Physiological Actions of Aldosterone

Aldosterone is synthesized in the zona glomerulosa of the adrenal gland cortex. Its production is restricted to this layer of the cortex because of zona-specific expression of aldosterone synthase (CYP11B2)(4), which is the key enzyme for aldosterone biosynthesis (5). The expression of CYP11B2 is controlled by aldosterone secretagogues. Previous immunohistochemistry studies of the adrenal gland reported that in early life, cells express CYP11B2 in a continuous mode, whereas with increasing age, expression of CYP11B2 is less continuous. Subsequently, in adults, CYP11B2-expressing cells are distributed in a diffuse manner in the subcapsular cortex among typical zona glomerulosa cells not expressing the enzyme, whereas the CYP11B2-expressing area decreases with age (5,6). Aldosterone secretion is primarily stimulated by angiotensin II acting on ATR1 receptors in the adrenal zona glomerulosa and by elevated plasma potassium levels.

The renin–angiotensin–aldosterone system (RAAS) is the principal regulator of aldosterone production. Renin, an enzyme produced in the juxtaglomerular apparatus of the kidney, catalyzes the conversion of angiotensinogen (an inactive precursor peptide) to angiotensin I. Angiotensin I undergoes further enzymatic conversion by angiotensin-converting enzyme (ACE) to produce angiotensin II (Ang II). Ang II acts via the adrenal angiotensin receptor ATR1 to stimulate the release of aldosterone by increasing the transcription of aldosterone synthase.

The physiologic role of RAAS is to regulate sodium homeostasis and thereby intravascular plasma volume and arterial pressure. In normal physiology, renin secretion is stimulated by decreased delivery of chloride ion to the macula densa of the juxtaglomerular apparatus. This is typically the consequence of decreased systemic arterial pressure resulting in decreased renovascular pressure and glomerular filtration. Increased renin activity results in activation of the RAAS and increased synthesis of Ang II, an activator of Ca2+ influx and Ca2+/calmodulin-dependent protein kinases (CaMKs) stimulating transcription of CYP11B2 and aldosterone biosynthesis (5). Ang II has many functions to counter the initial hypotensive and hypoperfusion insult:

• It acts as a direct arterial vasopressor and can induce vasoconstriction to address systemic hypotension.
• It stimulates vasopressin (antidiuretic hormone) release to induce distal nephron water reabsorption and thus expand intravascular volume.
• It acts at the proximal renal tubule of the nephron to maximize proximal sodium (and therefore water) reabsorption to expand intravascular volume.
• It maximizes renal sodium reabsorption by stimulating adrenal aldosterone biosynthesis; aldosterone then acts at the principal cells to increase sodium reabsorption as described earlier.

The net effect of these actions is a feedback loop, whereby expansion of intravascular volume increases renal perfusion and glomerular filtration and decreases renin secretion (Figure 1).

Both potassium and angiotensin II can independently stimulate aldosterone secretion by increasing cytoplasmic calcium concentrations in zona glomerulosa cells, and act synergistically to amplify aldosterone production. Potassium, in addition, enhances the sensitivity of zona glomerulosa cells to angiotensin II. The calcium influx induced by potassium-mediated membrane depolarization activates intracellular signaling pathways that overlap substantially with those triggered by angiotensin II, augmenting aldosterone response to angiotensin II in hyperkalemic states. Beyond this permissive role, aldosterone secretion can also be directly stimulated by elevated serum potassium concentrations, which increase transcription of aldosterone synthase (CYP11B2) within the zona glomerulosa.

TWIK-related acid-sensitive potassium (TASK)-1 (KCNK3), TASK-2 (KCNK5), and TASK-3 (KCNK9) channels are two-pore-domain potassium channels, also referred to as K⁺-selective leak channels, that are predominantly expressed in the adrenal cortex (7,8). These channels generate background potassium currents, maintaining a highly polarized (negative) membrane potential in adrenocortical cells under resting conditions (7,8). Inhibition or genetic deletion of TASK channels leads to membrane depolarization, increased intracellular calcium, and overproduction of aldosterone (7,8). TASK-1 and TASK-3 can form homo- or hetero-meric channels, and their inhibition (by factors such as angiotensin II or extracellular protons) depolarizes the membrane, triggering aldosterone synthesis (7,8). The TASK channels are members of the KCNK family and exhibit sensitivity to extracellular pH (9,10). These channels are crucial for setting the resting membrane potential and are inhibited by extracellular protons within the physiological range(9). Kir3.4, encoded by the KCNJ5 gene, is a G protein-activated inwardly rectifying potassium channel that also contributes to maintaining the hyperpolarized state of adrenocortical cells. Mutations or dysfunction in Kir3.4 can disrupt potassium efflux, leading to depolarization and increased aldosterone production (7,8). Through the coordinated actions of these potassium channels, even small increases in extracellular potassium can result in a several-fold increase in aldosterone secretion. Activation of the renin–angiotensin–aldosterone system, typically occurring in response to reduced renal blood flow or sodium depletion, further augments aldosterone synthesis and secretion (5,11). Aldosterone’s production can be upregulated acutely following increased expression and phosphorylation of the StAR protein or more chronically due to increased expression of CYP11B2 (5).

Adrenocorticotropic hormone (ACTH) is another aldosterone secretagogue, although its effect is modest and transient; ACTH is a 39-amino acid peptide, resulting from the cleavage of its proopiomelanocortin (POMC) precursor. It is produced by the anterior pituitary corticotropes, but, to a lesser degree, can be produced in the brain, adrenal medulla, skin, and placenta (12). It binds to melanocortin type 2 receptor (MC2R), stimulating both cortisol and aldosterone secretion (12). However, earlier and more recent data have suggested that the ACTH effect on aldosterone secretion may be more complex and underestimated (13). It has been reported that increasing StAR expression, as well as activation of the PKA pathway and calcium/calmodulin-dependent protein kinase, may lead to increased aldosterone secretion (14). A recent study evaluated 61 normotensive and 113 hypertensive patients with normal aldosterone suppression in a combined fludrocortisone-dexamethasone suppression test (dexamethasone was administered to eliminate any stimulatory effect of ACTH on aldosterone secretion) who had normal findings in computed tomography. All the patients underwent stimulation tests with 0.03 μg ACTH, while among them, 26 also had genetic studies. The study found that 27% of the hypertensive group exhibited increased aldosterone secretion following the test. Sequencing of the KCNJ5 gene revealed that 2 patients had two different heterozygous germline mutations. Interestingly, MR antagonist therapy was effective for blood pressure normalization (15). These findings led to the hypothesis that glomerulosa cells were primed by chronic stress-induced ACTH secretion, and, hence, became more sensitive to ACTH and/or REN/angiotensin II (15,16). Additional modulators and mechanisms also include other substances:

