Introduction

Hypertension represents a significant public health issue affecting at least 1.278 billion adults aged 30-79 worldwide.¹ Looking from pathophysiological aspect, hypertension is usually classified as primary, often referred as essential hypertension, which is the most prevalent form and secondary hypertension. However, the categorization of hypertension into “primary” and “secondary” forms serves more as a practical framework than as a reflection of a definitive dichotomous division and oversimplifies the underlying complexities. Secondary hypertension is characterized by a specific, treatable cause leading to elevated blood pressure. However, this classification should not imply that primary hypertension lacks a cause. Instead, primary hypertension often signifies a complex interplay of factors, typically involving polygenic predisposition coupled with atherosclerosis and aspects of a Westernized lifestyle. For the purposes of this review, we will adhere to this traditional nosology rather than exploring more critical or innovative paradigms, as such an examination would exceed the intended scope of this paper.

Secondary hypertension accounts for approximately 5%-10% of all cases of systemic arterial hypertension.² This indicates that a single identifiable and therefore potentially treatable condition causing hypertension is of significant prevalence, especially considering that systemic hypertension affects nearly 1 in 4 individuals worldwide. Among these cases of secondary hypertension, the identifiable cause sometimes lies in a specific gene, leading to what is known as “monogenic hypertension.”^3,4 This form of hypertension typically exhibits inheritance patterns that follow Mendelian genetics, and the majority of monogenic hypertension cases are attributed to modifications or activations within the renin–angiotensin–aldosterone system (RAAS) pathways.^4-6

As this review concentrates on heritable hypertensions due to germline mutations affecting the RAAS system, we will exclude discussion on other genetic conditions such as multiple endocrine neoplasia syndromes, familial pheochromocytoma, neurofibromatosis type 1, von Hippel–Lindau syndrome, chromosomal deletion syndromes, and hypertension and brachydactyly syndrome. These conditions, while hereditary, fall outside the scope of our current exploration.

Germline mutations affecting the RAAS pathways result in increased salt reabsorption, volume expansion, suppressed renin levels, and salt-sensitive hypertension through 3 primary mechanisms: (1) enhanced sodium reabsorption through mutant channels, (2) increased mineralocorticoid receptor activation from alterations in steroid metabolism or changes in receptor affinity, and (3) overproduction of mineralocorticoids accompanied by a breakdown in feedback regulation. Table 1 presents a summary of 3 categories of monogenic hypertension, detailing potassium levels, aldosterone concentrations, and OMIM (Online Mendelian Inheritance in Man) numbers for the implicated genes. But before delving into the disease, it is essential to review the RAAS pathway along with the physiology of the distal and connecting tubules for a comprehensive understanding of these mechanisms.

Distal Nephron Sodium Handling

Sodium Reabsorption via Distal Nephron Segments

There are 2 main pathways for sodium reabsorption in the distal segment of the nephron (Figure 1): the first, responsible for reclaiming up to 5% of filtered sodium, involves the Na–Cl cotransporter (NCC) in the distal tubules.⁷ The second major route occurs where the distal tubules meet the connecting tubules and in the cortical collecting tubules, facilitated by the epithelial sodium channel (ENaC), accounting for approximately 2%-3% of the total sodium reabsorbed. These pathways possess distinct dynamics, functioning in a complementary and competitive manner, and surprisingly activate upon aldosterone stimuli.⁸

