**1. Introduction**

The renin–angiotensin–aldosterone system plays a crucial role in volume, sodium, and potassium homeostasis. When renal hypofiltration is sensed, this hormonal system is activated via the secretion of renin, which catalyzes the generation of angiotensin I that is subsequently modified to generate angiotensin II. The potent vasoconstrictive properties of angiotensin II, in addition to its ability to stimulate the release of vasopressin and adrenal aldosterone secretion, help maintain arterial blood pressure and restoration of intravascular volume. Thus, physiologic activation of the renin–angiotensin–aldosterone system is characterized as a renin-dependent aldosteronism and serves to maintain blood pressure and volume in terrestrial mammals that evolved in a milieu of scarce dietary sodium intake. Despite this highly evolved physiology, low-renin hypertension (LRH) is currently a prevalent biochemical phenotype described in up to 30% of hypertensives, depending on age and race [1,2]. LRH is characterized by the physiologic suppression of renin, often in the context of intravascular volume expansion; however, there are many potential pathophysiological events that can result in hypertension with a low-renin phenotype that will be discussed in this review.

LRH has been described and investigated for nearly 50 years [3,4]. Shortly after Jerome Conn first described primary aldosteronism as a condition of aldosterone excess independent of renin [5], a phenotype of low renin activity in hypertension without overt hyperaldosteronism was described [3,4]. This phenotype was considered unique from primary aldosteronism and termed LRH, and subsequent studies described it as a condition more prevalent in individuals of African descent and elderly populations, who are also prone to salt-sensitive hypertension [6]. In subsequent decades, it was speculated that LRH might represent a heterogeneous mixture of etiologies that could include

states of excessive mineralocorticoid receptor (MR) activation, as initially supported by LRH subjects manifesting low salivary sodium-to-potassium ratios and marked decreases in blood pressure in response to spironolactone and aminoglutethimide (an adrenocortical steroid synthesis inhibitor) [7–9].

The potential role of MR activation in LRH is important, since LRH and primary aldosteronism are similarly associated with higher risk for cardiometabolic events and death [10,11], and the availability of oral MR antagonists permits a potential targeted therapy. Further, the LRH phenotype displays familial aggregation, where several polymorphisms and novel genes have been described [12]. In one study, family membership explained 35% of variance in renin levels, far beyond the classic low frequency monogenic causes [12]. The composite of evidence suggests that the LRH is likely a heterogeneous admixture of disease states that all converge on a phenotype of suppressed renin activity and high blood pressure. These disease states include primary aldosteronism (PA), as well as conditions that manifest with low aldosterone levels, such as endogenous hypercortisolism, the syndrome of apparent mineralocorticoid excess (AME), atypical forms of congenital adrenal hyperplasia, and alterations in the activity of the mineralocorticoid receptor or epithelial sodium channel (Liddle syndrome). Consistent with this differential diagnosis, LRH has been shown to exhibit a bimodal distribution of aldosterone levels in population-based studies, supporting the existence of two broad categories of LRH: those with suppressed aldosterone and those with normal or elevated aldosterone [13]. New evidence suggests that beyond these general etiologic categorizations, diseases such as PA, hypercortisolism, AME, and perhaps even Liddle syndrome, may exist across a phenotypic continuum that extends from their overt and "classical" presentations to milder and "non-classical" phenotypes; the recognition of these expanding phenotypic continuums may improve our understanding of the pathogenesis and treatment of LRH and essential hypertension. Finally, environmental and nutritional factors, such as obesity, diabetes, and especially high dietary sodium intake, also play an important role in the development of the LRH phenotype. Putative mechanisms for these links include, new MR interactions, such as ligand independent activation of MR by sodium-RAC1 [14] and epigenetic modifications of LRH-related genes by DNA methylation (e.g., *HSD11B2* or adducin gene), histone modifications (e.g., epithelial sodium channel gene) or noncoding RNA (e.g., renin-angiotensin-aldosterone pathway genes) [15].

Herein, we will review known conditions that manifest with a phenotype of LRH, while focusing especially on postulated genetic mechanisms and the role of excessive MR activation.