• Adipokines: The adipokine CTRP-1 can directly stimulate aldosterone secretion from human adrenocortical cells in vitro. Other factors or states, such as leptin, insulin, insulin resistance, and sympathetic nervous system activation, can also increase aldosterone secretion, particularly in overweight or obese individuals, partly by sensitizing adrenocortical cells to angiotensin(17),
• Osmolarity: The adrenal gland is intrinsically osmo-sensitive. Increased osmolarity (by as little as 10 mosmol/l) strongly reduces angiotensin-stimulated aldosterone secretion, indicating that plasma salinity modulates its secretion independently of renin and angiotensin (18).
• Magnesium (Mg2+): Mg2+ modulates aldosterone secretion by blocking K+ and Ca2+ channels in adrenal glomerulosa cells. Higher extracellular Mg2+ reduces both basal and angiotensin II-stimulated aldosterone secretion in vitro and in vivo. In humans, Mg2+ depletion augments angiotensin II-stimulated aldosterone secretion, which can be partially reversed by Mg2+ repletion (19) and
• Parathyroid Hormone (PTH): PTH can stimulate aldosterone secretion by acting directly on adrenal zona glomerulosa cells and potentiating angiotensin II effects. Conversely, aldosterone excess can induce renal calcium loss, leading to hypocalcemia and secondary hyperparathyroidism (20).

Figure 1.

Renin-dependent Aldosteronism. The physiologic relation between the renin-angiotensin system and aldosterone is referred to as “Renin-dependent Aldosteronism,” also referred to as “Secondary Aldosteronism.” Decreased renal-vascular perfusion resulting in decreased glomerular filtration is sensed by juxtaglomerular cells. The consequent release of renin activates the renin-angiotensin system resulting in the synthesis of angiotensin II (Ang II). Ang II induces systemic vasoconstriction, increases proximal tubular sodium reabsorption, and stimulates aldosterone secretion. The net effect is increased renal sodium reabsorption and intravascular volume expansion which closes the feedback loop and corrects the initial stimulus to raise renin.

Pathophysiologic Actions of Aldosterone

Emerging evidence has implicated aldosterone, and specifically activation of the mineralocorticoid receptor, with cardiovascular and cardiometabolic diseases (12,23,24). The mineralocorticoid receptor is classically considered in the context of its expression in the distal nephron; however, it is now clear that this receptor is also expressed in the vasculature and heart and plays an important role in mediating cardiovascular pathophysiology. The non-classical effects of aldosterone have stemmed from dysregulated aldosterone physiology being linked to deleterious end-organ effects. Typically, this has been evidenced by inappropriately elevated levels of aldosterone in the setting of high dietary sodium intake (subclinical or clinical primary hyperaldosteronism). However, some evidence also suggests that inappropriately low levels of aldosterone on a restricted sodium diet, or in response to angiotensin II, are also associated with adverse cardiometabolic consequences (25–28).

Excess or inappropriate aldosterone activity has been associated with or shown to cause cardiac fibrosis, inflammation, and remodeling (28–30), pathologic insulin secretion and/or peripheral resistance, as well as the metabolic syndrome (27,31,32), kidney injury (33), and increased mortality (34). Interventional studies in animals and humans have supported these assertions by demonstrating the prevention of these deleterious effects with the use of mineralocorticoid antagonists (34,35). Taken together, this evolving body of evidence points towards subclinical aldosterone excess, particularly in the milieu of excessive dietary sodium intake, as a modifiable cardio-metabolic risk factor.

The mechanisms by which this can occur are many: 1) an adrenal tumor that autonomously secretes aldosterone; 2) unilateral or bilateral hyperplasia of the zona glomerulosa that oversecretes aldosterone; 3) or germline or somatic mutations that induce aldosterone hypersecretion that is decoupled from Ang II signaling. Autonomous aldosterone excess results in continuous renal sodium reabsorption, intravascular volume expansion, hypertension and renal-vascular hyperperfusion, and consequently suppression of the RAAS. Yet, despite this physiologic suppression of the RAAS, aldosterone secretion continues unabated, resulting in a vicious cycle of hypertension and, possibly, also hypokalemia (Figure 2). Patients with primary aldosteronism (PA), when compared with matched essential hypertensives, have increased left ventricular wall and carotid intima media thickness, as well as impaired diastolic pressure and endothelial function (24,36,37). A higher incidence of atrial fibrillation, often hypokalemia-induced, coronary artery disease, and heart failure have been reported (38,39). PA is also associated with a higher incidence of negative cardiovascular outcomes (myocardial infarction and stroke) than essential hypertension with a similar degree of blood pressure elevation (39–42). Therefore, PA is considered to induce increased cardiovascular risk independent of blood pressure effects alone. The excess cardiovascular events associated with PA were previously considered reversible if treatment with mineralocorticoid antagonists was administered in time (42,43). However, newer data suggest that PA patients treated with MR antagonists had an approximately two-fold higher incidence of adverse cardiovascular events. Patients with PA also had a significantly higher death risk, as well as a higher incidence of atrial fibrillation and diabetes mellitus than people diagnosed with essential hypertension. The adjusted 10-year cumulative incidence difference for occurrence of cardiovascular morbidity for patients with PA and treatment with MR antagonists was reported to be 14.1 (95% CI 10.1, 18.0) excess events per 100 individuals compared to those with essential hypertension (44).

Figure 2.

Renin-Independent Aldosteronism or Primary Aldosteronism (PA). The pathophysiologic relation between the renin-angiotensin system and aldosterone regulation in PA is referred to as “Renin-independent Aldosteronism”.

Renin-Independent Aldosteronism (Primary Aldosteronism)

PA is recognized as the most common form of secondary hypertension, with a prevalence ranging from 5% to 15% in hypertensive patients and up to 20%–30% in those with resistant hypertension (46–48)

The five established morphological subtypes of PA include: aldosterone-producing adenoma (APA), bilateral adrenal hyperplasia (BAH), unilateral adrenal hyperplasia (UAH), glucocorticoid-remediable aldosteronism (GRA), and, rarely, adrenocortical carcinoma (49,50). A potential sixth subtype may involve a morphologically normal adrenal gland (without any tumor or hyperplasia) that harbors clusters of increased expression of aldosterone synthase (the aldosterone producing cell cluster)(4,51,52). Recent advances in genetics and clinical research have dramatically enhanced our understanding of the pathogenesis of these subtypes and have raised the question of whether these entities are part of a larger spectrum of disorders that share genetic underpinnings (5,6).

