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
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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
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Dissertation
Pharmacodynamic monitoring of calcineurin inhibitor therapy in renal allograft recipients
Journal ArticleDOI
Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers
TL;DR: Ciclosporin and tacrolimus led to similar average suppression of NFAT-RGE in a dose interval despite considerably different RGEtmax, and pharmacodynamic monitoring of average NFAT -RGE should be considered.
Journal ArticleDOI
Correlation of Base-Line Trough Tacrolimus Level With Early Rejection
TL;DR: The aim of this study was to analyze the association between the baseline through (C0) tacrolimus level in the first day post transplant, with early rejection in living donor transplants.
Dissertation
Nouveaux outils de pharmacodynamie des immunosuppresseurs chez des receveurs pédiatriques de greffe d'organe
Journal ArticleDOI
Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers
David Czock,Bin Xu +1 more
TL;DR: In this paper , the average NFAT-RGE during a dose interval was reduced to approximately 50% with ciclosporin, considering circadian changes, and the different effect-time course with both tacrolimus and IC 50 204 ± 41 versus 15.1 ± 3.2 mcg/L, P < 0.001.
References
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Journal ArticleDOI
Improved Graft Survival after Renal Transplantation in the United States, 1988 to 1996
Sundaram Hariharan,Christopher P. Johnson,Barbara A. Bresnahan,S. Taranto,Matthew McIntosh,Donald Stablein +5 more
TL;DR: There has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors since 1988.
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Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation
TL;DR: It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
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Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens
Jacques Dantal,Maryvonne Hourmant,Diego Cantarovich,Magali Giral,Gilles Blancho,Brigitte Dréno,Jean-Paul Soulillou +6 more
TL;DR: It is found that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival, and the design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.
Journal ArticleDOI
Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology
Brian J. Nankivell,Richard Borrows,Caroline L.-S. Fung,Philip J. O'Connell,Jeremy R. Chapman,Richard D. M. Allen +5 more
TL;DR: CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation and strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.
Journal ArticleDOI
The temporal profile of calcineurin inhibition by cyclosporine in vivo.
TL;DR: CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation, relevant to nephrotoxicity.