Primary aldosteronism and low-renin hypertension: a continuum?

Primary aldosteronism (PA) was first described by Jerome Conn almost 60 years ago, and is thus sometimes called Conn’s syndrome. Although Conn believed that PA may constitute 20% of all hypertension, within a decade of his initial findings, it was thought (and taught) that PA was relatively benign, accounted for <1% of hypertension, with hypokalaemia required for diagnosis, none of which we now know to be the case. PA is now recognized as causing ∼10% of hypertension, frequently occurring with normokalaemia, and to carry a much higher level of cardiovascular risk—atrial fibrillation, non-fatal myocardial infarction and stroke—than age, sex and blood pressure (BP)-matched essential hypertensives [1]. The radically revised figure for the prevalence of PA reflects the currently widely accepted use of the plasma aldosterone to renin ratio (ARR) for potential case detection. If a patient has low levels of plasma renin activity (PRA: reflecting generation of angiotensin II from endogenous angiotensinogen) or of plasma renin concentration per se, coupled with a plasma aldosterone concentration (PAC) in the upper levels of the normal range or higher, they are candidates for the diagnosis of PA. PA is thus defined as inappropriate aldosterone secretion despite suppressed levels of renin plus normal or low levels of plasma [K + ], the two major stimuli of aldosterone secretion. Although the definition of a cut-off for normal versus elevated ARR varies between laboratories, most find ∼20% of hypertensives to have a raised ARR, of whom approximately half have PA as confirmed by subsequent testing, commonly involving PAC being less than normally responsive to acute sodium loading, or other tests (captopril challenge, fludrocortisone suppression). While levels of aldosterone in PA rarely equal those found in profound chronic sodium deficiency, the clinical picture differs markedly between the two. In sodium deficiency, the elevated PAC is homeostatic, to maximize epithelial sodium retention, and BP is low normal; in PA, the elevated PAC causes inappropriately high epithelial sodium retention and volume expansion. The vascular wall is a physiological target tissue for aldosterone, with the high PAC in sodium deficiency serving to maintain the vascular tone in the face of a reduced circulating volume; in PA, the elevated PAC is inappropriately vasoconstrictor, in the face of the expanded plasma volume. Taken together, the epithelial and vascular actions of inappropriately elevated aldosterone levels in PA provide a cogent explanation of the resultant BP elevation. This contrasts with low-renin hypertension (LRH), in which renin is suppressed (as is the case for PA), but PAC levels are apparently normal. This appears to be the case for ∼30% of hypertensives; given that renin is secreted in response to sympathetic stimulation, the elevated BP prima facie appears not to reflect increased systemic sympathetic overactivity; low renin rules out direct effects of angiotensin on sodium retention or vascular tone, as similarly do the apparently normal levels of PAC. In contrast with PA, then, LRH is a description of rather than a mechanism-based diagnosis for the observed BP elevation.