• Aldosterone-producing adenoma (APA): Estimates for the proportion of PA cases due to APA vary widely, with most recent data indicating that APA accounts for approximately 27%–35% of cases (46–48)
• Bilateral adrenal hyperplasia (BAH)/Idiopathic hyperaldosteronism (IHA): BAH is reported to account for about 60%–65% of PA cases (46–48)
• Unilateral adrenal hyperplasia (UAH): UAH is much less common, representing about 2% of cases of PA (46,53)
• Other rare causes: Familial hyperaldosteronism and aldosterone-producing adrenocortical carcinoma each account for less than 1% of PA cases (46,53).

There are some discrepancies in the literature, with one source reporting APA being as high as 65% and BAH as 35% (46,53). The majority of studies aligns with the 30–40% APA and 60–65% BAH distribution.

APAs are often small tumors, usually less than 2 cm in diameter. Histopathology of APA reveals hybrid cells which have histological features of both zona glomerulosa and zona fasciculata cells. Unilateral adrenal hyperplasia (UAH), sometimes referred to as primary adrenal hyperplasia, shares many biochemical features with APA. This diagnosis is often made on evidence of unilateral production of aldosterone in the absence of a discrete radiographic mass. Similarly to APA, the hypertension and biochemical abnormalities with UAH may be cured or substantially ameliorated with unilateral adrenalectomy (54,55).

BAH probably represents a spectrum of disorders (56–58). The extent of hyperaldosteronism is often milder in BAH than in APA, and consequently the severity of hypertension, hypokalemia, and suppression of PRA is often less.

Adrenal carcinomas are a rare cause of PA. At the time of diagnosis, adrenal carcinomas are generally large (>4 cm) and may be producing one or multiple adrenal cortical hormones, including cortisol, aldosterone, and adrenal androgens.

Epidemiology

In 1954, Conn first reported the clinical syndrome of hypertension, hypokalemia, and metabolic alkalosis resulting from autonomous production of aldosterone from an adrenal adenoma – a syndrome that continues to bear his name (59). Previous studies reported a prevalence of PA of 1-2%, even in patients with adrenal incidentaloma and hypertension (60). Since that time, numerous studies have investigated the prevalence of PA and reported rates ranging from 3% to 20% depending on the population and diagnostic approach. The prevalence is highest in patients with resistant hypertension and increases with the severity of hypertension. Improved screening, especially using the ARR, has led to greater recognition of PA, particularly among normokalemic patients who were previously missed (61–69). Initial studies primarily diagnosed patients with PA if they had both hypertension and spontaneous (not diuretic-induced) hypokalemia. More recent reports, however, describe hypokalemic PA in only the minority of PA cases (<40%) (53), and describe an intermediate phenotype of normotensive PA with milder manifestations than the classic hypertensive PA(70–77). Many (up to 63%) of patients with PA may be normokalemic (39,60). A recent study suggested that PA was diagnosed in 12% of normotensive and normokalemic people with adrenal incidentalomas (77) (Table 1).

In patients with resistant hypertension, the addition of a mineralocorticoid antagonist has been associated with substantial efficacy in blood pressure lowering, suggesting that subclinical hyperaldosteronism may be more prevalent than recognized, with a range between 17 and 23% (60,86–88). In a study involving 1616 patients with resistant hypertension, 21% (338 pts) had an ARR of > 65 with concomitant plasma aldosterone concentrations of > 416 pmol/L (15 ng/dl) (89). Low renin hypertension is not always easy to differentiate from PA (90). A recent study investigated 327 people with hypertension and 90 normotensive control subjects with normal adrenal imaging. Serum aldosterone, active renin levels, aldosterone/active renin ratio were measured before and after a combined sodium chloride, fludrocortisone and dexamethasone suppression test (FDST). Post-FDST values were compared to cut-offs obtained from controls. Combined results of post-FDST aldosterone levels and ARR, revealed that 28.7% of the hypertensive patients had PA (91).

Genetic Insights

Recent genetic insights have significantly advanced the understanding of PA, revealing a complex landscape involving both somatic and germline mutations in genes regulating ion channels, ATPases, and signaling pathways. These discoveries have important implications for diagnosis, classification, and personalized management of PA.

Familial Hyperaldosteronism Type I (FH-I) or Glucocorticoid-Remediable Aldosteronism GRA is an autosomal dominant disorder characterized by a chimeric duplication, whereby the 5’-promotor regions of the 11β-hydroxylase gene (regulated by ACTH) is fused to the coding sequences of the aldosterone synthase gene in a recombination event (gene defect in CYP11B1/CYPB2 -coding for 11beta-hydroxylase/aldosterone synthase). The result is that the aldosterone synthase gene (CYP11B2) is under the control of the promoter for the CYP11B1 gene, typically responsible for cortisol production under the regulation of ACTH (92). It leads to an ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata, making mineralocorticoid production regulated by corticotropin (93,94). The hybrid gene has been identified on chromosome 8. Under normal conditions, aldosterone secretion is mainly stimulated by hyperkalemia and angiotensin II. An increase of serum potassium of 0.1 mmol/L increases aldosterone by 35%. In familial hyperaldosteronism type 1, urinary hybrid steroids 18-oxocortisol and 18-hydroxycortisol are approximately 20-fold higher than in sporadic aldosteronomas. Intracranial aneurysms and hemorrhagic stroke are clinical features frequently associated with familial hyperaldosteronism type 1 (95). The diagnosis is made by documenting dexamethasone suppression of serum aldosterone using the Liddle’s Test (dexamethasone 0.5 mg q 6h for 48h should reduce plasma aldosterone to nearly undetectable levels (below 4 ng/dl) or by genetic testing (Southern Blot or PCR) (96).

Familial hyperaldosteronism type II (FH-II) is an inherited form of PA characterized by familial clustering of PA without distinctive clinical or biochemical features differentiating it from sporadic disease. FH-II is now known to be caused by germline mutations in the inwardly rectifying chloride channel gene CLCN2, which lead to zona glomerulosa cell depolarization, increased intracellular calcium signaling, and PA. Affected individuals may present with unilateral or bilateral disease and exhibit phenotypes indistinguishable from sporadic aldosterone-producing adenomas or bilateral adrenal hyperplasia. Consequently, diagnosis relies on family history and genetic testing rather than clinical phenotype alone (97,98).

