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Diagnosis and treatment of hypernatremia

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Hypernatremia is defined as a serum sodium level above 145 mmol/L. It is a frequently encountered electrolyte disturbance in the hospital setting, with an unappreciated high mortality. Understanding hypernatremia requires a comprehension of body fluid compartments, as well as concepts of the preservation of normal body water balance. The human body maintains a normal osmolality between 280 and 295 mOsm/kg via Arginine Vasopressin (AVP), thirst, and the renal response to AVP; dysfunction of all three of these factors can cause hypernatremia. We review new developments in the pathophysiology of hypernatremia, in addition to the differential diagnosis and management of this important electrolyte disorder.

Introduction

Hypernatremia is defined as an increase in the plasma Na+ concentration to >145 mM. Considerably less common than hyponatremia, hypernatremia is however associated with mortality rates of as much as 40–60%. Hypernatremia most commonly occurs in ICUs, mostly developing after admission, and has been associated with increased mortality and prolonged length of ICU stay [1]. A recent study showed that severity rather than duration of the hypernatremia following the ICU admission was associated with increased mortality and increased length of stay (40% and 28% increase, respectively) [2]. Secondary analysis of a recent prospective study in the ICU showed that almost 50% of pre-dialysis patients with acute kidney injury had a dysnatremia, mainly hypernatremia, and that there was an increase in mortality especially with severe hypernatremia (serum sodium ≥156) compared to normonatremic patients (89.1% versus 64.6% respectively) [3]. Preoperative hypernatremia is also associated with increased perioperative 30-day morbidity and mortality [4].

Understanding hypernatremia requires a comprehension of the main body fluid compartments as well as an appreciation of the basic concepts of maintenance of normal body water balance. Total body water (TBW) is a key physiological term in this context. TBW has been estimated to be about 60% of body weight in men and 50% in women; this notably is a simplified estimate. TBW is further divided into two main compartments, an extracellular fluid (ECF) and an intracellular fluid (ICF) compartment. The ECF compartment includes plasma, interstitial and lymph fluid, connective tissue and bone, transcellular fluid within body cavities, and adipose tissue [5].

Tonicity refers to the behavior of cell volume in a given solution and represents the action of effective osmoles across a membrane. Cellular volume expands when cells are bathed in relatively hypotonic solutions and contracts when bathed in relatively hypertonic solutions, due to movement of water in and out of the cell respectively to eventually reach a steady state tonicity. Effective or active osmoles include sodium (and associated anions) and glucose in the extracellular compartment, whereas the ionic osmotic driver in the intracellular compartment is primarily potassium (and associated anions). On the other hand, osmolality represents the sum of both effective and ineffective osmoles in any 1 kg of body fluid. Ineffective osmoles, typically urea and alcohol [6] can cross freely across cell membranes and hence do not generally alter cellular volume. Osmolality is a poor indicator of tonicity given the presence of these ineffective osmoles. While effects of tonicity on cellular size cannot be measured directly, serum sodium can serve as a useful surrogate for tonicity in all body compartments at steady state.

Hypertonicity (dehydration) refers to the loss of total-body water such that cellular volume contracts, whereas volume depletion is a term used to signify loss of extracellular fluid volume. These two distinct conditions have different clinical features as well as different therapeutic responses [6], [7].

Vasopressin secretion, thirst, and the renal response to vasopressin collaborate to maintain normal human body fluid osmolality between 280 and 295 mOsm/kg. Thirst and vasopressin secretion are under the control of osmoreceptor neurons within the central nervous system (CNS) (see Fig. 1). Classic canine experiments performed in the 1940s, correlating the effect on urine output of carotid infusion of various osmolytes, led to the postulation of a central “osmoreceptor” [8]. The primary “osmostat” within the CNS is encompassed within the organum vasculosum of the lamina terminalis (OVLT); this small periventricular region lacks a blood–brain barrier, allowing for direct sensing of the osmolality of circulating blood. Osmoreceptive neurons are however widely distributed within the CNS, such that vasopressin (AVP) release and thirst are controlled by overlapping osmosensitive neural networks [9], [10], [11], [12]. Osmosensitive neurons are thus found in the subfornical organ (SFO) and the nucleus tractus solitarii, centers which help integrate regulation of circulating osmolality with that of related phenomena, such as extracellular fluid volume [9], [10], [12] (see Fig. 1).

Osmosensitive neurons from the supraoptic nucleus differ dramatically from hippocampal neurons, in that they demonstrate exaggerated changes in cell volume during cell shrinkage (hypertonic media) or cell swelling (hypotonic media) [13]. In hippocampal neurons, cell swelling evokes a rapid regulatory volume decrease (RVD) response, whereas cell shrinkage evokes a regulatory volume increase (RVI) response. In consequence, if external tonicity is slowly increased or decreased these RVD and RVI mechanisms are sufficient to prevent any change in the cell volume of hippocampal neurons; in contrast, osmosensitive neurons exhibit considerable changes in cell volume during such osmotic ramps [13]. This relative lack of volume regulatory mechanisms maximizes the mechanical effect of extracellular tonicity and generates an ideal osmotic sensor.