Sodium reabsorption via the NCC in the distal tubule is an electroneutral process, meaning its activation does not alter the ion balance or electrical charge within the tubule. The distal tubule lacks water permeability, resembling the continuation of the ascending limb of Henle’s loop. Activation of Cl⁻ and Na–K ATPase occurs basolaterally. This area is also critical for calcium homeostasis, where calcium reabsorption occurs through a selective calcium channel on the apical surface and a Na–Ca exchanger channel basolaterally. This channel mechanism is notably unique, as the reabsorption of sodium on the basolateral side facilitates the extrusion of calcium into the interstitium, a rare occurrence since sodium is not a main intracellular cation and, according to the principles of the Nernst equation, should be pumped out of the cell. The intense activity of the basolateral Na/K ATPase is necessary to compensate for the sodium entering the cell in exchange for calcium extrusion. Considering that the amounts of sodium pumped out by the Na/K ATPase and taken back in by the Na–Ca exchanger are equal, the less sodium absorbed apically, the more balanced and successful the exchange at the basolateral side, resulting in higher calcium absorption. Conversely, increased sodium absorption apically means the Na/K ATPase must pump out more sodium from the tubule, leading to less sodium being exchanged for calcium and thus lower calcium absorption. This also explains why thiazide diuretics, which inhibit the apical NCC, or mutations causing NCC loss-of-function, as seen in Gitelman syndrome, are associated with enhanced calcium absorption and hypocalciuria. The activity and quantity of these channels are modulated by various proteins and transcription factors influenced by luminal sodium and serum potassium concentrations, volume status, and blood aldosterone levels.⁹

As we approach the cortical collecting ducts, principal cells and intercalated cells begin to appear (Figure 1). The ENaC found in principal cells are regulated by aldosterone, leading to the absorption of sodium exclusively. This absorption, unlike the electroneutral process mediated by thiazide-sensitive NCC in the distal tubule, creates electronegativity within the lumen.^7,10 Furthermore, the activity of the basolateral Na/K ATPase, drawing sodium into the interstitium, increases the intracellular potassium concentration. The lumen’s electronegativity then drives potassium secretion into the lumen via the renal outer medullary K (ROMK) channels. Thus, NCC and ENaC activations result in different effects and ion absorption patterns. The greater the expression of ENaC in the epithelial channel, the higher the potassium secretion, primarily regulated by aldosterone produced in the zona glomerulosa cells via the CYP11β2 enzyme. Activation of AT1 receptors by angiotensin II (Ag II) is a key regulator of the transcription of the CYP11β2 enzyme complex. This mechanism is distinct from the activation of the CYP11β1 enzyme complex in the zona fasciculata cells by adrenocorticotropic hormone (ACTH). The aldosterone produced binds to mineralocorticoid receptors in principal cells, inducing ENaC production and leading to sodium absorption followed by potassium secretion.

Aldosterone’s Bimodal Action

Aldosterone production and its mode of action are 2-fold, meaning it can be stimulated in 2 ways: firstly, in response to hypovolemia through the activation of the RAAS cascade triggered by released renin, and secondly, through the direct stimulation by hyperkalemia.⁸ These differing modes of stimulation reflect in their effects because the body is programmed to respond differently to hyperkalemia and hypovolemia. In the case of hyperkalemia, activation of ENaC in the cortical collecting tubules should take precedence, which has a lower potential for sodium retention but facilitates potassium secretion. Conversely, during hypovolemia, activating the distal tubule’s NCC channels, which have a higher sodium retention capacity without causing a significant shift in ion balance, would be more rational. Indeed, in the presence of hyperkalemia, NCC channels should be somewhat inhibited to ensure a high luminal sodium concentration is available for ENaC absorption, as potent sodium absorption by NCC would prevent ENaC from effectively absorbing sodium and secreting potassium. However, this presents another dilemma, as aldosterone activates both systems.¹¹ As simplified and illustrated in Figure 2, certain proteins and factors within tubular cells come into play to enable fine-tuning. Notably, the long isoform of WNK1 (L-WNK1), WNK3, WNK4, and the kidney-specific WNK (KS-WNK) of the WNK kinase family, along with the regulatory proteins SPAK, SGK1, and OSR1, orchestrate the activation of NCC and ENaC through phosphorylation processes.^12-15

