par Nutrimuscle-Conseils » 18 Nov 2021 17:19
Insights into Salt Handling and Blood Pressure
David H. Ellison N Engl J Med 2021; 385:1981-1993
Constancy of the milieu intérieur, defined by Claude Bernard in the late 1800s, is essential for terrestrial life. Sodium balance in humans is part and parcel of that environment and is maintained in the face of enormous variations in salt intake, typically consumed as sodium chloride (NaCl), through exquisite regulation of salt excretion. By matching urinary sodium excretion to sodium intake, the kidney prevents deleterious changes in electrolyte balance, extracellular fluid (ECF) volume, and blood pressure. It is widely accepted that minuscule changes in the effective circulating volume (ECV; the volume of arterial blood effectively perfusing tissue), which typically correlates directly with sodium intake, signals adjustments in the kidney to maintain sodium excretion equal to sodium dietary intake. The major underlying physiologic control systems are now well understood and are common targets of life-prolonging therapeutic interventions. Yet more recent challenges to canonical concepts posit that those traditional views are too limited and may be incorrect.1
In this review, we discuss controversies and distill the old with emerging concepts into a contemporary understanding of sodium homeostasis. The complex integrative interplay among kidney salt transport, salt storage in the skin and interstitium, adaptation of the vascular system, and neurohormonal signaling systems is highlighted.
A major reason for the popular focus on salt intake is its association with blood pressure. Observations dating back to the mid-20th century have suggested that humans who consume more salt have higher arterial pressures. Interventional trials also indicate that high salt intake raises blood pressure.2 Yet many persons are able to consume large amounts of salt without substantial rises in arterial pressure.3,4 A recent Cochrane review showed that dietary salt restriction, as compared with high salt intake, reduces mean arterial pressure by 0.4 mm Hg in normotensive persons and by 4 mm Hg in those with diagnosed hypertension.5 However, the individual effects of salt intake on blood pressure are highly variable, leading to contentious debates about public policy. Frequently observed associations between very low salt intake and excess mortality have been cited as a risk,6 but such associations may be confounded.7 As discussed below, the ratio of salt intake to potassium intake may be especially important. A recent large, cluster-randomized trial showed that persons who received a potassium-containing salt substitute (75% NaCl, 25% potassium chloride), rather than typical salt (100% NaCl), not only had lower blood pressure but also had lower rates of stroke, major cardiovascular events, and death from any cause.8
Nevertheless, it is clear that some people are especially sensitive to salt intake, and with a typical U.S. diet, hypertension develops in those people. Salt sensitivity is variably defined, but one useful definition is a difference in mean arterial pressure that is 10 mm Hg or greater when salt balance is altered by a combination of diet and loop diuretics.9 A pragmatic definition of salt sensitivity for busy clinicians, however, is wanting. It has been suggested that excessive salt intake may also have adverse effects independent of blood pressure, such as activation of the immune system.10
Three-Compartment Model of the Interstitium.
Ninety-eight percent of total-body sodium is confined in the ECF compartment in young, healthy humans. About 80% of exchangeable sodium is found in interstitial and connective tissues, and about 15% of exchangeable sodium (and about 10% of total-body sodium) is in plasma (Figure 1). Anhydrous bone contains a large amount of sodium, much of which is not easily accessible to infused isotopes and is deemed nonexchangeable.12 Sodium in the interstitium has been envisioned as existing in a free-flowing isotonic aqueous compartment. Instead, the interstitium appears to be triphasic, consisting of a fluid phase, a dense collagen-based matrix, and a glycosaminoglycan (GAG)–rich gel phase (Figure 2). Because GAGs are negatively charged and spatially restricted, they attract cations and generate a local osmotic pressure. Collagens are relatively rigid and generate a hydrostatic pressure that can counteract the osmotic pressure generated by GAGs.12 The role of GAGs and collagen in sodium homeostasis was recognized during the 1960s in the well-known model of body fluid dynamics,13 but more recently, their importance has been reemphasized because GAGs permit sodium storage and contribute to the effects of diet on blood pressure.14