Familial hyperaldosteronism type III (FH-III) (98) is associated with germline mutations in KCNJ5, a gene that encodes the inwardly-rectifying potassium channel GIRK4 (99) leading to an increase in aldosterone synthase expression and production of aldosterone (95). This type is characterized by severe childhood-onset hypertension, hypokalemia, remarkably high aldosterone-to-renin ratio, high concentrations of hybrid steroids and with marked adrenal enlargement and diffuse hyperplasia of the zona fasciculata (100,101).

This discovery set off international research efforts to investigate the role of potassium channel mutations in PA. Although the prevalence of KCNJ5 germline mutations is considered to be extremely low (75,94,102,103), investigators have now reported the presence of KCNJ5 somatic mutations in 30-50% of patients with APA’s (75,94,102–105). Hence, the discovery of a rare familial form of PA has resulted in understanding that somatic potassium channel mutations may be a highly prevalent cause of PA. In general, from the reports to date, somatic mutations in KCNJ5 appear to be associated with female gender, younger age, and higher aldosterone levels; however, these descriptions may reflect a significant sample selection bias.

Normally, adrenal zona glomerulosa cells maintain a hyperpolarized resting membrane potential that is largely regulated by potassium current. Depolarization of the cell (either by angiotensin II or hyperkalemia-mediated inhibition of the potassium current) results in the opening of voltage-gated calcium channels, increased intracellular calcium signaling, and stimulation of aldosterone synthase. A gain-of-function mutation in GIRK4 results in sodium influx, cell depolarization, and increased aldosterone synthesis (106–108) (Figure 4A-C). In this manner, mutations in channels that regulate the resting potential of zona glomerulosa cells have been implicated in the development of hyperaldosteronism. How these mutations may result in proliferation and adenoma production is not well understood. This understanding provoked further international collaborative research, especially among European research teams, to investigate the role of other cell membrane channels involved in maintaining zona glomerulosa cell resting potential. This research has resulted in the discovery of somatic mutations in the sodium-potassium-ATPase, calcium-ATPase, and voltage-gated calcium channel all in the zona glomerulosa cell membrane in the pathogenesis of PA (109).

Figure 4.

Adrenal zona glomerulosa cell membrane potential and KCNJ5 mutations. Normal resting equilibrium. The normal resting potential of zona glomerulsa cells is hyperpolarized thereby preventing calcium influx by inhibiting voltage-gated calcium channels.

Figure 5.

Adrenal zona glomerulosa cell membrane potential and KCNJ5 mutations. Normal aldosterone stimulation. Activation of the angiotensin receptor (ATR1) by angiotensin II (ANG II) or extracellular hyperkalemia results in depolarization of the cell and resultant calcium influx via activated voltage-gated calcium channels. Calcium influx activates signaling to increase expression of aldosterone synthase and ultimately aldosterone production.

Figure 6.

Adrenal zona glomerulosa cell membrane potential and KCNJ5 mutations. KCNJ5 mutations. Mutations in KCNJ5 result in permeability to Na⁺, resultant depolarization and calcium influx via voltage-gated calcium channels. Similarly, mutant Na⁺/K⁺ ATPase and Ca⁺⁺ ATPase result in cell membrane depolarization and calcium influx.

Familial hyperaldosteronism type IV (FH IV) results from germline mutations in the T-type calcium channel subunit gene CACNA1H (110). Germline mutations in CACNA1D (encoding a subunit of L-type voltage-gated calcium channel CaV1.3) are found in patients with PA sometimes associated with seizures, and other neurological abnormalities (111). Additional genes, such as PDE2A and PDE3B, have been associated with bilateral PA, further expanding the spectrum of genetic etiologies(112) (Table 2).

With continued collaborative research, it is expected the number of mutated gene products regulating the resting potential of zona glomerulosa cells implicated in the pathogenesis of PA will grow. Whether the identification of these mutations will translate to treatment modalities remains to be seen.

Histopathology (APCCs / APMs)

The histopathological discovery of aldosterone-producing cell clusters (APCCs) also referred to as aldosterone-producing micronodules (APMs), CYP11B2 expressing area and/or areas of abnormal foci of CYP11B2-expressing cells (6,113), sparked another leap in the understanding of PA pathogenesis. APCCs have now been identified in more than 50% of morphologically normal adrenal glands and are found with higher prevalence in older individuals (6,113). Recent studies reported decreased normal zona glomerulosa CYP11B2 expression and increased APCC expression with advancing age (6,113). Furthermore, APCCs harbor somatic mutations known to increase autonomous aldosterone secretion in APAs(52) (37). Although studies of APCCs to date lack biochemical or clinical correlates to confirm that this histopathological phenotype of aldosterone synthase overexpression induces renin-independent aldosteronism, they raised speculation that the APCC may represent a precursor for development of APA or BAH. For example, APCCs exist even in adrenal tissue adjacent to an aldosterone-producing adenoma (51), suggesting that APCCs have non-suppressible aldosterone synthase activity.

Several clinical studies to date have shown mild or “subclinical” renin-independent aldosteronism in normotensives and early stage hypertensives, and that this phenotype increases the risk for cardiometabolic and/or chronic kidney disease (27,114–118) However, even if APCCs/APMs are increasingly recognized as a histopathological substrate for subclinical PA, supporting the link between tissue pathology and the clinical phenotype, however, direct clinical-histopathological correlation is still being established (119–121). Therefore, future studies that integrate APCC histopathology with biochemical testing and incident clinical outcomes are needed to better characterize whether APCCs may represent the initial pathogenesis of PA.

Clinical Features

The clinical features of hyperaldosteronism are non-specific and variable, often resulting in or associated with hypertension. It is more important to distinguish whether hyperaldosteronism is primary or secondary, as this pathophysiologic designation dictates the likely clinical syndrome (Figure 7). Renal potassium wasting can result in hypokalemia. The phenotype depends largely on the underlying cause and the degree of the aldosterone excess, as well as the presence of other co-morbidities. The classic features of moderate-to-severe hypertension, hypokalemia, and metabolic alkalosis are highly suggestive of mineralocorticoid excess (usually PA). In most cases, however, only subtle clues of hyperaldosteronism exist, such as the recent onset of refractory hypertension (defined as refractory to treatment with three classes of antihypertensives, including a diuretic) (58).

