INTRODUCTION

The introduction of finerenone, a nonsteroidal mineralocorticoid receptor antagonist (nsMRA), offers new hope for managing residual cardiorenal risk in chronic kidney disease (CKD) and type 2 diabetes. By targeting mineralocorticoid receptor (MR) over-activation, finerenone effectively reduces albuminuria, slows the decline in estimated glomerular filtration rate (eGFR), and lowers the incidence of cardiovascular events [1–3]. Reflecting this robust evidence, several clinical practice guidelines—including the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease, the Korean Society of Nephrology (KSN) 2023 Practical Recommendations for the Management of Diabetic Kidney Disease, and the KSN 2025 Practical Recommendations for the Management of Hypertensive Kidney Disease—now recommend that nsMRA, particularly finerenone, be considered for patients with type 2 diabetes and albuminuria, even when they are on the maximum tolerated dose of renin-angiotensin system inhibitors [4–6]. While finerenone was initially approved to reduce the risk of kidney and cardiovascular events in adults with CKD and type 2 diabetes, it has also been authorized for treating heart failure with an ejection fraction of ≥40%, encompassing both mildly reduced and preserved categories, based on findings from the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) trial [7,8]. Furthermore, recent clinical trials suggest that the indications for finerenone may soon expand. The recent phase 3 Finerenone Efficacy and Safety in Chronic Kidney Disease and Type One Diabetes (FINE-ONE) trial demonstrated a 25% greater reduction in urinary albumin-to-creatinine ratio (UACR) compared to placebo over 6 months [9]. This reduction in albuminuria should be regarded as a bridging biomarker to support regulatory approval for type 1 diabetes, as it indicates a delay in the progression of CKD. Additionally, the phase 3 Finerenone Non-Diabetic Chronic Kidney Disease (FIND-CKD) trial recently demonstrated that finerenone significantly slowed eGFR decline and reduced the risk of kidney or cardiovascular events in patients with non-diabetic CKD, extending the renoprotective benefits of finerenone beyond diabetic kidney disease [10]. These findings address a major unmet need in the treatment of non-diabetic CKD and support the concept that MR antagonism may represent a broadly applicable renoprotective strategy across diverse CKD populations. In parallel with the rapid emergence of new evidence and expanding indications for kidney-protective therapies, the KDIGO Work Group has initiated an update to its 2024 CKD guideline. This update will focus on reassessing several therapies in individuals with CKD without diabetes, including nsMRAs, in light of newly available clinical trial data [11].

KIDNEY-PROTECTIVE EFFECTS OF NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS

Albuminuria reduction is the main mechanistic pathway by which finerenone reduces CKD progression

Finerenone significantly reduces the risk of composite kidney outcomes in patients with CKD and type 2 diabetes, including sustained declines in eGFR, kidney failure, and renal death [1,3]. Earlier studies, such as the Mineralocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTSDN), demonstrated a significant reduction in UACR with finerenone compared to placebo among patients with diabetic nephropathy, most of whom were also receiving an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB). Importantly, finerenone exhibited a safety profile comparable to that of placebo [12]. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial showed that finerenone led to a 31% greater reduction in UACR from baseline to month 4 compared to placebo, with this lower mean UACR maintained thereafter [1]. Researchers noted that the benefits of finerenone for kidney outcomes were evident after 12 months and for cardiovascular outcomes as early as 1 month, with these benefits persisting throughout the trial [1]. Similarly, the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial reported a 32% greater reduction in UACR with finerenone compared to placebo [2]. The pooled FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analysis (FIDELITY) analysis confirmed that the mean change in UACR from baseline to 4 months was significantly lower with finerenone than with placebo, showing a reduction of 32% [3].

Albuminuria is a well-known, critical early-warning biomarker that predicts the progression of CKD and increased cardiovascular risk, including heart attack, stroke, and heart failure [13,14]. A recent international collaborative meta-analysis of 38 cohort studies involving 146,390 participants found that the adjusted hazard ratio (HR) for kidney failure was approximately linear in relation to the percentage change in UACR (HR, 1.64; 95% confidence interval, 1.49 to 1.81) [15]. Therefore, lowering albuminuria levels through treatment reduces both renal and cardiovascular risk, making it an essential surrogate marker for therapeutic success [14]. Since persistent or residual albuminuria is common among patients and serves as one of the strongest predictors of residual risk for kidney and cardiovascular events [14], expanding the range of treatment options by introducing newer interventions or suggesting combinations of existing and/or new therapeutic agents could maximize albuminuria reduction and improve kidney and cardiovascular outcomes.

