Tönshoff B, Höcker B.
儿科I，儿童医院大学，海德堡，德国burkhard.toenshoff@med.uni-heidelberg.de

  在使用了钙调神经磷酸酶抑制剂(CNI)、环孢素A(CsA)和他克莫司之后，虽然肾异源移植的短期存活率显著提高，但长期存活率仍然是一个值得关注的问题，其中慢性移植肾肾病(CAN)是移植术后第一年移植物失功能的主要原因。这一点在小儿肾移植受体中尤为重要，因为与成年人相比，儿童的预期寿命更长。很多机制导致了CAN的发病，例如急性和慢性同种异体免疫反应、CNI肾毒性等。CNI诱发的肾毒性在其他类型（如肝脏和心脏）的实体器官移植受体中也是一个被长期关注的问题。预防移植肾肾病需要保持足够的免疫抑制平衡，同时还要避免CNI的毒性作用。单独使用骁悉(MMF)或联合使用新药可以减少对CNI的依赖，因此这种疗法可能代表了一种有效的治疗模式，能够维持移植肾的长期存活。通过分析有效数据可以发现，对CNI肾毒性的小儿肾移植和心脏移植受体来说，目前最安全的治疗方案是低剂量CNI +/-低剂量类固醇的基础疗法；对于小儿肝移植受体来说，无CNI的MMF免疫抑制疗法，有无类固醇对于该类患者都是可行的。对肾移植患者来说，排斥反应的相对重要性和整体肾功能仍需进一步的临床调查；无CNI的MMF或类固醇疗法对肾功能都有益处，但该疗法同时也会增加患者的排斥反应。雷帕霉素靶蛋白（mTOR）抑制剂的使用为结合两种抗增值剂（MMF和TOR抑制剂）的CNI联合疗法提供了可行性。关于肾移植长期存活的问题，以西罗莫司为基础的无CNI免疫抑制疗法要优于CNI最小化，而CNI对移植肾功能和结构仍然存在不良影响，尽管程度较轻。因此，可以考虑用mTOR抑制剂替代CNI，但是仍需通过大量的试验和长期的研究来验证这一点。
PMID: 16911497 [PubMed - indexed for MEDLINE]

Pediatr Transplant. 2006 Sep;10(6):721-9.
Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity
Tönshoff B, Höcker B.
Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany. burkhard.toenshoff@med.uni-heidelberg.de

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. his is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.
PMID: 16911497 [PubMed - indexed for MEDLINE]

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