in standard immunological risk patients. The objective of this study was to identify whether pretransplant donor-reactive interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assay results were associated with post-transplant clinical outcomes in patients receiving basiliximab induction therapy and whether this could be helpful for choosing an efficacious immunosuppressive regimen. In 154 living donor renal transplant recipients who received basiliximab induction therapy without desensitization, we determined pretransplant ELISPOT frequencies and correlated the results with clinical outcomes based on the use of calcineurin inhibitors (tacrolimus [TAC] or cyclosporine [CSA]). The ELISPOT (+) patients had higher rate of post-transplant biopsy-proven acute rejection (AR) than ELISPOT (-) patients (P = 0.001) regardless of immunosuppressive regimen. In the logistic and multivariate regression analysis, ELISPOT was the only significant correlate of AR (P = 0.002), and the patients with increased ELISPOT results and CSA therapy were associated with AR. Our results suggest that the pretransplant ELISPOT (+) may assess the risk of poor post-transplant outcomes in patients with basiliximab induction.
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Affiliation(s)
- Yonggoo Kim
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
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Calcineurin inhibitors and NFAT-regulated gene expression. Clin Chim Acta 2012; 413:1379-86. [DOI: 10.1016/j.cca.2011.09.041] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 09/21/2011] [Accepted: 09/27/2011] [Indexed: 12/20/2022]
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Abboudi H, Macphee IA. Individualized immunosuppression in transplant patients: potential role of pharmacogenetics. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2012; 5:63-72. [PMID: 23226063 PMCID: PMC3513229 DOI: 10.2147/pgpm.s21743] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Indexed: 12/29/2022]
Abstract
The immunosuppressive drugs used to prevent the rejection of transplanted organs have a narrow therapeutic index. Under treatment results in episodes of rejection leading to either damage or loss of the organ. Over immunosuppression increases the risk of infection and malignancy as well as drug specific complications including diabetes mellitus and nephrotoxicity. There is wide variation in the drug dose required to achieve target blood concentrations and there is often dissociation between pharmacokinetics and pharmacodynamics. Currently, immunosuppressive drug treatment is individualized based on a clinical assessment of the risk of rejection or toxicity. Therapeutic drug monitoring is routinely employed for several immunosuppressive drugs. Pharmacogenetics has the potential to complement therapeutic drug monitoring but clinical benefit has yet to be demonstrated. Novel biomarker-based approaches to risk stratification and pharmacodynamic monitoring are under development and are ready for clinical trials.
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Affiliation(s)
- Hamid Abboudi
- Division of Clinical Sciences, Renal Medicine, St George's, University of London, London, UK
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Ritchie SA, Patel MJ, Miller SJ. Therapeutic options to decrease actinic keratosis and squamous cell carcinoma incidence and progression in solid organ transplant recipients: a practical approach. Dermatol Surg 2012; 38:1604-21. [PMID: 22646842 DOI: 10.1111/j.1524-4725.2012.02452.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Solid organ transplant recipients (SOTRs) have a 50 to 250 times greater risk of squamous cell carcinoma (SCC) than the general population and experience higher rates of invasive and metastatic disease. These greater risks are a product of the tumorigenic effects of their immunosuppressive medications. As the number of transplantations and the life expectancy of SOTRs increase, SCCs are becoming a major source of morbidity and mortality. OBJECTIVE To present a practical approach for busy practicing clinicians to the care of SOTRs who are developing SCCs. Topics include assessment and treatment of new and neglected SOTRs; the dermatologist's role with the transplantation team; and practical considerations in the choice of topical agents, systemic agents, and immunosuppressive therapy manipulation. METHODS AND MATERIALS An extensive literature search of the understanding of SCC pathophysiology and treatment in SOTRs was conducted. RESULTS Presented here is a logical, concise guide to the care of SOTRs who are developing actinic keratoses and SCCs. CONCLUSION Proper assessment of patients, understanding therapeutic alternatives and their application, and early institution of preventative and adjuvant therapies can help to decrease skin cancer-related morbidity and mortality in SOTRs.
