**5. Congenital Adrenal Hyperplasia**

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders caused by mutations in genes involved in cortisol biosynthesis enzymes. More than 90% of described cases of CAH are 21-hydroxylase deficiency. Less common, and pertinent to the LRH phenotype, are CAH syndromes due to 11β-hydroxylase [P450c11β] and 17α-hydroxylase [P450c17] deficiency.

CAH caused by steroid 11β-hydroxylase deficiency is considered a rare recessive disorder, with an overall frequency of 1/100,000 live births. Unlike 21-hydroxylase CAH that is more frequent in Europe and North America, 11β-hydroxylase deficiency is more frequently described in the Middle East and Africa [70]. The gene *CYP11B1* encodes 11β-hydroxylase that catalyzes the conversion of 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone in the zona fasciculata. Thus, from a clinical perspective, deficiency of 11β-hydroxylase, results in low levels of cortisol and high levels of 11-deoxycortisol and 11-deoxycorticosterone (DOC) and a shunting of metabolites into the androgen synthesis pathway. Depending on the severity of the mutations and 11β-hydroxylase deficiency, patients may present with signs of hyperandrogenism (masculinization of genitalia, hirsutism, premature bone maturation and precocious puberty) and excessive MR activation due to increased DOC (hypertension and hypokalemia) [70]. The increased activation of the MR leads to sodium reabsorption, increased intravascular volume expansion, and consequently LRH. The diagnosis can be confirmed via elevated DOC and androgen levels (with or without cosyntropin stimulation) and/or genetic sequencing of 11β-hydroxylase. Treatment involves the use of MR antagonists in addition to glucocorticoids in order to suppress ACTH.

17α-hydroxylase deficiency is another rare form of CAH and results as a consequence of inactivating mutations in the *CYP17A1* gene that regulates steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most common presentation of 17α-hydroxylase deficiency is an adolescent female with absence of secondary sexual characteristics, amenorrhea, and LRH [71]. The 17α-hydroxylase deficiency phenotype is explained by impaired steroidogenesis in both the adrenals and the gonads: abnormal cortisol synthesis, elevation of DOC and resultant MR-mediated LRH, and impaired sex-steroid synthesis. These patients typically display low cortisol, but high levels of corticosterone, so adrenal crises are rarelyobserved. LRH is due to high levels of DOC that result in MR activation, hypertension, and hypokalemia [72], and treatment involves MR antagonists to normalize blood pressure and replacement of sex steroids [72].

#### **6. Liddle Syndrome**

The Liddle syndrome is a rare autosomal dominant monogenic disease caused by gain-of-function mutations of subunits of the epithelial sodium channel (ENaC). Since increased luminal ENaC in the distal nephron is the common final mechanism for MR-mediated sodium reabsorption, Liddle syndrome resembles states of mineralocorticoid excess. The classical clinical presentation is severe hypertension in a young patient, with hypokalemia and metabolic alkalosis, in the setting of suppressed renin; however, unlike PA, aldosterone levels are low or undetectable and the syndrome does not improve with MR antagonist therapy [73–76]. The diagnosis of Liddle syndrome can be confirmed by genetic sequencing of the *SCNN1B* and *SCNN1G* genes, which encode for the β and γ subunits of ENaC [75], or the *SCNN1A* gene [77], and the treatment of choice are ENaC inhibitors such as amiloride or triamterene [74].

In a similar theme to the aforementioned discussions on PA, hypercortisolism, and AME, Liddle syndrome may exist across a more extensive spectrum than currently recognized. "Classical" Liddle syndrome is rare and manifests with a severe phenotype; however, recent studies have suggested that a substantial proportion of LRH patients also have a low serum aldosterone [13,24]. Although there are potentially many mechanistic explanations for a phenotype of hypertension with low renin and aldosterone, a recent clinical trial demonstrated that treating African patients with a low-renin and aldosterone phenotype using ENaC inhibitors resulted in the most effective control of blood pressure [78], a finding that extended genetic studies demonstrating a high prevalence of *SCNN1B* variants in individuals of African descent with LRH [79].

