Mineralocorticoid receptor antagonists in dialysis patients

Tawada, Mitsuhiro; Suzuki, Yoshio; Sakata, Fumiko; Mizuno, Masashi; Ito, Yasuhiko

doi:10.1186/s41100-016-0077-4

Cited by 3 publications

(1 citation statement)

References 73 publications

(79 reference statements)

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“…Thus, potassium secretion from the intestine is increased in patients with advanced CKD or on dialysis therapy [29,34,35], and mineralocorticoid receptor blockers are reported to suppress this mechanism [38]. Indeed, several studies have reported that the administration of spironolactone is associated with increased incidence of hyperkalemia in patients on maintenance hemodialysis therapy [63][64][65] although pronounced hyperkalemia (serum potassium ≥ 6 mEq/L) does not occur commonly [66]. Notably, there are also reported a substantial number of studies showing that spironolactone does not cause significantly higher levels of serum potassium in patients on hemodialysis [47][48][49] or peritoneal dialysis therapy [50,51,67,68], when compared with placebo (Table 1).…”

Section: Aldosterone Blockade In Ckdmentioning

confidence: 99%

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Hayashi

Suzuki²,

Sakamaki

et al. 2018

Ren Replace Ther

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Cardiac hypertrophy is a life-threatening disorder and is frequently observed in patients with chronic kidney disease (CKD). Much attention has been focused on the derangement in hormonal factors, including aldosterone and FGF23, as novel causes of cardiac hypertrophy in CKD. Plasma aldosterone concentrations are elevated as renal function declines. Although aldosterone antagonists are available for the treatment of hypertension with cardiac hypertrophy, concern remains regarding the possible occurrence of serious hyperkalemia. Alternatively, certain types of calcium channel blockers suppress aldosterone synthesis or exert blocking action for mineralocorticoid receptors and could halt the progression of cardiac dysfunction. Recently, FGF23 is shown to be elevated as CKD progresses and may be responsible for the development of cardiac hypertrophy and heart failure. Furthermore, FGF23 not only inhibits the renal expression of angiotensin converting enzyme 2 but also enhances renin gene transcription, both of which could accelerate renin-angiotensin-aldosterone system. Although the increase in serum phosphate concentrations is a pivotal stimulus for FGF23 production, recent studies suggest that reduced iron status and elevated aldosterone levels, frequently seen in patients with CKD or on dialysis, might also contribute to the elevation in serum FGF23 levels. Conversely, phosphate binders and appropriate iron status could reduce serum FGF23, potentially leading to the alleviation of cardiac hypertrophy and heart failure. In conclusion, novel therapeutic strategies associated with aldosterone and FGF23 may confer a benefit in the management of cardiac disorders in CKD.

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Section: Aldosterone Blockade In Ckdmentioning

confidence: 99%

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Hayashi

Suzuki²,

Sakamaki

et al. 2018

Ren Replace Ther

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Mineralocorticoid receptor antagonism attenuates arteriovenous fistula stenosis by modulating the phenotype of vascular smooth muscle cells

Liu,

Chen,

Chen

et al. 2024

Nephrology Dialysis Transplantation

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Background Fistula stenosis is a primary contributor to arteriovenous fistula (AVF) failure in maintenance hemodialysis patients. Emerging data indicated excessive fibrotic remodeling was the primarily contributor to fistula stenosis during AVF remodeling. The mineralocorticoid receptor (MR) has been implicated in vascular remodeling across various cardiovascular pathologies. However, its role in AVF remodeling, particularly concerning fibrotic remodeling, remains elusive. Methods MR expression and the phenotypes of vascular smooth muscle cells (VSMCs) were assessed in dysfunctional AVF. The effects of MR on VSMC phenotypic switching were examined in vitro, and the protective effects of MR antagonists on AVF outcome were evaluated in a rat AVF model. Results Dysfunctional fistula exhibited significant medial fibrosis and extracellular matrix deposition, alongside markedly increased MR activity. In the dysfunctional fistula vessels, VSMC displayed reduced expression of the contractile marker SMMHC and featured characteristic of a synthetic phenotype, including increased osteopontin expression and heightened proliferation. In vitro studies with cultured VSMC revealed that MR overactivity induced by aldosterone led to phenotypic switching from contractile to synthetic state, concomitant with EGFR-ERK1/2 pathway overactivation. These effects were largely abolished by the MR antagonist fineronone. Knockdown of EGFR expression abrogated ERK1/2 phosphorylation and inhibited the VSMC phenotypic switching. Conversely, ectopic overexpression of EGFR in VSMC diminished the protective effect of finerenone. In rat AVF models, pharmacologic targeting of MR with finerenone significantly improved AVF outcomes, characterized by increased luminal diameters and flow volume, reduced medial fibrosis, and inhibited VSMC phenotypic switching. These beneficial outcomes were likely attributable to a restrained activity of EGFR-ERK1/2 pathway in VSMC and elevated NO production in endothelial cells. Conclusions Our study demonstrated that therapeutic targeting of MR may improve AVF outcome by modulating VSMC phenotypic switching. These findings offer promising avenues for further clinical investigations aimed at optimizing AVF outcomes in the hemodialysis population.

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Clinical Properties and Non-Clinical Testing of Mineralocorticoid Receptor Antagonists in In Vitro Cell Models

Varda,

Ekart,

Lainscak

et al. 2024

IJMS

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Mineralocorticoid receptor antagonists (MRAs) are one of the renin–angiotensin–aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.

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Mineralocorticoid receptor antagonists in dialysis patients

Cited by 3 publications

References 73 publications

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Mineralocorticoid receptor antagonism attenuates arteriovenous fistula stenosis by modulating the phenotype of vascular smooth muscle cells

Clinical Properties and Non-Clinical Testing of Mineralocorticoid Receptor Antagonists in In Vitro Cell Models

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