The utilization of sirolimus and the impact on wound‐healing complications in obese kidney transplant recipients

Hulbert, Amanda; Delahunty, A.; Rajab, Amer; Forbes, Rachel C.; Winters, Holli

doi:10.1111/ctr.12183

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…As we observed in this study, rapamycin inhibits wound closure and reendothelialization responses in vitro (59)(60)(61). Conflicting studies have reported sirolimus-associated wound-healing complications in transplant recipients at high doses (62,63), while other reports have not demonstrated sirolimusassociated wound-healing complications (64)(65)(66). A recent report showed that everolimus could be used in renalsparing immunosuppression without these adverse effects in liver transplant recipients (67).…”

Section: Discussionmentioning

confidence: 99%

Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently Than Sirolimus

Jin

Valenzuela

Ziegler

et al. 2014

American Journal of Transplantation

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Antibody (Ab) crosslinking of HLA I molecules on the surface of endothelial cells triggers proliferative and pro-survival intracellular signaling, which is implicated in the process of chronic allograft rejection, also known as transplant vasculopathy. The purpose of this study was to investigate the role of mammalian target of rapamycin (mTOR) in HLA I antibody-induced signaling cascades. Everolimus provides a tool to establish how the mTOR signal network regulates HLA I-mediated migration, proliferation, and survival. We found that everolimus inhibits mTORC1 by disassociating Raptor from mTOR, thereby preventing class I-induced phosphorylation of mTOR, p70S6K, S6RP, and 4E-BP1, and resultant class I-stimulated cell migration and proliferation. Furthermore, we found that everolimus inhibits class I-mediated mTORC2 activation (1) by disassociating Rictor and Sin1 from mTOR; (2) by preventing class I-stimulated Akt phosphorylation; and (3) by preventing class I-mediated ERK phosphorylation. These results suggest that everolimus is more effective than sirolimus at antagonizing both mTORC1 and mTORC2, the latter of which is critical in endothelial cell functional changes leading to transplant vasculopathy in solid organ transplantation after HLA I crosslinking. Our findings point to a potential therapeutic effect of everolimus in prevention of chronic antibody-mediated rejection.

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Section: Discussionmentioning

confidence: 99%

Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently Than Sirolimus

Jin

Valenzuela

Ziegler

et al. 2014

American Journal of Transplantation

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“…Because sirolimus is associated with impaired wound healing, caution is advised in obese patients (body mass index >30 kg/m 2 ), who may be more likely to experience problems with wound healing and surgical complications in the immediate posttransplantation period . Because impaired wound healing is dose dependent, lower initial sirolimus concentrations should be maintained, as well as careful surgical technique.…”

Section: Sirolimus For Use In Kidney Transplantationmentioning

confidence: 99%

Optimizing the clinical utility of sirolimus‐based immunosuppression for kidney transplantation

Tedesco‐Silva

Rial

Santiago

et al. 2019

Clinical Transplantation

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While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long‐term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection‐associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long‐term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI‐based regimens to sirolimus. Sirolimus‐containing regimens are associated with preservation of good renal function, with promising characteristics for improving long‐term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low‐dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI‐free combination with mycophenolate mofetil (following CNI‐to‐sirolimus conversion at 3‐6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

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“…Whilst short term graft survival is improving and acute rejection rates are dropping long term graft survival rates remain a major focus for clinical improvement. There are many factors that can impact the prognosis of a kidney transplant, from graft or donor considerations [2,3] , factors involving the immunosuppressant regime [4,5] , and issues concerning the recipient [6,7] . Tissue typing and stringent exclusion criteria are implemented pre-transplant to reduce the risk of donor related problems [3] .…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells for kidney transplantation

Lett¹,

Sivanathan²,

Coates³

2014

WJCU

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The long term consequence of immunosuppressive therapy in kidney transplantation has prompted investigation of alternative means to modify the immune response to the allograft. Cell based therapies are potentially attractive as they may provide a long lasting immunomodulatory effect, may repair tissues and reduce the necessity to take immunosuppressive drug therapy. Of the current cell therapies, mesenchymal stem cells have now been trialled in small numbers of human kidney transplantation with apparent safety and potential efficacy. Many issues however need to be resolved before these cells will become mainstays of transplant immunosuppression including ex vivo modification to enhance immunomodulatory properties, cell number, route and frequency of administration as well as cellular source of origin.

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The utilization of sirolimus and the impact on wound‐healing complications in obese kidney transplant recipients

Abstract: In our experience, sirolimus does not increase WHC in obese KTR and can be safely used as maintenance immunosuppression immediately following transplant.

Cited by 7 publications

References 15 publications

Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently Than Sirolimus

Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently Than Sirolimus

Optimizing the clinical utility of sirolimus‐based immunosuppression for kidney transplantation

Mesenchymal stem cells for kidney transplantation

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