Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

Abstract

In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extraadrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.

Is it time to screen all patients with hypertension for primary aldosteronism?

“…The low rates of diagnosis are also observed in GP clinics throughout Victoria, ranging from 0.1% to 0.45% of patients with hypertension (survey of ten GP clinics in Victoria, unpublished data). Although a younger age of onset of hypertension and associated hypokalaemia may prompt the clinician to consider a diagnosis of PA, both our clinical experience and previous studies have shown that the average age of onset of PA is 40–50 years and hypokalaemia is only present in 9–37% of patients 4 . Hence, age and potassium levels are not reliable clinical markers of PA.…”

“…Undiagnosed PA leads to poor BP control and increased cardiovascular, renal and metabolic morbidity and mortality related specifically to the effect of aldosterone excess mediated by the mineralocorticoid receptor 4 . Several research groups have independently shown the detrimental impact of mineralocorticoid receptor activation on cardiac inflammation and fibrosis in animal models 12 .…”

“…Active screening of patients newly diagnosed with hypertension is the best way to capture patients with PA early so as to maximise the benefits of treatment and minimise end‐organ damage, while avoiding the confounding effect of commonly used drugs. However, the ARR is not a perfect test and may be affected by restrictive or excessive salt intake, oestrogen status, impaired renal function and ageing 4 , 19 . Its diagnostic sensitivity ranges from 64% to 100% and specificity from 87% to 100%, depending on the assay, cut‐off threshold, pre‐test patient preparation and population characteristics 22 .…”

Computed Tomography and Adrenal Venous Sampling in the Diagnosis of Unilateral Primary Aldosteronism

“…[1][2][3][4][5] The excess aldosterone production that causes the disorder may be unilateral (confined to one adrenal) or bilateral and the 2 forms are preferentially treated by unilateral adrenalectomy or a mineralocorticoid receptor antagonist, respectively. 6,7 Unilateral PA is the most common surgically September 2018 correctable cause of hypertension with a highly variable proportion of patients achieving clinical remission after surgery between centers. [8][9][10] Patients with PA have a widely reported increased risk of prevalent cardiovascular and cerebrovascular complications and target organ damage relative to matched patients with primary hypertension who have otherwise similar cardiovascular risk profiles or compared with the general population with hypertension.…”

Is There a Role for Genomics in the Management of Hypertension?

“…The diagnosis is mainly clinical with subsequent identification of the causal mutation, that however, is not obtained in all cases, indicating that as yet unidentified genes are associated with this condition [24]. To date, mutations of 4 genes have been described: mutations in WNK1 and WNK4 kinases [25], and more recently KLHL3 and CUL3 mutations [26].…”