Hypertension is common among patients with PA. Hypertension results from inappropriately high aldosterone secretion because of plasma volume expansion and increased peripheral vascular resistance. Hypertension may be severe or refractory to standard antihypertensive therapies. However, some patients are normotensive or have minimal blood pressure elevations and, as a result, severe hypertension is not a sine qua non for this diagnosis (38,65,122–125).

Spontaneous hypokalemia in any patient with or without concurrent hypertension warrants consideration of hyperaldosteronism as an etiology. Additionally, patients that develop severe hypokalemia after institution of a potassium-wasting diuretic (such as hydrochlorothiazide or furosemide) should be investigated. It should be noted that in most PA cases serum potassium levels are normal (58,126).

PA results in extracellular volume expansion secondary to excess sodium reabsorption. However, after the retention of several liters of isotonic saline, an escape from the renal sodium-retaining actions of aldosterone occurs in part due to the increased secretion of atrial natriuretic peptide. Therefore, peripheral edema is rarely a feature of PA if cardiac and renal function are normal.

Metabolic alkalosis occurs secondary to renal distal tubule urinary hydrogen ion secretion. It is usually mild, causing no significant sequelae, and may go unnoticed. Hypomagnesemia and mild hypernatremia (likely secondary to resetting of the osmostat) can also be observed.

Rarely, patients experience neuromuscular symptoms, including paresthesias or weakness, due to the electrolyte disturbances caused by PA. Nephrogenic diabetes insipidus, caused by renal tubule antidiuretic hormone resistance due to hypokalemia, can cause nocturia and mild polyuria and polydipsia. Atrial fibrillation and cardiac arrhythmias may occur and can be life threatening.

Figure 7.

Clinical manifestations of primary aldosteronism.

Who to Screen

An updated Endocrine Society clinical practice guideline (2025) provides a comprehensive, evidence-based approach to the diagnosis and management of primary aldosteronism (PA), with a notable shift toward broader screening strategies (127). The guideline conditionally recommends screening all individuals with hypertension for PA using the ARR, measured alongside plasma aldosterone concentration, renin (either PRA or DRC), and potassium, to enable accurate interpretation (127). In addition, screening is specifically recommended for individuals with (a) hypertension and spontaneous or diuretic-induced hypokalemia (65,128–132), (b) resistant hypertension (uncontrolled on three antihypertensives including a diuretic, or controlled on four or more), (61–66,78–80,85) (c) hypertension with an adrenal incidentaloma (65,98,122,128,129,132), (d) hypertension and obstructive sleep apnea (OSA) (65,123,124,132), (e) a family history of early-onset hypertension or stroke (<40 years) (3,54,106,124,128,132–135), and (f) hypertensive first-degree relatives of individuals with confirmed PA (3,54,106,124,128,132–135)(127). The guideline also advises repeat testing in cases with negative initial results but a high pre-test probability (e.g., hypokalemia, suppressed renin, or use of interfering medications), and emphasizes the need to correct hypokalemia and, when feasible, withdraw interfering agents (e.g., β-blockers, ACE inhibitors, diuretics) prior to repeat testing to avoid false negatives (127). Complementing these recommendations, recent international consensus efforts, including the Primary Aldosteronism Medical Outcome (PAMO) study, emphasize that the true prevalence of PA is likely underestimated when relying solely on classical indicators such as hypokalemia (136). Notably, up to 80% of individuals with biochemically confirmed PA are normokalemic at diagnosis(136). Accordingly, some expert groups and national societies (e.g., Japan) now advocate for universal PA screening in all individuals with hypertension, regardless of serum potassium or adrenal imaging findings (136). The PAMO consensus also underscores the importance of screening before initiation of antihypertensive therapy, as many commonly used agents (e.g., diuretics, MRAs, β-blockers) can confound ARR interpretation by altering renin and aldosterone concentrations(136)

Figure 8.

Current screening recommendations for primary aldosteronism (PA) based on the 2025 Endocrine Society Clinical Practice Guideline (127) and the PAMO international expert consensus(136).

How to Screen

Evaluation for PA begins with hormonal screening, specifically determination of plasma aldosterone concentration (PAC) and plasma renin activity (PRA) with validated, sensitive assays, for calculation of plasma ARR, with ideal conditions (morning sample with individuals seated and avoiding dietary sodium restriction during the few days prior to screening, including correction of hypokalemia, withdrawal of interfering medications, and proper patient preparation). Potassium is measured not as a primary screening test, but to support accurate interpretation of aldosterone levels (127). A positive screening result for PA is generally defined by fulfillment of both of the following criteria:

• Suppressed renin with inappropriately elevated aldosterone is the pathophysiologic hallmark of PA. This is suggested when plasma renin activity (PRA) is ≤1 ng/mL/h or direct renin concentration (DRC) is ≤8.2 mU/L and aldosterone concentration is ≥10 ng/dL (≥277 pmol/L) when measured by immunoassay, or ≥7.5 ng/dL (≥208 pmol/L) when measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS).
• A substantially elevated ARR is consistent with PA. This is typically defined as an aldosterone (ng/dL)–to–PRA (ng/mL/h) ratio >20, or an aldosterone (pmol/L)–to–DRC (mU/L) ratio >70 when aldosterone is measured by immunoassay. When aldosterone is measured by LC-MS/MS, the ARR threshold suggestive of PA is approximately 25% lower (127).

Screening results should always be interpreted in the context of the individual patient’s pretest probability of PA, as well as the presence of potentially interfering medications or clinical conditions, recognizing that no single threshold provides perfect discrimination between PA and non-PA hypertension (127). Interpretation of the ARR should be made after confirming that renin is suppressed in the setting of inappropriately high endogenous aldosterone production. The absence of renin suppression should raise suspicion for secondary aldosteronism and/or the use of medications that raise renin (mineralocorticoid receptor antagonists, renin inhibitors, renin-angiotensin-aldosterone system inhibitors, ENaC inhibitors, other diuretics that induce volume contraction). If initial screening for PA is negative but clinical or biochemical factors that may cause a false-negative result are present, repeat testing is recommended. Where feasible and safe, screening should be repeated on a separate occasion after correction of hypokalemia and temporary withdrawal of interfering medications, as these can raise renin or suppress aldosterone. Suggested washout periods are 4 weeks for mineralocorticoid receptor antagonists, epithelial sodium-channel inhibitors (eg, amiloride, triamterene), and other diuretics, and 2 weeks for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Accurate potassium assessment is essential. Plasma potassium should be measured using careful phlebotomy techniques to avoid pseudo-hyperkalemia, including slow blood collection with a syringe and needle (preferably avoiding vacuum tubes), avoidance of fist clenching, waiting at least 5 seconds after tourniquet release before venipuncture, and prompt separation of plasma from cells within 30 minutes of collection. If the initial screening test is negative but the pretest probability of PA is moderate to high—such as in the presence of hypokalemia, resistant hypertension, or suppressed renin with aldosterone concentrations of 5–10 ng/dL (138–277 pmol/L) by immunoassay—repeat testing on a separate day is recommended.

