Sirolimus in pediatric patients: Results in the first 6 months post‐renal transplant

Hymes, Leonard C.; Warshaw, Barry L.

doi:10.1111/j.1399-3046.2005.00324.x

Cited by 52 publications

(45 citation statements)

References 9 publications

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“…13,23 This observation is of concern for proposed trials in children with generalized arteriopathy because rapamycin can have serious side-effects in pediatric transplant recipients even at the dose used for immunosuppression. 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.…”

Section: Discussionmentioning

confidence: 96%

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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Section: Discussionmentioning

confidence: 96%

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

Qin

et al. 2013

ATVB

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“…Previous unreported defective linear growth associated with SRL may be explained by the fact that only 3% of pediatric KTx recipients received SRL 1 month after the transplant and fewer afterwards [11]. SRL has been used for children at the early post-transplant phase [12], but many patients had to be switched to CNIs because of frequent side effects such as infection, pneumonitis, surgical wound healing problems or lymphoceles [13]. However, SRL is commonly used to replace CNIs in cases of steroidresistant acute rejection, malignancy, diabetes, neurotoxicity, or nephrotoxicity [4], and chronic allograft dysfunction is the main indication for SRL in children with transplants [2].…”

Section: Discussionmentioning

confidence: 99%

Growth failure associated with sirolimus: case report

Rangel

Ariceta

2009

Pediatr Nephrol

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An 11-year-old girl, who was a renal transplant recipient, developed linear growth failure associated in time with sirolimus (SRL) treatment. After 5 years of functional graft [creatinine clearance (CCr) 90 ml/min per 1.73 m(2) body surface area], she developed acute renal failure due to calcineurin inhibitor-related hemolytic uremic syndrome, and cyclosporine A was replaced by SRL. Before the drug change, she had been growing normally (5.5 cm/year) and had reached the 33.9 percentile (P) of height (z-height -0.41), similar to her target. Two years later, her height had decreased to P 6th (z-height -1.54), as her growth velocity had diminished to 2.2 cm/year, despite optimal renal function (CCr 68 ml/min per 1.73 m(2)). Human recombinant growth hormone was needed to promote her catch-up growth and achieve the P 49th of height (z-height -0.03). SRL may have deleterious effects on growing children due its characteristic anti-proliferative and anti-angiogenic properties. Pediatric transplant recipients' linear growth should be cautiously monitored while they are being given SRL.

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“…Use immediately posttransplant has been described in conjunction with a calcineurin inhibitor in a series of 66 pediatric renal transplant recipients, with effective immunosuppression but adverse effects necessitating drug withdrawal in 20% of patients [10]. The combination of interleukin (IL)-2 receptor antibody, sirolimus and mycophenolate, has been used occasionally [11][12][13] and, as it avoids the need for nephrotoxic drugs, there is potential for this combination to increase long-term graft survival.…”

Section: Introductionmentioning

confidence: 99%

Early experience with conversion to sirolimus in a pediatric renal transplant population

2007

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Sirolimus is an immunosuppressive agent that offers potentially significant benefits for young transplant patients facing life-long treatment. Its action of reducing cell proliferation may reduce the risk of chronic allograft nephropathy and posttransplant neoplasia. Twenty-nine children were converted from calcineurin inhibitors to sirolimus after renal transplantation and followed for a minimum of 12 months. Glomerular filtration increased transiently in those converted before 12 months after transplantation but not in those converted later, when chronic histological changes had developed. Mild acute rejection occurred after conversion in 10%, and side effects led to cessation of sirolimus in 31%. Anemia occurred in 55% of patients and responded well to darbepoetin. Most side effects (anemia, hypercholesterolemia, mouth ulcers, and myalgias) became less severe with time. The number of antihypertensive drugs required decreased significantly on sirolimus. Although side effects are frequent on sirolimus, in the majority of children, they are mild enough to allow the patient to continue taking the drug, and for these children the long-term benefits are potentially valuable.

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Sirolimus in pediatric patients: Results in the first 6 months post‐renal transplant

Cited by 52 publications

References 9 publications

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

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

Growth failure associated with sirolimus: case report

Early experience with conversion to sirolimus in a pediatric renal transplant population

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