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Calcineurin Inhibitor Sparing in Paediatric Solid Organ Transplantation

Managing the Efficacy/Toxicity Conundrum

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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.

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Acknowledgements

The authors are grateful to Siham Al Baghani for her contributions to data collection during the early stages of preparing this review. No sources of funding were used in the preparation of this review. Professor Dhawan has received unrestricted educational grants from Astellas, Novartis and Roche, and Dr Tredger from Astellas. Dr Brown has declared no conflicts of interest.

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  1. Institute of Liver Studies, King’s College Hospital and King’s College London School of Medicine, Denmark Hill, London, SE5 9RS, UK

    J. Michael Tredger & Nigel W. Brown

  2. Paediatric Liver Centre, King’s College Hospital and King’s College London School of Medicine, London, UK

    Anil Dhawan

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  1. J. Michael Tredger
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Correspondence to J. Michael Tredger.

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Tredger, J.M., Brown, N.W. & Dhawan, A. Calcineurin Inhibitor Sparing in Paediatric Solid Organ Transplantation. Drugs 68, 1385–1414 (2008). https://doi.org/10.2165/00003495-200868100-00004

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