Although classical diagnostic algorithms recommend withdrawing interfering antihypertensive agents before screening for primary aldosteronism (PA), medication discontinuation is often impractical or unsafe in routine clinical practice. Emerging evidence (137,138)demonstrates that ARR-based screening performed while patients remain on their usual antihypertensive therapy still provides clinically meaningful diagnostic information, particularly when renin remains suppressed and aldosterone is inappropriately elevated. Consistent with these data, the 2025 Endocrine Society Clinical Practice Guideline acknowledges that screening while on medication is an acceptable and frequently necessary approach, with subsequent decisions—such as drug washout or confirmatory testing—guided by the pre-test probability of PA and the initial biochemical pattern. In practice, an initial ARR measured during ongoing therapy can stratify individuals into low-, intermediate-, and high-likelihood categories, allowing clinicians to decide selectively whether medication withdrawal is required for diagnostic clarification (Tables 3,4).

In patients with chronic kidney disease, renin concentrations typically decline in proportion to nephron loss, except in the presence of renovascular ischemia, where renin may be elevated. Aldosterone levels may also be increased, thereby raising the likelihood of false-positive screening results, and results should therefore be interpreted with particular caution in this population(127).

Role of Aldosterone Suppression Testing

The traditional diagnostic pathway for PA consists of an initial screening step—measurement of ARR—followed by confirmatory aldosterone suppression testing. However, the incremental value of suppression testing remains uncertain. Specifically, it is unclear whether confirmatory testing meaningfully improves diagnostic accuracy beyond screening alone, reduces false-positive results, influences clinical outcomes such as blood pressure control or cardiovascular risk, or reliably predicts lateralizing disease. Given these uncertainties, the guideline assessed whether aldosterone suppression testing should routinely inform management in patients with a positive PA screen. It concludes that suppression testing should be selectively used—specifically in individuals with an intermediate likelihood of unilateral, surgically curable disease and when the clinician and patient agree that pursuing potential surgical cure is appropriate (conditional recommendation; low certainty of evidence).

Aldosterone suppression testing is not required prior to PA-specific therapy:

• Individuals with resistant hypertension or hypertension with hypokalemia and unequivocal biochemical evidence of renin-independent aldosterone excess (eg, markedly suppressed renin with clearly elevated aldosterone). In such cases, suppression testing is discouraged because the risk of false-negative results may exceed the risk of false-positive screening.
• Individuals unwilling or unable to undergo AVS or adrenalectomy, in whom empiric treatment with mineralocorticoid receptor antagonists (MRAs) based on screening results alone is appropriate, although suppression testing may still aid diagnostic documentation in selected cases.
• Individuals from families with known germline mutations causing familial hyperaldosteronism, where genetic testing—rather than suppression testing—is recommended for first-degree relatives and for patients with very early-onset PA.
• Individuals with a very low likelihood of lateralizing PA, such that pursuing a formal diagnosis is not justified (eg, normokalemia with relatively low aldosterone concentrations despite a positive ARR).

In summary, aldosterone suppression testing should be applied selectively rather than routinely, primarily to clarify candidacy for surgical treatment in cases with intermediate diagnostic certainty. In patients with clear biochemical PA, low likelihood of lateralization, or where management decisions would not be altered, suppression testing can be safely omitted(127).

Confirmatory Testing

In patients in whom a confirmatory test is required, methods to demonstrate autonomy of aldosterone production focus on volume-expanding maneuvers. Options for volume expansion include oral sodium loading or intravenous saline infusion. Confirmatory tests also include fludrocortisone suppression and the captopril challenge(126). Combined protocols—using dexamethasone, captopril, and valsartan to block the RAAS and ACTH stimulation—have been proposed. For oral sodium loading, patients should consume a high-sodium diet (200 mmol/day) for 4 days, typically achieved by adding 4 bouillon packets daily (each contains 48 mmol sodium). Sodium chloride tablets are an alternative but may cause GI upset. On day 4, a 24-hour urine collection is performed for aldosterone, creatinine, and sodium. In normal individuals, salt loading suppresses the RAS; aldosterone excretion >10–12 mcg/24h with urinary sodium >200 mmol confirms PA (76,139)(Figure 9). This outpatient test is convenient but contraindicated in patients with uncontrolled hypertension or untreated moderate/severe hypokalemia. BP and potassium should be monitored throughout, as sodium loading may exacerbate both. For the saline suppression test, 2 liters of isotonic saline are infused over 4 hours (500 mL/h). This test is contraindicated in patients with impaired cardiac function due to the risk of pulmonary edema. In normal individuals, PAC falls below 5 ng/dL; levels >10 ng/dL confirm PA, while 6–10 ng/dL are indeterminate(140,141).

Figure 9.

Confirming the Diagnosis of PA.

Determining Etiology

Once the biochemical diagnosis of PA has been established, further evaluation is required to determine the underlying etiology and to localize the source of autonomous aldosterone production. Differentiation between unilateral forms, most commonly aldosterone-producing adenoma (APA) or unilateral adrenal hyperplasia (UAH) and bilateral disease, typically bilateral adrenal hyperplasia (BAH), is critical, as it directly informs therapeutic decision-making. Less common subtypes, including familial hyperaldosteronism (eg, glucocorticoid-remediable aldosteronism [GRA]), require tailored diagnostic and therapeutic approaches.

Several clinical and biochemical characteristics are associated with unilateral disease, including younger age (<50 years), spontaneous or severe hypokalemia (<3.0 mmol/L), and markedly elevated plasma aldosterone concentrations (>20–25 ng/dL depending on assay. The coexistence of hypokalemia with a unilateral adrenal nodule >1 cm on imaging is highly specific for APA, particularly in younger patients. However, although these features may increase pre-test probability, they lack sufficient validation in large prospective cohorts and should not be used in isolation to determine laterality in individual patients (127).

