Klotho in Kidney Transplantation: A New and Important Target?
Klotho in Kidney Transplantation: A New and Important Target?
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肾移植中的 Klotho：一个新的重要目标？
DOI：
10.1097/tp.0000000000004332
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发表时间：
2023
期刊：
影响因子：
6.2
通讯作者：
Hato,Takashi
中科院分区：
文献类型：
--
作者：
Lim,Kenneth;Chen,Neal;Hato,Takashi
2019 年 7 月 10 日，关于促进美国肾脏健康的总统行政命令促成了肾病患者护理服务的彻底重组。 1 这一历史性举措制定了第一个解决特定疾病状况的国家战略，将肾脏疾病提升为国家优先事项，并且重要的是设定了到 2030 年将可供移植的肾脏数量增加一倍的目标。 2 作为最佳肾脏替代方式，肾移植相对于透析的优越性已得到充分证实。肾移植与生活质量、心血管发病率和生存率的改善相关。 3 尽管如此，不幸的是，“目前获得的肾脏中有 20% 没有用于移植”，考虑到可用器官的等待名单已经很长，这一点非常令人担忧。因此，器官的可用性一直是移植手术的一个关键障碍。因此，填补肾移植供需之间日益扩大的缺口的策略引起了人们对使用扩展标准供体（ECD）肾脏来增加供体库的兴趣日益增长。这涉及利用以前不被认为具有较高风险的捐献器官，其中涉及年龄较大的捐献者，并且需要量身定制的免疫抑制方案。由于对肾脏的需求不断增加，并且 ECD 移植物功能不良的风险增加，因此更需要新的药理学策略来降低同种异体移植排斥和与免疫抑制相关的并发症的风险，并优化医疗管理。此外，使用老化的肾脏会增加急性肾损伤（AKI）的易感性并降低组织再生能力。因此，新的策略，例如基于 α-Klotho 的新型治疗方法，通过使用 ECD 中的老化肾脏来改善肾同种异体移植结果的潜力，是当前的研究重点。α-Klotho（本文称为 Klotho）是一种具有强大抗衰老特性的非凡蛋白质，其鉴定对于接受肾移植的患者特别重要。随着肾功能障碍的发生和年龄的增长，血清中的总 Klotho 蛋白水平会下降。 4 此外，Klotho 缺乏症现已与多种重要的临床结果相关，包括心血管疾病风险增加、AKI 进展和慢性肾病 (CKD) 以及最近的肾移植后同种异体移植物功能。 5, 6 值得注意的是，Klotho 基因敲除小鼠会出现与 CKD 患者相似的过早衰老表型，并且寿命缩短。 7 然而，在 Klotho 缺陷小鼠中恢复 Klotho 可以改善这些变化，而且这些小鼠的寿命比野生型小鼠长 30%。 7-9 因此，这些惊人的发现为开发可针对肾脏的潜在的基于 Klotho 的治疗干预措施提供了基本原理。此外，随着 ECD 导致肾脏老化的接受度不断提高，Klotho 的抗衰老特性特别令人感兴趣，这表明肾脏老化是一个活跃的、严格调控的细胞介导过程，可能是可改变的。在本期《移植》中，Donate-Correa 等人10 全面回顾了我们目前对肾移植中 Klotho 的理解。该文章强调了肾移植受者血清 Klotho 水平的重要变化。术后短期内循环 Klotho 水平通常较低，并且随着同种异体移植功能的改善，随着时间的推移逐渐恢复，尽管仅部分恢复到健康对照中观察到的水平（参见……中的表 3）
On July 10, 2019, the presidential Executive Order on Advancing American Kidney Health catalyzed a radical reconfiguration in the delivery of care for patients with kidney disease. 1 This historic initiative establishes the first national strategy for addressing a specific disease state, elevating kidney disease to a national priority ‚and ‚significantly, sets a target to double the number of kidneys available for transplant by 2030. 2 The superiority of kidney transplantation over dialysis as the optimal renal replacement modality is well established. Kidney transplantation is associated with improved quality of life, cardiovascular morbidity, and survival. 3 Despite this, unfortunately ‚~ 20% of procured kidneys are currently not utilized for transplant ‚and this is exceedingly worrying given the already long waitlist for available organs. The availability of organs has therefore been a critical obstacle to transplant procedures. Therefore, strategies to fill the growing gap between demand and supply for kidney transplants has led to a growing interest in the use of expanded criteria donor (ECD) kidneys to increase the donor pool. This involves utilizing donor organs that previously would not have been considered at higher risk, involving donors who are older ‚and requiring tailored immunosuppressive regimens. Because of the rising demand for kidneys and increased risk of poor graft function with ECDs, there has therefore been a greater need for novel pharmacologic strategies to reduce the risk of allograft rejection and complications associated with immunosuppression and to optimize medical management. Additionally, the use of aging kidneys increases susceptibility to acute kidney injury (AKI) and reduces tissue regenerative capability. Therefore, new strategies such as the potential for a novel α-Klotho–based therapeutic to improve renal allograft outcomes with the use of aging kidneys from ECDs are therefore a current research priority.The identification of α-Klotho (herein, called Klotho), a remarkable protein that confers powerful antiaging properties ‚is of particular relevance in patients undergoing kidney transplantation. Total Klotho protein levels decline in serum as kidney dysfunction ensues and with advancing age. 4 Moreover, Klotho deficiency has now been linked with a variety of important clinical outcomes, including increased risk of cardiovascular disease, progression of AKI, and chronic kidney disease (CKD) and ‚more recently, allograft function after kidney transplantation. 5, 6 Significantly, Klotho knockout mice develop a premature aging phenotype that resembles patients with CKD and exhibits shortened life span. 7 However, restoration of Klotho in Klotho-deficient mice ameliorated these changes ‚and these mice lived 30% longer than wild type. 7-9 These striking discoveries have therefore provided fundamental rationale for the development of potential Klotho-based therapeutic interventions that could target the kidneys. Furthermore, with the increasing acceptance of aging kidneys from ECDs, the antiaging properties of Klotho are of particular interest and suggest that aging of the kidneys is an active, tightly regulated cell-mediated process that could be potentially modifiable. In this issue of Transplantation, Donate-Correa et al10 present a comprehensive review of our current understanding of Klotho in kidney transplantation. The article highlights important variations in serum Klotho levels in kidney transplant recipients. Circulating Klotho levels are generally low in the short-term postoperatively and exhibit gradual restoration over time with improving allograft function, though only partially recovering to levels observed in healthy controls (see Table 3 in …