Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients

Crettol, Séverine; Venetz, Jean-Pierre; Fontana, Massimiliano; Aubert, John‐David; Ansermot, Nicolas; Fathi, Marc; Pascual, Manuel; Eap, Chin B.

doi:10.1097/fpc.0b013e3282f7046f

Cited by 84 publications

(54 citation statements)

References 36 publications

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“…[11][12][13] This effect might be sustained by increased intracellular CsA concentration secondary to depressed CsA efflux via P-glycoprotein transport in this population. 9,10 Although this is consistent with findings that both acute and chronic CsA nephrotoxicity are associated with oxidative stress and can be limited by free radical scavengers acting to block ROS, [25][26] ad hoc studies using mass spectrometry technology to measure intracellular CsA concentration are needed to specifically address this working hypothesis.…”

Section: Discussionmentioning

confidence: 49%

“…7 CsA is a substrate of an efflux transporter-the P-glycoprotein (P-gp) encoded by the multidrug resistance-1 gene (now referred as ABCB1)-which actively transports lipophilic drugs and other xenobiotics from the intracellular to the extracellular domain. 8 This transporter is expressed in lymphocytes, 9 and in other leukocytes, 10 as well as in hepatocytes and on the brush border of enterocytes and proximal tubular cells. 8 Reduced expression or functional inhibition of this efflux-pump invariably results in increased intracellular and tissue drug concentrations, 8,9 but may have unpredictable effects on CsA blood levels.…”

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confidence: 99%

“…8 This transporter is expressed in lymphocytes, 9 and in other leukocytes, 10 as well as in hepatocytes and on the brush border of enterocytes and proximal tubular cells. 8 Reduced expression or functional inhibition of this efflux-pump invariably results in increased intracellular and tissue drug concentrations, 8,9 but may have unpredictable effects on CsA blood levels. Indeed, CsA blood levels increased, decreased, or did not change in different settings, likely because of different balances between enhanced distribution into the tissue compartment and decreased excretion into the gastrointestinal lumen or urinary tract.…”

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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: 49%

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confidence: 99%

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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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“…This finding was confirmed in kidney, liver, and lung transplant. 59 Kidney, 60,61 heart, 62 and liver 63 transplant recipients who carry the ABCB1 3435C→T TT genotype (low-P-gp expressers) are less likely to develop acute rejection than their counterparts, carriers of CC or CT genotypes (high P-gp expressers), regardless of the whole blood level of CNI. These findings suggest that, despite maintenance of drug concentrations in the therapeutic range, some patients could have either increased intracellular levels and therefore could be overimmunosuppressed or have inadequate intracellular concentrations and therefore underimmunosuppressed.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

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2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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“…In addition, attention was focused on those SNPs previously investigated in transplant recipients: C3435T (rs1045642), 10,11,17 G2677T/A (rs2032582), 11 C1236T (rs1128503), 11 C129T (rs3213619) 34 and G1199A (rs2229109). 35 For the PPIA (cyclophilin A, Cyp) gene, HapMap revealed six SNPs with minor allele frequencies of .5% in the CEU population present within this 6475-bp region. The Tagger pairwise function within HapMap assigned the three tag SNPs-rs6970925, rs6463247, and rs9638978-to capture .80% of the common variation within this gene and surrounding area.…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Moore

McKnight

Döhler

et al. 2012

Journal of the American Society of Nephrology

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The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.

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Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients

Cited by 84 publications

References 36 publications

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

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

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Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

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