Imaging

All patients with confirmed PA should undergo adrenal imaging, typically with thin-slice (≤3 mm) computed tomography (CT), primarily to exclude large adrenal masses suspicious for carcinoma (>4 cm) and to delineate adrenal anatomy for potential surgical planning. Aldosterone-producing adenomas are often small (<2 cm), lipid-rich (<10 Hounsfield units), and demonstrate rapid contrast washout; however, CT has limited sensitivity and specificity for functional localization.

Multiple studies have demonstrated that CT imaging alone incorrectly predicts both etiology and lateralization in a substantial proportion of patients, largely due to the high prevalence of non-functioning adrenal incidentalomas—particularly in individuals over 40 years of age—and the frequent occurrence of bilateral adrenal abnormalities in PA. Accordingly, radiographic findings do not reliably correlate with functional aldosterone secretion, and CT should not be used as the sole determinant of treatment strategy in patients considering surgery (127).

Adrenal Venous Sampling

Adrenal venous sampling (AVS) remains the reference standard for distinguishing unilateral from bilateral aldosterone hypersecretion in patients who are potential surgical candidates. AVS involves bilateral adrenal vein catheterization with simultaneous measurement of aldosterone and cortisol, allowing correction for dilutional effects and assessment of lateralization.

The use of adrenocorticotropic hormone (ACTH, cosyntropin) stimulation during AVS remains debated. While ACTH may improve procedural success rates in less experienced centers by stabilizing cortisol secretion, it can also increase aldosterone secretion from the contralateral gland and thereby attenuate lateralization. Current consensus suggests that ACTH stimulation may be appropriate in low-volume centers, whereas experienced centers may preferentially perform unstimulated AVS to optimize lateralization accuracy (127).

Despite its widespread endorsement, AVS was not evaluated in a randomized controlled trial until the SPARTACUS study, which showed no significant difference in short-term blood pressure outcomes between CT-guided and AVS-guided management. However, important limitations, including short follow-up, heterogeneous disease severity, and lack of cardiovascular outcome data, preclude abandoning AVS in surgical decision-making. Consequently, current guidelines continue to recommend AVS for most patients considering adrenalectomy, with the exception of carefully selected young patients (<35 years) with marked biochemical PA, hypokalemia, and a clear unilateral adrenal lesion (127)

Functional PET/CT

11C-metomidate PET/CT is an advanced molecular imaging modality that facilitates the localization of aldosterone-producing adenomas in patients with primary aldosteronism (142,143). Compared to conventional imaging techniques such as CT, MRI, and adrenal scintigraphy, it demonstrates superior sensitivity and specificity. Notably, it distinguishes adrenal cortical lesions from noncortical ones, with significantly different median standardized uptake values (SUVs) of 18.6 versus 1.9. This modality is especially valuable for identifying small (<1 cm) adenomas that may be missed on standard cross-sectional imaging. Despite its diagnostic potential, several limitations constrain its routine clinical application; a: Restricted availability, due to the short half-life of carbon-11, limits use to specialized centers, b: Technical limitations, including the possibility of tracer uptake in nonfunctioning adenomas, necessitate dexamethasone pretreatment for ACTH suppression to enhance specificity, c: Limited concordance with AVS, since one study showed agreement between PET findings and adrenal venous sampling (AVS) in only 51%, particularly in cases lacking standardized dexamethasone suppression protocols.

Recent studies evaluated 18F-Chloroetomidate (18F-CETO), a fluorinated analog of etomidate that retains affinity for key adrenocortical enzymes, binding to both CYP11B1 and CYP11B2 gene products. When labeled with fluorine-18, 18F-CETO exhibits high adrenal cortex specificity (144). Compared to 11C-labeled tracers, 18F offers notable logistical advantages: its longer half-life (120 minutes vs. 20 minutes for 11C) allows for centralized synthesis, distribution to regional PET facilities, multiple imaging sessions per production batch, and lower nonspecific background uptake—particularly in the liver. When preceded by dexamethasone pretreatment (1g daily for 3–5 days), 18F-CETO PET/CT has demonstrated comparable performance to 11C-metomidate PET in detecting lateralized aldosterone production, using the same lateralization threshold (SUV ratio >1.25). While AVS remains the reference standard for lateralization, recent evidence and updated clinical guidelines increasingly support functional PET/CT as a useful adjunct or alternative, particularly in cases where AVS is unsuccessful, contraindicated, or yields discordant results with anatomic imaging (142–146).

Surgical Management

Unilateral adrenalectomy is the preferred treatment for lateralized PA and results in normalization of hypokalemia in nearly all patients and cure of hypertension in approximately 30–70%, with higher rates of partial clinical improvement (127). In contrast, bilateral adrenalectomy in BAH is rarely curative for hypertension (<20%) and is not routinely recommended. Consequently, surgical therapy is favored in unilateral PA, whereas lifelong medical therapy is recommended for bilateral disease and familial forms such as GRA (127).

For patients with lateralized PA, laparoscopic unilateral adrenalectomy is the treatment of choice and is associated with high rates of biochemical cure and substantial clinical benefit. Blood pressure improvement typically evolves over several months, whereas hypokalemia resolves promptly. Factors associated with incomplete clinical cure include long-standing hypertension, older age, family history of hypertension, and requirement for multiple antihypertensive agents pre-operatively.

Post-operatively, transient hypoaldosteronism due to contralateral adrenal suppression may occur, necessitating careful monitoring for hyperkalemia, hypotension, and volume depletion. Mineralocorticoid receptor antagonists (MRAs) and potassium supplementation should be discontinued after surgery, and renin–aldosterone axis recovery may take weeks to months(127).

Radiofrequency ablation has emerged as a potential alternative for select patients with unilateral APA who are not surgical candidates. Although early data suggest comparable short-term biochemical and blood pressure outcomes to surgery, the absence of histopathological confirmation and the risk of procedure-related complications currently limit its routine use.

Medical Management and the PAMO Framework

Medical therapy is the cornerstone of treatment for bilateral PA and for patients with unilateral disease who are not surgical candidates or decline surgery. MRAs—primarily spironolactone or eplerenone—are first-line agents and effectively reverse hypokalemia, reduce blood pressure, and mitigate aldosterone-mediated cardiovascular and renal injury.

The 2025 international consensus introduced the PA Medical Outcome (PAMO) criteria, providing standardized definitions for biochemical and clinical response to medical therapy. Complete biochemical response is defined by correction of hypokalemia without supplementation and normalization of renin activity or concentration, whereas complete clinical response requires normalization of blood pressure without non-PA-specific antihypertensive agents (136).