The three phases of the interstitial fluid are in equilibrium, but the sodium concentrations in the phases can differ. The thirst reflex, vasopressin, and the kidney maintain a relatively constant sodium concentration in free-flowing ECF, matching the concentration in plasma. ECF compartments with very high concentrations of GAGs, such as cartilage, however, have fixed anionic charges that attract sodium ions, favoring swelling, which in turn is counteracted by the rigid collagen matrix. These countervailing forces maintain cartilage structure and flexibility.15
Diet, Total-Body Sodium, and Water
When dietary salt intake increases, urinary sodium excretion increases, but it does not match intake immediately and thus generates a positive sodium balance until excretion again equals intake. The ingested anion also affects internal sodium distribution, since NaCl increases body weight and ECF volume more than equimolar sodium citrate,16 in which case, the sodium is partially exchanged for potassium inside cells. Increasing NaCl intake also increases body water in most situations,17,18 although this does not result predominantly from more fluid consumption (see below) but rather from fluid retention.19 When dietary salt intake rises from low to moderate levels, body water increases. When salt intake rises further, sodium accumulation may occur without an increase in water.20
The steady-state relation between the cumulative sodium balance and urinary sodium excretion is usually linear,21 although weekly cyclic patterns of sodium excretion, independent of aldosterone,22 mean that a single 24-hour urinary sodium measurement may not reflect intake.23 In patients with chronic kidney disease, the time to reach a steady state after a dietary change is prolonged, making blood pressure more salt-sensitive.24
Pressure sensors in the vascular space and kidney detect the ECV as part of a mechanism to determine the adequacy of capillary perfusion. Small changes in the ECV are considered a primary trigger for altering sodium excretion to match intake. When salt intake is restricted, angiotensin II, aldosterone,25 norepinephrine, and epinephrine5 all increase, contributing to sodium retention. Owing to direct cardiovascular and sympathetic effects, these neurohormones link the ECV and vasoconstriction. Conversely, salt loading increases the ECV and stimulates the release of natriuretic factors, including atrial natriuretic peptide and endothelin. In nonmodulating hypertension, the kidney vasculature and adrenal gland fail to respond normally to changes in angiotensin II levels.26 The effects of dietary salt intake on glucocorticoid metabolism are not as clear. Most studies in humans show that high salt intake increases urinary free cortisol levels without altering the plasma cortisol level.27
In recent years, it has become evident that nonvascular ECF compartments also have roles in sodium balance. Vascular, renal epithelial, and immune cells directly sense changes in sodium and emit signals that adjust urinary sodium excretion accordingly. The skin, which has a large interstitial space relative to its cellular space and is rich in GAGs, has been a focus of much attention as a possible sodium depot. It is now believed that fluid filtration occurs along the entire length of most capillary beds (Figure 2), not only along the proximal portion, as previously suggested.28 This means that lymphatics, which return fluid to the circulation, play key roles in salt and water homeostasis. Although it is often stated that total-body sodium is isotonically distributed in ECF, this is an oversimplification, as noted by Edelman and Leibman, who identified an excess of sodium, relative to chloride, in certain tissues.11 Sodium can be sequestered in these compartments.
The osmotic activity of interstitial sodium has been debated. Dietary salt loading has been suggested to cause osmotically inactive sodium storage.29 Bhave and Neilson, however, point out that excess sodium storage does not necessarily imply that the stored sodium is osmotically inactive.12 Sodium may also accumulate in excess of water,14 causing interstitial hypertonicity. Local hypertonic environments in the skin provide an attractive mechanism to explain the interplay of salt, immune-system activation, and blood pressure. Indeed, hypertonicity activates the transcription factor TonEBP/NFAT5 in mononuclear phagocytes,10,30 which remodel the lymphatic network through a vascular endothelial growth factor–signaling pathway. An observation that is consistent with this process was reported by Nikpey and colleagues, who detected an osmolarity gradient in the skin, with the epidermis and epidermal interstitial fluid being hypertonic as compared with plasma.14 Others, however, could not detect such a hypertonic compartment in the skin; precise parallel monitoring of interstitial water and sodium indicated that sodium accumulates in skin and other tissues primarily as isotonic edema fluid.31 Despite the isotonicity, sodium accumulation was still sufficient to activate TonEBP/NFAT5 in immune cells. Thus, it appears that interstitial sodium storage itself, rather than hypertonicity, may be the primary contributor to immune-cell activation and blood-pressure changes.