The precise mechanisms by which nsMRAs improve kidney outcomes remain uncertain

Surprisingly, the mechanisms through which finerenone offers cardiorenal benefits have not yet been fully understood [16]. The FIDELIO-DKD trial observed an early reduction in albuminuria, an early separation of the Kaplan–Meier curves for the key secondary outcome (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), and a modest reduction in blood pressure (without affecting glycated hemoglobin levels or body weight). This suggests that some of finerenone’s benefits may be partially mediated by natriuretic mechanisms [1]. Preclinical studies indicate that the cardiorenal protective effects of finerenone are multifactorial, driven by the regulation of metabolism, antioxidant properties, anti-inflammatory effects, and anti-fibrosis mechanisms [1,16,17]. However, the early improvements in cardiovascular outcomes associated with finerenone likely arise from its immediate therapeutic effects, including renal hemodynamic changes. In contrast, the anti-fibrotic and anti-hypertrophic activities of finerenone may represent long-term results of cumulative structural healing [18]. Indeed, activation of the MR initially leads to sodium (Na⁺) retention, followed by the generation of reactive oxygen species, inflammation, and fibrosis over days to weeks, and ultimately results in hypertrophy and remodeling over months [18]. Although early separation of cardiovascular outcome curves may be observed sooner than kidney outcome curves in clinical trials, early albuminuria reduction should not be interpreted as a cardiovascular-specific marker. Rather, it is a shared surrogate marker of cardiorenal risk. In the FIDELITY mediation analysis, reduction in UACR by month 4 mediated 84% of the kidney benefit and 37% of the cardiovascular benefit of finerenone, suggesting that albuminuria reduction is a major pathway for kidney protection, while cardiovascular protection may additionally involve albuminuria-independent mechanisms [19]. This recognized association between early changes in albuminuria and kidney and cardiovascular events in individuals with and without type 2 diabetes or CKD is primarily based on interventions that inhibit the renin-angiotensin-aldosterone system and sodium-glucose cotransporter-2 (SGLT2) [20,21]. Similar to other kidney-protective agents, the early reduction of albuminuria, coupled with an early decline in eGFR, may be a key mechanism through which finerenone exerts its renal protective effects.

NATRIURETIC EFFECTS OF MINERALOCORTICOID RECEPTOR ANTAGONISTS

Sodium reabsorption along the nephron is regulated by aldosterone and MR

Aldosterone primarily regulates sodium reabsorption and potassium (K⁺) secretion in the distal nephron, playing a crucial role in maintaining volume and blood pressure homeostasis (Fig. 1) [22]. Its action begins when aldosterone binds to the MR, a ligand-dependent transcription factor. This receptor then interacts with specific hormone response elements [22]. The process of transepithelial Na⁺ reabsorption in the renal distal nephron occurs through a two-step mechanism that facilitates the efficient transfer of Na⁺ from the apical side (lumen) to the basolateral side (blood) [23,24]. Rapid or acute changes in Na⁺ reabsorption primarily take place at the apical membrane via the epithelial Na⁺ channel (ENaC). In contrast, longer-term regulation of transepithelial Na⁺ reabsorption is achieved by altering the expression and activity of the basolateral Na⁺/K⁺-ATPase [23]. The MR exhibits a high affinity for both aldosterone and glucocorticoids (cortisol in humans and corticosterone in rodents) [22]. However, since cortisol circulates at concentrations 100 to 1,000 times higher than aldosterone and has a similar affinity for the MR, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protects the MR from premature activation by cortisol. This pre-receptor mechanism is vital for maintaining proper salt and water balance, enabling the MR to respond specifically to aldosterone despite elevated glucocorticoid levels [22,25].

Aldosterone binds to cytosolic MR, causing them to dimerize and translocate to the nucleus. This process induces the transcription of early aldosterone-induced genes, primarily serum and glucocorticoid-regulated kinase 1 (SGK1). SGK1 then phosphorylates and inhibits the ubiquitin ligase neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2), preventing the degradation of ENaC and increasing their presence on the cell surface [26]. Additionally, the aldosterone-MR complex, through SGK1, alleviates the suppression of the ENaC promoter by the disruptor of telomeric silencing alternative splice variant a (Dot1a)-ALL1-fused gene from chromosome 9 (Af9) complex, resulting in enhanced ENaC expression [27]. Besides these genomic changes, aldosterone also triggers rapid, nongenomic effects, such as increasing the trafficking of ENaC subunits to the apical membrane [28]. Experimental studies have shown that ENaC current can be detected within 2 minutes after aldosterone treatment in cortical collecting duct (CCD) cells [28,29]. Collectively, these actions of aldosterone enhance ENaC stability and surface expression, driving Na⁺ retention.