Low potassium induces L-WNK1 production and an increase in the L-WNK1/KS-WNK ratio will activate NCC via Ste20 proline-alanine rich kinase (SPAK), leading to electroneutral sodium reabsorption.¹⁶ This reduces sodium delivery to the connecting tubule, providing less substrate for ENaC. Conversely, WNK4 inhibits NCC’s movement to the plasma membrane, leading to its degradation.¹⁷ WNK3 and WNK1 act similarly, although WNK3 is more susceptible to inhibition by WNK4. WNK1 suppresses WNK4, presenting 2 patterns: WNK4 dominance versus WNK1-3 dominance.¹⁸ In Xenopus oocytes, the NCC activation by L-WNK1/SPAK was not observed, but the alleviation of WNK4-mediated inhibition was confirmed on both ends.¹⁴ Thus, in environments where L-WNK1 is dominant, NCC activation occurs. When L-WNK1 is inactive due to high potassium levels and cannot inhibit WNK4, WNK4 then inhibits WNK3 and leads to NCC degradation, increasing sodium delivery to the connecting tubules. Under these conditions, ROMK channels, also inhibited by WNK1 in high potassium settings, facilitate potassium secretion as ENaC enhances sodium absorption.

While the predominant outcome of WNK4’s activity is the inhibition of NCC, angiotensin II can transform WNK4 into an activator of NCC, thereby promoting sodium reabsorption more proximally in the nephron and increasing dependency on NCC.^11,19 This means that angiotensin II can directly stimulate NCC, enhancing sodium reabsorption independently of aldosterone, an effect observed even in organisms without adrenal glands.²⁰ Na–Cl cotransporter-driven sodium reabsorption is more potent than that mediated by ENaC, especially during hypovolemia. Conversely, under a high potassium load without hypovolemia or angiotensin II, aldosterone stimuli will induce ENaC via SGK1, shifting sodium reabsorption to the less potent distal connecting tubules with potassium secretion.²¹ This shift causes relative sodium loss and aids blood pressure control, indicating a potassium-rich diet directs sodium reabsorption from the distal tubules to the connecting tubules.

In familial hyperkalemic hypertension, mutations in the WNK family or its pathways, increased WNK1/KS-WNK ratios, and inhibition of WNK4 leads to NCC activation and electroneutral salt absorption.²² Potassium cannot be secreted due to the low sodium availability for ENaC, leading to less proton secretion. Conversely, intercalated cells absorb protons in exchange for potassium, causing metabolic acidosis.⁷ In this disorder, the body behaves as if it is constantly under a hypovolemia threat. This clinical syndrome, known as Gordon’s syndrome, is characterized by hyperkalemia, metabolic alkalosis, and hypertension.^23,24 It is noteworthy that most familial hypertension syndromes are associated with hypokalemia and metabolic alkalosis, highlighting the dramatic difference that a simple shift from ENaC-mediated sodium reabsorption in the connecting tubule to NCC-mediated sodium reabsorption in the distal tubule can cause in sodium reabsorption physiology.

Augmented Sodium Ion Reabsorption via Overactive Channels

Alterations in Steroid Synthesis or Receptor Affinity

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) encompasses a spectrum of enzyme deficiency syndromes that interrupt the steroidogenesis process, necessitating distinct enzyme catalyzation for the synthesis of 3 different groups of steroid hormones (Figure 3). These deficiencies are typically associated with increased corticotropin (ACTH) stimulation due to the absence of negative feedback inhibition, leading to adrenal gland hyperplasia. Two specific forms of CAH that are linked to hypokalemic hypertension are the deficiencies of the enzymes 11β-hydroxylase (type IV CAH) and 17α-hydroxylase (type V CAH).⁴⁰

In the case of 11β-hydroxylase deficiency, the absence of enzyme activity prevents the production of corticosterone and cortisol, leading to the accumulation of 11-DOC, a precursor with mineralocorticoid activity.^41,42 Accumulated precursors will be directed to adrenal sex steroid production pathway. This results in a clinical profile characterized by hypokalemia and hypertension due to the action of DOC, alongside precocious puberty and virilization caused by the secretion of adrenal androgens.⁴² The primary androgens that accumulate are androstenedione and dehydroepiandrosterone (DHEA), which serve as key markers for laboratory confirmation.⁴³ Given that the predominant trigger is ACTH stimulation resulting from the absence of cortisol’s inhibitory feedback, treatment primarily involves administering the minimal yet effective doses of glucocorticoids.

