Osmoregulation of Vasopressin

Plasma osmolality is the most important determinant of AVP secretion. The osmoregulatory systems for thirst and AVP secretion, and in turn the actions of AVP on renal water excretion, maintain plasma osmolality within narrow limits of 284 to 295 mOsmol/kg. The relationship between plasma osmolality and plasma AVP concentration has 3 characteristics.

• The osmotic threshold or 'set point' for AVP release.
• The shape of the line describing changes in plasma AVP concentration with changing plasma osmolality
• The sensitivity of the osmoregulatory mechanism coupling plasma osmolality and AVP release.

Increases in plasma osmolality increase plasma AVP concentrations in a linear manner (Figure 6). The abscissal intercept of this line indicates the mean 'osmotic threshold' for AVP release (284 mOsmol/kg): the mean plasma osmolality above which plasma AVP increases in response to increases in plasma osmolality. AVP levels increase from a basal rate through activation of stimulatory osmoreceptor afferents, and decrease to minimal values when this drive is removed and synergistic inhibitory afferents are activated. The slope of the line relating plasma osmolality to plasma AVP concentration reflects the sensitivity of osmoregulated AVP release. There are considerable inter-individual variations in both the threshold and sensitivity of AVP release. However, they are remarkably reproducible within an individual over time (17).

Figure 6.

The relationship of plasma AVP concentration to changes in plasma osmolality during controlled hypertonic stimulation. AVP concentration determined during progressive hypertonicity induced by infusion of 855 mmol/l saline in a group of healthy adults. Increases in plasma osmolality increase plasma AVP concentrations in a linear manner, defined by the function, plasma AVP = 0.43 (plasma osmolality - 284), r = +0.96. The abscissal intercept of this regression line indicates the mean 'osmotic threshold' for AVP release: the mean plasma osmolality above which plasma AVP starts to increase. The shaded area represents the range of normal response. LD represents the limit of detection of the assay, 0.3 pmol/l.

There are situations where the normal relationship between plasma osmolality and AVP concentration breaks down:

• Rapid changes of plasma osmolality: rapid increases in plasma osmolality result in exaggerated AVP release.
• During the act of drinking: drinking rapidly suppresses AVP release, through afferent pathways originating in the oropharynx.
• Pregnancy: the osmotic threshold for AVP release is lowered in pregnancy.
• Whether aging is accompanied by changes in AVP concentrations is controversial.

As befits its major function and physiological role, AVP production by the neurohypophysis is influenced by sensory signals reflecting osmotic status and blood pressure/circulating volume. The relationships of the SON and PVN with the autonomic afferents and central nervous system nuclei responsible for osmo- and baroregulation are key to the physiological regulation of AVP. Functional osmoreceptors are situated in anterior circumventricular structures: the subfornicular organ (SFO), and the organum vasculosum of the lamina terminalis (OVLT). Local fenestrations in the blood brain barrier at these sites allow neural tissue direct contact with the circulation. Subsequent sensory input to the SON and PVN is via glutaminergic afferents. Moreover, these neurons integrate osmolar status with additional endocrine signals reflecting circulating volume status through the action of angiotensin II (A-II), relaxin, and atrial natriuretic peptide (ANP). A-II and relaxin excite both OT and AVP magnocellular neurons. In contrast, ANP inhibits AVP neuron activity. AVP neurons themselves have independent osmo-sensing properties and V-Rs are present on vasopressinergic neurons of both the PVN and SON, highlighting the potential for auto-control of AVP release through direct osmoregulation and short loop feedback (18). AVP magnocellular neurons in the SON and PVN co-express the peptide Apelin and its G-protein coupled receptor. A ‘yin and yang’ relationship has been proposed between AVP and these 36 amino-acid peptides (and indeed it’s shorter active derivatives Apelin-17 and Apelin-13). Intra-cerebroventricular injection of Apelin-17 inhibits the phasic firing of AVP magnocellular neurons, reducing AVP release and stimulating aquaresis. Hypertonic stress and water loading have reciprocal effects on plasma AVP and Apelin concentrations. Apelin receptors are also co-expressed in AVP target cells in the renal collecting duct. AVP and Apelin are thus regulated in opposite directions to maintain volume and osmolar homeostasis (19-22).

