Sirolimus (Rapamycin)-Based Therapy in Human Renal Transplantation

Groth, Carl G.; Bäckman, Lars; Morales, J. M.; Calne, R. Y.; Kreis, Henri; Lang, Philippe; Touraine, Jean‐Louis; Claesson, Kerstin; Campistol, Josep M.; Durand, Dominique; Wramner, Lars; Brattström, C; Charpentier, B

doi:10.1097/00007890-199904150-00017

Cited by 811 publications

(151 citation statements)

References 21 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…However, the inhibitory SIR concentrations required were at least one order of magnitude higher than the ones observed here for primary RPTECs, and hence in the clinically toxic range 51, 52, 53. This suggests that the susceptibility to BKPyV might be enhanced by the transformed phenotype of cancer host cells, which often involve altered signal transduction and metabolic pathways 54, 55.…”

Section: Discussionmentioning

confidence: 58%

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

Hirsch

Yakhontova

et al. 2016

American Journal of Transplantation

108

View full text Add to dashboard Cite

BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV‐specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)‐ and calcineurin‐inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR–SP6‐kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC‐1 kinase inhibitor torin‐1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP‐12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP‐12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation.

show abstract

Section: Discussionmentioning

confidence: 58%

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

Hirsch

Yakhontova

et al. 2016

American Journal of Transplantation

108

View full text Add to dashboard Cite

show abstract

“…In an open-labeled study of renal allograft recipients comparing sirolimus with cyclosporine (all patients were administered corticosteroids and azathioprine), the incidence of wound infection was doubled in sirolimus patients (10% v 5%); there was no reported wound dehiscence and treatment was not discontinued because of wound infection. 9 Dosing of sirolimus was concentration-controlled, with a target trough level of 30 ng/mL in the first 2 months after transplantation.…”

mentioning

confidence: 99%

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Dunkelberg

Trotter

Wachs

et al. 2003

Liver Transplantation

115

View full text Add to dashboard Cite

Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13. S irolimus, a new immunosuppressive agent, is being used increasingly in liver transplantation. 1-4 Sirolimus and tacrolimus are structurally related macrolides that bind the same intracellular receptor (FK506-binding protein-12 [FKBP12]) and potently inhibit T-cell proliferation. 5,6 The tacrolimus-FKBP12 complex, like the cyclosporine-cyclophilin complex, binds to and inhibits the Ca 2ϩ -dependent serine-threonine phosphatase calcineurin, thereby inhibiting cytokine-induced T-cell gene transcription and G 0 to G 1 transition. Conversely, the sirolimus-FKBP12 complex inhibits the target of rapamycin kinase, thereby inhibiting protein synthesis, G 1 to S transition, and cytokinedriven T-cell proliferation.Sirolimus has shown benefit in renal transplant recipients and therefore was approved for use in renal transplantation by the Food and Drug Administration in 1999. In two recent studies, a fixed dose of 2 or 5 mg/d of sirolimus in combination with cyclosporine decreased the acute rejection rate in the first year by 50% without an increase in immunosuppressant-related side effects. 7,8 Wound infection rates were not increased with sirolimus.Two recent trials have shown that liver transplantation may be performed successfully with minimal use of corticosteroids by using sirolimus and either tacrolimus or cyclosporine A. Low-dose sirolimus in the absence of prednisone in liver transplant recipients at our center was associated with a 50% decreased incidence of rejection, and the incidence of steroid-resistant rejection was decreased by 90% (compared with historic controls). 4 Similar efficacy was reported by McAlister et al 2 in an open-label report of 56 patients administered low-dose tacrolimus and sirolimus with prednisone up to 6 months after transplantation. The acute cellular rejection rate was 14%, which was approximately 50% lower than the historic rejection rate. None of the patients had steroid-resistant rejection.The well-established side-effect profile of sirolimus includes dose-dependent hyperlipidemia, thrombocytopenia, anemia, and leukopenia with an absence of neurotoxicity, nephrotoxicity, and diabetogenesis. There are anecdotal reports from some centers that sirolimus is associated with an increased incid...

show abstract

“…Sirolimus has shown a similar efficacy to CyA when used alone with respect to graft rejection rates and short-term graft survival, either in combination with steroids and azathioprine or with steroids and mofetil mycophenolate (MMF). 2,3 With the objective of a low rejection rate and the minimization of CyA nephrotoxicity a multicenter, randomized, phase III trial at 3 years is currently ongoing in 57 centers in Europe, Canada, and Australia with a total of 525 patients enrolled. This trial compares two arms, a control arm (A) using CyA, fixed doses of sirolimus, and steroids, and a study arm (B) with CyA, concentration-controlled sirolimus, and steroids with suspension of CyA at 3 months' postransplant.…”

mentioning

confidence: 99%

Early cyclosporine a withdrawal in kidney transplant recipients under a sirolimus-based immunosuppressive regimen: pathological study of graft biopsies at 1-year posttransplant

Ruiz

Campistol²,

Mota

et al. 2002

Transplantation Proceedings

View full text Add to dashboard Cite

Sirolimus (Rapamycin)-Based Therapy in Human Renal Transplantation

Abstract: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Cited by 811 publications

References 21 publications

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications

Early cyclosporine a withdrawal in kidney transplant recipients under a sirolimus-based immunosuppressive regimen: pathological study of graft biopsies at 1-year posttransplant

Contact Info

Product

Resources

About