#### **7. Glucocorticoid Resistance Syndrome**

Inactivating mutations of the glucocorticoid receptor gene (*NR3C1*) in chromosome 5q31–q32 cause familial glucocorticoid resistance [80–82]. All severe described cases are secondary to mutations that affect the function of either the ligand binding or the DNA binding domain. This is a rare syndrome, inherited either as an autosomal recessive or dominant disease, that is characterized by the classical biochemical pattern seen in endocrine receptor resistance syndromes: hypercortisolism and increased ACTH but without the classic clinical features of Cushing's syndrome [81]. Although the increased ACTH and cortisol are necessary to try and overcome glucocorticoid receptor resistance, the undesired effects are ACTH-induced hypersecretion of adrenal mineralocorticoids and androgens, and hypercortisolism-mediated renal-MR activation. Thus, the classic phenotype of glucocorticoid resistance is LRH, hypokalemia, hirsutism in females, alopecia in males, acne, precocious puberty and menstrual irregularities, in addition to chronic fatigue and malaise as a consequence of relative glucocorticoid deficiency [83]. The treatment is usually overnight low dose dexamethasone to suppress ACTH, and thus improving ACTH-induced hypercortisolism, excess mineralocorticoids, and hyperandrogenism. The addition of spironolactone can further help to control hypertension and hirsutism in females as well. Interestingly, haploinsufficiency of the GR receptor can also present with LRH due to MR activation by elevated cortisol rather than increased DOC as observed in classical glucocorticoid resistance [84].

#### **8. Gordon Syndrome**

Gordon Syndrome (GS) was described in the 1960s and is a very rare familial hypertension syndrome that presents with low renin and hyperkalemia. GS is considered to have autosomal dominant inheritance, although new molecular studies suggest some recessive cases [85]. Mutations in *WNK1*, *WNK4*, *CUL3* and *KLHL3* genes have all been identified in GS [85], due their interaction with the thiazide sensitive Na/Cl cotransporter (NCC) in the distal nephron, responsible for sodium reabsorption, but also reducing cell-surface expression of renal outer medullary potassium channel (ROMK), explaining the lower potassium excretion in the collecting ducts [86].

Subjects with GS have suppressed renin levels consistent with their high volume state, with relatively low aldosterone levels (that may still fall in the reference range) despite their hyperkalemia, that can be occasionally severe and with periodic paralysis [86]. Both hypertension and hyperkalemia can be reversed by dietary sodium restriction and/or low doses of thiazide diuretics.

#### **9. MR Activating Mutations**

This is a novel entity secondary to a gain of function mutation, by a substitution of leucine for serine at codon 810 (abbreviated as S810L), in the MR gene. The S810L mutation was recently described and is responsible for an MR-mediated LRH that has also been described as worsening during pregnancy [87]. The worsening in pregnancy is explained by the activation of the mutant S810L MR by progesterone, where progesterone typically antagonizes wild-type MR. In males and non-pregnant females, cortisone and 11-dehydrocorticosterone (cortisol and corticosterone metabolites respectively) can activate the mutant MR and result in increased sodium reabsorption [87]. Spironolactone is surprisingly ineffective since it has agonist properties on the mutant MR and can paradoxically increase MR activation [88]. Recently, Amazit et al. described that in addition to amiloride to inhibit ENaC, the novel and potent nonsteroidal selective MR antagonist finerenone has MR antagonistic properties and may therefore represent a useful treatment option [89].

#### **10. Proposed Approach to the Patient with Low-Renin Hypertension**

Prior to considering an elaborate differential diagnosis for LRH, it is important to confirm the phenotype. First, factors than can reversibly suppress renin include, increased intra-vascular volume, certain medications (see below), supine posture, menstrual phase and high dietary sodium intake, and therefore must all be considered [16,90,91]. The diagnosis of LRH inherently assumes a chronic phenotype, and therefore, it is important to ensure that a single measure of low renin was not induced by a confounding or transient factor. Second, it is important that renin levels are measured in a reliable laboratory using a validated technique. Renin activity assays are increasingly being measured via LC-MS/MS and the global forecast suggests that commercial renin activity assays may be largely replaced by assays of renin concentration [92]. To avoid misinterpretation, the most ideal confirmation of LRH entails measurement of renin in a seated posture, while on unrestricted dietary sodium intake, during the follicular phase of the menstrual cycle (in women), and ideally without the confounding effects of MR antagonists, β-blockers, diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers [16,18,93]. Although most patients in industrialized countries consume sufficient sodium to maintain a dietary sodium balance of greater than 100–150 mmol/24 h, it has been shown that severe dietary sodium restriction (<40 mmol/24 h) can raise renin even among patients with overt PA; thus, emphasizing the importance of recommending unrestricted dietary sodium intake when phenotyping renin status, and consideration of confirming 24 h urinary sodium balance [94].