As MR and 11βHSD2 have a restricted distribution in the kidney, their co-localization in the connecting tubule (CNT) and principal cells of the collecting duct defines the aldosterone-sensitive distal nephron (ASDN). The abundance of 11βHSD2 decreases along a gradient from the CCD, through the CNT, to the distal convoluted tubule (DCT) [30]. It has been reported that N⁺-Cl⁻ cotransporter (NCC) and 11βHSD2 are not co-localized at the protein level [31]. Although hydroxysteroid 11-beta dehydrogenase 2 (Hsd11b2) mRNA is either absent or only weakly expressed in DCT cells, its physiological significance remains unclear, suggesting that the protective role of 11βHSD2 for MR is less robust in the DCT than in the CNT and cortical collecting tubule [31]. Additionally, random deletion of MR in renal tubule cells may lead to dysregulation of ENaC but not NCC, indicating that MR plays a less significant role in NCC regulation [32]. Another study revealed that NCC in the early DCT (DCT1) is largely insensitive to aldosterone, while the NCC level in the late DCT (DCT2) is highly dynamic, potentially responsible for aldosterone-mediated fine-tuning of Na⁺ reabsorption in the DCT [33]. Although NCC abundance may be affected by aldosterone, changes in most NCC expression may result from secondary consequences of MR activation in the CNT and CCD rather than direct MR activation in DCT cells. For example, alterations in K⁺ status due to aldosterone-induced changes in distal K⁺ transport could influence NCC expression via aldosterone-independent pathways [31,34].

Aldosterone can also influence the Na⁺-K⁺-2Cl⁻ cotransporter 2 (NKCC2) in the loop of Henle (TALH), but its effect is the opposite of that on other transporters: aldosterone has been shown to downregulate NKCC2 expression in the thick ascending limb of TALH as part of the so-called escape phenomenon [35,36]. However, the direct regulation of NKCC2 by aldosterone appears to be less straightforward than its effect on the ENaC. Additionally, aldosterone has been reported to act on the renal proximal tubule to stimulate Na⁺ reabsorption and acid-base regulation, likely via MR [37,38]. Aldosterone increases the expression and activity of the basolateral Na⁺/K⁺-ATPase in proximal tubule cells, driving higher Na⁺ reabsorption [37]. Furthermore, it upregulates the expression and activity of the apical Na⁺/H⁺ exchanger isoform 3 (NHE3), which increases reabsorption of proximal NaCl and NaHCO₃ [38]. Besides the classical MR pathway, aldosterone-mediated actions can also occur through rapid, nongenomic mechanisms, such as the activation of extracellular signal-regulated kinase (ERK) 1/2 [39]. Interestingly, evidence suggests that MR is expressed in the proximal tubules only in the juxtamedullary cortex, specifically in the renal pyramids, but not in the proximal tubules of the superficial cortex [37]. While superficial (cortical) nephrons are designed for general filtration, the 15% of nephrons that are juxtamedullary are specialized for intense urine concentration [40]. Since juxtamedullary nephrons play a crucial role in Na⁺ reabsorption to create a high-osmolality environment necessary for concentrating urine, the aldosterone-MR pathway may significantly contribute to the function of juxtamedullary nephrons.

Given the localization of MR and the role of aldosterone along the nephron, mineralocorticoid receptor antagonists (MRAs) such as spironolactone, eplerenone, and finerenone act as K⁺-sparing diuretics by blocking aldosterone from binding to MRs, mainly in the ASDN and, in part, in proximal tubule. Reducing Na⁺ uptake through the ASDN and, in part, the proximal tubule by MRAs is usually expected to increase Na⁺ delivery to downstream sites, resulting in increased urinary Na⁺ excretion (natriuresis) and, due to osmotic forces, increased urine volume (diuresis) (Fig. 1).

nsMRAs cause mild natriuretic and diuretic effects

Pressure natriuresis is a crucial renal mechanism in which increased renal perfusion pressure (blood pressure in the kidney) leads to higher excretion of Na⁺ and water in the urine [41]. This system serves as a long-term regulator of arterial blood pressure by reducing extracellular fluid volume when blood pressure rises, thereby ensuring homeostasis. Several pathological conditions can influence this process: increased renal sympathetic tone can blunt pressure natriuresis, while reduced kidney function shifts the pressure-natriuresis curve, making it more difficult for the body to manage Na⁺ balance [41,42]. In addition to conventional diuretics, SGLT2 inhibitors and angiotensin receptor neprilysin inhibitors can interact with and restore abnormal pressure natriuresis [41]. MRAs are also recognized as one of the most effective add-on treatments for resistant hypertension, due to their ability to reduce thoracic volume, which highlights the importance of their natriuretic capacity [43]. Interestingly, previous experiments have shown that eplerenone, a steroidal MRA, can induce natriuresis even in the absence of aldosterone by blocking MR activation along the late DCT and early CNT [43].