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Affiliation(s)
- Simon A Ritchie
- Department of Dermatology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.
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Zhu H, Ge W. Future of the pharmacogenomics of calcineurin inhibitors in renal transplant patients. Pharmacogenomics 2012; 12:1505-8. [PMID: 22044409 DOI: 10.2217/pgs.11.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Billing H, Breil T, Schmidt J, Tönshoff B, Schmitt CP, Giese T, Engelmann G. Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients. Pediatr Transplant 2012; 16:187-94. [PMID: 22360403 DOI: 10.1111/j.1399-3046.2012.01660.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparable CNI blood concentrations frequency and severity of adverse effects vary considerably among individual patients. Determining the RGE of NFAT-regulated genes in leukocytes is a new pharmacodynamic approach to measure directly the functional consequences of calcineurin inhibition in T-lymphocytes. We compared clinical outcome parameters and RGE of activated T-cells after pLtx. We measured prospectively RGE of NFAT regulated genes in 33 pLTX recipients in the maintenance period after pLTX. CsA-treated patients with recurrent infections had significantly lower RGE rates (27%) than children without recurrent infections (50%; p = 0.04), whereas pharmacokinetic parameters of CsA and the concomitant immunosuppressive therapy were comparable between both groups. In patients on tacrolimus-based IS therapy NFAT RGE was only slightly reduced (90%). Pharmacodynamic monitoring of CsA by measurement of RGE in T-lymphocytes has the potential to identify over-immunosuppressed pediatric liver transplant recipients on a CsA-based IS therapy, while in children on low-dose tacrolimus therapy, RGE measurement does not provide additional clinically useful information.
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Affiliation(s)
- Heiko Billing
- Department of Pediatrics I, University Children's Hospital Surgery, University of Heidelberg, Heidelberg, Germany
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Biomarkers. Ther Drug Monit 2012. [DOI: 10.1016/b978-0-12-385467-4.00016-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Pharmacodynamic Disparities in Tacrolimus-Treated Patients Developing Cytomegalus Virus Viremia. Ther Drug Monit 2011; 33:373-9. [DOI: 10.1097/ftd.0b013e318226dac7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Zahn A, Schott N, Hinz U, Stremmel W, Schmidt J, Ganten T, Gotthardt D, Meuer S, Zeier M, Giese T, Sommerer C. Immunomonitoring of nuclear factor of activated T cells-regulated gene expression: the first clinical trial in liver allograft recipients. Liver Transpl 2011; 17:466-73. [PMID: 21445930 DOI: 10.1002/lt.22254] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Long-term calcineurin inhibitor (CNI) treatment can cause serious side effects in liver allograft recipients. An optimal risk-to-benefit ratio for CNI blood levels has not been established. Pharmacodynamic drug monitoring through the measurement of the CNI biological activity, that is, the expression of nuclear factor of activated T cells (NFAT)-regulated genes, seems to be a promising approach. The residual gene expression (RGE) of NFAT-regulated genes 2 and 1.5 hours after cyclosporine A (CsA) and tacrolimus (FK-506) intake was measured in 100 liver allograft recipients with 1 or more years of follow-up post-transplantation. The mean RGE in all patients was 62% ± 33%. A significant negative correlation between the CsA (P < 0.0001, r = -0.8026) and FK-506 peak levels (P < 0.0001, r = -0.6982) and the RGE of all NFAT-regulated genes was observed. Clinical reliability was proven too. In conclusion, the data presented in this pilot study reveal the applicability of the pharmacodynamic monitoring of CNI efficacy in liver allograft recipients. To confirm the advantage of individualized pharmacodynamic drug monitoring over pharmacokinetic drug monitoring with respect to clinical outcomes, controlled, prospective studies are needed.
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Affiliation(s)
- Alexandra Zahn
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
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