Changes in the osmotic environment of osmo-sensitive neurons in the OVLT, SFO and vasopressinergic neurons of the SON and PVN result in altered cell volume. These physical changes alter the activity of the stretch-sensitive cationic channel TRPV1, expressed on the cell surface of these neurons. TRPVI thus acts as the transduction mechanism linking changes in osmolality to altered membrane potential and firing frequency. Osmoregulatory function is not lost in Trpv1−/−mice, indicating additional osmo-sensing pathways must be in operation (23).

A related, but distinct osmo-sensory input feeds additional data on peripheral osmolar status to the neurohypophysis. Hepatic portal blood vessels contain sensory neurons responsive to changes in the osmolality of peripheral blood. In contrast to central mechanisms, the key transducing element of the peripheral process is the stretch-sensitive ion channel, TRPV4. Plasma osmolality is frequently elevated in patients after liver transplant in which the donor organ is denervated, demonstrating the function of this peripheral pathway (24).

Osmosensitivity of AVP release is influenced by circadian rhythms. AVP release increases during sleep. This effect is mediated by clock neurons projecting from the suprachismatic nucleus, increasing the activity of osmosensory afferent input to the SON (25).

Baroregulation of Vasopressin

Reductions in circulating volume stimulate AVP release. Falls in arterial blood pressure of 5 to 10 per cent are necessary to increase circulating AVP concentrations in man. Progressive reduction in blood pressure produces an exponential increase in plasma AVP, in contrast to the linear increases of osmoregulated AVP release. Baroregulatory influences on neurohypophyseal AVP release derive from aortic arch, carotid sinus, cardiac atrial, and great vein stretch-sensitive afferents via cranial nerves IX and X. Ascending projections are via the nucleus tractus solitarius (NTS) in the brain stem. From the NTS, further afferents project to the SON and PVN, which also receive additional adrenergic afferents from other brain stem nuclei involved in cardiovascular control, such as the locus coeruleus. These nuclei integrate a number of afferent inputs that reflect volume status. Ascending baroregulatory pathways must affect some tonic inhibition of AVP release, as interruption increases plasma AVP levels (26, 27). Osmoregulated AVP responses can be modified by factors triggered as part of the coordinated neurohumoral response to changes in circulating volume and blood pressure. A-II amplifies the proportional relationship between osmolality and action potential firing in the SON. The peptide produces this effect through polymerization of intracellular actin filaments, resulting in altered cell shape, a mechanism that is synergistic with those mediating responses to changes in extracellular osmolality. A-II thus enhances osmosensitivity. This mechanism underpins the changes in osmo-regulated AVP release in hypo- and hypervolemia: the osmotic threshold and sensitivity of AVP release is lowered by hypovolemia; while the converse is found in hypervolemia and hypertension (19).

Additional Mechanisms Regulating Vasopressin Release

A number of other stimuli influence AVP release independent of osmotic and hemodynamic status.

• Nausea and emesis
• Unspecific stress
• Pain
• Manipulation of abdominal contents
• Immune-response mediators and inflammatory triggers

These stimuli contribute to high plasma AVP values observed in acute illness and after surgery.

Cardiovascular Effects

AVP is a potent pressor agent; its effects mediated through a specific receptor (V1-R) expressed by vascular smooth muscle cells. Though systemic effects on arterial blood pressure are only apparent at high concentrations, AVP is important in maintaining blood pressure in mild volume depletion. The most striking vascular effects of AVP are in the regulation of regional blood flow. The sensitivity of vascular smooth muscle to the pressor effects of AVP varies according to the vascular bed. Vasoconstriction of splanchnic, hepatic and renal vessels occur at AVP concentrations close to the physiological range. Furthermore, there are differential pressor responses within a given vascular bed. Selective effects on intrarenal vessels lead to redistribution of renal blood flow from medulla to cortex. Baroregulated AVP release thus constitutes one of the key physiological mediators of an integrated hemodynamic response to volume depletion.4.2.

Effects on the Pituitary

AVP is an ACTH secretagogue, acting through pituitary corticotroph-specific V1b-Rs. Though the effect is weak in isolation, AVP and CRF act synergistically. AVP and CRF co-localize in neurohypophyseal parvocellular neurons projecting to the median eminence and the neurohypophyseal portal blood supply of the anterior pituitary. Levels of both AVP and CRF in these neurons are inversely related to glucocorticoid levels, consistent with a role in feedback regulation.