When 100 mg/day of spironolactone, a steroidal MRA, was selectively administered to patients with acutely decompensated heart failure, no significant difference was observed in spot urinary Na⁺ excretion between patients receiving spironolactone and those not receiving it. However, the level of spot urinary Na⁺ on day 3 was higher in the spironolactone group compared to the control group (84.1±28.7 mmol/L vs. 70.7±34.4 mmol/L, P=0.04) [44]. This indicates that the natriuretic and diuretic effects of spironolactone are usually delayed, taking 2 to 3 days to fully develop, as the process of blocking MRs involves slower genetic changes in the kidneys. Previous short-term studies demonstrated that 8- or 12-week treatment with 25 mg/day of spironolactone in patients with CKD already treated with ACEi and/or ARB significantly reduced urinary protein excretion without significant effects on blood pressure [45,46]. Given the noted associations among expanded extracellular volume (ECV), obesity, hypertension, and potentially albuminuria [47], even mild natriuretic and diuretic effects leading to slight ECV reduction may explain the beneficial effects of MRAs.

Since the next-generation MRAs have been developed to improve biodistribution, potency, selectivity, physicochemical properties, and ultimately the balance between clinical efficacy and side effects, disruptions in renal Na⁺ and K⁺ homeostasis are expected to be minimized [48]. In an animal model of rapidly progressive glomerulonephritis, BR-4628, a precursor to finerenone, significantly suppressed kidney injury through anti-inflammatory and anti-fibrotic actions, without affecting urinary Na⁺ and K⁺ excretion or inducing hyperkalemia [49,50]. These minimal effects of finerenone on urinary Na⁺ and volume indicate that it is not a strong natriuretic agent on its own. Since major clinical trials, including the FIDELIO and FIGARO trials, have not reported serial urinary Na⁺ measurements [1,2], natriuretic and diuretic profiles for finerenone are largely unavailable in human data. However, a prespecified analysis of the FINEARTS-HF trial demonstrated that although finerenone did not significantly reduce the initiation of a loop diuretic in patients not taking loop diuretics at baseline compared to placebo, it did reduce the need for loop diuretic dose intensification and led to a decrease in the mean loop diuretic dose [51]. This suggests that finerenone may have indirect clinical signals for improved Na⁺ balance despite its mild natriuretic and diuretic effects.

As reflected in the FIDELIO-DKD and FIGARO-DKD trials [1,2], finerenone produces only a modest reduction in systolic blood pressure, with an average decrease of 2–3 mm Hg compared to placebo [52]. An exploratory analysis adjusting for changes in office systolic blood pressure suggests that a small proportion of the effect of finerenone on kidney and cardiovascular outcomes may be attributed to variations in office systolic blood pressure [53]. The major clinical trials of finerenone indicate that the cardiovascular benefits of the drug became apparent earlier than the kidney benefits [53]. This cardiovascular benefit appears to be partly driven by short-term natriuretic or hemodynamic mechanisms, even though these effects did not result in a stronger reduction in blood pressure. Esaxerenone, a nonsteroidal MRA, has demonstrated a more potent antihypertensive effect. When administered as a single agent for 52 weeks to patients with essential hypertension, esaxerenone exhibited sustained and stable antihypertensive activity (−23.5/−13.1 mm Hg at week 52, P<0.001 vs. baseline). However, urinary Na⁺ excretion, K⁺ excretion, and urine volume decreased significantly (all P<0.05 vs. baseline) [54]. In this study, urinary Na⁺ excretion decreased consistently over 52 weeks, with statistically significant changes observed at 12 weeks (−53.1 mEq/day; geometric mean change, −24.5%, P=0.0019 vs. baseline) and at 52 weeks (−44.0 mEq/day; geometric mean change, −18.9%, P= 0.0307 vs. baseline). These results indicate that Na⁺ excretion decreased after 12 weeks and continued until the end of the study [54]. This finding contradicts expectations that Na⁺ excretion should have increased due to the blockade of MRs with esaxerenone administration. Up to 2 weeks after esaxerenone administration, Na⁺ excretion would be transiently increased, accompanied by increased urine output, and after excess Na⁺ is sufficiently eliminated from the body, urinary Na⁺ excretion and urine output would be normalized [54]. The rationale for this is that serum K⁺ levels increased within 2 weeks of initiating esaxerenone, with no further increases observed during esaxerenone dose escalation [55]. Collectively, MRAs, whether steroidal or nonsteroidal, induce transient natriuretic effects and accompanying mild natriuresis by blocking aldosterone-mediated Na⁺ reabsorption, thereby reducing ECV, regardless of the extent of blood pressure reduction, during the days to weeks following their administration. These effects may explain the immediate and early impacts of MRAs, both nonsteroidal and steroidal, on albuminuria or proteinuria, although there have been no experimental data with nsMRA. Meanwhile, long-term cardiorenal protection is proven only with the use of nsMRAs, especially finerenone, which may result from effects on non-hemodynamic factors such as reduced vascular stiffness, improved endothelial function, modulation of sympathetic tone, and reversal of vascular and cardiac remodeling [56,57].

