Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Webster, Angela C; Lee, Vincent; Chapman, Jeremy R.; Craig, Jonathan C.

doi:10.1002/14651858.cd004290.pub2

Cited by 73 publications

(54 citation statements)

References 231 publications

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“…14 Apart from the association of anti-CD3 mAbs with posttransplantation lymphoproliferative disease, 15 the clinical evidence for one treatment regimen over another in reducing posttransplantation malignancy is varied and not compelling. This analysis suggests that longer term follow-up of recent comparative immunosuppressive trials (e.g., Efficacy Limiting Toxicity Elimination [ELITE]-Symphony Trial 13 ) could provide important data on cancer outcomes and that better markers of the degree of immunosuppression may also aid in reducing cancer risk.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Gallagher¹,

Kelly²,

Jardine³

et al. 2010

Journal of the American Society of Nephrology

183

121

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Cancer is a widely recognized complication of transplantation, and the effects of various immunosuppressive drugs on cancer risk remains controversial. This randomized trial allocated 489 recipients of first cadaveric renal transplants to one of three groups: Azathioprine and prednisolone, cyclosporine monotherapy, or cyclosporine monotherapy followed by a switch to azathioprine and prednisolone after 3 months. Here, we report cancer outcomes by non-skin cancer (including melanoma) and skin cancer (excluding melanoma) for 481 patients during a median follow-up of 20.6 years. A total of 226 patients developed at least one cancer: 95 with non-skin cancer and 171 with skin cancer. In the intention-to-treat analysis, mean times to first non-skin cancer (16.0, 15.3, and 15.7 years for groups 1 through 3, respectively) and first skin cancer (13.6, 14.3, and 15.2 years, respectively) were not different among the three groups or between any subgroup. In multivariate analyses, non-skin cancer associated with increasing age and previous smoking history, whereas skin cancer associated with increasing age, nonbrown eye color, fairer skin, and a functioning transplant. Treatment allocation did not associate with development of either form of cancer in multivariate analyses. In conclusion, these immunosuppressive regimens, widely used in recent decades, carry similar risks for carcinogenicity after kidney transplantation.

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Section: Discussionmentioning

confidence: 99%

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Gallagher¹,

Kelly²,

Jardine³

et al. 2010

Journal of the American Society of Nephrology

183

121

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“…Sirolimus is indicated for the prophylaxis of organ rejection in patients aged !13 years receiving renal transplants in combination with cyclosporine (6). However, outcomes of sirolimus-based therapy after LTx are less clear.…”

Section: Introductionmentioning

confidence: 99%

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

Asrani

Wiesner

Trotter

et al. 2014

American Journal of Transplantation

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We studied whether the use of sirolimus with reduceddose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000)(2001)(2002)(2003), adult primary liver transplant recipients (n ¼ 222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p ¼ 0.009) and patient death (20% vs. 8%, p ¼ 0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p ¼ 0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p ¼ 0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

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“…1,2 Randomized trials of sirolimus-based immunosuppressive regimens in solid organ transplantation have observed decreased cumulative incidence of CMV disease in patients receiving sirolimus. 28,29 We reported a reduced incidence of CMV reactivation in an initial experience with a combination of sirolimus and tacrolimus for GVHD prophylaxis, 30 although that trial was limited to matched-related HSC transplant recipients and the incidence of acute GVHD was low. 31 Thus, in the present study we sought to evaluate whether sirolimus exposure during early transplantation had an effect on CMV infection particularly compared with calcineurin inhibitors cyclosporine and tacrolimus, as well as other risk factors for early CMV reactivation, in a recent cohort of adult HSC transplant recipients at our institution.…”

Section: Introductionmentioning

confidence: 99%

Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Marty

Bryar

Browne

et al. 2007

Blood

134

109

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Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Cited by 73 publications

References 231 publications

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

Long-Term Cancer Risk of Immunosuppressive Regimens after Kidney Transplantation

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

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