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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Book ChapterDOI
Chapter 6 – Biomarker monitoring in immunosuppressant therapy: An overview
TL;DR: The number of regulatory T cells and a signature of B cell differentiation genes seem to be promising indices of tolerance in this context of immunosuppression minimization.
Journal ArticleDOI
DNA binding activity of nuclear factor of activated T cells in mononuclear cells from renal transplant patients with and without BK virus viruria
TL;DR: Renal transplant patients receive calcineurin inhibitors to suppress the calcineURin-nuclear factor of activated T cells (NFAT) pathway but there was no relationship between tacrolimus blood levels and NFATc1 activity in renal transplant patients.
Journal ArticleDOI
Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs
Eberhard Wieland,Maria Shipkova +1 more
TL;DR: The field of biomarker research to complement TDM for a better individualization of immunosuppression is still in its infancy, and controlled prospective clinical trials are needed to unravel or dismiss the potential of particular biomarkers or biomarker combinations in various patient cohorts with different grafts.
Journal ArticleDOI
Pharmacodynamic Monitoring of Calcineurin Inhibitor in Pediatric Kidney Transplantation
TL;DR: RGE of NFAT-regulated genes and ImmuKnow did not show significant correlation with clinical manifestation of under- or over-suppression of immune function in pediatric kidney allograft recipients, and further studies are required for optimal pharmacodynamic monitoring for pediatric kidney transplantation recipients.
Journal ArticleDOI
Topics in transplantation medicine for general nephrologists.
Jagdeep S. Obhrai,Jennifer Kay Leach,Jordana Gaumond,Eric Langewisch,Anuja Mittalhenkle,Ali J. Olyaei +5 more
TL;DR: This work provides evidence-based management strategies for common clinical issues and links the approach with the data allows the clinician to explore each subject in greater depth to tailor care to individual patients.
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.