Journal ArticleDOI
Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies.
Claudia Sommerer,Mathias H. Konstandin,Thomas J. Dengler,Jan Schmidt,Stefan Meuer,Martin Zeier,Thomas Giese +6 more
TLDR
Recurrent infectious complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients are correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation.Abstract:
BACKGROUND: At present it is unclear which dose and consecutive blood levels of cyclosporine A (CsA) are optimal with respect to immunosuppressive efficacy and drug specific side effects at the level of individual patients. Several pharmacodynamic measures of CsA effects have been proposed, but have not become clinical routine yet. Besides the lack of practicability, the biological relevance of these assays has not been determined so far. METHODS: Residual expression of nuclear factor of activated T-cells (NFAT)-regulated genes two hours after drug intake was used as molecular pharmacodynamic marker to assess CsA effects on lymphocytes and correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation. RESULTS: Recurrent infectious complications were observed in 44% and malignancies in 20% of the 133 patients studied. Patients with a strong suppression of NFAT-regulated genes by CsA--as judged by a residual level of transcription of less than 15% after drug intake--develop more frequent infections (53% vs. 29%; P = 0.005) and malignancies (22% vs. 4%; P = 0.002). The lack of correlation between the incidence of these complications and CsA blood concentration might point to the interindividual differences in the sensitivity towards calcineurin inhibition. CONCLUSION: The data presented here reveal a clear relation between the frequency of infectious and malignant complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients. Therefore, pharmacodynamic monitoring of CsA efficacy in transplanted patients might be a useful tool to adjust immunosuppressive therapy in individual patients.read more
Citations
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Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report
Mercè Brunet,Teun van Gelder,Anders Åsberg,Vincent Haufroid,Vincent Haufroid,Dennis A. Hesselink,Loralie J. Langman,Florian Lemaitre,Pierre Marquet,Christoph Seger,Maria Shipkova,Alexander A. Vinks,Alexander A. Vinks,Pierre Wallemacq,Eberhard Wieland,Jean-Baptiste Woillard,Markus J. Barten,Klemens Budde,Helena Colom,Maja Theresa Dieterlen,Laure Elens,Kamisha L. Johnson-Davis,Paweł K. Kunicki,Iain MacPhee,Satohiro Masuda,Binu S. Mathew,Olga Millán,Tomoyuki Mizuno,Tomoyuki Mizuno,Dirk Jan A.R. Moes,Caroline Monchaud,Ofelia Noceti,Tomasz Pawinski,Nicolas Picard,Ron H.N. van Schaik,Claudia Sommerer,Nils Tore Vethe,Brenda C. M. de Winter,Uwe Christians,Stein Bergan +39 more
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Journal ArticleDOI
Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist
TL;DR: The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications and discusses the effect of adjunctive immunosuppressive agents on CNI Pharmacokinetic and dosing.
Journal ArticleDOI
New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation
TL;DR: New insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) are highlighted and the possible consequences are discussed.
Journal ArticleDOI
Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation
Mercè Brunet,Maria Shipkova,Teun van Gelder,Eberhard Wieland,Claudia Sommerer,Klemens Budde,Vincent Haufroid,Uwe Christians,Marcos López-Hoyos,Markus J. Barten,Stein Bergan,Nicolas Picard,Olga López,P. Marquet,D. A. Hesselink,Ofelia Noceti,Tomasz Pawinski,Pierre Wallemacq,Michael Oellerich +18 more
TL;DR: A 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.
Journal ArticleDOI
Experience with immune monitoring in lung transplant recipients: correlation of low immune function with infection.
Shahid Husain,K. Raza,Joseph M. Pilewski,Diana Zaldonis,Maria Crespo,Y. Toyoda,Kathleen A. Shutt,Kathy Spichty,Carolyn Bentlejewski,Diana L. Pakstis,M.E. Carey,Kenneth R. McCurry,Adriana Zeevi +12 more
TL;DR: Cylex ImmuKnow assay monitoring has the potential to identify the patients atrisk of developing infection and those colonized with fungus that are at risk of developing disease.
References
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Journal ArticleDOI
Analysis of NFAT-regulated gene expression in vivo: a novel perspective for optimal individualized doses of calcineurin inhibitors
TL;DR: Quantitative measurement of NFAT-regulated gene expression in CsA-treated patients represents a potent new approach to assess the biological effectiveness of Cs a therapy and has the potential to enable individualized immunosuppressive regimens.
Journal ArticleDOI
Cyclosporin A Toxicity of the Renal Allograft – a Late Complication and Potentially Reversible
Claudia Sommerer,Olaf Hergesell,Anna-Maria Nahm,Vedat Schwenger,Rüdiger Waldherr,Konrad Andrassy,Martin Zeier +6 more
TL;DR: Reduction of CsA improves renal function, reduces graft resistive index and systolic blood pressure, with no acute rejection episodes after modification of immunosuppressive therapy.
Journal ArticleDOI
Limitations of C2 monitoring in renal transplant recipients
Gunilla Einecke,Manuela Schütz,Ingrid Mai,Lutz Fritsche,Markus Giessing,Petra Glander,Hans-H. Neumayer,Klemens Budde +7 more
TL;DR: C( 2) monitoring alone does not detect toxicity in poor and/or slow absorbers, who constitute a significant proportion of patients, and analysis of dose changes indicated that C(2) levels are not dose-proportional.
Journal ArticleDOI
Conversion to C2 monitoring of cyclosporine A exposure in maintenance kidney transplant recipients: Results at 3 years
Salvatore Di Paolo,Annalisa Teutonico,Antonio Schena,Barbara Infante,Giovanni Stallone,Giuseppe Grandaliano,Pasquale Ditonno,Michele Battaglia,Francesco Paolo Schena +8 more
TL;DR: In maintenance renal transplant recipients, conversion to C2 monitoring is a seemingly safe option with good graft performance after 3 years, and mean C2 levels greater than 661 ng/mL seem to be associated with better long-term graft function and a lower prevalence of biopsy-proven chronic allograft nephropathy, at least during a 3-year follow-up.