In contrast, 17α-hydroxylase deficiency blocks the production of cortisol and adrenal sex steroids, redirecting steroid synthesis towards aldosterone. This enzyme deficiency similarly leads to increased ACTH, resulting in adrenal hyperplasia and a clinical presentation that includes ambiguous genitalia in males, delayed sexual development in females, and hypokalemic hypertension.⁴⁰ Unlike with 11β-hydroxylase deficiency, levels of DHEA will be reduced, and stimulation by ACTH will lead to increased production of pregnenolone and progesterone, without elevating 17α-progesterone or 17α-pregnenolone. The therapeutic approach should encompass glucocorticoids to suppress ACTH and include replacement therapy for sex hormones.⁴⁴

Geller Syndrome

Geller syndrome is characterized by a gain-of-function mutation in the mineralocorticoid receptor that increases its affinity for non-mineralocorticoid steroids, including cortisone and progesterone, particularly notable during pregnancy, which can induce hypokalemia and hypertension.^45,46 Like other gain-of-function mutations, Geller syndrome is inherited in an autosomal dominant manner, making the mutant receptor susceptible to activation by other steroids, especially progesterone. Patients with this syndrome typically present with intractable hypokalemia and hypertension during pregnancy, although the onset of hypertension may precede pregnancy. As a type of low-renin, low-aldosterone monogenic hypertension, management strategies include strict dietary salt restriction for blood pressure control and supplementation of electrolytes in severe cases. However, post pregnancy, the hypertension, metabolic alkalosis, and hypokalemia generally resolve spontaneously.⁴⁷ Outside of pregnancy, the optimal management of Geller syndrome has yet to be clearly defined but may involve conventional antihypertensive drugs, with a cautionary note against the use of spironolactone, a steroidal drug, due to its potential to aggravate hypertension.⁴⁸

Chrousos Syndrome

Familial or sporadic glucocorticoid resistance, also known as Chrousos syndrome, arises from mutations in the glucocorticoid receptor gene, leading to reduced effectiveness of cortisol in tissues.^49,50 This resistance in the pituitary gland causes increases in ACTH, cortisol, adrenal androgens, and deoxycorticosterone levels. Symptoms of this glucocorticoid effect deficiency can range from non-existent to chronic fatigue, as elevated cortisol levels might still support somewhat normal glucocorticoid activity in tissues. The severity of resistance often reflects the clinical presentation, including possible hyperandrogenism or mineralocorticoid excess.

Differential diagnosis relies on measuring 24-hour urinary free cortisol over consecutive days, revealing elevated levels without typical hypercortisolism signs.⁵¹ The degree of cortisol and androgen increase, alongside urinary cortisol excretion, indicates the glucocorticoid signal transduction impairment severity. Plasma ACTH levels may vary from normal to high. After initial evaluation, diagnostic procedures should include testing HPA axis responsiveness to dexamethasone.⁵¹ Higher-than-normal dexamethasone doses may be necessary to achieve a 50% reduction in serum cortisol levels compared to healthy individuals.

Treatment for Chrousos syndrome aims to curb excess ACTH and adrenal steroid production. This involves high doses of mineralocorticoid-sparing glucocorticoids, like dexamethasone, taken nightly to reduce ACTH secretion and prevent potential development of pituitary and adrenal adenomas.

Excess Mneralocorticoid Synthesis

This category of monogenic hypertension is marked by excessive aldosterone production resulting from pathogenic gene rearrangements or germline mutations, inherited through Mendelian patterns, commonly known as “familial hyperaldosteronism.” The 4 types of familial hyperaldosteronism disorders, inherited in an autosomal dominant manner, fall under the low-renin, high-aldosterone form of monogenic hypertension. Consequently, their laboratory profiles mimic those of primary hyperaldosteronism, necessitating differentiation from it.

