Mazzieri Alessio, Timio Francesca, Patera Francesco, Trepiccione Francesco, Bonomini Mario, Reboldi Gianpaolo
Diabetes Clinic, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Division of Nephrology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Kidney Blood Press Res. 2024;49(1):1041-1056. doi: 10.1159/000542621. Epub 2024 Nov 18.
Aldosterone is the principal mineralocorticoid hormone and the final effector of the renin-angiotensin-aldosterone system. This hormone is primarily synthesized by the CYP11B2 enzyme and produced by the adrenal zona glomerulosa. Through genomic and non-genomic effects, it plays an important role in cardiovascular and renal disease. To counteract aldosterone-mediated damage, steroidal mineralocorticoid receptor antagonists are recommended by international guidelines, but endocrine side effects often limit their use in a substantial proportion of patients. Conversely, nonsteroidal mineralocorticoid receptor antagonists, with an improved selectivity and safety profile, are gaining a prominent position among therapeutic pillars. However, blocking the mineralocorticoid receptors does not completely inhibit aldosterone effects because of escape mechanisms and non-genomic activity. Thus, inhibiting aldosterone synthesis could be a promising strategy to prevent aldosterone-mediated cardiorenal damage. The limited specificity for CYP11B2 and side effects due to off-target activity hampered the development of first-generation aldosterone synthase inhibitors (ASIs).
The development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Additionally, a recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria.
The strength of the clinical evidence collected so far is still limited, and larger outcome-based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.
醛固酮是主要的盐皮质激素，也是肾素-血管紧张素-醛固酮系统的最终效应物。这种激素主要由CYP11B2酶合成，由肾上腺球状带产生。通过基因组和非基因组效应，它在心血管和肾脏疾病中发挥重要作用。为了对抗醛固酮介导的损害，国际指南推荐使用甾体类盐皮质激素受体拮抗剂，但内分泌副作用往往限制了它们在相当一部分患者中的使用。相反，具有更好选择性和安全性的非甾体类盐皮质激素受体拮抗剂在治疗手段中占据了突出地位。然而，由于逃逸机制和非基因组活性，阻断盐皮质激素受体并不能完全抑制醛固酮的作用。因此，抑制醛固酮合成可能是预防醛固酮介导的心脏和肾脏损害的一种有前景的策略。第一代醛固酮合酶抑制剂（ASI）由于对CYP11B2的特异性有限以及脱靶活性导致的副作用，阻碍了其研发。
高特异性ASI的研发在难治性和未控制高血压患者中进行了成功的临床试验。此外，最近的一项随机临床试验表明，ASI对慢性肾脏病和蛋白尿患者有显著益处。
目前收集到的临床证据的力度仍然有限，需要进行更大规模的基于结局的临床试验，以证实ASI在心脏和肾脏损害中的潜在作用。
