Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium–glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.

中文翻译：

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心肾疾病中的非甾体盐皮质激素受体拮抗剂

尽管有现有的治疗方法，心力衰竭和慢性肾脏病 (CKD) 患者仍处于不良结局和进展为终末期疾病的高风险中。螺内酯和依普利酮等甾体盐皮质激素受体拮抗剂 (MRA) 可降低死亡率，但由于存在高钾血症和激素副作用的风险，其处方仍然不足。非甾体 MRA 的发现代表了心肾疾病治疗的一个重要新维度。非甾体 MRA 对盐皮质激素受体 (MR) 具有高亲和力和特异性，并且在重要的物理化学、药效学和药代动力学参数方面与两种甾体药物不同。与类固醇对应物相似，它们在肾脏中具有有益的抗炎、抗重塑和抗纤维化特性，心脏和脉管系统。有几种非甾体 MRA 正在开发和临床评估中；其中，只有 esaxerenone 和 Finerenone 被批准用于全球治疗。在日本，esaxerenone 被批准用于治疗原发性高血压，并已在糖尿病肾病中进行了研究。与甾体 MRA 相比，finerenone 更有效地抑制 MR 共调节因子募集和纤维化，并且在心脏和肾脏之间分布更均匀。具有里程碑意义的 III 期试验 FIGARO-DKD 和 FIDELIO-DKD 表明，在与 2 型糖尿病相关的 CKD 患者中，除了最大耐受的肾素-血管紧张素-醛固酮系统抑制作用之外，finerenone 还减少了主要肾脏和心血管事件。非甾体 MRA 目前正在评估心力衰竭和与钠 - 葡萄糖转运蛋白 2 抑制剂的协同治疗。这些突破性的药物可能成为跨越心肾疾病谱的重要疗法。