Better Actual 10-Year Renal Transplant Outcomes of 80% Reduced Cyclosporine Exposure With Sirolimus Base Therapy Compared With Full Cyclosporine Exposure Without or With Concomittant Sirolimus Treatment

Pliszczyński, Jacek; Kahan, Barry D.

doi:10.1016/j.transproceed.2011.10.052

Cited by 13 publications

(9 citation statements)

References 26 publications

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“…Rapamycin–the mammalian target of rapamycin (mTOR) inhibitor -blocks DC maturation [18], [19], inhibits capacity of DC to stimulate T cells even following exposure to LPS [20], and prolongs organ allograft survival [21]. Thus, we hypothesized that 10 μg donor imDex combined with a short course of minimally effective rapamycin could induce immunological tolerance and effectively promote allograft survival.…”

Section: Resultsmentioning

confidence: 99%

Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model

Yang

et al. 2012

PLoS ONE

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BackgroundDendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model.MethodsImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model.ResultsDonor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4+CD25+ T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to naïve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients.ConclusionCombined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.

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Section: Resultsmentioning

confidence: 99%

Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model

Yang

et al. 2012

PLoS ONE

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“…In fact, an average biopsy-proven acute rejection rate as low as 2.7%/year was achieved in another study when a SIR + low-dose CyA was continued for 10 years. 11 In the final analysis, we believe that the advantage of preserved glomerular filtration rate achieved in our protocol outweighs the significance of a 1%/year reduction in the chances of acute rejection.…”

Section: Discussionmentioning

confidence: 84%

“…10 The long-term numeric survival advantage of the SIR-based protocol in our study is supported by the 10-year data on 592 patients, where patient survival was 80% in patients receiving a combination of 80% Abbreviations: ITT, intention-to-treat; POT, patients on therapy reduced CyA + SIR, 73% received a combination of full-dose CyA + SIR, and only 68% on conventional CyA and MMF. 11 On the other hand, no positive effect of SIR on patient survival was observed in other trials. For example, in a large historical cohort of United States kidney transplant recipients with 8-year followup, 12 the risk of death was highest in patients who received mTORs without CNIs (3237 patients), intermediate in those who received a combination of mTORs and CNIs (10 510 patients), and least in those on CNI without mTORi (125 623 patients).…”

Section: Discussionmentioning

confidence: 94%

Untitled

2015

Exp Clin Transplant

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Objectives: To describe the long-term results of a previously developed a sirolimus-based sequential immunosuppression protocol for kidney transplant comprising 2 phases: sirolimus + cyclosporine + prednisolone for 3 months followed by sirolimus + prednisolone + mycophenolate mofetil with steroid minimization the first year. Two-year outcomes of patients on this protocol (group A) showed equivalent patient and graft survival, yet with significantly better function, compared with those on cyclosporine + mycophenolate mofetil + prednisolone (group B). Materials and Methods: We report the 8-year outcomes in the same cohort (76 patients in group A and 37 in group B). Results: 42% switched from group A to B versus 43% switching from B to A. Intent-to-treat patient survivals at 5 and 8 years were 88% and 85.5% for group A, and 78% and 73% for group B. Deathcensored graft survivals were 93% for group A and 95% for group B. Graft function was significantly better at 8 years, with 91% of group A patients compared with 50% in group B having estimated glomerular filtration rates > 45 mL/min/1.73 m 2 , and a significantly lower incidence of chronic allograft nephropathy in the former. Secondary parameters including blood pressure control, new onset diabetes mellitus, proteinuria and other drug-related adverse events showed no significant differences between the groups. Conclusions: The sirolimus-based sequential immunosuppression protocol was well tolerated in 58% of patients. The intent-to-treat and patients-ontherapy analyses revealed that it was equivalent to the widely used cyclosporine + mycophenolate mofetil + prednisolone protocol regarding patient and graft survival. It is associated with better graft function and lower incidence of chronic allograft nephropathy in 8 years' follow-up. The incidence of drug-related adverse reactions was not statistically different from those in the comparator.

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“…In fact, tacrolimus trough levels were statistically comparable in the first 2 months post-transplantation and generally higher than the proposed target levels. Contrary to an important and bigger study [25] using a sirolimuscyclosporine combination in which cyclosporine dose was reduced by 80%, we decided for a modest 25% reduction of the tacrolimus dose (0.15 mg/kg/day) in our study group that may have been insufficient to achieve a clear-cut difference on tacrolimus exposure between groups. We also believe that during the follow-up, the nephrologists' reluctance in properly decreasing tacrolimus exposure probably contributed to a smaller reduction in its serum levels and might have been the main reason for these results.…”

Section: Discussionmentioning

confidence: 97%

New Recipes With Known Ingredients: Combined Therapy of Everolimus and Low-dose Tacrolimus in De Novo Renal Allograft Recipients

Santos

Macário

et al. 2015

Transplantation Proceedings

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Better Actual 10-Year Renal Transplant Outcomes of 80% Reduced Cyclosporine Exposure With Sirolimus Base Therapy Compared With Full Cyclosporine Exposure Without or With Concomittant Sirolimus Treatment

Cited by 13 publications

References 26 publications

Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model

Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model

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New Recipes With Known Ingredients: Combined Therapy of Everolimus and Low-dose Tacrolimus in De Novo Renal Allograft Recipients

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