The exact definition of what constitutes low renin is not well established. Suppression of renin below the limit of detection is probably the most commonly used definition, however, in non-clinical research settings, more elaborate physiological maneuvers have been employed to characterize a phenotype of low renin or a renin that does not adequately stimulate to physiological provocation [4,27,94–96]. Once there is confidence that the phenotype represents LRH, the examination of aldosterone levels in the context of renin suppression can provide insight into potential underlying mechanisms of disease (Figure 1). An inappropriately high aldosterone level narrows the differential diagnosis to PA. The most severely elevated aldosterone levels (>15–20 ng/dL) require little confirmation, and similarly, even levels > 10 ng/dL are highly suggestive among patients with LRH that can be confirmed using a variety of confirmatory tests (sodium or fludrocortisone suppression or captopril challenge). However, milder forms of PA are common and may not exhibit marked elevations in aldosterone or blood pressure [22–25], and therefore, these non-classical instances of PA may represent missed opportunities at mitigating the age-dependent cardiometabolic consequences of autonomous aldosterone secretion [10,11]. Future studies, and a renewed commitment to better

understanding the true prevalence and severity spectrum of PA, will be needed to identify new and efficient methods for identifying non-classical PA, including novel biomarkers of MR activation [97].

**Figure 1.** A proposed approach to the patient with low-renin hypertension. ENaC = epithelial sodium channel; 11-βHSD2 = 11-β hydroxysteroid dehydrogenase type 2; 11β-OH = 11-β hydroxylase; 17α-OH = 17-α hydroxylase.

A phenotype of LRH whereby aldosterone levels are clearly suppressed or very low generates a broad consideration of underlying mechanisms. Acquired or non-genetic etiologies include essential (or idiopathic) hypertension in the context of high dietary sodium intake, as well as severe hypercortisolism or reversible inhibition of 11BHSD2 (Figure 1). The classical genetic syndromes that result in a low renin and aldosterone phenotype are rare, and include classical AME, activating mutations in the MR or ENaC (Liddle syndrome), atypical forms of CAH, Gordon syndrome, and glucocorticoid resistance syndrome. The default explanation for LRH with low aldosterone, once these infrequent and classical diseases have been excluded, is essential hypertension with high dietary sodium consumption.

Finally, a great deal of progress has been made in identifying "non-classical" phenotypes that represent a milder continuum of classical disease states. These non-classical conditions should be considered when aldosterone levels are normal or not in the extremes: neither markedly elevated nor remarkably suppressed. Mild and moderate variants of PA, hypercortisolism, AME, and potentially even Liddle's syndrome, may be common and the early recognition and treatment of these phenotypes may prevent years of untreated hypertension and cardiovascular risk. Gordon's syndrome may also present with this phenotype. MR antagonists have already been shown to be the most effective add-on therapy in low-renin resistant hypertension [98], however, the adoption of MR antagonists as effective anti-hypertensives that can be used early in the treatment of hypertension using a renin- and aldosterone-based phenotyping approach has not been evaluated with sufficient evidence for widespread recommendation. Non-classical PA, hypercortisolism, and non-classical AME may all potentially respond well to MR antagonists, and therefore, future studies are needed to evaluate the efficacy of early initiation of MR antagonists in the treatment of LRH to formulate evidence-based clinical practice recommendations.

**Acknowledgments:** Rene Baudrand was funded by Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) 1150327, 1150437, 1160836, 1160695, and Corporacion de Fomento de la Produccion de Chile (CORFO) 13CTI-21 526-P1. Anand Vaidya supported by the National Institutes of Diabetes and Digesttive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award number R01DK107407, by grant 2015085 from the Doris Duke Charitable Foundation.

**Conflicts of Interest:** The authors declare no conflict of interest.