Spironolactone remains the preferred initial MRA due to availability and cost, typically initiated at low doses and titrated every 2–4 weeks. Eplerenone is an effective alternative with fewer anti-androgenic side effects but requires higher and more frequent dosing. Importantly, renin-guided titration has emerged as a key therapeutic principle: failure to raise renin despite MRA therapy is associated with persistently elevated cardiovascular risk, whereas normalization or rise of renin correlates with improved outcomes, including reduced atrial fibrillation, stroke, and mortality (136).

Dose escalation must be balanced against the risk of hyperkalemia, particularly in patients with chronic kidney disease. When MRAs are poorly tolerated or insufficient, epithelial sodium-channel inhibitors (amiloride or triamterene), calcium-channel blockers, dietary sodium restriction, weight control, and structured exercise may provide adjunctive benefit (136).

Aldosterone-synthesis inhibitors represent a promising new therapeutic strategy for primary aldosteronism, targeting the disorder at its biochemical source. Early first-generation agents showed limited clinical utility due to substantial increases in 11-deoxycorticosterone, which attenuated their antihypertensive effects. Recently, however, more selective second-generation inhibitors—most notably baxdrostat—have demonstrated encouraging results. In the phase 2a SPARK study (147), baxdrostat produced a marked reduction in systolic blood pressure (mean −25 mmHg at 12 weeks), corrected hypokalemia, and reduced the aldosterone-renin ratio by approximately 97%, without evidence of cortisol suppression. Most participants achieved the prespecified biochemical and blood-pressure targets, and the drug was generally well tolerated. Although long-term safety, durability of biochemical remission, and comparative effectiveness versus MRAs or surgery remain to be established, these agents are currently under regulatory review and may soon expand the therapeutic options for patients with primary aldosteronism, particularly for those with bilateral disease or those who cannot tolerate mineralocorticoid receptor antagonists.

Congenital Adrenal Hyperplasia

Another mineralocorticoid-excess state with low plasma renin activity is congenital adrenal hyperplasia (CAH). The most common cause of CAH is 21-hydroxylase deficiency, which can result in variable insufficiencies of cortisol and aldosterone. However, much rarer forms of CAH, for example, 11β-hydroxylase deficiency and 17^α-hydroxylase deficiency can result in monogenic hypertension due to hyper-mineralocorticoidism, caused by elevated deoxycortisol and deoxycorticosterone levels, and resultant excessive mineralocorticoid receptor activation (148,149)(Figure 3).

Apparent Mineralocorticoid Excess (AME) and Liddle’s Syndrome

AME results from abnormal activation of the Type I mineralocorticoid receptor in the kidney by cortisol, secondary to an acquired (licorice ingestion or chewing tobacco) or congenital deficiency of the renal isoform of the type II isoenzyme of the corticosteroid 11-β-dehydrogenase. This isoenzyme converts cortisol to the inactive cortisone in the renal distal convoluted tubule (148,150). However, in case of this isoenzyme’s deficiency, the type I mineralocorticoid receptor is no longer ‘protected’ from activation by cortisol and responds to it as if it were aldosterone.

Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) is the main cause of this rare autosomal recessive disorder, apparent mineralocorticoid excess or AME, which is a form of low renin hypertension(151). The most common clinical manifestations are cardiovascular complications, severe hypertension, left ventricular hypertrophy, and hypertensive retinopathy and nephrocalcinosis associated with hypokalemia. Death caused by cardiac arrest in adolescence has been reported (151).

In Liddle syndrome, constitutive activation of the renal epithelial sodium channel (ENaC) results from activating mutations in the ENaC gene. In both AME and Liddle’s syndromes, the intrinsic renal abnormalities described lead to unregulated and excessive sodium reabsorption, and therefore a biochemical phenotype of suppressed PRA, hypokalemia, and undetectable levels of plasma aldosterone (150).

Glucocorticoid-remediable aldosteronism is treated primarily with low-dose glucocorticoids to suppress ACTH-driven aldosterone synthesis, using the minimal effective dose to avoid long-term adverse effects. MRAs remain effective adjuncts or alternatives when glucocorticoids are contraindicated or poorly tolerated (152).

Secondary Aldosteronism in Normotensive or Hypotensive States

The most common causes of secondary aldosteronism in normotensive or hypotensive patients are conditions associated with reduced effective circulating volume, including congestive heart failure, cirrhosis with ascites, and nephrotic syndrome. In these settings, renal sodium retention and aldosterone excess represent appropriate physiological responses to perceived hypovolemia, and correction of the underlying disorder or restoration of effective arterial volume results in RAAS normalization. Inherited renal salt-wasting disorders, such as Gitelman syndrome and Bartter syndrome, should also be considered in normotensive patients with secondary aldosteronism, particularly when hypokalemia and metabolic alkalosis are present. Chronic or excessive diuretic use is another frequent cause and may mimic renovascular hypertension biochemically by inducing volume depletion, renal hypoperfusion, increased renin release, and secondary aldosterone excess. Surreptitious diuretic use should be suspected in patients with unexplained hypokalemia and secondary aldosteronism, particularly in health-care workers or individuals engaged in weight-loss behaviors. In such cases, urine diuretic screening may be required to establish the diagnosis.

Secondary Aldosteronism in Hypertensive States: Renovascular Hypertension and Related Disorders

Renovascular hypertension is defined as hypertension caused by hemodynamically significant renal ischemia, leading to excess renin secretion due to activation of the renin-angiotensin-aldosterone system (RAAS) from the affected kidney and subsequent secondary aldosteronism (153,154).

Importantly, although renal artery stenosis is relatively common particularly in older adults, only a minority of patients with anatomical renal artery disease develop clinically relevant renovascular hypertension. The most common etiology is atherosclerotic renal artery stenosis, accounting for approximately 90% of cases and typically affecting older individuals (154). Fibromuscular dysplasia, responsible for fewer than 10% of cases, predominantly affects younger women and may involve one or both renal arteries (155,156). Less commonly, renal hypoperfusion may result from coarctation of the aorta, producing a similar RAAS-mediated mechanism. (Table 5). In rare cases, renin-secreting juxtaglomerular cell tumors of the kidney may cause severe hypertension with markedly elevated renin and aldosterone levels, hypokalemia, and an identifiable renal mass. Confirmation requires demonstration of unilateral renin hypersecretion in the absence of renal artery stenosis, and surgical excision is often curative.