Effects of AVP on Regulation of Bone Mass

AVP exerts its action both on osteoblasts and osteoclasts thru AVPR1 and AVPR2 receptors (28). Mice studies showed that AVP upregulates osteoclast differentiation genes and inhibits osteoblast formation. Mice rendered deficient in AVPr1a (Avpr1a-/-) have a high bone mass, and they show an increase in osteoblastogenesis after additional inhibition of AVPR2 (29) .

The AVP effect is opposed by oxytocin, which stimulates osteoblast formation and inhibits mature osteoclast activation. Mice studies showed that both haploinsufficiency for oxytocin and deletion of the oxytocin receptor (Oxr-/-) result in osteopenia (30). The role of both hormones in the regulation of skeletal physiology remains to be further explored (31).

Behavioral Effects of Vasopressin

Vasopressinergic fibers and V-Rs are present in CNS neural networks anatomically and functionally independent of the neurohypophysis, including the cerebral cortex and limbic system. An increasing amount of data highlight the role of central vasopressinergic systems in mediating complex social behavior. Data in Man link V1a-R gene sequence variation with a range of normal and abnormal behavior patterns, including gender dimorphic behavior. Dysregulation of central AVP action may be a distal end point in complex conditions characterized by altered social and emotional behavior (32, 33).

Thirst

Renal free water clearance can be reduced to a minimum by the antidiuretic actions of vasopressin, but water loss is not completely eliminated, and insensible water loss from respiration and sweating is a continuous process. To maintain water homeostasis, water must also be consumed to replace the obligate urinary and insensible fluid losses. This is regulated by thirst. Thirst and drinking are key processes in the maintenance of fluid and electrolyte balance. Thirst perception and the regulation of water ingestion involve complex, integrated neural and neurohumoral pathways. As with those mediating AVP release, the osmoreceptors regulating thirst are situated in the OVLT, effectively outside the blood-brain barrier and distinct from those mediating AVP release. Neural activity in and around the OVLT remains active in hyperosmolar states following immediate satiety of thirst, indicating that other centers must be involved in thirst perception. The anterior cingulate cortex and insular cortex receive input from osmo-sensitive afferents and have been implicated as key higher centers in thirst pathways (20). There is a linear relationship between thirst and plasma osmolalities in the physiological range. The mean osmotic threshold for thirst perception is 281 mOsm/kg, similar to that for AVP release. Thirst occurs when plasma osmolality rises above this threshold. As with osmoregulated AVP release, the characteristics of osmoregulated thirst remain consistent within an individual on repeated testing, despite wide inter-individual variation.

As with AVP release, there are also specific physiological situations in which the relationship between plasma osmolality and thirst breaks down.

• The act of drinking: reduces osmotically stimulated thirst.
• Extracellular volume depletion: this stimulates thirst through volume-sensitive cardiac afferents and the generation of circulating and intra-cerebral A-II, a powerful dipsogen.
• Pregnancy, the luteal phase of the menstrual cycle and super ovulation syndrome: these states reduce the osmolar threshold for thirst.
• Aging: both thirst appreciation and fluid intake can be blunted in the elderly

The act of drinking reduces thirst perception before any change in plasma osmolality. This effect is produced through three mechanisms: oropharyngeal sensory afferents; gastro-intestinal stretch-sensitive afferents; and peripheral osmoreceptors in the hepatic portal vein. Recent data have highlighted how thirst-promoting neurons in the SFO integrate sensory inputs from the oropharynx (drinking and food composition) with central osmolar status to influence thirst perception. This complex mechanism effectively explains anticipatory changes in water consumption that precede changes in plasma osmolality (34). As with AVP release, hypovolemia resets the relationship between plasma osmolality and thirst. A-II is one of the key mediators of this physiological response. Peripheral A-II generation can act on central osmoreceptors, to increase both thirst and AVP release. An independent, intra-cerebral A-II system is activated in parallel. A-II is a powerful central dipsogen.

Central Diabetes Insipidus (CDI) (Arginine Vasopressin Deficiency)

CDI (also known as neurogenic or cranial DI) is the result of partial or complete lack of osmoregulated AVP secretion. Plasma AVP concentrations are inappropriately low with respect to prevailing plasma osmolalities. Presentation with CDI implies destruction or loss of function of more than 80% of vasopressinergic magnocellular neurons. It is rare (estimated prevalence of 1: 25000), with an equal gender distribution. Though persistent polyuria can lead to dehydration, most patients can maintain water balance through appropriate polydipsia if given free access to water.

