Epstein Murray
Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA.
Diabetes Ther. 2022 Apr;13(4):583-588. doi: 10.1007/s13300-022-01236-w. Epub 2022 Mar 16.
The classic focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function and maintaining volume homeostasis. In contrast, many recent studies have demonstrated a much wider and expanded role for aldosterone and for the mineralocorticoid receptor (MR). Activation of the MR promotes inflammation, collagen formation, fibrosis, and necrosis with consequent renal injury. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of both diabetic and nondiabetic chronic kidney disease (CKD). By promoting cascades of injury encompassing inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and consequently its associated morbidity and mortality. Based on this mechanism of action, blockade of the MR with the nonsteroidal MR antagonist finerenone is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes (T2D) who were treated with finerenone manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure or a sustained decrease of ≥ 40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Based on the success of these major clinical trials, finerenone was approved by the FDA on 9 July 2021 as a novel treatment for retarding CKD progression in patients with T2D ( https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease ). Podcast Video (MP4 258973 KB).
传统上对醛固酮作用机制的关注主要集中在其在调节肾脏排泄功能和维持容量稳态方面的作用。相比之下，最近的许多研究表明醛固酮和盐皮质激素受体（MR）具有更广泛和扩展的作用。MR的激活会促进炎症、胶原蛋白形成、纤维化和坏死，进而导致肾损伤。越来越多的证据表明，MR的病理生理过度激活是糖尿病和非糖尿病慢性肾脏病（CKD）进展的主要决定因素。通过促进包括炎症和纤维化在内的一系列损伤级联反应，MR的过度激活构成了CKD进展及其相关发病率和死亡率的关键决定因素。基于这种作用机制，目前正在研究使用非甾体类MR拮抗剂非奈利酮阻断MR，作为延缓CKD进展的一种新治疗方案。最近报道的FIDELIO-DKD（非奈利酮降低糖尿病肾病患者肾衰竭和疾病进展）研究表明，与安慰剂组患者相比，接受非奈利酮治疗的CKD和2型糖尿病（T2D）患者出现复合主要结局事件的风险更低（复合主要结局事件定义为肾衰竭或估计肾小球滤过率自基线持续下降≥40%，或死于肾脏原因）。此外，非奈利酮组患者出现关键次要结局事件的风险也更低（关键次要结局事件定义为死于心血管原因、非致命性心肌梗死、非致命性中风或因心力衰竭住院）。基于这些大型临床试验的成功，非奈利酮于2021年7月9日被美国食品药品监督管理局（FDA）批准为一种新型药物，用于延缓T2D患者的CKD进展（https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease）。播客视频（MP4 258973 KB）
