Vidigal Ana Cláudia, de Lucena Débora D, Beyerstedt Stephany, Rangel Érika B
Nephrology Division, Department of Medicine, Federal University of São Paulo, SP, Brazil.
Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, SP, São Paulo, Brazil.
Expert Opin Drug Metab Toxicol. 2023 Jul-Dec;19(7):405-427. doi: 10.1080/17425255.2023.2243808. Epub 2023 Aug 9.
Despite significant advancements in immunosuppressive regimens and surgical techniques, the prevalence of adverse events related to immunosuppression remains a major challenge affecting the long-term survival rates of pancreas and kidney allografts.
This article presents a comprehensive review of the literature and knowledge (Jan/2012-Feb/2023) concerning glucose metabolism disorders and nephrotoxicity associated with tacrolimus and mammalian target of rapamycin inhibitors (mTORi). Novel signaling pathways potentially implicated in these adverse events are discussed. Furthermore, we extensively examine the findings from clinical trials evaluating the efficacy and safety of tacrolimus, mTORi, and steroid minimization.
Tacrolimus-based regimens continue to be the standard treatment following pancreas transplants. However, prolonged use of tacrolimus and mTORi may lead to hyperglycemia and nephrotoxicity. Understanding and interpreting experimental data, particularly concerning novel signaling pathways beyond calcineurin-NFAT and mTOR pathways, can offer valuable insights for therapeutic interventions to mitigate hyperglycemia and nephrotoxicity. Additionally, critically analyzing clinical trial results can identify opportunities for personalized safety-based approaches to minimize side effects. It is imperative to conduct randomized-controlled studies to assess the impact of mTORi use and steroid-free protocols on pancreatic allograft survival. Such studies will aid in tailoring treatment strategies for improved transplant outcomes.
尽管免疫抑制方案和手术技术取得了重大进展，但与免疫抑制相关的不良事件的发生率仍然是影响胰腺和肾脏同种异体移植长期存活率的主要挑战。
本文全面综述了有关他克莫司和雷帕霉素哺乳动物靶点抑制剂（mTORi）相关的葡萄糖代谢紊乱和肾毒性的文献和知识（2012年1月至2023年2月）。讨论了可能与这些不良事件有关的新信号通路。此外，我们广泛研究了评估他克莫司、mTORi和最小化类固醇的疗效和安全性的临床试验结果。
基于他克莫司的方案仍然是胰腺移植后的标准治疗方法。然而，长期使用他克莫司和mTORi可能会导致高血糖和肾毒性。理解和解释实验数据，特别是关于钙调神经磷酸酶-NFAT和mTOR通路之外的新信号通路的数据，可以为减轻高血糖和肾毒性的治疗干预提供有价值的见解。此外，批判性地分析临床试验结果可以确定基于个性化安全性方法以最小化副作用的机会。必须进行随机对照研究，以评估使用mTORi和无类固醇方案对胰腺同种异体移植存活的影响。此类研究将有助于制定治疗策略以改善移植结果。
