Conversion Therapy to Everolimus in Renal Transplant Recipients: Results After One Year

Girón, Fernando Fernández; Baez, Y.; Niño-Murcia, Alejandro; Rodríguez, J.; Salcedo, S.

doi:10.1016/j.transproceed.2008.03.012

Cited by 9 publications

(6 citation statements)

References 9 publications

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“…Rapamycin, an mTORC1 inhibitor, has a well established role as an immunosuppressant to limit transplant rejection (9, 10) as well as a smooth muscle cell growth inhibitor in vascular stents (11, 12). In addition, Bissler et al have shown recently in a Phase 1-2 trial that rapamycin has promising activity in decreasing the size of TSC-associated renal angiomyolipomas to an average of 53% of their starting volume in 20 patients who stayed on drug for a year, suggesting possible improvement in pulmonary function in patients with LAM (13).…”

Section: Introductionmentioning

confidence: 99%

Renal and liver tumors inTsc2+/− mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

Finlay

Malhowski

Polizzi

et al. 2009

Molecular Cancer Therapeutics

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Inactivating mutations of the tumor suppressor gene TSC2 are associated with tumorigenesis in tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Statins, as 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have the potential to limit the growth of these tumors by limiting the isoprenylation of activated GTPases in Tsc2-null cells. We tested atorvastatin as a therapy for (a) ethylnitrosourea (ENU)-enhanced renal cystadenoma and (b) spontaneous liver hemangioma in 129Sv/Jae Tsc2 +/− mice. ENU-treated Tsc2 +/− mice were given atorvastatin chow (0.1%, w/w) for 1 or 3 months before sacrifice at 6 months; 129Sv/Jae Tsc2 +/− mice were given atorvastatin chow (0.1%, w/w) for 6 months before sacrifice at 12 months. All treatment groups were compared with mice of identical genotype and strain background that were fed control chow. Pathologic analyses revealed a predominance of renal cystadenoma in ENU-treated and liver hemangioma in non-ENU-treated 129Sv/Jae Tsc2 +/− mice. In both cohorts, serum cholesterol levels and levels of phosphorylated S6 and GTP-RhoA in healthy tissue were significantly (>50%) reduced in atorvastatin-treated mice as compared with controls. Following atorvastatin treatment, no significant reduction in tumor size, morphology, or phosphorylated S6 levels was observed for either ENU-associated renal cystadenoma or spontaneous liver hemangioma as compared with the untreated groups. In conclusion, although the marked reduction in cholesterol levels indicates that atorvastatin was effective as an 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, it did not inhibit the growth of tumors that develop in these Tsc2 +/− models, suggesting that it is unlikely to have benefit as a single-agent therapy for TSC-associated tumors.

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Section: Introductionmentioning

confidence: 99%

Renal and liver tumors inTsc2+/− mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

Finlay

Malhowski

Polizzi

et al. 2009

Molecular Cancer Therapeutics

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“…Worse outcomes in African Americans compared to whites have been attributed to having more comorbid conditions [56], higher immunological risk due to greater variation in human leukocyte antigen polymorphisms [57][58][59][60], poorer control of hypertension [56,61]; requiring higher doses of immunosuppressive drugs [62][63][64] and variability in the pharmacokinetics of immunosuppressive drugs [65,66]. In Hispanics, there are few reports: the 1-year graft survival in Hispanics was not affected by broad sensitization compared with African Americans [67], and they need less immunosuppression [68,69]. Thus, it is unclear whether biological mechanisms adequately explain variations in transplant outcomes for Hispanics.…”

Section: Introductionmentioning

confidence: 99%

Ethnic advantages in kidney transplant outcomes: the Hispanic Paradox at work?

Gordon¹,

Caicedo

2008

Nephrology Dialysis Transplantation

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1-year survival rates surpassing 91%, long-term graft survival remains inadequate [1]. The 3-year, 5-year and 10-year deceased donor unadjusted graft survival rates are 78.6%, 67.1% and 40.8%, respectively, among all kidney recipients in the United States (USA) [2].The loss of transplanted grafts is a major public health problem. Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD) since it provides a longer length of life, better quality of life [3,4] and is more cost-effective than dialysis [5,6]. When kidney grafts fail, patients return to dialysis, creating an even greater demand for scarce kidney (re-)transplants and further burdening society with greater costs [7][8][9]. Mortality rates on dialysis following a failed kidney transplant are

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“…While dyslipidemia was observed in the majority of studies, proteinuria was not consistently observed. [73][74][75][76][77][78][79][80] A retrospective review of registry data for 272 patients followed for six months after introduction of everolimus was reported after approval of everolimus in Europe in 2005. Everolimus was preferentially introduced as a conversion strategy (93.8%) after the first month of transplantation.…”

Section: Preservation Of Allograft Functionmentioning

confidence: 99%

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

Tedesco‐Silva¹,

Felipe²,

Freitas³

et al. 2011

TRRM

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Everolimus is an immunosuppressive agent used for the prophylaxis of acute rejection after kidney transplantation. Everolimus inhibits the activity of the serine/threonine kinase mammalian target of rapamycin (mTOR), a key enzyme that controls cell growth and metabolism, producing cell cycle arrest from the G1 to S phase. As a consequence, everolimus has antiproliferative and antineoplastic effects. Everolimus is a drug with a narrow therapeutic index. The pharmacokinetics of everolimus indicates a need for twice-daily dosing. Intra-and interindividual variability and drug-drug interactions suggest the need for therapeutic drug monitoring to maximize the efficacy/toxicity ratio. The good correlation between exposure (area under the concentration-time curve) and trough concentration indicates that monitoring of everolimus trough concentrations is an adequate strategy after kidney transplantation. Everolimus is indicated for low-to moderate-risk de novo kidney transplant candidates. There are no conclusive studies thus far indicating that everolimus can be used in high-risk patients, such as sensitized patients, retransplants, and African Americans. In de novo kidney transplant recipients, the recommended initial dose of everolimus is 0.75 mg twice daily, adjusted to maintain blood trough concentrations of 3-8 ng/mL, in combination with progressive reduction in blood trough cyclosporine concentrations to 25-50 ng/mL. In combination with reduced trough blood tacrolimus concentrations of 4-7 ng/mL the recommended initial dose of everolimus is 1.5 mg twice daily, adjusted to maintain trough blood concentrations of 3-8 ng/mL. Everolimus can also be used as a conversion strategy, mainly to preserve renal function and to manage patients with malignancy. There is no definition of the ideal strategy for conversion, ie, abrupt or sequential, initial dose of everolimus, or target therapeutic trough blood concentrations. Intensive monitoring is recommended after conversion, especially for acute rejection and proteinuria. Because mTOR is ubiquitous and central to many intracellular processes, an array of adverse reactions may occur, including delayed tissue regeneration, proteinuria, dyslipidemia, diabetes, myelosuppression, infertility, ovarian cysts, and mouth ulcers. Because long-term benefits are the goal of any immunosuppressive strategy, further investigations aiming to understand, prevent, and manage everolimus-related adverse reactions are necessary to mitigate the risks and improve tolerability, allowing maximization of all the benefits of this drug.

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Conversion Therapy to Everolimus in Renal Transplant Recipients: Results After One Year

Cited by 9 publications

References 9 publications

Renal and liver tumors inTsc2+/− mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

Renal and liver tumors inTsc2+/− mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

Ethnic advantages in kidney transplant outcomes: the Hispanic Paradox at work?

Impact of everolimus: update on immunosuppressive therapy strategies and patient outcomes after renal transplantation

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