Most cases of CDI are acquired. Trauma (head injury or surgery) can produce CDI through damage to the hypothalamus, pituitary stalk, or posterior pituitary. Pituitary stalk trauma may lead to a triphasic disturbance in water balance, an immediate polyuric phase followed within days by a more prolonged period (up to several weeks) of antidiuresis suggestive of AVP excess. This second phase can be followed by reversion to CDI, or recovery. This characteristic 'triple response' reflects initial axonal damage; the subsequent unregulated release of large amounts of pre-synthesized AVP; and either recovery or development of permanent CDI (as determined by the magnitude of initial damage to vasopressinergic neurons). All phases of the response are not apparent in all cases.

Hypothalamic tumors (e.g., craniopharyngioma) or pituitary metastases (e.g., breast or bronchus) can present with CDI. However, primary pituitary tumors rarely cause CDI. In childhood, craniopharyngioma and germinoma/teratoma are a relatively common cause (81).

When obvious causes are not present, most cases of CDI will be “idiopathic”. However, the possibility of an autoimmune process should be considered, as many idiopathic cases are considered to be autoimmune in origin (82). A well-recognized cause of autoimmune CDI is lymphocytic infundibulohypophysitis (83).

Familial forms are rare, but are a recognized cause of CDI in childhood. Most reported cases are expressed as autosomal dominant and the genetic defect is usually in the biologically inactive neurophysin or in the signal peptide of the pre-prohormone. Lack of normal cleavage of the signal peptide from the prohormone and abnormal folding of the vasopressin/neurophysin precursor are thought to produce fibrillar aggregations in the endoplasmic reticulum, which is cytotoxic to the neuron, explaining the dominant phenotype (84, 85). Wolfram syndrome is a rare autosomal recessive disease with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD). The genetic defect is for the protein wolframin that is found in the endoplasmic reticulum and is important for folding proteins (86). Wolframin is localized to chromosome 4. It is involved in beta-cell proliferation and intracellular protein processing and calcium homeostasis, producing a wide spectrum of endocrine and central nervous system (CNS) disorders. Diabetes insipidus is usually a late manifestation and is associated with decreased magnocellular neurons in the paraventricular and supraoptic nuclei (87, 88).

Primary Polydipsia (PP)

PP is a polyuric syndrome secondary to excess fluid intake. PP can be associated with organic structural brain lesions, e.g. sarcoidosis of the hypothalamus (89) and craniopharyngioma (90). It can also be produced by drugs that cause a dry mouth or by any peripheral disorder causing an elevation of renin and/or angiotensin. However, mostly there is no identifiable pathologic etiology; in this circumstance the disorder is often associated with psychiatric syndromes. Series of patients in psychiatric hospitals have shown that as many as 42% have some form of polydipsia and for over half of those there was no obvious explanation for the polydipsia (91). It also seems to be increasingly prevalent in health conscious people who voluntarily change their drinking habits with the aim to improve their well-being, in which case it is often called habitual polydipsia (92).

Nephrogenic Diabetes Insipidus (NDI)

NDI is due to renal resistance to the antidiuretic effects of AVP. Genetic variants of NDI usually present in infancy (93). In these forms, NDI can occur as a result of mutations in the V2 receptor and mutations of the aquaporin 2 water channels. Over 90% of cases are X-linked recessive in males, and over 200 different mutations of the V2 receptor have been reported affecting all aspects of receptor function: expression; ligand binding; and G-protein coupling. Most lead to complete loss of function, though a few are associated with a mild phenotype. 10% of kindreds with familial NDI have an autosomal recessive form, with normal V2-R function. Affected individuals harbor loss of function mutations of the AQP2 gene. Most mutations occur in the region coding for the transmembrane domain of the protein. Additional rare kindreds have been described harboring a mutation in the portion of the gene encoding the carboxyl-terminal intracellular tail of AQP2. The NDI of these kindreds is inherited as an autosomal dominant trait, mutant protein sequestering the product of the wild type AQP2 allele within mixed tetramers in a dominant-negative manner.

