Genetic variance in ABCB1 and CYP3A5 does not contribute toward the development of chronic kidney disease after liver transplantation

Tapirdamaz, O.; Hesselink, Dennis A.; Bouazzaoui, Samira El; Azimpour, Mohammad; Hansen, Bettina E.; Laan, Luc J. W. van der; Polak, Wojciech; Kwekkeboom, Jaap; Schaik, Ron H.N. van; Gelder, Teun van; Metselaar, Herold J.

doi:10.1097/fpc.0000000000000063

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…[23] Several studies show a prevalence of > 50% of the LT recipients with a CKD defined as an eGFR of <60 mL/min/1.73 m 2 . [7,8] Our ITT and PP analysis showed lower rates with a prevalence of 30% to 50% of the LT recipients having an eGFR of <60 mL/min/1.73 m 2 . This difference could be explained by the height of the TAC trough levels.…”

Section: Discussionmentioning

confidence: 81%

Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial

Mulder

Hoek

Berg

et al. 2023

Liver Transplantation

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The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%–59.9%) vs. 43.7%, 95% CI: 32.8%–52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.

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Section: Discussionmentioning

confidence: 81%

Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial

Mulder

Hoek

Berg

et al. 2023

Liver Transplantation

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“…Evaluation of parameters related to selection showed that in all of the studies, sample population was representative of the community and both genotype groups were selected from the same population except one in which patients with developed acute cellular rejection were selected, eleven studies did not obtain blood samples at the same time for all participants and that was one of the reasons for their exclusion from the analyses, seven studies did not begin their experiments from first post‐transplant day, when tacrolimus was administered for the first time . Two parameters were checked as confounders, and apart from five studies, others did not assess one or both of them.…”

Section: Resultsmentioning

confidence: 99%

“…Two parameters were checked as confounders, and apart from five studies, others did not assess one or both of them. Appraisal of outcomes revealed that in 23 studies, outcomes of interest were not presented (eg, because of nonsignificant data) or presented improperly (eg, as median) which led to the exclusion of the study from the analyses or obligated us to estimate required data . Eight studies did not continue blood level measurement at specified time points for at least one month or did not mention the time of measurement clearly .…”

Section: Resultsmentioning

confidence: 99%

“…They reported various parameters in different forms at a variety of time points post‐transplantation; therefore, it was not possible to pool them in meta‐analysis. Four studies reported rejection events, five studies evaluated kidney function to follow tacrolimus side effect, Fathy et al. only reported overall incidence of post‐transplant complications, infectious‐related events were also checked in two studies, and other tacrolimus‐related adverse effects were reported by Muraki et al .…”

Section: Resultsmentioning

confidence: 99%

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Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

Hendijani

Azarpira

Kaviani

2018

Clinical Transplantation

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We systematically collected eligible data to measure the effect of CYP3A5*1 expression on personalized tacrolimus therapy. Six databases were searched for studies on adult liver transplant recipients and donors of liver graft which reported tacrolimus dose requirement, trough blood concentration, and/or concentration/dose (C/D) ratio in expressers and nonexpressers of CYP3A5*1. Eligible data were pooled by meta-analysis. Sixteen observational studies (1309 recipients, 1044 donors of liver graft) were included in the analyses. Tacrolimus C/D ratio was lower, and the dose was higher in recipient expressers of CYP3A5*1 and/or carriers of expresser liver graft at 1-4 weeks and 2-4, 6, and 12 months post-transplantation. Tacrolimus blood concentration was lower at the first two weeks. Pair expressers were affected by about twofold, and the effect was different between ethnic groups. CYP3A5*1 expression in recipients increased tacrolimus required dose by 0.023 at first, 0.022 at third, and 0.012 mg/kg/day at sixth month. Its expression in graft tissue increased tacrolimus required dose by 0.024 at first, 0.035 at third, and 0.032 mg/kg/day at sixth month. Considering CYP3A5*1 polymorphism can be helpful in individualization of tacrolimus efficient dose prior to administration, and it can remove initial high-risk lag time (over/underdose period before reaching target blood level) at first few days post-transplantation.

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“…Respect to CYP3A5, Fukudo et al [165] did not find a significant association in donors, although they only used changes in serum creatinine concentrations (and not creatinine clearance) for diagnosing chronic nephrotoxicity. Tapirdamaz et al [166] reported that neither the CYP3A5 6989A>G nor ABCB1 3435C>T genotype of either donor or recipient was associated with risk of chronic kidney disease, but they did not consider as exclusion criteria other different causes of chronic kidney disease, so further studies are needed.…”

Section: Impact Of Pharmacogenetics On Clinical Outcomesmentioning

confidence: 99%

Pharmacogenetics of Immunosuppressants in Solid Organ Transplantation: Time to Implement in the Clinic

Herrero¹,

Megías²,

Bosó³

et al. 2016

Frontiers in Transplantology

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Our aim in this chapter is to present the state of the art, including our own group research, in the field of immunosuppressant pharmacogenetics in the four main types of solid organ transplantation kidney, heart, lung, and liver. The main focus will be on those findings in the field that have been widely investigated and then in those that are close to clinical implementation, mainly CYP " genotyping for the adjustment of the initial tacrolimus dose. This recommendation will be discussed in more detail, explaining its clinical potential as well as its limitations. To end, a short opinion about the feasibility of implementation in the health systems as well as discussion about private companies selling pharmacogenetic tests will be presented.

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Genetic variance in ABCB1 and CYP3A5 does not contribute toward the development of chronic kidney disease after liver transplantation

Abstract: An individual's risk of developing CKD after LT is not associated with genetic variation in either recipient or donor CYP3A5 or ABCB1 genotype status.

Cited by 10 publications

References 43 publications

Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial

Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta‐analysis

Pharmacogenetics of Immunosuppressants in Solid Organ Transplantation: Time to Implement in the Clinic

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