Low-renin and nonmodulating essential hypertension.

Low-renin hypertension (LREH) accounts for an important subset of the hypertensive human population and is associated with salt-sensitivity and diuretic response and is also common in black patients. An interesting finding in LREH is the presence of normal plasma aldosterone levels.1,2 The ratio of plasma aldosterone to renin activity is used to screen for adrenal adenomas and hyperplasia3 and is usually .100 when plasma renin activity is expressed in ng/mL/hr and the aldosterone concentration is expressed in ng/dL. The plasma aldosterone/plasma renin activity ratios may be somewhat elevated in LREH (.30 but ,100), which is especially relevant if the concurrent urinary sodium excretion exceeds 200 mEq/24 hours.4 It is not known what regulates aldosterone secretion in this setting or whether there is actual mineralocorticoid excess. Undue prior emphasis may have been placed on the continued suppression of plasma renin activity during severe salt restriction or volume depletion in LREH,1 and the suppression of plasma renin activity and basal aldosterone secretion5 in the elderly can also confound the analysis of LREH. Studies by Fisher et al2 focus on adrenal and pressor responsiveness to angiotensin II (Ang II) as a function of dietary salt intake in patients with LREH, normal-renin hypertension, and normal controls. Especially striking are the functional similarities between LREH and “ nonmodulating” essential hypertension with normal plasma renin activity (NMEH), including: (1) salt-sensitivity of the blood pressure; (2) blunted plasma aldosterone responses to Ang II infusion and upright posture after 5 days of rigid dietary sodium restriction; and (3) relatively low basal plasma aldosterone levels. These differences compared with normal controls and “modulating” hypertensive subjects disappeared when the dietary salt intake was increased to 200 mEq. The latter results are consistent with suppression of plasma Ang II activity during high-salt intake with resensitization of Ang II receptors and improved Ang II responsiveness. If so, then perhaps the blunted responsiveness to Ang II during sodium restriction could reflect the continuing formation of Ang II, with angiotensin receptor downregulation. Fisher et al2 based the definition of LREH and the Ang II responsiveness on patients who had undergone 5 days of sodium salt restriction (10 mEq/24 hours) rather than “short” protocols with concomitant diuretic administration. It is important to determine if the subjects had actually come into sodium balance because that would affect the interpretation of the basal plasma aldosterone levels. The low basal plasma aldosterone levels in the LREH and NMEH subjects could have reflected relative volume expansion despite the dietary salt restriction. In this regard, at 5 days, the 24-hour urinary sodium excretion rates were slightly (and significantly) higher in these 2 groups compared with the normal controls and normalmodulating hypertensive subjects (See Table 1 in Reference 2). Our understanding of renal tubule transport defects has expanded in the last several years, providing unique insights into epithelial transport processes and clinical syndromes that result from mutations of these transporters.6 A major focus of these studies has been the epithelial sodium channel (ENaC), which is the rate-limiting barrier for regulating sodium absorption in the mineralocorticoidresponsive renal collecting tubule.7 ENaC can be directly affected by mutations or by changes in the response to or production of mineralocorticoids.8,9 As a result, we now have defined Mendelian syndromes in which ENaC activity is “dysregulated” with subsequent development of disorders of systemic blood pressure that can be attributed to a primary renal mechanism. The mutations that directly affect the subunits of the ENaC channel can result in gain of function (Liddle’s syndrome) or loss of function (pseudohypoaldosteronism type 1), with the predictable clinical phenotype in the affected individuals.6 The normal response to dietary salt surfeit is downregulation of ENaC activity so that sodium reabsorption by the collecting tubule is reduced; any impairment in this process would account for dysregulation of ENaC activity, continuing sodium reabsorption, and volume expansion. The original descriptions of genetically-proven Liddle’s syndrome involved whites.10,11 With the re-emphasis of the clinical phenotype,12 it was quickly appreciated that patients of African ancestry could also be defined with severe low renin hypertension and markedly suppressed aldosterone secretion, often with hypokalemic metabolic alkalosis.13 Despite the promise of defining a cause of LREH in this important target population, numerous screening efforts of various ethnic populations have not changed the original view that Liddle’s syndrome, with striking suppression of aldosterone secretion, is a rare cause of human LREH. Although there are polymorphisms in the ENaC subunits that can be associated with enhanced ENaC sensitivity to CAMP14 and/or associated with suppressed The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Nephrology, University of Alabama at Birmingham. Correspondence to David G, Warnock, MD, Professor of Medicine and Physiology Director, Division of Nephrology, University of Alabama at Birmingham, 647 Tinsley Harrison Tower, 1900 University Blvd, Birmingham, AL 35294-0007. E-mail [email protected] (Hypertension. 1999;34:395-397.) © 1999 American Heart Association, Inc.