The development of NDI in an adult is less likely to reflect a genetic cause. The commonest cause of acquired NDI in clinical practice is lithium therapy, with other causes including hypokalemia, hypercalcemia, and release of bilateral urinary tract obstruction associated with downregulation of aquaporin 2 and decreased function of vasopressin (94, 95). NDI secondary to lithium is characterized by dysregulated AQP2 expression and trafficking along the whole collecting duct as well as dysregulated expression of the amiloride-sensitive epithelial sodium channel (ENaC) in the cortical collecting duct. Lithium enters collecting duct cells through ENaC expressed on the apical cell membrane and leads to inhibition of glycogen synthase kinase type 3 (GSK-3) signaling pathways. NDI secondary to lithium toxicity can persist after drug withdrawal, and may be irreversible. Demeclocycline is another commonly recognized drug to causes NDI and is sometimes used clinically to treat SIAD. The final common pathway producing NDI in many of these cases is down-regulation of AQP2 expression (96).

Gestational Diabetes Insipidus

In normal pregnancy, physiologic adaptations include expansion of blood volume and decreased plasma osmolality and serum sodium. Thirst and increased fluid intake are commonly reported in pregnancy, but in some patients the increased thirst is driven by marked polyuria, which may point to the presence of diabetes insipidus. Two types of transient diabetes insipidus must be differentiated in pregnancy, both caused by the placental enzyme cysteine aminopeptidase, named oxytocinase, which enzymatically degrades oxytocin (97). Because of the close structural homology between AVP and oxytocin, this enzyme also metabolizes AVP. In the first type of pregnancy-associated DI, the activity of oxytocinase is abnormally elevated. This syndrome has been referred to as vasopressin resistant diabetes insipidus of pregnancy (98) and has been reported to be associated with preeclampsia, acute fatty liver, and coagulopathies. Symptoms usually develop at the end of the second or early third trimester and it is more common during multiple pregnancy (99). In the second type of pregnancy-associated DI, the accelerated metabolic clearance of vasopressin produces DI in a patient with borderline pre-existing vasopressin function from a mild nephrogenic diabetes insipidus or partial central diabetes insipidus. Vasopressin is rapidly destroyed and the neurohypophysis is unable to keep up with the increased demand. Symptoms in this second type usually appear early in pregnancy (100).

Treatment of Central DI

The primary aim of treatment in patients with diagnosed central DI should be to reduce polyuria and polydipsia to levels that allow maintenance of a normal lifestyle. The treatment of choice for those with significant symptoms is the synthetic, long-acting AVP analogue DDAVP. The long half-life, selectivity for AVPR2 and availability of multiple preparations renders desmopressin an ideal treatment for central DI. Optimal dosage and dosing intervals should be determined for each patient. The available treatment options are the intranasal spray, oral tablets, sublingual tablets or a parenteral injection, in divided doses. Oral preparations provide greater convenience and are usually preferred by patients. However, starting with a nasal spray initially is preferable because of greater consistency of absorption and physiological effect, after which the patient can be switched to an oral preparation. After trying both preparations, the patient can then choose which they prefer for long-term treatment. A satisfactory schedule can generally be determined using modest doses of desmopressin. The maximum dose of desmopressin required rarely exceeds 0.2 mg orally, 120 µg sublingually or 10 µg (one nasal spray) given 2–3 times daily. These doses usually produce plasma desmopressin levels higher than those required to cause maximum antidiuresis but reduce the need for more frequent treatment (120).

Hyponatremia is the major complication of desmopressin therapy — a 27% incidence of mild hyponatremia (serum sodium 131–134 mmol/l) and a 15% incidence of more severe hyponatremia (serum sodium ≤130 mmol/lm) have been reported after long-term follow-up of patients with chronic central DI (121). Hyponatremia usually occurs if the patient is antidiuretic while continuing normal fluid intake. Severe hyponatremia in patients with central DI who are treated with desmopressin can be avoided first by monitoring serum electrolyte levels frequently during initiation of therapy and second, patients should be instructed to delay a scheduled dose of desmopressin once or twice weekly until polyuria recurs, thereby allowing excess retained fluid to be excreted. A recent publication showed that patients using this approach had a significantly lower the risk of hyponataemia compared to those who did not follow this approach (OR 0.4, 95%CI 0.3-0.7, p<0.01) (122).

