Growth of kidney-transplanted pediatric patients treated with sirolimus

Anseán, David; Garcia, Clotilde Druck; Azócar, Marta; Waller, Simon; Alonso, A.; Ariceta, Gema; Mejía, Natalia; Santos, Fernando

doi:10.1007/s00467-011-1811-3

Cited by 41 publications

(29 citation statements)

References 26 publications

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“…Growth inhibition has been reported in kidney-transplanted pediatric patients receiving sirolimus. 13 In our case, the rate of height and weight gain was not changed by treatment. However, the long-term effect of everolimus on physical development of TSC patients is not known.…”

Section: Figurementioning

confidence: 42%

Possible Prevention of Tuberous Sclerosis Complex Lesions

2013

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Tuberous sclerosis complex (TSC) is a genetic disorder characterized by mammalian target of rapamycin (mTOR) activation and growth of benign tumors. Some TSC lesions, such as cardiac rhabdomyomas and cortical tubers in the brain, occur in fetuses, and some, such as renal angiomyolipomas (AMLs) and skin angiofibromas, develop over years. Recently, the mTOR inhibitor everolimus was shown to be effective in the treatment of subependymal giant cell astrocytomas (a brain tumor) and renal AMLs (kidney tumors) in TSC patients. We present monozygotic twin sisters affected with TSC. Since age 4 years, 1 of the sisters has been treated with everolimus; the other sister received no mTOR inhibitor treatment. After 24-month follow-up, everolimus treatment resulted in a significant brain tumor volume decrease in the treated twin. This child presents no facial angiofibroma, and no renal AMLs. The brain tumor in the nontreated sister is stable in size, but in the meantime, she has developed significant facial angiofibroma and renal AMLs. This observation indicates that early mTOR inhibition in TSC patients may prevent the development of TSC lesions and alter the natural history of the disease.

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Section: Figurementioning

confidence: 42%

Possible Prevention of Tuberous Sclerosis Complex Lesions

2013

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“…24 Besides our study, somatic growth retardation by rapamycin has been observed in mouse embryos 16 and in young rats. 25 This phenomenon in children is controversial with one study finding adverse effects of rapamycin on growth of pediatric transplant recipients, 26 whereas another study found normal linear growth in a similar cohort. 27 On the other hand, similar doses of mTOR inhibitors seem to be better tolerated and not cause growth retardation in children without organ transplants or the concurrent use of multiple other immunosuppressive agents, for example, in the treatment of astrocytomas associated with tuberous sclerosis.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Inhibits Smooth Muscle Cell Proliferation and Obstructive Arteriopathy Attributable to Elastin Deficiency

Qin

et al. 2013

ATVB

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Objective-Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency. Approach and Results-As previously reported, Eln−/− mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln +/− mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln −/− pups and prevented medial hyperlamellation in Eln +/− weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln −/− pups, and it retarded the somatic growth of juvenile Eln +/− and Eln +/+ mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome. and rapamycin reduces the incidence of intimal thickening in coronary arteries of rejecting cardiac allografts. Conclusions-mTOR11 The therapeutic benefit of mTOR inhibitors in arteriosclerosis is ascribed to their potent antimitogenic effect.12,13 We hypothesized that inhibition of SMC proliferation by rapamycin will also prevent obstructive arteriopathy mediated by elastin deficiency, and we tested this strategy in experimental systems of SVAS and WS.14,15 Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Murine Models of Elastin-Deficient AortopathyTo investigate pathogenetic mechanisms and therapeutic opportunities in SVAS and WS, we used an established murine model in which a targeted mutation of exon 1 disrupts the Eln allele. 4 As previously reported, 4-6 pups homozygous for loss of Eln died by 3 days of birth with severe stenosis of the thoracic aorta sparing its root ( Figure 1A), whereas heterozygote animals survived long term characterized by modestly decreased aortic diameter ( Figure 1B) with an increased number of medial elastic lamellae ( Figure 1C). Ultrastructural analysis of aortas from adult Eln haploinsufficient mice showed the elastic laminae to be thinner structures, whereas SMC morphology seemed normal ( Figure I in the online-only Data Supplement). Thus, newborn and mature animals offer different arteriopathy end points to assess depending on gene dosage. Increased mTOR Signaling in ElastinDeficient Aortas Is Inhibited by RapamycinWe examined for dysregulation of mTOR signaling, because this pathway plays a crucial role in SMC proliferation in other obstr...

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“…A recent study involving pediatric kidney transplant recipients undergoing treatment with rapamycin suggests that growth rate is reduced in the treated group, at least for the 2 y of data available. 55 Nevertheless, considering the severity of the disease, the benefits may outweigh the potential side effects, and perhaps they can be controlled with careful dosing schedules, for instance, intermittent periods of treatment, followed by recovery periods, rather than chronic treatment.…”

Section: Therapeutic Limitations Of Rapamycinmentioning

confidence: 99%