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Published on: March 27, 2018
Current issues in pediatric transplantation
1The Liver Unit, Birmingham Children's Hospital NHS Trust, Birmingham, UK. Deirdre.Kelly@bch.nhs.uk
Insights
Pediatric solid organ transplant recipients face long-term side effects from immunosuppressants, including viral infections and organ damage. Optimizing immunosuppression strategies is key to improving quality of life and graft survival in these young patients.
Area of Science:
- Pediatric Transplantation
- Immunosuppression
- Long-term Outcomes
Background:
- Pediatric solid organ transplantation survival rates exceed 80%, necessitating focus on long-term quality of life and minimizing side effects.
- Current intensive immunosuppressive regimens (cyclosporine, tacrolimus, mycophenolate mofetil, steroids) effectively prevent rejection but cause significant adverse effects like viral infections, renal dysfunction, hypertension, and stunting.
- While cytomegalovirus (CMV) mortality is reduced, morbidity persists; Epstein-Barr virus (EBV) infections remain a concern, though post-transplant lymphoproliferative disease is manageable.
Purpose of the Study:
- To review the long-term side effects of immunosuppressive therapy in pediatric solid organ transplantation.
- To discuss current and emerging strategies for optimizing immunosuppression to improve patient outcomes.
- To highlight challenges in managing adolescent transplant recipients and ensuring long-term graft survival.
Main Methods:
- Review of current immunosuppressive protocols and their associated toxicities in pediatric solid organ transplant recipients.
- Analysis of strategies to mitigate side effects, including reducing calcineurin inhibitor doses and exploring steroid-free regimens.
- Discussion of challenges related to viral infections (CMV, EBV) and post-transplant lymphoproliferative disease management.
- Examination of the impact of immunosuppression on renal function, growth, and the development of de-novo autoimmune conditions.
- Consideration of non-adherence and psychosocial factors in adolescent transplant care.
Main Results:
- Intensive immunosuppression leads to substantial long-term side effects, including a 30% reduction in renal function with calcineurin inhibitors (cyclosporine, tacrolimus) and potential chronic renal failure.
- Strategies like using IL-2 inhibitors with low-dose calcineurin inhibitors and renal-sparing agents (MMF, sirolimus) show promise in preventing renal dysfunction.
- Steroid-free regimens may reduce stunting and renal issues but can increase the risk of de-novo autoimmune hepatitis.
- Effective management of CMV and EBV, alongside strategies for post-transplant lymphoproliferative disease, is crucial for reducing morbidity.
Conclusions:
- Optimizing immunosuppression in pediatric solid organ transplantation is vital to balance rejection prevention with minimizing long-term side effects.
- Novel protocols, including steroid-free and reduced-intensity regimens, are essential for improving graft and patient survival.
- Addressing adolescent non-adherence and psychosocial challenges is critical for long-term transplant success, especially during the transition to adult care.
Abstract:
Pediatric solid organ transplantation is so successful that >80% of children will survive to become teenagers and adults. Therefore, it is essential that these children maintain a good quality life, free of significant long-term side effects. While intensive immunosuppressive regimens (containing CsA, tacrolimus, MMF, and steroids) effectively reduce acute or chronic rejection, they can produce long-term side effects including viral infection, renal dysfunction, hypertension, and stunting. The development of effective methods of diagnosis, prevention, and treatment of CMV means that this is no longer a significant cause of mortality, but morbidity remains high. In contrast, infection rates of EBV remain high in EBV-negative pre-transplant patients. However, pre-emptive reduction of immunosuppression or treatment with rituximab or adoptive T-cell therapy is effective in preventing/treating post-transplant lymphoproliferative disease. Recent protocols have concentrated on reducing CsA immunosuppression, to prevent unacceptable cosmetic effects, and to reduce the hypertension, hyperlipidemia, and nephrotoxicity. Both CsA and tacrolimus cause a 30% reduction in renal function, with 4-5% of patients developing severe chronic renal failure. The use of IL-2 inhibitors for induction therapy with low-dose calcineurin inhibitors, in combination with renal-sparing drugs such as MMF or sirolimus for maintenance immunosuppression, should prevent significant renal dysfunction in the future. The concept of steroid-free immunosuppression with IL-2 inhibitors, tacrolimus, and MMF is an attractive option, which may reduce stunting and renal dysfunction. However, these regimens may be associated with the increased development of de-novo autoimmune hepatitis in 2-3% of children. The most important challenge to long-term survival in transplanted children is the management of non-adherence and other adolescent issues, particularly when transferring to adult units, as this is the time when many successful transplant survivors lose their grafts.
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