Osmosensitive neurons depolarize after cell shrinkage induced by exposure to hypertonic stimuli, with a marked increase in neuronal spike discharges; the associated current is due to activation of a nonselective cation channel [14], with five-fold higher permeability for Ca2+ over Na+ [15]. Hypotonic stimuli in turn hyperpolarize the cells and abolish spike discharges [14]. Depolarization and spike discharges, in the absence of hypertonicity, can also be evoked by suction-induced changes in cell volume during whole-cell voltage recording, suggesting involvement of a stretch-inactivated cation channel [14].

Mechanosensitive, stretch-inactivated cation channels, linked to the cytoskeleton [16], are thought be key components of the osmoreceptor complex. The TRPV1 channel (transient receptor potential vanilloid channel 1) appears to be a critical component of the mechanosensitive osmoreceptor, with loss of osmoreceptive neuronal depolarization and neuronal activation after hypertonic stimuli in TRPV1 −/− mice [17], [18]. Specifically, an N-terminal splice variant of TRPV1 has been implicated in this process, with detectable expression of TRPV1 C-terminal exons by RT-PCR in neurons from the SON without detectable expression of N-terminal exons; these AVP-positive neurons also stain positive with a C-terminal TRPV1 antibody, suggesting the involvement of an N-terminal splice-form. More recently, the relevant alternatively spliced isoform (TRPV1dn) has been cloned and characterized; TRPV1dn has an alternative start codon with a truncated N-terminus [19]. TRPV1dn encodes a shrinkage-activated channel and can rescue the phenotype of osmoreceptor neurons from TRPV1 −/− mice [19]. The swelling-activated TRPV4 channel is also expressed in osmoreceptor neurons, where it may play an inhibitory role, limiting the thirst response in hypotonicity and perhaps downregulating osmotic-induced AVP release; however, there are substantial differences in the reported phenotypes of TRPV4 knockout mice ∗[20], [21], such that the exact role of TRPV4 is still controversial.

At the neuronal network level, OVLT and adjacent circumventricular regions collaborate to regulate water intake and AVP release, in a number of different species [22], [23] (see Fig. 1). In humans, functional magnetic resonance imaging (fMRI) studies have revealed thirst-associated activation of the anterior wall of the third ventricle, encompassing the OVLT, in subjects treated with a rapid infusion of hypertonic saline [24]. In sheep, ablation of the OVLT or SFO alone does not affect osmotic-induced drinking; combined ablation of both regions is more effective, but still only partially effective. Complete abolition of thirst is however seen in sheep after combined ablation of the OVLT, the adjacent median preoptic nucleus (MnPO), and much of the SFO [25]. Similar observations can be made in respect to AVP release, in that combined ablation of the OVLT, SFO, and MnPO is required to fully abolish osmotic-induced release of AVP; notably, “non-osmotic” stimuli such as hemorrhage and fever are still effective in inducing AVP release in these animals [23].

Classically, the onset of thirst, defined as the conscious need for water, was considered to have a threshold of ∼295 mOsm/kg, i.e. ∼10 mMosm/kg above that for AVP release [26]. However, more recent studies using semi-quantitative visual analog scales to assess thirst suggest that the osmotic threshold is very close to that of AVP release, with a steady increase in the intensity of thirst as osmolality increases above this threshold [27]. Thirst and AVP release share a potent “off” response to drinking, with a rapid drop that precedes any change in circulating osmolality. Teleologically, this reflex response serves to prevent over-hydration [27]. Peripheral osmoreceptors in the oropharynx, upper GI tract, and/or portal vein are postulated to sense the rapid change in local osmolality during drinking, via TRPV4 channels [28], and relay the information back through the vagus nerve and splanchnic nerves [12].

As with AVP release (see below), thirst is stimulated by hypovolemia, although this requires a deficit of 8–10% in plasma volume, versus the 1–2% increase in tonicity that is sufficient to stimulate osmotic thirst [29]. Angiotensin is a particularly potent dipsogenic agent, particularly when infused directly into the brain or, more recently, overproduced in the SFO in transgenic mice [30]. The neuronal effects of angiotensin-II are evidently required for hypovolemic thirst, but not osmotic thirst [31].

Vasopressin is an endogenous peptide that serves multiple regulatory functions related to preservation of blood pressure, water balance, platelet function and thermoregulation [32], ∗[33]. Vasopressin is synthesized in magnocellular neurons within the hypothalamus; the distal axons of these neurons project to the posterior pituitary or neurohypophysis, from which AVP is released into the circulation. AVP secretion is stimulated as osmolality increases above a threshold level, beyond which there is a linear relationship between circulating osmolality and AVP (see Fig. 2). The X intercept of this relationship in healthy humans is ∼285 mOsm/Kg; AVP levels are essentially undetectable below this threshold.