ROLE OF ALDOSTERONE IN REGULATING INTRAGLOMERULAR PRESSURE

Aldosterone affects afferent and efferent arterioles

In a study examining the vascular effects of aldosterone on the renal afferent and efferent arterioles in rabbits, researchers found that aldosterone-induced dose-dependent constriction in both arterioles. This effect was mediated by the activation of phospholipase C, leading to calcium mobilization through L- or T-type voltage-dependent calcium channels, with efferent arterioles exhibiting higher sensitivity (Fig. 2) [58]. Although both arterioles constricted simultaneously, the greater sensitivity of the efferent arteriole likely increased intraglomerular pressure overall. Notably, the vasoconstrictor effect of aldosterone was not influenced by spironolactone [58], indicating that these immediate vasoconstrictor actions are likely nongenomic and mediated by membrane-bound receptors. Additionally, the study revealed that endothelial disruption heightened the sensitivity of the afferent arteriole to aldosterone, enhancing its vasoconstrictor response [59]. The researchers proposed that endothelium-derived nitric oxide (NO) modulates these nongenomic vasoconstrictor actions through the activation of both inositol 1,4,5-triphosphate (IP₃) and protein kinase C (PKC) pathways [59].

Interestingly, opposing results were also reported: in the same animal model, it was found that aldosterone had no effect on internal diameter at any concentration and instead abolished the ability of KCl to induce vascular contraction [60]. This effect was reversed by the MRA spironolactone but not by the glucocorticoid receptor antagonist mifepristone [60]. Similar to aldosterone, the NO donor sodium nitroprusside inhibited K⁺-induced vascular contraction [60]. This mechanism appears to be mediated by the MR and involves the activation of phosphatidylinositol-3 kinase and the stimulation of NO generation, suggesting that this rapid response may serve as a brief counter-regulatory mechanism to prevent excessive initial constriction. Although there is ongoing controversy regarding the vascular effects of aldosterone, it seems clear that endothelial dysfunction, characterized by reduced endothelial NO synthase activity, may influence aldosterone’s effects on the renal vasculature [61]. A major limitation of these studies is that the results may reflect an in vitro phenomenon and may not have direct relevance to the in vivo action of aldosterone [58].

Apart from the contentious results on the nongenomic vascular action of aldosterone, the genomic actions of aldosterone on renal arterioles may have a more important role in pathological conditions such as CKD. According to previous studies, chronic treatment with spironolactone markedly diminished proteinuria and renal lesions of malignant nephrosclerosis, with little or no effect on systolic arterial blood pressure in saline-drinking stroke-prone spontaneously hypertensive rats [62]. Additionally, 2-week pharmacological antagonism with eplerenone prevented the development of proteinuria and tended to reduce renal arteriolopathy in 1% saline-drinking Wistar rats, independent of its effects on systolic blood pressure, with angiotensin II and N^ω-nitro-l-arginine methyl ester (L-NAME) [63]. Meanwhile, the effect of endothelial MR on the renal vasculature was assessed by deleting the nuclear receptor subfamily 3 group C member 2 (Nr3c2) gene in endothelial cells. This deletion did not result in the development of hypertension, endothelial dysfunction in the renal artery, or any alterations in renal plasma flow, afferent arteriole contractility, or overall kidney function and morphology [64]. Therefore, the beneficial effects of pharmacologic antagonism of MR on the kidney may arise from the blockade of MR in smooth muscle cells rather than in endothelial cells [64].

Aldosterone may collectively exert vasoactive effects on renal arterioles through its nongenomic or genomic pathways; however, under pathological conditions, this balance may shift toward a more unfavorable direction. Due to conflicting findings, it remains uncertain whether aldosterone induces constriction of the afferent and efferent arterioles or inhibits their constriction. Nonetheless, its more pronounced effect on the efferent arteriole may ultimately influence intraglomerular pressure.

