15-Year Follow-up of a Multicenter, Randomized, Calcineurin Inhibitor Withdrawal Study in Kidney Transplantation

Roodnat, Joke I.; Hilbrands, Luuk B.; Hené, Ronald J.; Sévaux, R.G.L. de; Gregoor, P. J. H. Smak; Gestel, Judith A. Kal-van; Konijn, Cynthia; Zuilen, Arjan van; Gelder, Teun van; Hoitsma, Andries J.; Weimar, Willem

doi:10.1097/01.tp.0000442774.46133.71

Cited by 36 publications

(25 citation statements)

References 27 publications

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“…Steroids have multiple adverse effects, such as increased risk of infection, hyperglycemia, accelerated atherosclerosis, and gastrointestinal bleeding, while calcineurin inhibitors are associated with neurotoxicity and nephrotoxicity, as well as risk of infection and an increased risk of cancer (Arnold et al, 2013; Crutchlow and Bloom, 2007; Guba et al, 2004; Hoorn et al, 2012; Roodnat et al, 2014). In this regard, we propose that our anti-metabolic regimen has certain advantages over conventional treatments in terms of avoiding some of these side effects.…”

Section: Discussionmentioning

confidence: 99%

“…However, long-term use of immunosuppressants results in a broad range of co-morbidity. For example, calcineurin inhibitors are associated with hyperlipidemia, hyperglycemia, neuro- and nephro-toxicity, as well as an increased risk of malignancy (Arnold et al, 2013; Crutchlow and Bloom, 2007; Guba et al, 2004; Hoorn et al, 2012; Roodnat et al, 2014). In addition, such agents inhibit negative regulatory and tolerance-inducing responses (Wu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Preventing Allograft Rejection by Targeting Immune Metabolism

et al. 2015

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SUMMARY Upon antigen recognition and co-stimulation, T lymphocytes up-regulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. While such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. We therefore hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving a glycolytic inhibitor, 2-Deoxyglucose (2-DG), an anti-Type II diabetes drug (metformin) and an inhibitor of glutamine metabolism, 6-Diazo-5-oxo-L-norleucine (DON). Using this triple drug regimen we were able to prevent/delay graft rejection in fully mismatched skin and heart allograft transplantation models.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preventing Allograft Rejection by Targeting Immune Metabolism

et al. 2015

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“…Secondary end points (6,12,18, and 24 months) included incidence of AR, eGFR, 28 allograft and subject survival rates, and percentage of subjects with de novo post-transplant DSA.…”

Section: Clinical End Pointsmentioning

confidence: 99%

“…4,5 The adverse effects of CNIs, including drug-induced renal parenchymal fibrosis, allograft dysfunction, and cardiovascular morbidity among others, have raised concerns that CNIs may contribute to poor long-term outcomes and have resulted in a desire to develop immunosuppression protocols that avoid, withdraw, or minimize their use. [6][7][8] Published studies of CNI withdrawal in unselected cohorts of kidney transplant recipients taking standard three-drug immunosuppression indicate that elimination of CNI increases the risk of AR, 6,7,[9][10][11][12][13][14][15][16] which can potentially precipitate a fibrogenic process that contributes to graft failure. Some of these previous trials targeted patients who are apparently low risk as defined by relatively limited conventional clinical criteria, including living donor source, human leukocyte antigen (HLA) matching (particularly at class II loci), and lack of HLA sensitization.…”

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confidence: 99%

Adverse Outcomes of Tacrolimus Withdrawal in Immune–Quiescent Kidney Transplant Recipients

Hricik

Formica

Nickerson

et al. 2015

Journal of the American Society of Nephrology

171

149

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Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that .16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-g ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

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“…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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116

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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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15-Year Follow-up of a Multicenter, Randomized, Calcineurin Inhibitor Withdrawal Study in Kidney Transplantation

Abstract: Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.

Cited by 36 publications

References 27 publications

Preventing Allograft Rejection by Targeting Immune Metabolism

Preventing Allograft Rejection by Targeting Immune Metabolism

Adverse Outcomes of Tacrolimus Withdrawal in Immune–Quiescent Kidney Transplant Recipients

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

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