
==== Front
Hypertens Res
Hypertens Res
Hypertension Research
0916-9636
1348-4214
Springer Nature Singapore Singapore

38914705
1757
10.1038/s41440-024-01757-w
Comment
Urinary chloride-to-potassium ratio as a potential novel index for MR activity in patients with hypertension
Nagasawa Hajime h-nagasawa@med.shimane-u.ac.jp

12
Okuma Teruyuki 12
Ueda Seiji 12
1 https://ror.org/01jaaym28 grid.411621.1 0000 0000 8661 1590 Division of Kidney Health and Aging, the Center for Integrated Kidney Research and Advance, Shimane University Faculty of Medicine, Izumo, Shimane Japan
2 https://ror.org/01692sz90 grid.258269.2 0000 0004 1762 2738 Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
24 6 2024
24 6 2024
2024
47 9 25922594
20 4 2024
20 5 2024
28 5 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords

Hypertension
Mineralocorticoid receptor
Primary aldosteronism
Urinary chloride-to-pottasium ratio
issue-copyright-statement© The Japanese Society of Hypertension 2024
==== Body
pmcHypertension is closely related to the development and progression of various cardiovascular and renal diseases [1, 2]. Primary aldosteronism (PA) is a major cause of secondary hypertension and the clinically accepted measure of PA screening is the plasma aldosterone to renin ratio [3]. PA is characterized by excess aldosterone secreted from unilateral or bilateral adrenal glands; if a patient with PA has unilateral adrenal abnormalities, unilateral resection of the abnormal side is recommended for treatment of PA. On the other hand, if a patient with PA has bilateral adrenal abnormalities, mineralocorticoid receptor antagonist (MRA) is the primary recommended treatment option for PA. Overactivation of MR promotes pathophysiological processes associated with multiple physiological systems, leading to the development of cardiovascular disease, chronic kidney disease, and diabetes. MRA plays an important therapeutic role in these diseases [4, 5]. Aldosterone binds to MR and triggers protein transcription. These proteins cooperate to produce a genomic response in the cell [6]. Thus, aldosterone can be an indicator of MR activity, and the aldosterone-MR axis has attracted attention as a therapeutic target. RAS-related C3 botulinum toxin substrate 1 (Rac1) also is known to be involved in MR activation due to increased nuclear translocation of the MR via an aldosterone-independent pathway. Although it is considered important to confirm the indicator of MR activity in order to understand the pathogenesis of the diseases that promote overactivation of MR activity, there is currently no easily measurable indicator of MR activity.

The present study by Ikemoto et al. demonstrated that although the detailed mechanism is not known, urinary chloride-to-potassium (Cl/K) levels were significantly and positively correlated with estimated daily salt intake and urinary Cl/K ratio exhibited a significant positive correlation with the degree of blood pressure reduction caused by MRA treatment in patients with PA [7].

Restriction of dietary salt can reduce the risk of cardiovasucular disease in patients with hypertension [8]. Previous studies have shown that high salt intake leads to the development of atherosclerosis and causes hypertension [9, 10]. It is well known that measurement of urinary sodium (Na) is useful for estimating salt intake, however, the results of this study showed that the urinary Cl/K levels were significantly positively correlated with estimated daily salt intake. In fact, urinary Na and salt intake do not correlate with blood pressure variability in some papers, and the relationship of urinary Na and salt intake is still controversial [11, 12]. Given these papers, salt restriction may not always be appropriate as a treatment for hypertension. In addition, several papers have reported that Cl intake, not Na intake, is believed to be involved in blood pressure elevation [13, 14]. For example, when healthy elderly subjects drank low Na water, high Na bicarbonate water, and high NaCl water while consuming a low-Na diet and compared their blood pressure after 4 weeks, the report suggested that the groups with low Na water and high Na bicarbonate water decreased blood pressure compared to the baseline, while high NaCl water prevented blood pressure decrease due to low Na diet consumption [14].

Patients with PA have salt-sensitive hypertension via excessive aldosterone elevation, and since MR is activated via aldosterone-dependent and aldosterone-independent pathways via Rac 1, patients with PA are considered to have particularly excessive MR activity via both pathways. Thus, aldosterone and Rac1 may be useful indicators of MR activity, however, reports suggesting that they correlate with MR activity are still scarce.

In the present study, the urinary Cl/K ratio was found to be a potential new indicator of MR activity by showing a correlation with MRA-dependent blood pressure lowering effects in patients with PA. The causes of aldosterone-independent pathway activation include not only excessive salt intake but also hyperglycemia, obesity, ventricular hypertrophy and so on, and therefore, whether the urinary Cl/K ratio is also an indicator of MR activation in these activated MR-related diseases is currently elucidated and awaits further study (Fig. 1).Fig. 1 The potential of the urinary chloride-to-potassium ratio as an indicator of MR activity in patients with primary aldosteronism presented in this study and the issue for the future study. MR mineralocorticoid receptor