Salt and Thirst
Body water is derived from dietary intake, retained by the kidneys, and produced by carbohydrate, fat, and protein metabolism. Urinary water excretion varies to match intake and metabolic generation, less insensible losses. Metabolic water production is directly proportional to energy expenditure and averages 250 to 350 ml per day in humans, a value that can rise substantially after exercise. Most body water in humans derives from consumption, which is evolutionarily programmed by thirst. In contrast, water balance in hibernating bears is maintained through metabolic water generation.32
Many experimental studies fail to appreciate the need to ingest electrolyte-free fluid in order to maintain normal metabolism and prevent stress.33 Use of saline drinking solutions to increase salt intake is problematic because they increase protein catabolism, glucocorticoid production, and urea generation, whereas salt loading through diet, with access to free water, does not.33 This difference probably reflects the body’s need to generate metabolic water if exogenous water is not available, making the organism behave like hibernating bears.32 In contrast, normal humans on high-salt diets typically maintain normal rates of metabolism.25
The effect of salt intake on thirst has been recognized since the early 1900s. Gamble and colleagues discovered that rats consume water in proportion to salt intake,34 establishing the principle that salt-induced thirst is aversive.35 Nevertheless, a direct relationship between salt and fluid intake has been harder to discern in humans. Some studies have suggested that high-salt diets are associated with more fluid intake,36 whereas a more recent study suggested an inverse relationship.37 Most large analyses, including worldwide comparisons, suggest that there is little relationship between salt and fluid intake, with sodium excretion modulated primarily by the urinary sodium concentration.38 Yet a recent analysis of data from the large Dietary Approaches to Stop Hypertension (DASH)–Sodium trial showed that higher dietary salt intake stimulated thirst and increased urinary volume.25 It seems likely that the failure to discern a relationship between dietary salt intake and fluid consumption in humans reflects the behavioral determinants of fluid intake. Forty-four percent of fluid intake in the United States is from beverages other than water39; furthermore, thirst-independent water intake is often advocated in the lay press, although supportive data are thin.40 Daily fluid consumption from all sources in adults in the United States may approach 3 liters, even when salt intake is low, a volume that is likely to be in excess of physiological need.40,41
Volume and Thirst Sensors in the Brain.
Several studies provide striking details about the molecular basis of thirst. Populations of neurons in the lamina terminalis circumventricular organs that are unprotected by the blood–brain barrier are primarily responsible (Figure 3). These excitatory neurons drive fluid consumption rapidly as a corrective behavior.35 In contrast, ECF volume depletion (salt loss) stimulates separate sets of neurons, some of which respond to angiotensin II and aldosterone. Like aldosterone-responsive distal nephron cells,43 aldosterone-sensitive neurons express 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), conferring aldosterone selectivity. In mice, neuronal deletion of 11βHSD2 causes persistent activation of mineralocorticoid receptors by glucocorticoids, increasing salt appetite.44 The distinct sensory pathways in the brain may explain the preference for electrolyte-containing sports drinks after intense exercise. Other pathways in the oropharynx45 and gastrointestinal tract46 monitor the water and salt content of recently ingested food and rapidly communicate to the central thirst centers, creating a high-gain, feed-forward system.47
The plasma sodium concentration is tightly controlled by thirst and arginine vasopressin, but the plasma or cerebrospinal fluid sodium concentration has been postulated to play a role in neurogenic hypertension. One mechanism may involve a subset of glial cells in the lamina terminalis with sodium channels, called Nax,48 which act as sodium sensors.49 However, plasma sodium concentrations have a narrow range and do not correlate with blood pressure in large study cohorts.50,51 Arginine vasopressin itself may affect blood pressure because it stimulates the epithelial sodium channel in the aldosterone-sensitive distal nephron. Yet counteracting factors mitigate vasopressin-induced sodium retention, except when aggravating factors confer a predisposition to hypertension.52
Salt and Blood Pressure
There has been interest for many years in mechanisms by which salt intake raises blood pressure. Guyton suggested that salt handling by the kidneys must be altered for hypertension to develop,53 but alternative hypotheses have been proposed. The best-developed hypotheses are those suggesting primary vascular dysfunction,54 primary sympathetic nervous system dysfunction,55 and immune activation, perhaps related to skin hypertonicity.10 The intensity of disagreement about mechanisms rivals the intensity of disagreement regarding the optimal diet and impedes both scientific and social progress. In this section, we describe findings that help reconcile the several hypotheses, although space does not permit a comprehensive review.
Nearly all known monogenic disorders of blood pressure affect kidney salt metabolism.56 The mirror-image disorders, Gitelman’s syndrome and Gordon’s syndrome (familial hyperkalemic hypertension) are illustrative. Both disorders affect the thiazide-sensitive NaCl cotransporter (NCC), expressed predominantly in the distal convoluted tubule, but they do so in opposite directions. In Gitelman’s syndrome, loss-of-function NCC mutations lead to salt wasting and hypotension, despite an activated renin–angiotensin–aldosterone system. In familial hyperkalemic hypertension, aberrant WNK (with no lysine [K]) kinase signaling activates NCC, leading to excessive salt reabsorption and hypertension, despite normal aldosterone levels. Both hypertension and hyperkalemia in patients with familial hyperkalemic hypertension are corrected with thiazides, suggesting that excessive salt absorption by NCC is responsible for the disorder.
