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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.

27 Nov 2006-Transplantation (Transplantation)-Vol. 82, Iss: 10, pp 1280-1285
TL;DR: 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.

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Journal ArticleDOI
TL;DR: Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK–PD models are proposed to realize the full clinical benefit.
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.

2 citations

Journal Article
TL;DR: The present study suggests that the cyclosporine levels for Iranian kidney transplant patients are lower compared to the recommended levels in western countries.
Abstract: INTRODUCTION Clinical information concerning cyclosporine dose reduction in Iranian kidney transplant recipients is limited. There are data in Asian, Caucasian, and Iranian ethnic kidney transplant recipients that recommend the trough level (C0) and 2-hour postdose level (C2) of cyclosporine may be different. Our aim was to determine therapeutic levels of C0 and C2 at different time after transplantation among Iranian transplant patients. MATERIALS AND METHODS Blood concentrations of cyclosporine were assessed in 4419 samples of kidney transplant recipients between 2008 and 2010. The patients were divided into 3 groups according to the time of laboratory studies ( 1 year after transplantation). Both univariable and multivariable analyses were performed to determine the correlation between cyclosporine blood levels and serum creatinine. RESULTS A total of 1270 kidney transplant patients with 4419 blood samples enrolled. The mean age of the donor was 28 ± 6 years (range, 6 to 64 years) and 82.6% were men and 17.4% were women. In the subset of patients with serum creatinine values of at least 1.6 mg/dL for men and 1.4 mg/dL for women, we determined C0 and C2 levels between therapeutic and undertherapeutic creatinine ranges at 3 different time interval after transplantation, as follows: the first 3 months, 230 ng/mL to 240 ng/mL and 725 ng/mL to 775 ng/mL; 4 to 12 months, 135 ng/mL to 156 ng/mL and 535 ng/mL to 612 ng/mL; and after 1 year, 95 ng/mL to 120 ng/mL and 420 ng/mL to 479 ng/mL for C0 and C2, respectively. CONCLUSIONS The present study suggests that the cyclosporine levels for Iranian kidney transplant patients are lower compared to the recommended levels in western countries.

2 citations

Journal ArticleDOI
TL;DR: In this article, a review includes biomarkers that the Scientific Community in Solid Organ Transplantation currently considers to have potential as diagnostic and prognostic biomarkers of graft evolution, focusing on recent scientific advances and expert recommendations regarding the role of specific and non-specific pharmacodynamic biomarkers in the T-cell mediated response.
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.

1 citations

References
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Journal ArticleDOI
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.
Abstract: Background The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. Methods We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. Results From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased...

1,723 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...With the introduction of calcineurin inhibitors, long-term allograft survival has significantly improved (1), primarily by reduction of acute rejection episodes....

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Journal ArticleDOI
25 Jun 1992-Nature
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.
Abstract: THE immunosuppressive drugs cyclosporin A (CsA) and FKS06 both interfere with a Ca2+-sensitive T-cell signal transduction pathway1–4thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A)1,5–7involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors8–10, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro12We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report 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. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.

1,639 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...Calcineurin is a key component of T-cell activation and serves as the target of the CsA cyclophilin complex (16)....

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Journal ArticleDOI
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.

676 citations

Journal ArticleDOI
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.
Abstract: BACKGROUND The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented. METHODS The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity. RESULTS The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology. CONCLUSIONS Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.

469 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...However, rational means to balance both the benefits and side effects of CsA treatment are not sufficiently established yet (2, 3)....

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Journal ArticleDOI
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.
Abstract: Background Cyclosporine (CsA) acts by inhibiting the phosphatase calcineurin (CN), but the time course and extent of inhibition in vivo are unknown. We examined the effect of single oral CsA doses on CN activity in humans and mice in vivo. Methods In humans, blood CsA levels were determined and CN activity was measured in whole blood and in blood leukocytes of patients up to 12 hr after CsA dosing (just before the second dose). Samples were collected from patients receiving a first single dose (2.5 mg/kg), and up to 14 days later after repeated dosing. In mice, after CsA dosing (12.5-200 mg/kg) by oral gavage, CsA levels in blood and tissue (spleen, kidney) were determined and CN activity was measured in spleen and kidney. Results In humans, peak CsA levels of 800-2285 microg/L at 1-2 hr produced 70-96% CN inhibition. Inhibition correlated closely with the rise and fall of CsA levels with no observable lag at the times sampled. Repeated doses showed similar CN inhibition to first dose, with no significant adaptation. In mice, CsA peaked at 1 hr in blood, spleen, and kidney, with higher concentrations in spleen and kidney than in blood. CN inhibition closely followed CsA concentrations/doses, and was greater in kidney than spleen. Conclusion Thus 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. The high CsA concentrations and CN inhibition in kidney may be relevant to nephrotoxicity.

314 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...(11) demonstrated that the immunosuppressive action for CsA, when measured as inhibition of calcineurin activity in lymphocytes, is inversely correlated with CsA blood levels....

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  • ...In humans, peak CsA blood levels at one to two hours after oral CsA uptake resulted in a 70 to 96% inhibition of calcineurin, which was rapidly reversed when CsA blood levels came down to the trough levels (10, 11)....

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