Mostly, Desmopressin is a lifelong treatment. An exception is treatment of postsurgical central DI. If the patient is awake and responds to thirst, thirst is a sufficient guide for water replacement. If the duration of diabetes insipidus is transient, it is therefore acceptable to treat simply with fluid replacement, parenterally or orally. However, most patients who develop diabetes insipidus require desmopressin 0.5 to 2 μg subcutaneously, intramuscularly, or intravenously. Urine output will be reduced in 1 to 2 hours and the duration of effect is 6 to 24 hours. Care should be taken that hypotonic intravenous fluids are not given excessively after administering desmopressin, as the combination can lead to profound hyponatremia. Because there is always the possibility of developing the triphasic response due to pituitary stalk damage, it is recommended that polyuria should be recurrent before a decision to administer subsequent doses of desmopressin is made (123).

Patients with hypernatremia due to osmoreceptor dysfunction (adipsic central DI) should be treated acutely with the same treatment as any hyperosmolar patient. The long-term management of osmoreceptor dysfunction syndromes requires a thorough search for potentially treatable causes, combined with measures to prevent dehydration. Because hypodipsia cannot be cured, the focus of management is based on education of the patient and family about the importance of regulating their fluid intake according to their hydration status (124). This can be accomplished most efficaciously by establishing a daily schedule of fluid intake regardless of the patient's thirst, which can be adjusted in response to changes in body weight (125). As these patients will not drink spontaneously, daily fluid intake must be fixed and prescribed. If the patient has polyuria, desmopressin should also be prescribed, as in any patient with central DI. The success of the fluid prescription should be monitored periodically by measuring serum Na⁺ concentration. In addition, periodic recalculation of the target weight (at which hydration status and serum Na⁺ concentration are normal) might be required.

Treatment of NDI

Treatment of acquired nephrogenic DI should target the underlying cause (e.g., correction of hypercalcemia or hypokalemia), if possible. If not, different approaches are possible.

• Low salt diet to minimize the osmotic load
• For patients on long-term lithium therapy, amiloride prevents uptake of lithium in the collecting duct epithelial cells and thus the inhibitory effects of intracellular lithium on water transport (126).
• Hydrochlorothiazide has been shown to reduce urine output in both central and nephrogenic DI (127, 128). Thiazides decrease salt reabsorption by inhibiting the thiazide-sensitive co-transporter SLC12A3 in the distal tubule. The loss of sodium reduces plasma volume, so that less water is presented to the collecting duct and lost in the urine.
• In an animal model of nephrogenic DI, use of the NSAID indomethacin reduced water diuresis independently of AVP (129). A similar effect of prostaglandin synthesis inhibitors was later reported in patients with nephrogenic DI (130). Since these early studies, prostaglandin synthesis inhibitors have become an essential component of the treatment of nephrogenic DI
• High dose DDAVP can produce a response in partial NDI

Treatment of PP

Treatment of primary polydipsia entails reduction of excessive fluid intakes, best done in a graded fashion to allow patients to slowly achieve a level of intake that reduced urine volume below polyuric levels (50 mL/kg BW). Measures to reduce mouth dryness (e.g., ice chips, hard candy to stimulate salivary flow) are useful adjuncts to reduce thirst. Pharmacologic therapies have been tried but without consistent evidence of success. A recent study suggests that GLP-1 analogues reduce fluid intake, urine output, and thirst perception(131).

Treatment of Gestational DI

Desmopressin is the only therapy recommended for treatment of diabetes insipidus during pregnancy. Desmopressin is reported to be safe for both the mother and the child (132, 133). During delivery, patients can maintain adequate oral intake and are therefore safe to continue administration of desmopressin. Physicians should be cautious about over administration of fluid parenterally during delivery because these patients will not be able to excrete the fluid and can develop water intoxication and hyponatremia. After delivery, plasma oxytocinase decreases and patients can recover completely or be asymptomatic with regard to fluid intake and urine excretion.

Etiology of SIAD

Many conditions have been reported to cause SIAD, though the mechanism(s) of inappropriate AVP release are not clear in many cases (Table 6). SIAD is a non-metastatic manifestation of small cell lung cancer and other malignancies. Some tumors express AVP ectopically. However, excessive posterior pituitary AVP secretion also occurs in association with malignancy. The normal osmoregulated AVP release found in the Type D syndrome suggests an increase in renal sensitivity to AVP, or the action of an additional antidiuretic factor.