Aldosterone blunts tubuloglomerular feedback and sensitizes connecting tubule glomerular feedback

In the juxtaglomerular apparatus (JGA), aldosterone acts on the macula densa (MD) to suppress the tubuloglomerular feedback (TGF) response. Through various methods, including investigations of aldosterone’s effects on TGF using microdissected and perfused JGA in vitro and micropuncture studies in vivo, it was found that aldosterone reduces TGF by stimulation of NO synthesis within the MD. This effect is mediated through the activation of MR, as eplerenone completely blocked the influence of aldosterone on TGF [65]. Since NO is a potent vasodilator that counteracts the TGF-mediated vasoconstriction of the afferent arteriole, the overall TGF response is blunted. Although aldosterone also increases superoxide (O₂⁻) production, which typically enhances TGF by scavenging NO, the net effect of chronic aldosterone elevation is a reduction in TGF sensitivity [65]. By resetting TGF to a lower sensitivity, the kidney allows for a higher glomerular filtration rate (GFR) and increased distal delivery of Na⁺, even when distal Na⁺ reabsorption is maximally stimulated by aldosterone (Fig. 2).

In addition to MD, CNT, another segment of the distal nephron, is in direct contact with the afferent arteriole of the same nephron. An increase in Na⁺ delivery to ENaC in the CNT dilates the afferent arteriole, a process known as connecting tubule glomerular feedback (CTGF) [66]. A previous study utilizing isolated perfused rabbit afferent arterioles and their associated CNTs demonstrated that aldosterone in the CNT lumen sensitizes CTGF via a nongenomic pathway involving G protein-coupled receptor 30 (GPR30) and the stimulation of ENaC [66]. In this study, eplerenone completely blocked the effect of aldosterone on CTGF, while G36, a specific antagonist of GPR30, also completely inhibited the effect of aldosterone on CTGF. This suggests that aldosterone sensitizes CTGF through nongenomic actions via the GPR30 receptor [66]. Based on these findings, the overall effect of the attenuation of TGF and the sensitization of CTGF by aldosterone could lead to significant dilation of the afferent arterioles (Fig. 2).

RENAL HEMODYNAMIC EFFECTS OF NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS

MRAs may be effective in attenuating glomerular hyperfiltration under pathological conditions

First, aldosterone appears to modulate the resistance of both the afferent and efferent arterioles, which increases intraglomerular capillary pressure. In the efferent arterioles, aldosterone acts as a potent vasoconstrictor, increasing resistance to outflow and subsequently raising the hydrostatic pressure within the glomerular capillaries. Second, while there are conflicting data regarding aldosterone’s vasoconstrictive potential, its net effect in a living system seems to favor dilation of the afferent arteriole due to the blunting of TGF and sensitization of CTGF. Collectively, these effects of aldosterone could increase GFR. An older study reported that chronic aldosterone infusion, at rates that raised plasma concentrations to five to six times normal, increased GFR and renal plasma flow in dogs [67] and eplerenone treatment markedly attenuated the glomerular hyperfiltration associated with obesity in dogs fed a high-fat diet [68]. However, it has also been reported that the injection of aldosterone alone had no significant vasoconstrictive effect in healthy humans [69]. This suggests that aldosterone has little to no direct net effect on GFR under normal conditions. Therefore, the pathological role of aldosterone in kidney and cardiovascular disease becomes more significant in the presence of conditions such as diabetes, obesity, or CKD [70].

Aldosterone levels, in relation to a cofactor of plasma renin activity, increase as GFR decreases; thus, CKD is considered a state of relative hyperaldosteronism. This relative hyperaldosteronism, despite ECV expansion, leads to MR activation [71]. Although RAS inhibitors have been traditionally recommended for the treatment of CKD in numerous clinical practice guidelines [4–6], 10% to 50% of patients on long-term therapy experience unexpected increases in serum aldosterone levels, a phenomenon termed aldosterone breakthrough [71,72]. This paradoxical increase in aldosterone levels could contribute to the development or aggravation of glomerular hyperfiltration. Accordingly, MRAs could reverse this aldosterone-mediated efferent arteriolar constriction and restore TGF blunting and CTGF sensitivity.

Do nonsteroidal MRAs, compared to steroidal MRAs, reduce glomerular hyperfiltration more effectively?