It has been argued that these and other monogenic disorders of blood pressure do not provide evidence that increased renal salt reabsorption drives hypertension because the involved genes are also expressed outside the kidney.57 WNK kinases and mineralocorticoid receptors, for example, are both expressed in the nervous system and vasculature.58,59 The development of a molecular toolbox for the kidney has recently permitted investigators to address this question directly. One series of experiments revealed that kidney-cell–specific manipulation of NCC is sufficient to drive salt-dependent changes in blood pressure. NCC activity depends on STE20/SPS1–related proline/alanine–rich kinase (SPAK), which binds to and phosphoactivates NCC. Cell-specific expression of a constitutively active form of SPAK in the distal convoluted tubule is sufficient to cause sodium retention and salt-sensitive hypertension, correctable with thiazide diuretics.60
Human salt-sensitive hypertension was originally proposed to result from excessive salt retention,61 but more recent studies indicate that this is not universal among those affected.17 All investigators recognize that an increase in sodium intake raises total-body sodium, but the vasodysfunction hypothesis argues that N-methyl-d-arginine–mediated failure of vasodilatation during salt loading differentiates salt-sensitive from salt-insensitive persons.54 When HumMod, the sophisticated progeny of the Guyton and Coleman “kidney-centric” mathematical model,62 was used to test mechanisms of salt sensitivity, it showed that expansion of ECF volume is not required and that kidney vascular dysfunction can play a generative role. The model, however, showed that primary differences in peripheral vascular resistance cannot lead to salt sensitivity, so there must be a renal component.63 Nevertheless, excess salt and water retention are characteristic of certain forms of salt sensitivity, such as chronic kidney disease, which is typically highly responsive to diuretic agents.64
Salt and Vascular Tone
Another mystery is the link between ECF volume and vascular tone. People with Gitelman’s syndrome caused by NCC dysfunction in the kidney have peripheral vasodilatation, despite high circulating angiotensin II levels.65 The vasodilatation appears to be mediated by secondary disruption of the α subunit of a heterotrimeric guanine nucleotide–binding protein (G-protein), a key signaling molecule in angiotensin II–mediated vasoconstriction. This disruption causes increased expression of nitric oxide synthase.65 Conversely, mineralocorticoid-induced hypertension is mediated by ECF volume expansion initially, but after 5 to 8 weeks, the plasma volume falls toward the normal range and hypertension is maintained by increased systemic vascular resistance.66
Once again, studies using the molecular toolbox have allowed investigators to separate renal and extrarenal effects. Deletion of mineralocorticoid receptors or the epithelial sodium channel in the kidney nephron in mice leads to the development of severe urinary salt wasting, weight loss, and hypotension, a phenotype that recapitulates both hypoaldosteronism and pseudohypoaldosteronism type 1.67,68 Direct vascular effects of aldosterone may play a part when the dysfunction is systemic, especially during aging,69 but they do not appear to be necessary.
The mechanistic basis for the link between ECF volume and vascular tone remains contentious. Whole-body autoregulation, whereby blood flow is adjusted to meet tissue demands for oxygen and nutrients, may account for the link, at least in part. This phenomenon probably explains the vasodilatation and increased cardiac output observed in patients with chronic anemia70 and in an animal model of arteriovenous fistulas.71 Yet many investigators question the role of whole-body autoregulation.72 Schalekamp and colleagues concluded that the time course of mineralocorticoid-induced vasoconstriction is inconsistent with local autoregulatory processes,73 an observation that suggests an effect related to interstitial congestion.74
Dietary Patterns That Mitigate Salt Sensitivity
The DASH-Sodium trial suggested that beyond lowering salt intake, an overall modification of the dietary pattern is important for lowering blood pressure. Among the many factors that lower blood pressure and improve cardiovascular health,75 high levels of dietary potassium and fiber have recently garnered considerable attention.
The Potassium Switch.
