Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients

Koziolek, Michael; Riess, R; Geiger, Helmut; Thévenod, Frank; Hauser, Ingeborg A.

doi:10.1046/j.1523-1755.2001.00782.x

Cited by 90 publications

(74 citation statements)

References 43 publications

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“…In animals, an inverse relationship among periglomerular and interstitial fibrosis, CsA deposits in renal tissue, and the level of P-gp expression in proximal tubular cells was observed (7). In agreement with these data, we have shown in a histopathologic study that low expression of P-gp in renal parenchymal cells was associated with the occurrence of CsA nephrotoxicity, namely chronic interstitial fibrosis, arteriolopathy, and tubular vacuolization (8). Because CsA is a P-gp substrate, these data indicate that factors that modulate P-gp expression could have an impact on CsA nephrotoxicity as a result of an accumulation of CsA within renal cells in patients with low expression of P-gp.…”

supporting

confidence: 83%

“…CsA-treated renal transplant patients with acute tubular necrosis, acute allograft rejection, or chronic allograft nephropathy expressed P-gp in nephron structures that are predominately affected by CsA-induced nephrotoxicity (8,28). In rats that were treated chronically with CsA, intrarenal angiotensin II deposits, peritubular fibrosis, and CsA deposits were inversely related to renal P-gp expression, i.e., the lower the tubular P-gp expression, the higher the histologic signs of severe nephrotoxicity (7).…”

Section: Discussionmentioning

confidence: 99%

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ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Hauser

Schaeffeler²,

Gauer³

et al. 2005

Journal of the American Society of Nephrology

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204

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Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C3 T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C3 T and 2677G3 T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity ( 2 ‫؍‬ 10.5; P ‫؍‬ 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor's ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P ‫؍‬ 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

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supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Hauser

Schaeffeler²,

Gauer³

et al. 2005

Journal of the American Society of Nephrology

Self Cite

204

118

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“…In the kidney, P-gp is constitutively expressed mainly on the brush border of the proximal and distal tubular cells. 46,48 Low activity of this efflux pump caused by either low protein expression induced by a genetic mutation such as the ABCB1 3435C→T TT genotype 41,49 or its inhibition by a drug 46,50 or a natural substance such as grapefruit juice, a well-established potent P-gp inhibitor, [50][51][52] can lead to renal toxicity within therapeutic drug blood level ranges as a result of increased intracellular drug concentration and can lead to an exaggerated deleterious injury, when unfavorable genetics, demographics, and environmental conditions are combined. 21,41,46,47,[49][50][51][52] Chronic cyclosporine nephrotoxicity is inversely related to P-gp expression in the renal tubule.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

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, del Moral et al demonstrated that the up-regulation of P-glycoprotein was inversely related to the incidence of arteriolar hyalinosis, interstitial fibrosis, and periglomerular fibrosis (286). Human studies confirmed this upregulation of tubular epithelial P-glycoprotein expression with cyclosporine treatment, as well as lower expression of P-glycoprotein in renal allograft biopsies with CNI nephrotoxicity (288,289). These human studies confirm the animal data and suggest that interindividual variability in local renal P-glycoprotein expression contributes to the local susceptibility to CNI nephrotoxicity.…”

Section: Local Renal Exposure To Cyclosporine and Tacrolimusmentioning

confidence: 97%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,266

1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients

Cited by 90 publications

References 43 publications

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Untitled

Calcineurin Inhibitor Nephrotoxicity

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