Emerging therapeutic options for managing diabetic kidney disease.
Emerging therapeutic options for managing diabetic kidney disease.
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治疗糖尿病肾病的新兴治疗选择。
DOI：
10.1097/mnh.0000000000000345
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发表时间：
2017
影响因子：
3.2
通讯作者：
Navaneethan,SankarD
中科院分区：
文献类型：
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作者：
Walther,CarlP;Whaley-Connell,Adam;Navaneethan,SankarD
本杂志的读者不需要提醒糖尿病流行的规模，但提醒人们人口水平的数据仍然令人震惊。目前估计，全球每 11 名成年人中就有 1 人患有糖尿病，导致每年的直接费用接近 1 万亿美元 [1, 2]。应对现代文明的这一公共卫生困境是许多国际管理机构的重点。鉴于糖尿病已经是全球终末期肾病的主要原因，肾脏病学界在组织应对这一挑战方面发挥着主导作用[3]。墨西哥城是最近举办的 2017 年世界肾脏病大会的举办地，该大会的重点是糖尿病肾病 (DKD)。它是受影响最严重的国家之一的首都，该国每七个成年人中就有一个患有糖尿病，多年来糖尿病一直是该国死亡的主要原因[4]。任何击败糖尿病流行的机会肯定需要针对整个生命周期采取多管齐下的方法：从胎儿发育到儿童和成年期的超重和肥胖，再到预防糖尿病并发症并在发生时管理器官功能障碍。蛋白尿发生背后的机制在我们对 DKD 管理的理解和治疗目标中发挥着核心作用；然而，人们越来越认识到蛋白尿的存在对于严重、进行性 DKD 来说并不是必要的 [5]。肾素-血管紧张素系统（RAS）抑制剂的开发和应用是现代医学的伟大成就之一，其在DKD治疗中的价值是毋庸置疑的。尽管如此，令许多肾脏科医生感到非常沮丧的是，即使在服用 RAS 抑制剂时也观察到残余风险，并且接受 RAS 抑制剂治疗且血压和血糖控制充足的患者仍然不可避免地会发展为肾衰竭。真正控制 DKD 进展需要有效针对糖尿病对肾小球、肾小管、间质和脉管系统恶性影响的替代机制的额外治疗策略。在本期《肾脏病学和高血压最新观点》中，我们荣幸地介绍了一组由专家作者撰写的优秀文章，讨论了对 DKD 的最新理解，以及不同发展阶段的有希望的治疗操作。 Agarwal 和 Panagiotis [6] 回顾了内皮素受体拮抗剂的初步发展。 Endothelin-1 是一种针对糖尿病中许多代谢紊乱而表达的激素，可通过多种途径影响肾功能，包括血管收缩、促进炎症和纤维化途径以及足细胞损伤。多项试验表明，即使在最大程度抑制 RAS 的情况下，已确诊的 DKD 患者的蛋白尿也能得到改善；然而，到目前为止，心力衰竭风险的增加似乎超过了有益的影响[7]。这些数据为正在进行的糖尿病肾病研究奠定了基础，该试验在一组因充血性心力衰竭和水肿风险较低而选择的 DKD 患者中进行 [8]。 Persson 和 Palm [9] 概述了 DKD 组织缺氧的病理生理学（由于线粒体功能障碍导致耗氧量增加）以及缺氧诱导因子 (HIF) 的潜在治疗调节。他们总结了关于 HIF 在不同肾细胞群的不同实验操作中的有益和有害作用的复杂临床前证据。在肾小球中，高血糖以不依赖缺氧的方式增强其表达，
Readers of this journal need no reminder of the scale of the diabetes pandemic, but a reminder of the population level data is still staggering. Current estimates are that one of every eleven adults worldwide has diabetes, resulting in annual direct costs approaching $1 trillion [1, 2]. Combating this public health dilemma of modern civilization is a focus of a number of international governing bodies. Given that diabetes is already the primary cause of end-stage kidney disease across the globe, the nephrology community is taking a leading role in organizing against this challenge [3]. Mexico City was an especially appropriate location for the recently held World Congress of Nephrology 2017 focusing on diabetic kidney disease (DKD). It is the capital of one of the most severely affected countries, where one of every seven adults is afflicted with diabetes, and where diabetes has been the leading cause of mortality for years [4]. Any chance of defeating the diabetes pandemic will certainly require a multipronged approach targeting the entire lifecycle: from fetal development, to overweight and obesity in childhood and adulthood, to prevention of diabetic complications and managing organ dysfunction when it occurs. The mechanisms behind the development of albuminuria play a central role in much of our understanding and therapeutic targeting for the management of DKD; however, it is increasingly recognized that the presence of albuminuria is not necessary for serious, progressive DKD [5]. Development and application of inhibitors of the renin–angiotensin system (RAS) is one of great accomplishments of modern medicine, and their value in management of DKD is beyond question. Nonetheless, a great frustration for many nephrologists is the residual risk observed even while on RAS inhibitors, and having patients on RAS inhibition with adequate blood pressure and glycemic control still progress inexorably to kidney failure. True control of DKD progression will require additional therapeutic strategies effectively targeting alternative mechanisms of diabetes’ malign effects on the glomerulus, tubules, interstitium, and vasculature. In this issue of Current Opinion in Nephrology and Hypertension, we have the honor of introducing an exceptional group of articles by expert authors discussing the latest understanding of DKD, and promising therapeutic manipulations in various stages of development.Agarwal and Panagiotis [6] review the preliminary development of endothelin receptor antagonism. Endothelin-1 is a hormone expressed in response to many of the metabolic derangements in diabetes that impacts kidney function through multiple pathways, including vasoconstriction, promotion of inflammatory and fibrotic pathways, and podocyte injury. Several trials have demonstrated improvements in proteinuria in established DKD even in the setting of maximal RAS inhibition; however, thus far the beneficial effects seem to be outweighed by the increased risk of heart failure [7]. These data set the stage for the ongoing Study of Diabetic Nephropathy with Atrasentan trial in a group with DKD selected for low risk of congestive heart failure and edema [8]. Persson and Palm [9] outline the pathophysiology of tissue hypoxia in DKD–because of increased oxygen consumption from mitochondrial dysfunction–and the potential therapeutic modulation of hypoxia inducible factor (HIF). They summarize the complex preclinical evidence regarding the salutary and damaging effects of HIF in different experimental manipulations in various kidney cell populations. In the glomerulus, its expression is potentiated by hyperglycemia in a hypoxia-independent manner,