The nsMRAs, especially finerenone, have shown clear CKD outcome benefits because they combine effective MR blockade with a better kidney safety and tolerability profile, allowing sustained use on top of ACEis or ARBs in CKD populations [1,12,50]. Some hemodynamic contributions may explain their renoprotection, but the experimental and clinical evidence that they specifically and preferentially reduce glomerular hyperfiltration is sparse. There have been no data indicating that nonsteroidal MRAs are uniquely better than steroidal MRAs for hyperfiltration reduction in CKD. In fact, steroidal MRAs can also reverse hyperfiltration in some settings [73,74]. Therefore, for CKD broadly, it is more accurate to say that nsMRAs have demonstrated superior clinical tractability and outcome evidence, not proven superiority for the isolated endpoint of natriuretic and diuretic action or hyperfiltration correction.

The nsMRAs, including finerenone, esaxerenone, and aparerenone, are known as ‘bulky’ antagonists that bind to the ligand-binding site of the MR. This binding displaces one helix of the receptor, preventing the recruitment of coactivators to the site [75]. Finerenone, a more well-known nsMRA, functions more like a complete antagonist/inverse agonist, effectively impairing MR nuclear translocation and cofactor recruitment compared to steroidal agents, which may exhibit partial agonist behavior in certain contexts [74,76]. This likely results in stronger suppression of the maladaptive MR-driven transcriptional program. Additionally, finerenone has a more balanced heart–kidney distribution than spironolactone or eplerenone [77]. Clinically, this is significant because steroidal MRAs often become limited by hyperkalemia and worsening kidney function in CKD, especially when combined with RAS inhibitors [50,78]. In the ARTS and ARTS-DN studies, finerenone achieved albuminuria reduction with less hyperkalemia than spironolactone and demonstrated acceptable short-term effects on eGFR, facilitating large outcome trials [12,77].

Unlike steroidal MRAs, nsMRAs have a short half-life and no active metabolites [50]. This characteristic may make the initial hemodynamic dip in GFR more predictable and transient, enabling the kidney to adapt more safely to reduced hyperfiltration. Thus, the early decrease in GFR observed with finerenone should be considered a restoration of autoregulation rather than a loss of function. Even a small reduction in glomerular hyperfiltration can be beneficial, as it serves as a renoprotective mechanism that alleviates stress on the glomeruli. This decrease, in response to pharmacologic therapies, appears to reflect kidney protection by diminishing glomerular hyperfiltration in the long term [79]. Restoring this overactive state to a more normal level is a key strategy for safeguarding the kidneys from long-term damage. Therefore, although it cannot be definitively asserted that nsMRAs improve glomerular hyperfiltration more effectively than steroidal MRAs, their pharmacological properties seem to facilitate stable and consistent regulation of intraglomerular pressure while minimizing side effects.

UNRESOLVED MECHANISMS AND FUTURE DIRECTIONS OF NONSTEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONISTS

Some questions regarding the effects and mechanisms of nsMRAs remain unresolved. A recent exploratory causal mediation analysis from the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint (CONFIDENCE) suggested that the additive benefit of finerenone is not mediated through hemodynamics but may stem from other mechanisms, such as its direct anti-inflammatory and anti-fibrotic effects [80]. However, this interpretation is limited because mediation analyses rely on untestable assumptions, lack direct physiological measurements, and are based on temporally sparse data. Therefore, the observed relationships between eGFR changes and albuminuria reduction should be considered hypothesis-generating rather than causal. Further studies are required to evaluate the efficacy and safety of finerenone monotherapy, especially in patients who cannot tolerate ACEis or ARBs. A small retrospective study indicated that finerenone could reduce albuminuria even as monotherapy [81]. When compared to the combination of an nsMRA with an ACEi or ARB, nsMRA monotherapy may have slightly different effects on glomerular hemodynamics. Additionally, the exact downstream effects of steroidal versus nsMRAs on renal Na⁺ and K⁺ excretion remain to be fully elucidated. Nonsteroidal MRAs may affect K⁺ handling differently from steroidal MRAs due to unique transcription targets, a shorter half-life, a lack of active metabolites, and their distribution in both the heart and kidneys [75]. Beyond MRAs, it is also of interest to explore how newly emerging agents, such as selective aldosterone synthase inhibitors, may affect renal hemodynamics [82].

With recent advances in CKD treatment, including nsMRAs [83], the therapeutic goal in CKD is gradually shifting from simply slowing progression toward achieving meaningful disease modification or remission [84]. Although the global burden of CKD continues to increase [85], established renoprotective therapies and emerging agents may improve long-term outcomes. As a leading class of kidney-protective therapies, nsMRAs highlight the clinical importance of aldosterone-mediated pathways. A deeper understanding of these mechanisms may provide a foundation for future drug development and more individualized CKD treatment strategies. Until such therapies are further developed and become widely available, nsMRAs are likely to remain a key component of current renoprotective strategies.

