Loss of Nephrin Expression in Glomeruli of Kidney‐Transplanted Patients Under m‐TOR Inhibitor Therapy

Biancone, Luigi; Bussolati, Benedetta; Mazzucco, Gianna; Barreca, Antonella; Gallo, Eugenio; Rossetti, Maura; Messina, Maria; Nuschak, Barbara; Fop, Fabrizio; Medica, Davide; Cantaluppi, Vincenzo; Camussi, Giovanni; Segoloni, Giuseppe

doi:10.1111/j.1600-6143.2010.03259.x

Cited by 28 publications

(16 citation statements)

References 28 publications

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“…These histologic findings have been reported to be associated with mTOR inhibitor monotherapy or in combination therapy with CNI and at therapeutic concentrations, in both animal and human models. 7,11,[16][17][18][21][22][23]46,47 In fact, Piao and associates 47 recently demonstrated, using an in vivo experimental animal model, that combined treatment with cyclosporine and the mTOR inhibitors (rapamycin and everolimus) significantly increased cyclosporine or mTOR inhibitor concentrations in kidney tissue versus treatment with cyclosporine or mTOR inhibitor alone, despite similar whole blood levels of either drug. This increase in tissue concentration of both drugs was associated with an exaggeration in oxidative stress and an aggravation in renal injury with significant deterioration in renal function in the combination therapy group versus with monotherapy.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

“…13,14 In contrast, low dose of everolimus, commonly used during organ transplant, failed to induce EMT in the same experimental settings. 10 Therefore, mTOR inhibitor-associated nephrotoxicity is characterized predominantly by a possible apoptotic renal epithelial cell injury 15 that affects both podocytes [7][8][9]11,[16][17][18][19] in the glomerular compartment and renal tubular epithelial cells 10,[20][21][22][23][24] in the tubulointerstitial compartment. Consequently, the IFTA observed with mTOR inhibitor therapy may be the result of a cumulative toxic renal tubular injury induced by the podocytopathy-associated proteinuria and/or by the direct toxic tubular insult of the drug itself.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

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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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Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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“…The idea that rapamycin can impair podocyte function is supported by the observation that its application on cultured podocytes decreases the protein abundance of nephrin, TRPC6, and Nck and reduces cell adhesion and motility (171). Nephrin expression is also reduced in glomeruli of kidney-transplanted patients undergoing mTOR inhibition therapy (172). However, rapamycin can prevent the protamine sulfate–induced and Ca 2+ -dependent disruption of the podocyte actin cytoskeleton, suggesting a potential beneficial effect of rapamycin on proteinuria (72).…”

Section: Podocyte Mammalian Target Of Rapamycin Signaling and Autophagymentioning

confidence: 99%

Cell Biology and Pathology of Podocytes

Greka

Mündel

2012

Annu. Rev. Physiol.

432

447

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As an integral member of the filtration barrier in the kidney glomerulus, the podocyte is in a unique geographical position: It is exposed to chemical signals from the urinary space (Bowman’s capsule), it receives and transmits chemical and mechanical signals to/from the glomerular basement membrane upon which it elaborates, and it receives chemical and mechanical signals from the vascular space with which it also communicates. As with every cell, the ability of the podocyte to receive signals from the surrounding environment and to translate them to the intracellular milieu is dependent largely on molecules residing on the cell membrane. These molecules are the first-line soldiers in the ongoing battle to sense the environment, to respond to friendly signals, and to defend against injurious foes. In this review, we take a membrane biologist’s view of the podocyte, examining the many membrane receptors, channels, and other signaling molecules that have been implicated in podocyte biology. Although we attempt to be comprehensive, our goal is not to capture every membrane-mediated pathway but rather to emphasize that this approach may be fruitful in understanding the podocyte and its unique properties.

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“…[6][7][8]. Potential mechanisms for mTOR-associated proteinuria include decreased vascular endothelial growth factor synthesis, and inhibition of key podocyte proteins that comprise the glomerular slit diaphragm, including nephrin (9,10). In particular, proteinuria has been reported following calcineurin inhibitor (CNI) withdrawal with mTOR introduction in both the early (1-6 months; Refs.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

Wiseman

McCague

Kim

et al. 2013

American Journal of Transplantation

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Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time-dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA-treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3-8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose-dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.

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Loss of Nephrin Expression in Glomeruli of Kidney‐Transplanted Patients Under m‐TOR Inhibitor Therapy

Cited by 28 publications

References 28 publications

Untitled

Untitled

Cell Biology and Pathology of Podocytes

The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

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