Declining Intracellular T-Lymphocyte Concentration of Cyclosporine A Precedes Acute Rejection in Kidney Transplant Recipients

Falck, Pål; Åsberg, Anders; Guldseth, Heidi; Bremer, Sara; Akhlaghi, Fatemeh; Reubsaet, Léon; Pfeffer, Per; Hartmann, Anders; Midtvedt, Karsten

doi:10.1097/tp.0b013e31815feede

Cited by 66 publications

(44 citation statements)

References 28 publications

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“…Increased intracellular CsA concentration is also associated with excess inhibition of lymphocyte function in vivo, 17 which is likely to underlie the significant increase in infections and CMV reactivations as well as the six-fold increase in neoplasms we observed during the study period in T variant compared with wild-type carriers. Differences in the incidence of neoplasms, however, were only marginally significant, most probably because the small number of events reduced the statistical power of comparative analyses.…”

Section: Discussionmentioning

confidence: 83%

“…Ideally, treatment should be titrated to intracellular CsA levels. 17 More pragmatically, CsA dose could be titrated by considering the ABCB1genotype. Because delayed or partial renal function recovery after kidney transplantation strongly predict decreased graft survival in the long term, 3,29 this approach might help to improve long-term allograft survival in patients at increased risk of CsA nephrotoxicity because of their genotype.…”

Section: Discussionmentioning

confidence: 99%

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ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cattaneo

Ruggenenti

Baldelli

et al. 2009

Journal of the American Society of Nephrology

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Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8-and 3.5-fold higher risk for DGF, respectively (P ϭ 0.022 and P ϭ 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes. The introduction of cyclosporine A (CsA) therapy in the early 1980s opened a new era in organ transplantation. Compared with steroid-and azathioprine-based regimens, immunosuppressive protocols including this inhibitor of calcineurin-a key enzyme involved in T cell activation 1 -decreased the incidence of acute rejections from 40% to 50% to 20% to 30% and increased one-year survival rates of the grafts from 60% to between 80% and 90%. 2 Thirty years later, CsA remains a cornerstone of immunosuppressive therapy for recipients of both renal and nonrenal transplants worldwide. However, standard recommended doses are associ-

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cattaneo

Ruggenenti

Baldelli

et al. 2009

Journal of the American Society of Nephrology

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“…To predict the degree of CsA-mediated inhibition of OATP1B1 PS int , we used 12-h pharmacokinetic profiles of CsA from nine renal transplant patients (Falck et al, 2008). Inhibition of uptake was presented as a function of time over the dosing interval for total whole blood and unbound plasma concen-1500 AMUNDSEN ET AL.…”

Section: Methodsmentioning

confidence: 99%

“…(mean of four published values) (Wang et al, 2004;Piñeyro-López et al, 2007;Yang et al, 2009;Åsberg et al, 2010) and 4.86 h Ϫ1 (mean of two published values (Jusko et al, 1995;Sam et al, 2006), f u of 0.038 (Falck et al, 2008) and 0.012 (Zahir et al, 2001), and R b/p of 1.58 (mean of three published values) (Atkinson et al, 1984;Zaghloul et al, 1987;Akhlaghi and Trull, 2002) and 3.4 (Zahir et al, 2001) were made for CsA and Tac, respectively. For the absorption of CsA, a lag time of 0.483 h was applied (Åsberg et al, 2010).…”

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confidence: 99%

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

Amundsen¹,

Christensen²,

Zabihyan³

et al. 2010

Drug Metab Dispos

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127

107

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ABSTRACT:The aim of this study was to investigate the potential of calcineurin inhibitors [cyclosporine A (CsA) and tacrolimus (Tac)] to inhibit cellular uptake of atorvastatin mediated by the liver-specific organic anion-transporting polypeptide 1B1 ( The IVIVE showed that clinically obtainable concentrations of CsA, but not Tac, inhibit OATP1B1 transport of atorvastatin. CsA inhibition ranged from 28 to 77% within a dosing interval, whereas it was less than 1% for Tac, considering free concentrations and assuming competitive inhibition. This does not fully explain the clinically observed interaction with CsA, suggesting that a more complex inhibitory mechanism may be present. This is also supported by the decreased IC 50 value of CsA after preincubation. This study provides evidence that OATP1B1 inhibition is a relevant mechanism for the interaction observed between CsA and atorvastatin.

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“…Pharmacokinetic outlines and drug-drug interactions at this level are not monitored by current CsA level measurement. To more accurate level determination, intracellular T-cell drug concentration assays have been established (28). CsA levels are used as a replacement marker of kidney function, but do not certainly display a relationship with pharmacological response (29).…”

Section: Contextmentioning

confidence: 99%

A Systematic Review about an Advance in Cyclosporine Monitoring in Kidney Transplant Recipients

Einollahi

Teimoori

2017

Nephro-Urol Mon

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Context: An immunosuppressive drug, Cyclosporine (CsA), has been commonly used in kidney transplants. A safe dosing of CsA often causes nephrotoxity, bone marrow toxicity, and infection. Pharmacokinetic characteristics of CsA and CsA marker relation to the immune suppression have not been completely described in clinical practices yet. Objectives: This review summarizes our achievements on pharmacokinetic and CsA level Marker in kidney transplant patients. Search methods and Selection criteria: A literature review was done using the National Center for Biotechnology Information's Pubmed Medline, Ovid Medline and Embase, and Iranian registries (Iranmedex, SID, MagIran, and IranDoc). Titles and abstracts were then reviewed to select studies based upon the predefined inclusion criteria. Our study defined a population of adult solid organ transplant recipients receiving the cyclosporine that Cyclosporine monitoring was done. Data Collection and Analysis: Two reviewers independently appraised the quality of each trial and extracted the data from the included trials. Results: CsA pharmacokinetics is very different between kidney transplant recipients, in order to CsA profiling, no pharmacodynamic tools has been confirmed yet in clinical practices and the best way to individualize calcineurin inhibitor therapy is still a controversial issue. C0 levels do not exactly predict the CsA level or rejection risk, patient monitored by C2 levels have upper doses of CsA and have a lower frequency of early acute allograft rejection than patients profiled with C0 and although CA is highly heterogeneous closely post-transplant and seems to be unhelpful early after post-transplant it is more favorable after first months after. Conclusions: Establishing a biological CsA marker may be helpful in clinical decisions on the dose. It seemed to be logical that we should re-inspect the possibility of using them as a supplementary tool towards better therapeutic drug monitoring of cyclosporine or it needs to be reevaluated and needs to find a new target for a therapeutic plan in kidney transplant patients.

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Declining Intracellular T-Lymphocyte Concentration of Cyclosporine A Precedes Acute Rejection in Kidney Transplant Recipients

Cited by 66 publications

References 28 publications

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

A Systematic Review about an Advance in Cyclosporine Monitoring in Kidney Transplant Recipients

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