Tacrolimus Variability: A Cause of Donor-Specific Anti-HLA Antibody Formation in Children

Aksoy, Gülşah Kaya; Çomak, Elif; Koyun, Mustafa; Akbaş, Halide; Akkaya, Bahar; Aydınlı, Bülent; Uçar, Fahri; Akman, Sema

doi:10.1007/s13318-019-00544-0

Cited by 12 publications

(13 citation statements)

References 34 publications

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“…Elevated CV has been associated with increased risk of rejection and dnDSA formation in pediatric kidney transplant recipients 13,48–52 . Median CV in patients with BPAR has ranged from 44–53%, compared with 24–33% in nonrejecters 13,48,51 .…”

Section: Resultsmentioning

confidence: 99%

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Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

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Section: Resultsmentioning

confidence: 99%

“…Median CV in patients with BPAR has ranged from 44–53%, compared with 24–33% in nonrejecters 13,48,51 . Authors have attempted to identify a CV cutoff for poor allograft outcomes with results ranging 31–41% 13,49,50 . There are several differences between studies worth highlighting.…”

Section: Resultsmentioning

confidence: 99%

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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“…High IPV (CV% = 30%) was the strongest risk factor for dnDSA development and DCGL, as acute rejection and re-transplantation, whereas mismatches, age, sex and mean Tac levels were not related to dnDSA development [17]. Recently, Kaya Aksoy et al showed that high Tac IPV influenced the formation of anti-HLA antibody in paediatric recipients of living-donor kidney transplants [10]. Considering the distribution of TTC beyond and within the target therapeutic range (6 -10 ng/mL), most of the TTC < 6 ng/mL during 6 -12 months posttransplantation were observed in the high-IPV group (> 40%; Chi-Square = 25.175, p < 0.001).…”

Section: Resultsmentioning

confidence: 99%

Insight Into the Potential Influence of Inter- And Intra-Individual Variability of Tacrolimus Exposure on Graft Function Decline in Three-Year Period Following Kidney Transplantation

Stefanović¹

2020

FARMACIA

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The main goal of the present study was to evaluate the association of tacrolimus (Tac) exposure parameters (trough concentration (TTC), dose-adjusted TTC (C0/D)), Tac intra-individual variability (IPV), and Tac-related gene polymorphisms (CYP3A5 and ABCB1) with kidney function in three-year period after kidney transplantation (Tx). The study enrolled 103 Caucasian patients who were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T polymorphism. High IPV, lower average C0/D, kidney function at 6 months post-transplantation, and acute rejection were independent predictors of worse eGFR values between 13 and 36 months after Tx. Significant eGFR decline was observed in the low C0/D (p = 0.010) and high IPV patients' group (p = 0.018) between 13-24 and 25-36 months. The carriers of CYP3A5*1 allele had lower C0/D values compared to the CYP3A5*3/*3 carriers during entire observation period, while ABCB1 3435 gene polymorphism did not affect C0/D. Tailoring Tac treatment based on IPV, C0/D and CYP3A5 genotype in clinical practice may identify patients at risk for graft function decline. Rezumat Scopul principal al prezentului studiu a fost de a evalua asocierea parametrilor de expunere la tacrolimus (Tac) (concentrați e minimă (TTC), TTC ajustată la doză (C0/D)), variabilitatea intra-individuală a Tac (IPV) și polimorfismul genetic determinat de Tac (CYP3A5 și ABCB1), cu funcția renală pe o perioadă de trei ani după transplantul renal (Tx). Studiul a înrolat 103 pacienți caucazieni care au fost genotipați (polimorfismul CYP3A5 6986A>G și ABCB1 3435C>T). IPV ridicat, C0/D mediu mai scăzut, funcția renală la 6 luni după transplant și respingerea acută au fost predictori independenți ai valorilor eGFR mai slabi între 13 și 36 de luni după Tx. Scăderea semnificativă a eGFR a fost observată în grupul de pacienți cu C0/D scăzut (p = 0,010) și în grupul de pacienți cu IPV ridicat (p = 0,018) între 13-24 și 25-36 de luni. Purtătorii alelei CYP3A5*1 au avut valori C0/D mai mici comparativ cu purtătorii CYP3A5*3/*3 pe întreaga perioadă de observație, în timp ce polimorfismul genei ABCB1 3435 nu a afectat C0/D. Adaptarea tratamentului Tac bazat pe genotipul IPV, C0/D și CYP3A5 în practică poate identifica pacienții cu risc de rejectare a grefei.

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“…More recently, Kaya Aksoy et al described that a tacrolimus CV cutoff value of 32% was most accurate for identifying dnDSA development in their patient cohort of 67 pediatric kidney transplant recipients (AUC 0.713) [72]. De novo DSA development during the course of the follow-up period was associated with a higher percentage of patients with a tacrolimus CV >32% between 6 and 12 months and over 1 year after transplantation (67% vs 31% and 83% vs 47%, respectively).…”

Section: De Novo Dsa Development In Kidney Transplant Recipients On Tmentioning

confidence: 99%

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

Rojas

Hesselink

Besouw

et al. 2019

Expert Review of Clinical Immunology

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Tacrolimus Variability: A Cause of Donor-Specific Anti-HLA Antibody Formation in Children

Cited by 12 publications

References 34 publications

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Insight Into the Potential Influence of Inter- And Intra-Individual Variability of Tacrolimus Exposure on Graft Function Decline in Three-Year Period Following Kidney Transplantation

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

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