CONCLUSIONS

In conclusion, both steroidal and nonsteroidal MRAs may induce transient natriuretic effects by blocking aldosterone-mediated Na⁺ reabsorption, primarily in the ASDN and, to a lesser extent, the proximal tubule. MRAs may also modulate intrarenal hemodynamics by attenuating aldosterone-mediated efferent arteriolar constriction and regulating TGF and CTGF responses, thereby potentially lowering intraglomerular pressure and attenuating glomerular hyperfiltration. However, current evidence does not establish the superiority of nsMRAs over steroidal MRAs for the isolated endpoint of hyperfiltration correction. Instead, the proven clinical value of nsMRAs—particularly finerenone— appears to derive from effective MR blockade combined with improved safety, tolerability, and sustained use in CKD. As our understanding of aldosterone-mediated renal hemodynamics continues to evolve, nsMRAs may serve not only as established therapeutic agents, but also as a mechanistic foundation for the development of future precision kidney-protective therapies.

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (the Ministry of Science and ICT) (No. NRF-2021R1F1A1051955). All figures were created with BioRender.com (Confirmation of Publication and Licensing Rights Agreement Number: NW29LU2IVE and US29LU2STY).

Fig. 1

Aldosterone-mediated regulation of sodium (Na⁺) reabsorption along the nephron. Aldosterone binds to the mineralocorticoid receptor (MR) in the aldosterone-sensitive distal nephron (ASDN), particularly in the connecting tubule and collecting duct, where 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) provides ligand specificity. Upon activation, the aldosterone-MR complex translocates to the nucleus and induces the transcription of target genes, including serum- and glucocorticoid-regulated kinase 1 (SGK1). SGK1 enhances epithelial Na⁺ channel (ENaC) activity by inhibiting neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2)–mediated degradation and promoting channel expression at the apical membrane, resulting in increased Na⁺ reabsorption and K⁺ secretion. Additionally, rapid nongenomic effects of aldosterone further enhance ENaC trafficking. Basolateral Na⁺/K⁺-ATPase activity is also upregulated, facilitating transepithelial Na⁺ transport. In other nephron segments, aldosterone exerts variable effects; it may indirectly downregulate the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) in the thick ascending limb as part of the escape phenomenon, although this mechanism remains incompletely defined. Aldosterone also enhances Na⁺ reabsorption in the proximal tubule via the Na⁺/H⁺ exchanger 3 (NHE3) and Na⁺/K⁺-ATPase, predominantly in juxtamedullary nephrons. Mineralocorticoid receptor antagonists (MRAs) inhibit these processes, reducing Na⁺ reabsorption, increasing distal Na⁺ delivery, and promoting natriuresis and diuresis. ROMK, renal outer medullary K⁺ channel.

Fig. 2

Renal arteriolar and tubuloglomerular effects of aldosterone on renal hemodynamics. Aldosterone has complex effects on renal afferent and efferent arterioles through both nongenomic and genomic mechanisms. Acute exposure to aldosterone can cause vasoconstriction in both arterioles by activating phospholipase C, mobilizing intracellular calcium, and engaging voltage-dependent calcium channels. The efferent arteriole is particularly sensitive to these changes, which may increase intraglomerular pressure. These rapid responses largely occur independently of the mineralocorticoid receptor (MR) and may be influenced by endothelial nitric oxide (NO). Conversely, some studies indicate that aldosterone can inhibit vasoconstriction through MR-dependent activation of phosphatidylinositol 3-kinase and NO production, underscoring the context-dependent and sometimes controversial nature of its vascular actions. The chronic genomic effects of aldosterone, especially under pathological conditions, contribute to renal vascular injury, while mineralocorticoid receptor antagonists (MRAs) help reduce proteinuria and arteriolar damage, likely by acting on vascular smooth muscle cells rather than endothelial cells. In the JGA, aldosterone influences feedback mechanisms that regulate glomerular filtration. At the macula densa, it suppresses tubuloglomerular feedback (TGF) by increasing NO production via MR activation, which reduces afferent arteriolar vasoconstriction and allows for a higher glomerular filtration rate (GFR) and increased distal sodium (Na⁺) delivery. In contrast, aldosterone enhances connecting tubule glomerular feedback (CTGF) by boosting epithelial Na⁺ channel (ENaC) activity in the connecting tubule through a rapid, nongenomic pathway involving G protein-coupled receptor 30 (GPR30), resulting in afferent arteriolar dilation. The combined effects of TGF suppression and CTGF sensitization promote afferent arteriolar dilation and alter intraglomerular hemodynamics. MRAs may counteract these processes by reducing aldosterone-mediated constriction of the efferent arteriole and restoring TGF responsiveness and CTGF sensitivity.

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