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Lawes CMM Hoorn SV Rodgers A International Society of Hypertension. Global burden of blood-pressure-related disease, 2001 Lancet 2008 371 1513 8 10.1016/S0140-6736(08)60655-8 18456100
Lawes CMM, Hoorn SV, Rodgers A. International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513–8.18456100 10.1016/S0140-6736(08)60655-8
2. Wright JT Jr Bakris G Greene T Agodoa LY Appel LJ Charleston J African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease; results from the AASK trial JAMA 2002 288 2421 31 10.1001/jama.288.19.2421 12435255
Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease; results from the AASK trial. JAMA 2002;288:2421–31.12435255 10.1001/jama.288.19.2421
3. Funder JW Carey RM Mantero F Murad MH Reincke M Shibata H The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline J Clin Endocrinol Metab 2016 101 1889 916 10.1210/jc.2015-4061 26934393
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:1889–916.26934393 10.1210/jc.2015-4061
4. Ingelsson E Pencina MJ Tofler GH Benjamin EJ Lanier KJ Jacques PF Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study Circulation 2007 116 984 92 10.1161/CIRCULATIONAHA.107.708537 17698726
Ingelsson E, Pencina MJ, Tofler GH, Benjamin EJ, Lanier KJ, Jacques PF, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study. Circulation. 2007;116:984–92.17698726 10.1161/CIRCULATIONAHA.107.708537
5. Shibata S Nagase M Yoshida S Kawarazaki W Kurihara H Tanaka H Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease Nat Med 2008 14 1370 6 10.1038/nm.1879 19029984
Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6.19029984 10.1038/nm.1879
6. Berger S Bleich M Schmid W Greger R Schütz G Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism Kidney Int 2000 57 1295 8 10.1046/j.1523-1755.2000.00965.x 10760057
Berger S, Bleich M, Schmid W, Greger R, Schütz G. Mineralocorticoid receptor knockout mice: lessons on Na+ metabolism. Kidney Int. 2000;57:1295–8.10760057 10.1046/j.1523-1755.2000.00965.x
7. Ikemoto M Morimoto S Ichihara A Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism Hypertens Res 2024 10.1038/s41440-024-01651-5 38548912
Ikemoto M, Morimoto S, Ichihara A. Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism. Hypertens Res. 2024. 10.1038/s41440-024-01651-538548912 10.1038/s41440-024-01651-5
8. Mente A O’Donnell M Rangarajan S Dagenais G Lear S McQueen M Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies Lancet 2016 388 465 75 10.1016/S0140-6736(16)30467-6 27216139
Mente A, O’Donnell M, Rangarajan S, Dagenais G, Lear S, McQueen M, et al. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. Lancet. 2016;388:465–75.27216139 10.1016/S0140-6736(16)30467-6
9. He FJ Marciniak M Visagie E Markandu ND Anand V Dalton RN Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and asian mild hypertensives Hypertension 2009 54 482 8 10.1161/HYPERTENSIONAHA.109.133223 19620514
He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, et al. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and asian mild hypertensives. Hypertension. 2009;54:482–8.19620514 10.1161/HYPERTENSIONAHA.109.133223
10. Zhou TL Henry RMA Stehouwer CDA Sloten TTV Reesink KD Kroon AA Blood pressure variability, arterial stiffness, and arterial remodeling Hypertension 2018 72 1002 10 10.1161/HYPERTENSIONAHA.118.11325 30354707
Zhou TL, Henry RMA, Stehouwer CDA, Sloten TTV, Reesink KD, Kroon AA. Blood pressure variability, arterial stiffness, and arterial remodeling. Hypertension. 2018;72:1002–10.30354707 10.1161/HYPERTENSIONAHA.118.11325
11. Diaz KM Muntner P Levitan EB Brown MD Babbitt DM Shimbo D The effects of weight loss and salt reduction on visit-to-visit blood pressure variability: results from a multicenter randomized controlled trial J Hypertens 2014 32 840 8 10.1097/HJH.0000000000000080 24366034
Diaz KM, Muntner P, Levitan EB, Brown MD, Babbitt DM, Shimbo D. The effects of weight loss and salt reduction on visit-to-visit blood pressure variability: results from a multicenter randomized controlled trial. J Hypertens. 2014;32:840–8.24366034 10.1097/HJH.0000000000000080
12. Takashima N Ohkubo T Miura K Okayama A Okuda N Nakagawa H Factors associated with intra-individual visit-to-visit variability of blood pressure in four countries: the INTERMAP study J Hum Hypertens 2019 33 229 36 10.1038/s41371-018-0129-z 30420643
Takashima N, Ohkubo T, Miura K, Okayama A, Okuda N, Nakagawa H, et al. Factors associated with intra-individual visit-to-visit variability of blood pressure in four countries: the INTERMAP study. J Hum Hypertens. 2019;33:229–36.30420643 10.1038/s41371-018-0129-z
13. Kotchen TA Luke RG Ott CE Galla JH Whitescarver S Effect of chloride on renin and blood pressure responses to sodium chloride Ann Intern Med 1983 98 817 22 10.7326/0003-4819-98-5-817 6303178
Kotchen TA, Luke RG, Ott CE, Galla JH, Whitescarver S. Effect of chloride on renin and blood pressure responses to sodium chloride. Ann Intern Med. 1983;98:817–22.6303178 10.7326/0003-4819-98-5-817
14. Schorr U Distler A Sharma AM Effect of sodium chloride- and sodium bicarbonate-rich mineral water on blood pressure and metabolic parameters in elderly normotensive individuals: a randomized double-blind crossover trial J Hypertens 1996 14 131 5 12013486
Schorr U, Distler A, Sharma AM. Effect of sodium chloride- and sodium bicarbonate-rich mineral water on blood pressure and metabolic parameters in elderly normotensive individuals: a randomized double-blind crossover trial. J Hypertens. 1996;14:131–5.12013486
