STEROIDS VERSUS STEROID-FREE TACROLIMUS BASED IMMUNOSUPPRESSION IN PEDIATRIC REN

类固醇与无类固醇他克莫司对小儿肾病的免疫抑制

• 批准号: 7376602
• 负责人: DAVID Berrey KERSHAW
• 金额: $ 0.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376602
• 关键词: immunosuppression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Successful renal transplantation offers the best hope to the child to restore normal growth, development and life style after ESRD. Over the last decade, advances in immunosuppression have improved graft survival and reduced the incidence of early immunological adverse events such as acute rejection in the first post-transplant year to about 27% in recipient of living donor kidneys. In the absence of tolerance to the graft, immunosuppressive medications have to be taken for the life of the organ. Morbidities associated with immunosuppressive drugs include undesirable cosmetic effects (which contribute to noncompliance) as well as conditions that increase cardiovascular risk such as hypertension, dyslipidemias, and diabetes mellitus. Corticosteroids have been the invariant drug in immunosuppressive protocols. Corticosteroids have been the cornerstone of immunosuppressive therapy for renal transplantation for 40 years, however corticosteroids have numerous undesirable side effects, including Cushingoid habitus, poor growth, infection, hypertension, hyperlipidemia, glucose intolerance, diabetes mellitus, bone loss, cataracts, acne and changes in mood and behavior. In children, the Cushingoid habitus greatly impacts compliance and growth retardation comes at a very unfortunate stage for children and adolescents who are going through their major growth periods. Elimination of steroid therapy in children with renal transplants would appear to be greatly beneficial. Nevertheless, it has proven difficult, if not impossible, to withdraw steroids in these patients without increased acute and chronic rejection. There are several theoretical reasons to believe that steroid use makes the recipient steroid dependent, including the numerous observations that subsequent steroid withdrawal has been associated with a detrimental outcome and that immunomodulatory effects of steroids, once reversed, may have untoward side effects. It is likely that steroid dependency cannot develop in a patient not previously exposed to steroids. If suppression of the immune response becomes conditioned to steroid exposure, then subsequent steroid withdrawal has the potential for a detrimental outcome, as has been demonstrated clinically. In addition, steroids appear to impact peripheral tolerance by a Fas mediated mechanism. Similarly, by blocking signaling through the T cell receptor, steroids may prevent the induction of apoptosis. Steroid withdrawal after previous steroid exposure can therefore theoretically increase the risk of acute graft rejection. In other words, steroid-adapted suppression of the immune response is destined to increase the risk of acute rejection on attempted steroid withdrawal. This is most pertinent in an immunogenic organ, like the kidney. It has been hypothesized that a completely steroid-free immunosuppressive protocol should avoid steroid dependent suppression of the immune response, which makes either steroid withdrawal or alternate dosing hazardous for rebound acute rejection. Late steroid withdrawal (after the first transplant year) has been successful in a small number of patients with stable graft function, but the small target population that can benefit from this approach may be difficult to predict and remains limited.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。成功的肾移植为终末期肾病患儿恢复正常的生长发育和生活方式提供了最好的希望。在过去的十年中，免疫抑制的进步提高了移植物存活率，并将早期免疫不良事件的发生率降低到约27%，例如活体供肾受体在移植后第一年的急性排斥反应。在移植物不耐受的情况下，必须在器官的生命周期内服用免疫抑制药物。与免疫抑制药物相关的疾病包括不良的美容效果（导致不依从）以及增加心血管风险的疾病，如高血压、血脂异常和糖尿病。 皮质类固醇是免疫抑制方案中不变的药物。40年来，皮质类固醇一直是肾移植免疫抑制治疗的基石，然而皮质类固醇具有许多不良副作用，包括库欣样体质、生长不良、感染、高血压、高脂血症、葡萄糖耐受不良、糖尿病、骨质流失、白内障、痤疮以及情绪和行为的改变。在儿童中，库欣样体质极大地影响了依从性，对于正在经历主要生长期的儿童和青少年来说，生长迟缓是一个非常不幸的阶段。在肾移植儿童中取消类固醇治疗似乎是非常有益的。然而，已经证明，在这些患者中停用类固醇而不增加急性和慢性排斥反应是困难的，如果不是不可能的话。 有几个理论上的理由认为，类固醇的使用使受体类固醇依赖，包括大量的观察结果，随后的类固醇停药已与有害的结果和类固醇的免疫调节作用，一旦逆转，可能有不利的副作用。以前未接触过类固醇的患者可能不会产生类固醇依赖。如果免疫反应的抑制成为类固醇暴露的条件，那么随后的类固醇戒断有可能产生有害的结果，正如临床上已经证明的那样。此外，类固醇似乎通过Fas介导的机制影响外周耐受性。类似地，通过阻断通过T细胞受体的信号传导，类固醇可以防止细胞凋亡的诱导。因此，从理论上讲，在既往类固醇暴露后停用类固醇会增加急性移植排斥反应的风险。换句话说，类固醇适应性抑制免疫反应注定会增加尝试停用类固醇时急性排斥反应的风险。这在免疫原性器官如肾脏中最为相关。 据推测，完全无类固醇的免疫抑制方案应避免类固醇依赖性的免疫应答抑制，这使得类固醇停药或交替给药对急性排斥反应的反弹是危险的。晚期类固醇停药（第一个移植年后）在少数移植功能稳定的患者中取得了成功，但可以从这种方法中受益的小目标人群可能难以预测，并且仍然有限。