A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation

Graav, Gretchen N. de; Baan, Carla C.; Groningen, Marian C. Clahsen-van; Kraaijeveld, Rens; Dieterich, M.; Verschoor, Wenda; Thüsen, J.H. von der; Roelen, Dave L.; Cadogan, Monique; Wetering, Jacqueline van de; Rosmalen, Joost van; Weimar, W; Hesselink, Dennis A.

doi:10.1097/tp.0000000000001755

Cited by 59 publications

(71 citation statements)

References 49 publications

(60 reference statements)

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“…Belatacept-based immunosuppression may result in improved long-term patient and graft survival but it is less effective than Tac in preventing acute rejection [11,12]. It thus remains to be seen whether belatacept will replace Tac as the first-line immunosuppressive drug anytime soon [13][14][15]. Multicenter, randomized clinical studies also showed higher incidences of acute rejection and dnDSA development in the Tac withdrawal or rapamycin-based groups compared with Tac-based regimen [1,3,16,17] In the foreseeable future, no other novel immunosuppressants are likely to emerge that can replace Tac.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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115

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Introduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure -research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

Self Cite

115

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“…However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23]. In the study by de Graav et al [23], no association between rejection and higher frequencies of CD4 1 CD57 1 PD-1was found. In the study by de Graav et al [23], no association between rejection and higher frequencies of CD4 1 CD57 1 PD-1was found.…”

Section: Introductionmentioning

confidence: 89%

“…All former and current cross-match cytotoxicity tests were negative prior to transplantation. [Colour figure can be viewed at wileyonlinelibrary.com] institutional review board of Erasmus MC (METC number 2012-421) [23]. The study was performed according to good clinical practice (GCP) guidelines and the declaration of Istanbul [27].…”

Section: Patients and Study Designmentioning

confidence: 99%

“…These authors also demonstrated that, after polyclonal stimulation, CD4 1 CD57 1 PD-1 -T cells produced high levels of the effector cytokines interferon (IFN)-g or tumour necrosis factor (TNF)-a, or exhibited cytotoxicity [20]. However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23]. However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…CD4 1 CD57 1 T cells were also found to infiltrate the kidney allograft during rejection, and genes involved in allograft rejection were up-regulated in this T cell subset [20]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21].…”

Section: Introductionmentioning

confidence: 99%

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Co-inhibitory profile and cytotoxicity of CD57+PD-1− T cells in end-stage renal disease patients

Kraaijeveld

Graav

Dieterich

et al. 2017

Clinical and Experimental Immunology

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Blockade of the CD80/86-CD28 pathway by belatacept after kidney transplantation is associated with an increased risk of rejection compared with standard, calcineurin inhibitor (CNI)-based therapy. CD28 T cells, which express CD57, are not susceptible to belatacept treatment. High numbers of CD4 CD57 programmed death 1 (PD-1) T cells pretransplantation have been associated with a higher chance of rejection, although conflicting data have been reported. To investigate the working mechanism behind this possible higher chance of rejection, we studied the expression of co-inhibitory molecules (CD223, CD244 and PD-1), proliferative capacity and cytotoxic potential of fluorescence activated cell sorted (FACS) CD4 CD57 PD-1 and CD8 CD57 PD-1 T cells, and their CD57 control populations, after alloantigen stimulation. The effect of belatacept on the cytotoxic capacity of pretransplantation peripheral blood mononuclear cells from 20 patients who received belatacept post-transplantation was also tested. Expression of co-inhibitory molecule CD223 increased by approximately 10-fold after allogeneic stimulation in all four T cell subsets. Proliferation and up-regulation of CD244 and PD-1 was observed for CD4 CD57 PD-1 T cells after allogeneic stimulation, but no up-regulation of these markers occurred on CD8 T cells or CD4 CD57 PD-1 T cells. However, CD4 CD57 PD-1 T cells and, to a lesser extent, CD8 CD57 PD-1 T cells displayed higher cytotoxicity as indicated by granzyme B expression. Belatacept inhibited the cytotoxic potential of CD4 CD57 PD-1 T cells (median of inhibition 31%, P < 0·01) and CD8 CD57 PD-1 T cells (median of inhibition 10%, P < 0·05). In conclusion, alloantigen-activated CD4 CD57 PD-1 T cells exhibited a less proliferative but more cytotoxic profile than their CD57 counterparts. Their cytotoxic capacity can be inhibited partly by belatacept and was not associated with development of rejection after kidney transplantation.

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Induction and Maintenance Immunosuppressants in Sensitized Renal Allograft Recipients

Kong

2019

Kidney Transplantation in Sensitized Patients

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A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation

Cited by 59 publications

References 49 publications

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Co-inhibitory profile and cytotoxicity of CD57+PD-1− T cells in end-stage renal disease patients

Induction and Maintenance Immunosuppressants in Sensitized Renal Allograft Recipients

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