Familial Hyperaldosteronism Type I or Glucocorticoid-Remediable Aldosteronism

To understand the topic comprehensively, the physiology of adrenal cortex ought to be summarized. Three adrenal cortex layers are subspecialized to produce steroid hormones with distinct properties (Figure 3). The outermost layer, the zona glomerulosa, utilizes the enzyme CYP11B2, also known as aldosterone synthase, for aldosterone production. 11β-hydroxylation is required in both layers, zona glomerulosa and zona fasciculata to convert deoxycorticosterone to corticosterone and 11-deoxycortisol to cortisol, respectively. In zona glomerulosa, CYP11B2 catalyzes the sequential hydroxylation of the steroid methyl group at C18 (18-hydroxylation) following initial 11β-hydroxylation, triggered by angiotensin II-induced transcription factors or elevated potassium levels. Although CYP11B2 and CYP11B1 share 93% homology and are located on the same chromosome, CYP11B2 does not strongly respond to corticotropin (ACTH). So, ACTH-sensitive steroidogenesis occurs in zona fasciculata, culminating in cortisol production. Unique to individuals with glucocorticoid remediable aldosteronism (GRA) is a mutation where the promoter region of CYP11B1 and the coding sequences of CYP11B2 are fused due to an unequal crossover event.^52,53 This fusion leads to the ACTH-dependent activation of aldosterone synthase, transforming the zona fasciculata into a layer that also produces aldosterone. Moreover, within the zona fasciculata, cortisol can be processed by CYP11B2, resulting in the creation of distinct cortisol derivatives (18-oxocortisol and 18-hydroxycortisol).^54,55 Measuring these specific cortisol products serves as an effective diagnostic tool for identifying GRA. An additional notable aspect of aldosterone production in this context is its insensitivity to potassium, normally a potent stimulant for CYP11B2.⁵⁶

Glucocorticoid-Remediable Aldosteronism is inherited in an autosomal dominant manner and appears to be the most common monogenic form of hypertension in humans.⁵⁷ The diagnostic challenge arises because routine lab tests, such as plasma renin activity and aldosterone levels, do not distinguish GRA from primary hyperaldosteronism. Clues that should prompt a clinician’s suspicion include the patient’s age and family history, as diagnosing GRA relies on a low threshold of suspicion. While hypokalemia might be anticipated, it is not consistently present in all cases, possibly due to the circadian rhythm of ACTH release.^56,58,59 Therefore, hypokalemia should not be considered a strong indicator of GRA, although significant hypokalemia following the administration of a thiazide diuretic is expected. More specific signs include dexamethasone suppressible hyperaldosteronism and increased levels of urinary 18-oxocortisol and 18-hydroxycortisol. Nonetheless, identifying the chimeric gene through genetic testing has emerged as the diagnostic gold standard, largely replacing the need for biochemical testing.⁶⁰

Published data indicate an unusually high rate of early cerebrovascular complications in GRA patients, particularly hemorrhagic strokes resulting from aneurysm rupture, with the mean age at the first event being 32 years.⁶¹ Thus, a family history of early hemorrhagic strokes, occurring before the age of 40, serves as another diagnostic clue, although this is not exclusive to GRA and can also be observed in Liddle’s syndrome. Consequently, it has been proposed that GRA patients should be screened using magnetic resonance angiography.⁶²

The treatment approach for GRA should be constructed on its underlying pathophysiology. Administering low-dose steroids can efficiently inhibit ACTH release, thereby correcting the excess aldosterone production.⁶² Taking the smallest effective amount of prednisone before sleep is aimed at countering the early morning rise in ACTH. Yet, the prolonged administration of even minimal doses of prednisone might not be suitable for children. For these patients, mineralocorticoid receptor antagonists provide a viable alternative. These drugs preserve the pituitary-adrenal axis’s function and respect the body’s natural ACTH rhythm, effectively controlling both hypertension and hypokalemia, if it exists.⁶³

Familial Hyperaldosteronism Type II

Familial hyperaldosteronism type II (FHT-II) shares some similarities with GRA in terms of lacking feedback control and exhibiting low-renin plasma activity. However, FHT-II’s mutation is not related to ACTH or any tropic hormones but is identified by a gain-of-function mutation in the CLCN2 gene, which encodes a voltage-gated chloride channel expressed in adrenal glomerulosa.⁶⁴ This mutation leads to hyper-depolarization, thereby promoting aldosterone synthase activity in zona glomerulosa cells.

