Multicenter trial of everolimus in pediatric renal transplant recipients: Results at three year

Department of Pediatrics, Mattel Children's Hospital, University of California Los Angeles, Los Angeles, CA 90095-1752, USA.
Pediatric Transplantation (Impact Factor: 1.44). 06/2008; 12(4):456-63. DOI: 10.1111/j.1399-3046.2007.00832.x
Source: PubMed


There are few prospective clinical trials of mTOR inhibitors (or proliferation signal inhibitors) combined with CNI inhibitors in de novo pediatric renal transplantation. Results reported here are from a multicenter, open-label study in de novo pediatric renal transplant patients (<or=16 yr), in which patients received everolimus with cyclosporine and corticosteroids for one yr, then entered an extension study for a further two yr. Nineteen patients completed the one-yr study, of whom three discontinued study medication. Fifteen of the remaining 16 patients entered the extension study, eight of whom were aged <10 yr (Group 1) and seven were aged 10-16 yr (Group 2). Mean daily dose of everolimus during the first 36 months was 1.53 mg/m(2) BSA. Biopsy-proven acute rejection occurred in three patients in Group 2 and in one patient in Group 1. Biopsy-proven chronic allograft rejection was reported in four patients (two in each age group). Graft survival at one yr was 100%; one patient in Group 2 lost their graft subsequently during the extension. For patients entering the extension, patient survival at three yr was 100%. There were three cases of viral infection, including one case of cytomegalovirus infection. At three yr, mean total cholesterol was 5.5 +/- 0.8 mm/L (213 +/- 31 mg/dL) and four patients received statin therapy. Mean serum creatinine at 36 months was 96 +/- 36 microm/L (1.1 +/- 0.4 mg/dL). This is the first long-term prospective study to demonstrate that a regimen of everolimus, cyclosporine, and corticosteroids provides good efficacy, tolerability, and safety in de novo pediatric renal transplant patients.

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    • "m2) after conversion (both P < 0.05), although three patients experienced rejection and side effects were common. More extensive experience is available in pediatric kidney transplantation [37–39], indicating that de novo use of everolimus with CsA offers effective immunosuppression and good renal function to three years aftertransplant [39]. Analyzing protocol biopsies at six months after renal transplantation, Kanzelmeyer et al. found a significantly lower number of pathological changes in patients treated with everolimus and low-dose CNI compared to standard CNI-based treatment [40]. "
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    ABSTRACT: The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.
    Journal of Transplantation 12/2013; DOI:10.1155/2013/683964
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    ABSTRACT: Despite their efficacy, the calcineurin inhibitors (CNIs) ciclosporin and tacrolimus carry a risk of debilitating adverse effects, especially nephrotoxicity, that affect the long-term outcome and survival of children who are given organ transplants. Simple reduction in dosage of CNI has little or no long-term benefit on their adverse effects, and complete withdrawal without threatening graft outcome may only be possible after liver transplantation. Until the last decade, the only option was to increase corticosteroid and/or azathioprine doses, which imposed additional long-term hazards. Considered here are the emerging generation of new agents offering an opportunity for improving long-term graft survival, minimizing CNI-related adverse events and ensuring patient well-being.A holistic, multifaceted strategy may need to be considered - initial selection and optimized use and monitoring of immunosuppressant regimens, early recognition of indicators of patient and graft dysfunction, and, where applicable, early introduction of CNI-sparing regimens facilitating CNI withdrawal. The evidence reviewed here supports these approaches but remains far from definitive in paediatric solid organ transplantation. Because de novo immunosuppression uses CNI in more than 93% of patients, reduction of CNI-related adverse effects has focused on CNI sparing or withdrawal.A recurring theme where sirolimus and mycophenolate mofetil have been used for this purpose is the importance of their early introduction to limit CNI damage and provide long-term benefit: for example, long-term renal function critically reflects that at 1 year post-transplant. While mycophenolic acid shows advantages over sirolimus in preserving renal function because the latter is associated with proteinuria, sirolimus appears the more potent immunosuppressant but also impairs early wound healing. The use of CNI-free immunosuppressant regimens with depleting or non-depleting antibodies plus sirolimus and mycophenolic acid needs much wider investigation to achieve acceptable rejection rates and conserve renal function. The adverse effects of the alternative immunosuppressants, particularly the dyslipidaemia associated with sirolimus, needs to be minimized to avoid replacing one set of adverse effects (from CNIs) with another. While we can only conjecture that judicious combinations with the second generation of novel immunosuppressants currently in development will provide these solutions, a rationale of low-dose therapy with multiple immunosuppressants acting by complementary mechanisms seems to hold the promise for efficacy with minimal toxicity until the vision of tolerance achieves reality.
    Drugs 02/2008; 68(10):1385-414. DOI:10.2165/00003495-200868100-00004 · 4.34 Impact Factor
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    ABSTRACT: 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/m²) /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 m². 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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