Epidemiologic studies76 and interventional studies77 indicate that high potassium intake not only lowers blood pressure but also strikingly reduces salt sensitivity. This reduction is probably due in part to direct effects of potassium on the vascular endothelium, possibly mediated by activation of Na+/K+ ATPase78 or changes in endothelial-cell deformability and nitric oxide release.79 Mounting evidence suggests that a new kinase-signaling pathway in the kidney controls a potassium switch, playing a central role. The existence of this switch pathway was first suggested when mutations in the WNK kinases were identified as a cause of a genetic intolerance to sodium and potassium.80 Subsequent studies revealed that WNK kinases are integral parts of a potassium-regulated signaling cascade that controls NCC in the distal convoluted tubule. This transporter interacts cooperatively with the aldosterone-regulated epithelial sodium channel downstream, maintaining sodium and potassium balance over widely varying levels of potassium intake.81 The switch pathway, minimally comprising basolateral potassium channels,82 WNK4 kinase,83 and SPAK,84,85 becomes physiologically activated during dietary potassium deficiency; this stimulates NaCl reabsorption by NCC to limit potassium secretion along the aldosterone-sensitive distal nephron at the expense of increasing sodium reabsorption (Figure 4). Conversely, when dietary potassium is plentiful, the WNK cascade is inhibited,86 suppressing NaCl absorption in the distal convoluted tubule and facilitating potassium secretion in the aldosterone-sensitive segment.
The existence of the potassium switch explains the “aldosterone paradox”: how a single hormone, aldosterone, can lead to kaliuresis under some conditions and to sodium retention under others. The switch appears to be ideally adapted for the more intermittent consumption patterns of ancient times, when dietary salt consumption was often low but potassium loads occurred intermittently. Because the switch prioritizes potassium retention over sodium excretion,81 however, it is not suited for a westernized diet, characterized by daily high-sodium and low-potassium intake. Since low potassium consumption presses the switch to conserve potassium at the expense of increasing sodium, it can drive salt sensitivity, providing an explanation for the way in which dietary potassium mitigates salt sensitivity.
It has been suggested that dietary fiber lowers blood pressure and alters salt sensitivity, perhaps through the gut microbiome.87 Commensal bacteria in the large intestine ferment fiber and generate short-chain fatty acids, which activate G-protein–coupled receptors (GPR43 and GPR109A) in the kidney, arteries, heart, and immune cells to stimulate antihypertensive responses, including stimulation of antiinflammatory regulatory T (Treg) cells. There is growing evidence that activation of inflammatory immune cells promotes hypertension and end-organ damage,88 and the Treg cells may counter these effects. High dietary sodium also changes the composition of the gut microbiota, causing depletion of lactobacillus species. The response activates type 17 helper T (Th17) cells and induces salt-sensitive hypertension. In a pilot interventional study in humans, an increase in blood pressure with high dietary salt consumption was correlated with reduced survival of gut lactobacillus and an increased number of Th17 cells.89 In large epidemiologic studies, a greater abundance of Lactobacillus paracasei was associated with lower blood pressure and lower dietary sodium intake,90 yet although a recent meta-analysis of controlled trials provided strong support for the DASH and Mediterranean diets, it provided minimal support for a high-fiber diet.91
Updated Mosaic Model.
The mosaic model proposes that hypertension is a response to different combinations of traits and stressors.92 In many ways, this model most accurately portrays the complex roles of salt intake, total-body sodium, and blood pressure. In the updated model (Figure 5), salt sensitivity appears to result from complex pleomorphic underpinnings, with altered renal, hormonal, vascular, and neurologic components according to age, environment, and social factors. A better understanding of the complex interplay among diet, salt, the kidney, and the vascular system is needed to develop effective public health measures for combatting hypertension.
Summary
Recent work emphasizes the roles that sodium storage and the immune system play in sodium balance. Yet this work complements, rather than replaces, more established effects of salt intake on cardiovascular and renal function. Potassium can mitigate the effects of salt excess, in part, through a potassium switch in the distal nephron, permitting homeostasis despite wide variations in intake.
in 878 participants (35 trials); adrenalin increased 7.55 pg/mL (95%CI: 0.85, 14.26) in 331 participants (15 trials); cholesterol increased 5.19 mg/dL (95%CI:2.1, 8.3) in 917 participants (27 trials); triglyceride increased 7.10 mg/dL (95%CI: 3.1,11.1) in 712 participants (20 trials); LDL tended to increase 2.46 mg/dl (95%CI: -1, 5.9) in 696 participants (18 trials); HDL was unchanged -0.3 mg/dl (95%CI: -1.66,1.05) in 738 participants (20 trials) (All high-quality evidence except the evidence for adrenalin).