Changes in blood volume and blood pressure are also potent stimuli for AVP release, albeit with a more exponential response profile (see Fig. 2). Of perhaps greater relevance to the pathophysiology of hyponatremia, extracellular fluid volume strongly modulates the relationship between circulating osmolality and AVP release, such that hypovolemia reduces the osmotic threshold and increases the slope of the response curve to osmolality; hypervolemia has an opposite effect, increasing the osmotic threshold and reducing the slope of the response curve [34] (see Fig. 2). A number of other stimuli have potent positive effects on AVP release, including nausea, angiotensin-II, acetylcholine, relaxin, serotonin, cholescystokinin, and a variety of related drugs [35].

The excretion or retention of electrolyte-free water by the kidney is modulated by circulating AVP [36]. AVP acts on renal V2 receptors in the thick ascending limb of Henle and principal cells of the collecting duct (CD), increasing cyclic-AMP and activating protein kinase A (PKA)-dependent phosphorylation of multiple transport proteins. The AVP- and PKA-dependent activation of Na+–Cl and K+ transport by the thick ascending limb of the loop of Henle (TALH) is thus a key participant in the countercurrent mechanism [37]. The countercurrent mechanism ultimately increases the interstitial osmolality in the inner medulla of the kidney, driving water absorption across the renal collecting duct [36]. However, water, salt, and solute transport by both proximal and distal nephron segments participates in the renal concentrating mechanism. Water transport across apical and basolateral aquaporin-1 water channels in the descending thin limb of the loop of Henle is thus involved [38], [39], as is passive absorption of Na+–Cl by the thin ascending limb, via apical and basolateral CLC-K1 chloride channels and paracellular Na+ transport [40], [41] (see Fig. 3). Renal urea transport in turn plays important roles in the generation of the medullary osmotic gradient and the ability to excrete solute-free water under conditions of both high and low protein intake [36] (see Fig. 3).

AVP-induced, PKA-dependent phosphorylation of the aquaporin-2 water channel in principal cells stimulates the insertion of active water channels into the lumen of the collecting duct, resulting in transepithelial water absorption down the medullary osmotic gradient. Under “anti-diuretic” conditions, with increased circulating AVP, the kidney reabsorbs water filtered by the glomerulus, equilibrating the osmolality across the collecting duct epithelium to excrete a hypertonic, “concentrated” urine (osmolality of up to 1200 mOsm/kg). In the absence of circulating AVP, insertion of aquaporin-2 channels and water absorption across the collecting duct is essentially abolished, resulting in secretion of a hypotonic, dilute urine (osmolality as low as 30–50 mOsm/kg). Abnormalities in this “final common pathway” are involved in most disorders of water homeostasis, e.g., a reduced or absent insertion of active aquaporin-2 water channels into the membrane of principal cells in both central and nephrogenic diabetes insipidus.

Hypernatremia increases osmolality of the ECF, generating an osmotic gradient between the ECF and ICF, an efflux of intracellular water, and cellular shrinkage. Initially, hypernatremia results in a reduced brain volume, which is reversed by cerebrospinal fluid movement into the brain with a subsequent increase in the interstitial volume [42], [43], in addition to cellular uptake of solutes by the cell as part of the RVI response [42], ∗[44], ∗[45]. This RVI process initially involves the uptake of inorganic ions (Na+, K+, and Cl) via transporters such as NKCC1 [46], followed by a more delayed accumulation of organic osmolytes, primarily myo-inositol, the amino acids glutamine, glutamate, and taurine ∗[44], ∗[45], [47], [48]. Some of the relevant osmolytes transporters are induced in neurons by the osmosensitive transcription factor TonEBP [49], whereas the slow induction of osmolytes transporters in oligodendrocytes and glia likely occurs through transcriptional mechanisms that are independent of TonEBP [48].

Section snippets

Etiology

Hypernatremia is usually the result of a combined water and electrolyte deficit, with losses of H2O in excess of Na+. This imbalance can also result from net water loss, which can be pure water or hypotonic fluid loss, or less frequently from a gain of hypertonic sodium. In order for the hypernatremia to be sustained, there needs to be a defect in the thirst mechanism or a lack of access to water. Notably, hypernatremia in the ICU is the predominant presentation, with the most common causes

Diagnosis

Thorough history, clinical examination and laboratory testing help establish the etiology of hypernatremia.

Treatment

The treatment of hypernatremia requires a comprehensive understanding of the predisposing mechanism. The most common form of hypernatremia is that due to water loss with impaired thirst mechanism or inability to administer water. Management is targeted towards treating the inciting factor and correcting the hyperosmolality [53]. A stepwise approach is helpful in order to address several considerations and can be summarized by the following points:

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