With great interest, I read the comprehensive review by Mogi [1] discussing the mechanisms underlying aldosterone breakthrough recently published in the journal. Aldosterone breakthrough has been defined as a rise in plasma concentration of Aldosterone during long-term angiotensin II blockade [2]. Since elevated aldosterone could promote target organ damage in addition to volume expansion and hypertension, the question that arises is what the more rational strategy is to reverse or counteract the aldosterone breakthrough. The renin response to the pharmacological blockade of the negative feedback of angiotensin II on the juxtaglomerular cells could provide a clue. Patients with aldosterone breakthrough tend to have a relatively lower plasma renin activity (PRA) than patients without aldosterone breakthrough [3, 4]. A reciprocal decrease in PRA would indicate volume expansion and therefore a pathogenic role of the elevated aldosterone. This is expressed as higher aldosterone to renin ratio (>3 ng/dL/ng/mL/h, as calculated from the reported data [3, 4]) and would suggest a greater benefit from adding a mineralocorticoid receptor antagonist to patients with aldosterone breakthrough. Accordingly, in patients with resistant hypertension, a higher aldosterone-to-renin ratio predicted a larger blood pressure reduction by the addition of spironolactone [5]. Conversely, an exaggerated increase in renin suggests secondary aldosteronism due to volume contraction rather than aldosterone breakthrough and prompts to review of the diuretic dosage and eventually add a beta-blocker instead of a mineralocorticoid receptor antagonist. Taking into account the renin level and the aldosterone-to-renin ratio could help to refine the therapeutic strategy in patients with unsuppressed aldosterone despite treatment with a renin-angiotensin blocker.
References
Mogi M. Aldosterone breakthrough from a pharmacological perspective. Hypertens Res. 2022;45:967–975. https://doi.org/10.1038/s41440-022-00913-4
Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981;91:457–65. https://doi.org/10.1677/joe.0.0910457
Horita Y, Taura K, Taguchi T, Furusu A, Kohno S Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton). 2006;11:462-6. https://doi.org/10.1111/j.1440-1797.2006.00665.x.
Sato A, Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens. 2003;16:781–8. https://doi.org/10.1016/s0895-7061(03)00913-0.
Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018;6:464–475. https://doi.org/10.1016/S2213-8587(18)30071-8.
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Alfie, J. Aldosterone breakthrough from a pharmacological perspective. Hypertens Res 46, 1350 (2023). https://doi.org/10.1038/s41440-023-01204-2
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DOI: https://doi.org/10.1038/s41440-023-01204-2
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