SIAD is a common mechanism of drug-induced hyponatremia, and can reflect direct stimulation of AVP release from the hypothalamus; indirect action on the hypothalamus; or aberrant resetting of the hypothalamic osmostat (table 7). The prevalence of hyponatremia in patients taking high dose dopamine antagonists is greater than 25%, and is not restricted to one class of these drugs. Hyponatremia secondary to antidepressants is well recognized, occurring with most SSRIs, and the related drug Venlafaxine. It can arise in the first few weeks of treatment. Anticonvulsants are another common cause of SIAD and hyponatremia. The frequency in patients treated with carbamazepine (CBZ) ranges from 4.8 to 40%. Increased sensitivity of central osmoreceptors and increased renal responses to AVP have both been described with CBZ.

Exercise Associated Hyponatremia

Extreme endurance exercise is a profound physiological stressor. While the magnitude of the physiological stress is likely to reflect a number of factors, duration of the event and the effort entailed are likely to be major contributors. Non-osmoregulated AVP release is a feature of extreme endurance exercise: a reflection of the stressed state. When combined with reduced renal blood flow, another feature of extreme endurance exercise, this can lead to a marked antidiuretic state (figure 10). If endurance athletes maintain a fluid intake in excess of water loss, hyponatremia will ensue. This can be further complicated if there is aggressive fluid resuscitation in the event of collapse. There is a positive correlation between the odds ratio for developing hyponatremia during extreme endurance exercise and the length of time taken to complete the event. Athletes developing hyponatremia also demonstrate weight gain over the course of the event, clearly implicating water intake in excess of water and electrolyte loss as the cause. Occasional runners should be advised to follow their thirst as they run and avoid rigid, time-based fluid intake. Health professionals attending endurance events need to be aware of the problem of exercise-associated hyponatremia. In addition, they should avoid attempting resuscitation with large volumes of hypotonic fluid in the absence of appropriate indications and without biochemical monitoring (144).

Figure 10.

Exercise associated hyponatremia in triathletes. 1089 triathletes were studied. The mean plasma sodium level at the finish was 140.5±4.2 mmol/L (range 111-152). Among athletes completing the study events, 10.6% had documented hyponatremia: 8.7% mild; 1.6% severe; and 0.3% critical (3 athletes in total with plasma sodium levels 120, 119, and 111 mmol/L respectively). Multivariate analysis showed a significant association between development of hyponatremia and the following factors: female gender; longer times to complete a race. Critical hyponatremia occurred in participants who finished in the 12th and 14th hours of the race (145).

Nephrogenic Syndrome of Inappropriate Antidiuresis

The G-protein-coupled V2-R mediates the action of AVP on renal water excretion. Rare kindreds have been found that harbor constitutively activating mutations in the V2-R that led to AVP-independent, V2-R mediated, antidiuresis associated with persistent hyponatremia (Figure 11). This nephrogenic syndrome of inappropriate antidiuresis (NSIAD) was initially described in male infants with persistent hyponatremia in keeping with the haploinsufficiency associated with the V2-Rgene being on the X chromosome. However, subsequent studies have found the condition is not limited to males, expression of the condition being clearly identified in heterozygous females. The true prevalence of NSIAD is not known. However, as some 10% of patients with SIAD have been described as having undetectable AVP, it seems likely that at least some of these cases may be due to activating mutations of the V2-R (146, 147).

Figure 11.

In vitro bioactivity of different V2-R constructs relative to wild type (WT) in a cAMP-dependent luciferase reporter system in the absence of AVP. The R137H construct is the V2-R found in X-linked NDI. R137C and R137L are receptor variants found in NSIAD. Constructs differ only by the amino acid at position 137. R137C and R137L found in NSIAD demonstrate constitutive, AVP-independent activity. R: arginine. H: histidine. C: cysteine. L: leucine.

Cerebral Salt Wasting

This acquired, primary natriuretic state remains a subject of controversy. It has been characterized as a combination of hyponatremia with hypovolemia associated with neurological or (more often) neurosurgical pathologies. The underlying mechanism(s) remain unclear, but increased release of natriuretic peptides and/or reduced sympathetic drive have been proposed. The diagnosis of cerebral salt wasting (CSW) hinges on the natural history: the development of hyponatremia being preceded by natriuresis and diuresis with ensuing clinical and biochemical features of hypovolemia. In contrast to SIAD, urea and creatinine are elevated and there may be postural hypotension. The simple observation of weight loss over the period in question can be helpful.

