Acute kidney injury
Acute kidney injury
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DOI：
10.1159/isbn.978-3-318-01456-3
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
S. Demirjian;J. Nally
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文献类型：
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作者：
S. Demirjian;J. Nally
急性肾损伤（AKI）是一个全球性的公共卫生问题，与高发病率、高死亡率和高医疗费用有关。除透析外，没有任何治疗干预措施能可靠地提高生存率、限制损伤或加速恢复。尽管体内动物模型存在公认的缺陷，但AKI及其后果慢性肾脏疾病（CKD）的潜在病理生理学具有丰富的生物学靶点。我们回顾了有关肾血管和细胞应激反应的最新发现，主要是未折叠蛋白反应、线粒体功能障碍、自噬和先天免疫反应的交叉。急性期后持续存在的不适应修复机制促进了慢性期的炎症和纤维化。巨噬细胞、生长阻滞的小管上皮细胞、内皮细胞和周围周细胞在慢性疾病的进展中起关键作用。更好地了解这些复杂的相互作用的病理生理机制，它们在人类中的相对重要性，以及生物标志物的应用，将导致预防和治疗AKI或阻止CKD或终末期肾脏疾病（ESRD）进展的治疗策略。293点击此处查看本文的在线特色：•以PPT形式下载图表•浏览链接参考文献•下载引文•浏览相关文章•搜索关键词年度评论进一步A . n . R . v。先生。[2] [6][67:2 93 -3] 07。现在我要从这里开始。2007年，美国国会通过了一项新法案。24个1。22日9。22 . 5 / 08 / 02 / 19急性肾损伤（AKI）：急性肾损伤（CKD）：慢性肾脏疾病（ESRD）：终末期肾脏疾病介绍尽管在临床定义和分期、临床使用的新型肾脏生物标志物的鉴定以及对潜在病理生理学的理解方面取得了进展，急性肾损伤（AKI）仍然是一个主要的未满足的医疗需求，没有任何药物治疗。它仍然是一个全球公共卫生问题，每年影响约1330万患者(1)。此外，尽管AKI与死亡之间的直接因果关系一直存在争议，但AKI与高发病率、成本增加和死亡率相关，每年约有170万人死亡(1)。在低收入和中等收入国家，缺乏训练有素的医疗保健专业人员，诊断测试和透析的利用不足，进一步加剧了本已很高的人类负担，并明显低估了AKI的真实患病率(2)，促使国际肾脏学会（International Society of Nephrology）在2015年制定了0by25倡议，即到2025年，AKI可预防的死亡为零(1)。此外，在发达国家，AKI往往表现在重症监护室的老年患者中，而在中低收入国家，年轻人和妇女特别容易发生并有死亡风险（3,4）。在存活的患者中，AKI的长期结局可能包括发展为慢性肾脏疾病（CKD）和终末期肾脏疾病（ESRD），或先前存在的CKD恶化加速进展为ESRD（5,6）。因此，AKI，以前被认为是患者康复后的良性过程，可能导致生活质量差和长期成本高（5,7）。由于这些原因，需要治疗来降低高发病率和死亡率，并改善肾功能的恢复；然而，AKI的多因素病因学和这一患者群体复杂的临床过程为寻找有效的药理学药物带来了挑战。在医院环境中，手术、败血症或创伤引起的肾脏全身性或局部缺血性损伤，以及对药物的毒性反应（通常是联合用药）是许多AKI病例的原因。毒素（放射造影剂、非甾体类抗炎药等）可直接损伤肾元或引起缺血性损伤或两者兼而有之。在社区获得性AKI中，脱水、感染和毒素通常与急性疾病相关，是常见的原因。这种多样化和复杂的病因加上异质性的患者群体为aki - ckd连续体提供了独特的治疗挑战和潜在的机会。在某些情况下，比如手术，侮辱的时间是已知的，人们可能会在侮辱之前进行干预。另一种选择是，在患者被诊断为AKI后进行干预，试图提高患者的恢复并减少高风险患者向CKD/ESRD的进展。在这篇综述中，我们强调了该领域的最新进展，特别关注在临床前动物模型中发现的新的病理生理机制，这可能为人类的治疗干预提供新的机会。
Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD). 293 Click here to view this article's online features: • Download figures as PPT slides • Navigate linked references • Download citations • Explore related articles • Search keywords ANNUAL REVIEWS Further A nn u. R ev . M ed . 2 01 6. 67 :2 93 -3 07 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g A cc es s pr ov id ed b y 20 7. 24 1. 22 9. 22 5 on 0 8/ 02 /1 9. F or p er so na l u se o nl y. ME67CH20-Bonventre ARI 7 December 2015 20:53 AKI: acute kidney injury CKD: chronic kidney disease ESRD: end-stage renal disease INTRODUCTION Despite harmonization in clinical definition and staging, identification of novel renal biomarkers for clinical use, and progress in understanding the underlying pathophysiology, acute kidney injury (AKI) remains a major unmet medical need without any pharmacological treatments. It continues to be a global public health concern impacting ∼13.3 million patients per year (1). Moreover, although direct causality between AKI and death has been controversial, AKI associates with high morbidity, increased costs, and mortality—about 1.7 million deaths per year (1). In lowerand middle-income countries, lack of access to trained healthcare professionals and underutilization of diagnostic tests and dialysis further contribute to the already high human burden and a marked underestimation of the true prevalence of AKI (2), prompting the International Society of Nephrology in 2015 to institute the 0by25 initiative, that is, zero preventable deaths from AKI by 2025 (1). Furthermore, whereas in the developed world AKI tends to manifest in older patients in the Intensive Care Unit, in lowerto middle-income countries young adults and women are particularly prone and at risk of death (3, 4). Among those patients who survive, long-term outcomes of AKI can include the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD), or exacerbation of pre-existing CKD accelerating the progression to ESRD (5, 6). Thus, AKI, previously thought to have a benign course in patients who recovered, can lead to poor quality of life and high long-term costs (5, 7). For these many reasons, treatments are needed to reduce the high morbidity and mortality and improve recovery of renal function; however, the multifactorial etiology of AKI and the complicated clinical course of this patient population has created challenges in the search for pharmacological agents that work. In the hospital setting, generalized or localized ischemic injury to the kidney due to surgery, sepsis or trauma, and toxic responses to medications (often in combination) account for many cases of AKI. Toxins (radiocontrast agents, nonsteroidal anti-inflammatories, etc.) can directly injure the nephron or cause ischemic injury or both. In community-acquired AKI, dehydration, infection, and toxins, usually in association with acute illness, are frequent causes. This diverse and complex etiology coupled with a heterogeneous patient population provide unique treatment challenges and potential opportunities in the AKI-to-CKD continuum. In some cases, such as surgery, the timing of the insult is known and one might intervene prior to the insult. Alternatively, one might intervene after the patient has been diagnosed with AKI to attempt to enhance recovery and reduce progression to CKD/ESRD in patients at high risk. In this review, we highlight recent progress in the field, with a particular focus on novel pathophysiological mechanisms found in preclinical animal models that may offer new opportunities for therapeutic intervention in humans.