Differing from GRA, FHT-II does not respond to dexamethasone suppression. This condition often correlates with bilateral adrenocortical adenomas due to the continuous activation of adrenocortical cells. Diagnosis relies heavily on clinical suspicion, particularly in individuals with a family history of early-onset hypertension and adrenal disorders (like bilateral adenomas), though biochemical tests may not offer definitive insights as FHT-II presents similarly to primary hyperaldosteronism. Genetic testing for the CLCN2 mutation may aid in diagnosis, with treatment options including mineralocorticoid receptor antagonists or unilateral adrenalectomy.

Familial Hyperaldosteronism Type III

Familial hyperaldosteronism type III (FHT-III), akin to FHT-II, results from gain-of-function mutations in the KCNJ5 gene, which encodes a potassium channel.^65,66 Disease-causing variants lose their ionic selectivity, leading to constant depolarization and subsequent aldosterone synthase activity. Similar to FHT-II, aldosterone levels are not suppressed by dexamethasone, and the treatment approach for FHT-III mirrors that of FHT-II. However, managing the excessive aldosterone production can be particularly challenging in FHT-III, as patients with KCNJ5 germline mutations often experience severe hyperaldosteronism and significant adrenal hyperplasia. In some instances, bilateral adrenalectomy may become necessary to effectively address the condition.^65,67

Familial Hyperaldosteronism Type IV

Familial hyperaldosteronism type IV (FHT-IV) is attributed to gain-of-function mutations in the CACNA1H gene, responsible for encoding a transiently opening calcium channel located in the zona glomerulosa.⁶⁸ These mutations render the channel more likely to open under baseline electrochemical conditions, causing an increased influx of calcium ions and thus stimulating aldosterone synthesis. The treatment strategy for FHT-IV is similar to that applied in FHT-II and FHT-III.

Conclusion

Mendelian forms of RAAS-related hypertension are also considered a group of rare diseases, making their diagnosis complex and demanding a blend of expertise, experience, and clinical insight. Despite each condition’s unique features, they share commonalities, such as significant hypertension onset before age 30, particularly among individuals with low renin levels, a familial history of monogenic hypertension disorders like multiple endocrine neoplasia or glucocorticoid-remediable aldosteronism, hypertension with accompanying hypokalemia in the patient or family, or a history of early-onset hemorrhagic stroke in a relative. Signs of abnormal sexual development or physical indications of associated syndromes also call for thorough evaluation. Initial diagnosis typically involves confirming low renin activity and assessing serum pH, potassium, and aldosterone levels. Targeted next-generation sequencing for specific gene analysis is recommended for precise genetic diagnosis, whereas broad, nonspecific gene testing is inefficient and impractical. A structured and targeted approach, as illustrated in Figure 4, enables timely and accurate diagnosis. Considering that most monogenic hypertension can be effectively managed with targeted therapies, such as specific channel blockers or low-dose corticosteroids, and the potential for serious complications, including cerebrovascular events and mortality, it is crucial to avoid delays in precise diagnosis.

Research into monogenic forms of hypertension has also revealed new molecular pathways that govern blood pressure and electrolyte balance. This knowledge not only aids in the development of novel hypertension treatments but also facilitates the classification of hypertension subgroups based on genotype–phenotype correlations. Additionally, it has enriched our understanding of tubular physiology and the actions of adrenal cortex hormones. Future advancements in hypertension management are anticipated to be more tailored, thanks to a more profound comprehension of kidney-related blood pressure regulation mechanisms.

Footnotes

Peer-review: Externally peer-reviewed.

Declaration of Interests: The author have no conflicts of interest to declare.

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