Plasma renin activity: blood pressure steps or salt-sensitivity slopes – or both?
Year: 2025
Type: article
Abstract: The review of Sealey and Blumenfeld [1] addresses the notorious inconsistencies between results of studies of the effects on arterial blood pressure (BP) of salt intake and antihypertensive medication. Scrutiny of these issues is warranted, but several details, including oversupply of hypotheses, tend to blur a proper perception of the present messages. In the present context, a hypothesis is a testable statement regarding a relationship between measurable variables. The statement may be right or wrong, but suitable for evaluation by data, available or upcoming. The title [1] includes two hypotheses: reactive increases in plasma renin activity (PRA) attenuate the fall in BP caused by (a) salt depletion, and by (b) renin–angiotensin system (RAS) inhibition. Validity of the former is textbook knowledge. The latter is less specific and not immediately testable. The abstract describes two hypotheses. The first is that inconsistencies in the effect of raising or lowering body salt on BP are caused in part by differences in PRA. This is not immediately testable. ‘Body salt’ is ill defined, at least functionally; and measurement of the fraction of total body sodium relevant to BP regulation is next to impossible. Daily sodium intake can be a surrogate variable [2] but is cumbersome to work with properly in the clinic. In addition, ‘differences in PRA’ is a vague expression. The second hypothesis is that PRA levels above 0.65 ng/ml/h lead to sufficient Ang II production to cause vasoconstriction, whereas lower levels do not. This is a clear statement open for testing as long as (i) one has access to a PRA analysis identical to that of the authors, and (ii) vasoconstriction is defined. As also mentioned here [1], specific levels of PRA in ng/ml/hr are not immediately comparable between laboratories (e.g. [3,4]). Reference to commercially available procedures [1], and the present statement [1] that a PRA level of 1 ng/ml/h is roughly equivalent to a PRC of 10 μIU/l do not appear operationally adequate when specific levels are proposed. This requires specific PRA levels in terms of the international standard. Vasoconstriction is a context-dependent term. To many, it means constriction of vessels, but to some – notably clinicians – it is synonymous with a (measurable) BP increase. The review [1] focuses on BP, and apparently ‘vasoconstriction’ here is synonymous with BP change. It would have been helpful had the term been applied unambiguously. Subsequently, the authors focus on the concept that – in normotensive as well as in hypertensive individuals – specific PRA values separate ranges of RAS operation within which the measurable effects of RAS on BP differ. With regard to the normotensive situation, it is stated (a) that PRA levels >0.65 ng/ml/h (opposite to lover levels) cause ‘vasoconstriction’, (b) that (‘high salt’ intake excepted) PRA is usually >0.65 ng/ml/h, and (c) that increases in PRA in this range, therefore, prevent BP from falling during reduction in salt intake. For hypertensives, it is stated (a) that 30% of the patients show baseline PRA <0.65 ng/ml/h at which salt reduction lowers BP because (adequate) vasoconstriction does not occur, and (b) that the 60% of the patients, in which baseline PRA is 0.65–4.5 ng/ml/h, reductions in salt intake also lower BP because the rise in PRA is inadequate to fully compensate; in these patients, elevations in PRA to levels >4.5 ng/ml/h are required to fully compensate for the effect of salt reduction on BP. Further, it is stated that ‘RAS inhibitors leave a small amount of renin unblocked’ and, therefore, ‘raise PRA enough to prevent BP form falling significantly’ and that such ‘reactive increases in PRA can prevent or attenuate the decrease in BP caused by excessive salt depletion, even during concurrent RAS inhibition’. The PRA limits of 0.65 and 4.5 ng/ml/h are described [1] to be based on iconic results of Laragh et al. from 1972 [5]. They are identical to the ‘normal range’ (0.65–4.5 ng/ml/h) described in 2013 by Sealey et al.[6] with reference to Sealey's earlier, detailed review on the matter [4]. Unexpectedly, these limits (0.65–4.5 mg/ml/h) are not mentioned neither in the 1972 Laragh papers [5,7] nor in the 1991 review of Sealey [4] cited by Sealey in 2013 [6] to do so. It is not a minor issue that the origin of these specific PRA levels, crucial to the hypothesized qualitative differences between the RAS effects on BP, is uncertain. The general notion that low PRA levels do not cause ‘hemodynamically significant’ vasoconstriction [1] is described to be backed by the finding that RAS inhibition does not lower BP in hypertensive patients with low PRA levels [8]. This could well be an overinterpretation. Until data demonstrate otherwise, it would be reasonable to assume that increases in circulating RAS activity cause vessel constriction (notably, picomolar amounts of angiotensin II increase BP (e.g., [9,10]) and reduce renal blood flow [11]), and that ACE inhibitors are very efficient, for example, ‘complete disappearance’ of plasma angiotensin II has been demonstrated at least after acute ACE inhibition [12]. The ground-breaking results on the relations between PRA and daily sodium excretion reported from the Laragh group in 1972 [5,7,13] are here [1] interpreted to show that ‘that when sodium excretion is high there is only a weak reciprocal relationship between PRA (and aldosterone) and urinary salt excretion, but when sodium excretion is low there is a strong reciprocal relationship’ [1]. This could be an inadequate assessment. The data (Fig. 4, [1]) are displayed with linear axes. When displayed in a log-linear format (Fig. 1) additional information emerges: (a) PRA is a linear function of the log of sodium intake; (b) therefore, the PRA salt sensitivity function (PRA-SS function) can be described by one set-point and one slope, (c) this linear PRA-SS function covers the entire range of sodium intakes, and (d) PRA values of 0.65 and 4.5 ng/ml/h do not seem to be the most informative limits. Notably, if the apparently linear PRA-SS function for the group of normal subjects is a product of individual linear PRA-SS relationships, then determination of the full range of personal PRA-SS functions is possible by measurement of PRA at two levels of sodium intake, and deviations from normal can be quantified as numeric deviations in set-point and/or slope.FIGURE 1: Relation between log10 of sodium excretion rates (mmol/day) and PRA (ng/ml/h) in 84 samples from 61 normal subjects after four or more days on a fixed dietary regimen. Data from the Laragh lab [7] also provided in Fig. 4 [1] manually digitized by the present author. Correction for repeated measures not possible. Line represents simple linear regression of log transformed rates of excretion of sodium (P < 0.0001, GraphPad Prism v.10). PRA increases by 5.7 ng/ml/h for each decade of reduction in sodium excretion over the entire range of sodium intakes. Five PRA results seem ‘high for sodium excretion rates’; the remaining 79 values provide a regression line of y = 13 – 4.8x. The funnel-shape of the apparently cohesive 79 data could support the hypotheses that total body sodium is proportional to sodium intake, that (some function hereof) determines PRA, and that individual differences between salt intake and renal excretion increase with decreasing salt intake. All appear plausible, but only the proportionality between sodium intake and total body sodium is supported by data, cf. [2].Based on 16 studies of changes in PRA and BP during reductions in salt intake and/or treatment with RAS inhibitors (by various groups over 34 years), it is concluded [1] (a) that during low-salt diets, PRA elevations are larger in normotensives than in hypertensives and the concurrent decrease in BP is smaller, and (b) during RAS inhibition, PRA in normotensives rises enough to prevent all but a small BP decrease, but in hypertensives the rise is not high enough to prevent BP from falling. Across these clinical studies, multiple circumstances differ, for example, baseline sodium metabolism, timelines and impacts of unspecified low salt diets, and, not least, the nature, degree, and duration of ‘RAS inhibition’. Conclusions with regard to specific, numeric levels of PRA based on such categorical (e.g., ‘RAS inhibition’) and semi-quantitative (e.g., ‘low salt’ diet) results seem less persuasive, particularly in the absence of appropriate statistical support. A few additional comments are warranted. (a) The Laragh data of sodium excretion cover a wide range of excretion rates (≈1.2–360 mmol/day, Fig. 1) fully adequate for all clinical purposes, but do not represent extremes; scientific reports include excretion rates of <0.5 mmol/day [14–16] to 800 mmol/day [17] underlining the impressive capacity of the human kidney, and (b) The PRA-SS mode of analysis of RAS reactivity to salt intake is not new [18,19]. In summary, (a) it is challenging to present new ideas about the role of RAS in health and disease in a few pages with some 40 references, (b) the notion [1] of residual RAS activity during clinical RAS inhibition may be drug and dose dependent thus disturbing the present line of arguments, (c) the concepts [1] of discontinuous functions of the RAS in the regulation of BP would require additional data to be attractive, (d) the analysis [1] of aberrant functions of the RAS in hypertension should include the possibility that non-RAS factors (e.g., potassium and/or non-RAS hormones) could co-determine the secretion of aldosterone, and (e) the (linear) response of PRA to (logarithmic) changes in sodium intake apparent from the Laragh data, may provide a doable – albeit demanding – approach to comprehensive analyses of PRA responses to changes in sodium intake. ACKNOWLEDGEMENTS Support: None. Conflicts of interest There are no conflicts of interest.
Source: Journal of Hypertension
Author: Peter Bie
Institution: University of Southern Denmark
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4409119592