Bone growth during rapamycin therapy in young rats

Sanchez, Cheryl P.; He, Yizhuo

doi:10.1186/1471-2431-9-3

Cited by 56 publications

(48 citation statements)

References 26 publications

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“…In spite of the methodological limitations resulting from the retrospective data collection and the relatively small number of patients included in the analysis, our study suggests that SRL has the potential to adversely affect the growth of these patients, at least during the first 2 years of treatment with SRL. This finding is in agreement with experimental studies showing that administration of pharmacological doses of SRL decreased the longitudinal growth rate in young rats due to mechanisms likely dependent on the inhibitory effects of SRL on cell proliferation and VEGF expression at long bone growth plate [12][13][14]. This deleterious effect on longitudinal growth was evident, in our study, by the lower growth velocity and the reduced increment in height SDS found in children treated with SRL in comparison to children not receiving this drug.…”

Section: Discussionsupporting

confidence: 94%

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Growth of kidney-transplanted pediatric patients treated with sirolimus

Anseán

Garcia²,

Azócar

et al. 2011

Pediatr Nephrol

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Experimental findings indicate that sirolimus (SRL) inhibits longitudinal growth by mechanisms potentially related to its inhibitory effects on both cell proliferation and expression of vascular endothelial growth factor (VEGF). The aim of this study was to investigate the growth pattern of kidney-transplanted children treated with SRL in a multicenter observational clinical study. Height, change in height SD (Δ height) and growth velocity of pediatric patients with renal transplant were calculated at 0, 6, 12, and 24 months after starting SRL. Controls of kidney-transplanted children not treated with SRL were matched by age, gender, renal function, and dose of corticosteroids. Sixty-eight children (34 SRL, 34 controls) were enrolled in the study. Nephrotoxicity was the most frequent indication to start therapy with SRL. SRL exerted an adverse effect on growth as demonstrated by significantly lower (p < 0.05) growth velocity (cm/year) and smaller change in height SD in the SRL group after 6 (4.08 vs. 6.56 and -0.05 vs. 0.14), 12 (4.44 vs. 6.11 and -0.03 vs. 0.28) and 24 (4.53 vs. 6.03 and -0.04 vs. 0.53) months of treatment. This study suggests that SRL therapy may interfere with growth of kidney-transplanted children. This undesirable effect needs to be taken into account when considering a switch to SRL and confirmed in further prospective trials including larger number of patients.

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Section: Discussionsupporting

confidence: 94%

“…However, experimental findings indicate that administration of SRL to fast-growing rats impairs longitudinal growth and induces marked alterations in growth-plate structure by mechanisms likely related to its inhibitory effects on cell proliferation and VEGF local expression [12][13][14].…”

Section: Introductionmentioning

confidence: 97%

Growth of kidney-transplanted pediatric patients treated with sirolimus

Anseán

Garcia²,

Azócar

et al. 2011

Pediatr Nephrol

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“…However, she presented linear growth failure later on. Although mild CKD and steroids could contribute to the observed delayed growth, we hypothesize SRL to be the main deleterious factor in her growth, as has been demonstrated in growing rats [5,8]. rhGH allowed our patient's growth to catch up; her stature increased by ∼9 cm/year, as reported [16], normalizing her height, despite mild renal dysfunction and treatment with SRL [17].…”

Section: Discussionmentioning

confidence: 68%

“…When given to young rats, SRL significantly decreased endochondral bone growth too [8]. Despite the fact that linear growth may be adversely affected in young children, little is known about the effects of SRL on growing children.…”

Section: Introductionmentioning

confidence: 95%

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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“…(25) and decreased endochondral bone growth (26). A girl was described that stopped growing after switch from CsA to Sirolimus in one case report (27).…”

Section: We Recognized Problems With Wound Healing In Two Children Wmentioning

confidence: 99%

De novoTherapy with Everolimus, Low‐Dose Ciclosporine A, Basiliximab and Steroid Elimination in Pediatric Kidney Transplantation

Pape

Offner

Kreuzer

et al. 2010

American Journal of Transplantation

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The number of acute rejections and infections after pediatric kidney transplantation (KTX) could not be reduced in the last years. To reduce these events, we investigated a new immunosuppressive protocol in a prospective trial. After KTX, 20 children (median age 12 years, range 1-17) were initially treated with Basiliximab, ciclosporine A (CsA) (trough-level = C0 200-250 ng/mL) and prednisolone. After 2 weeks, CsA dose was reduced to 50% (C0 75-100 ng/mL, after 6 months: 50-75 ng/mL) and everolimus (1.6 mg/m 2 /day) was started (C0 3-6 ng/mL). Six months after KTX prednisolone was set to alternate dose and stopped 3 months later. All 20 protocol biopsies 6 months after KTX showed no acute rejection or borderline findings. Indication biopsies resulted in no acute rejections and two borderline findings. Mean glomerular filtration rate (GFR) 1 year after KTX was 71 ± 25 mL/min/ 1.73 m 2 . Without cytomegalovirus (CMV)-prophylaxis, only two primary CMV infections were seen despite a donor/recipient-CMV-constellation pos./neg. in 10/ 20 children. In pediatric KTX, de novo immunosuppression with low-dose CsA, everolimus and steroid withdrawal after 9 months led to promising results according to numbers of acute rejections and infections. Further follow up is needed. Future larger trials will have to confirm our findings.

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Bone growth during rapamycin therapy in young rats

Abstract: Background: Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties.

Cited by 56 publications

References 26 publications

Growth of kidney-transplanted pediatric patients treated with sirolimus

Growth of kidney-transplanted pediatric patients treated with sirolimus

Growth failure associated with sirolimus: case report

De novoTherapy with Everolimus, Low‐Dose Ciclosporine A, Basiliximab and Steroid Elimination in Pediatric Kidney Transplantation

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