Recent Advances and Perspectives on the Use of Mineralocorticoid Receptor Antagonists for the Treatment of Hypertension and Chronic Kidney Disease: A Review

Figures

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  Figure 1. Comparison of the effects of MRAs on blood pressure and serum K+ concentrations. This figure shows the characteristics of the steroidal MRAs (spironolactone and eplerenone) and the non-steroidal MRAs (esaxerenone and finerenone). Finerenone has a less marked antihypertensive effect than the other three drugs, and non-steroidal MRAs appear to be less effective at increasing serum K+ concentrations than conventional steroidal MRAs. This figure was summarized from references [8,9,12,14,15]. The three-dimensional structure of each MRA was created using PubChem3D. *, using RAASi treatment; †, between baseline and 1 year; §, between baseline and 4 weeks.

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  Figure 2. Differences in the ENaC activity and phenotype of AS-KO and MR-KO mice. (A) ENaC activity of AS-KO and MR-KO mice. The ENaC activity of MR-KO mice was low in both DCT2/CNT1 and CNT2/CCD, whereas that of AS-KO mice was low in CNT2/CCD but not in DCT2/CNT1. (B) DCT2/CNT phenotypes of wild-type, AS-KO, and MR-KO mice. Whereas MR-KO mice exhibited a salt-loss state, accompanied by a high serum K+ concentration and a low serum Na+ concentration, the AS-KO mice showed only slightly high serum K+ concentration and slightly low expression of phosphorylated NCC. Under conditions of LS diet-feeding, MR-KO mice showed persistently high urinary Na+ excretion. By contrast, the high urinary Na+ excretion in AS-KO mice was transient, but eplerenone treatment increased urinary Na+ excretion, and this was accompanied by high serum K+ and blood urea nitrogen concentrations, resulting in a salt-loss state similar to that of the MR-KO mice. AS: aldosterone synthase, MR: mineralocorticoid receptor, DCT2: late distal convoluted tubule, CNT1: early connecting tubule, CNT2: late connecting tubule, CCD: cortical collecting duct, Aldo: aldosterone, Cort: cortisol, 11βHSD2: 11beta-hydroxysteroid…

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  Figure 3. Results of the FIDELITY analysis, an analysis of data from the FIGARO-DKD and FIDELIO-DKD trials. (A) Inclusion and exclusion criteria for the FIGARO-DKD and FIDELIO-DKD trials. A total of 13171 patients were included in the FIDELITY integrated analysis, with a follow-up period of 3 years. (B) Results of the composite cardiovascular outcome in the FIDELITY analysis. Finerenone reduced the risk of an initial occurrence of the cardiovascular composite outcome by 14% and the risk of hospitalization because of heart failure by 22% versus placebo. (C) Results of the composite kidney outcome in the FIDELITY analysis. Finerenone reduced the risk of an initial occurrence of the composite renal outcome by 23% and the risk of the initiation of renal replacement therapy by 20% versus placebo. UACR: urinary albumin creatinine ratio, RAAS-i: renin–angiotensin–aldosterone system inhibitor, HFrEF: heart failure with reduced ejection fraction, NYHA: New York Heart Association classification, ESKD: end-stage kidney disease. These figures were summarized from references [12,13,57].

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  Figure 4. Management and incidence of hyperkalemia in the FIDELIO-DKD and FIGARO-DKD trials. (A) The potassium management algorithm used in the FIDELIO-DKD and FIGARO-DKD trials. (B) Incidences of hyperkalemia, related adverse events, and discontinuation of each MRA because of hyperkalemia. The incidence of hyperkalemia was higher in the finerenone group than in the placebo group (14.0% vs. 6.9%), but there were no deaths and few instances of severe hyperkalemia. The incidence of discontinuation owing to hyperkalemia was also lower than those for other MRAs. AKI: acute kidney injury. These figures were summarized from references [12,13,14,55,56,57].

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  Figure 5. MR activation in mouse models of diabetes. (A) Activation of the Rac1–MR pathway in glomerular podocytes and distal nephrons. The Rac1–MR pathway was activated in db/db mice fed a high-salt diet for 10 weeks after unilateral nephrectomy versus control mice (UNx-HS db/m mice), resulting in glomerular damage and hypertension with massive albuminuria. (B) MR stabilization by O-GlcNAcylation. O-GlcNAcylation increased the sensitivity of the db/db mice to aldosterone by stabilizing MR activity. (C) MR activation in endothelial cells. The hypertrophy of the heart and kidneys, massive albuminuria, and inhibition of the vasorelaxation response in mesenteric arteries that characterized the STZ WT mice were reduced in the STZ ECMR-KO mice. T2DM: type 2 diabetes mellitus, UNx: unilateral nephrectomy, HS: high-salt, O-GlcNAcylation: O-linked-N-acetylglucosamine, T1DM: type 1 diabetes mellitus, STZ: streptozotocin, WT: wild type, ECMR: endothelial cell-specific MR. These figures were based on references [90,91,92].