SIAD can occur in the same group of patients in whom CSW has been reported. Both CSW and SIAD are associated with urine sodium concentrations greater than 40mmols/L. However, the natriuresis of CSW is much more profound than that of SIAD and precedes the development of hyponatremia. CSW is a particular concern for the neurosurgical patient in whom autoregulation of cerebral blood flow is disturbed and in whom small reductions in circulating volume can reduce cerebral perfusion. The management of CSW is volume replacement with 0.9% saline; while the cause-directed approach to SIAD would often involve restriction of fluid. The clinical and practice context, together with the opposed cause-directed management approaches to CSW and SIAD can lead to significant tension. A cause-independent approach to the management of the neurosurgical patient with hyponatremia is often the practical and pragmatic approach to take: balancing management of hyponatremia with the need to avoid threatening cerebral perfusion and avoidable vasospasm (148). Importantly, in a prospective, single center study of 100 patients developing hyponatremia after subarachnoid hemorrhage not a single case of CSW was identified: hyponatremia was attributable to SIAD, glucocorticoid deficiency, or inappropriate fluid administration (Figure 12). Therefore, CSW is probably a very rare condition.

Figure 12.

Hyponatremia after subarachnoid hemorrhage. Prospective study of 100 patients. Demographics, outcomes and etiology of hyponatremia noted. SAH: subarachnoid hemorrhage (149).

Management of Hyponatremia Associated with Severe or Moderately Severe Symptoms

Hyponatremia associated with severe or moderately severe symptoms requires urgent management as an emergency. Treatment is cause-independent. Treatment should be given priority over establishing the etiology of hyponatremia. The aim of treatment is to reduce immediate risk through increasing serum sodium to a level that decreases morbidity and mortality. Importantly, the rate of increase in serum sodium must be at a rate that does not result in harm through precipitating ODS (Figure 13). The immediate target should not be to normalize serum sodium. Once the patient is stable, investigations to establish the cause of hyponatremia can begin, the outcome of which subsequently guiding cause-directed therapy (140, 150, 151).

Figure 13.

Immediate, cause-independent management of hyponatremia associated with severe or moderately severe symptoms.

Previous strategies for the emergency management of hyponatremia have stratified patients based on presumed duration of the electrolyte disturbance. Furthermore, some have advocated hypertonic fluid administration volume and rates based on calculated deficits in serum sodium using a standard formula (152). A more pragmatic and reliable approach to patient stratification is to base the decision on use of hypertonic fluid on patient symptoms and signs; while the determining hypertonic fluid prescription by calculated serum sodium deficit is associated with a significant risk of over-correction (153). Over-correction of hyponatremia (increase in serum sodium above the recommended rate) should prompt review of the fluid regimen and consideration of active management with hypotonic fluid, with or without concurrent use of DDAVP (140, 154).

Two recent studies have compared bolus versus infusion hypertonic saline, both in favor of a bolus regimen. An Irish observational study compared outcomes for 22 hyponatremic patients treated with bolus 100ml 3% NaCl, compared to a historical cohort of 28 patients managed with 20ml/hour 3% NaCl infusion (155). Bolus hypertonic saline was associated with a faster elevation of serum sodium at 6 hours and significantly greater improvement in Glasgow Coma Scale at 6 hours. There were no cases of ODS in either group. A larger randomized trial from Korea included 178 patients with hyponatremia who were randomized to either bolus or infusion NaCl 3% (156). The results showed that both therapies were effective and safe, with no significant difference in overcorrection risk, but there was less need for therapeutic relowering in the bolus group compared to the slow continuous infusion. Bolus therapy is therefore currently recommended in guidelines.

Management of SIAD Associated with Mild to Moderate Symptoms

Fluid restriction: Fluid restriction of 0.5–1L/day is the first-line treatment recommended by EU and US guidelines (157). It is a reasonable initial intervention when the clinical condition is not critical. All fluids need to be included in the restriction. As SIAD is associated with a degree of natriuresis, sodium intake should be maintained. Fluid restriction may need to be maintained for several days before sodium levels normalize and it is important that a negative fluid balance is confirmed during this period. As cause-directed therapy progresses (e.g., treatment of underlying infection or removal of drug causing SIAD), fluid restriction may be relaxed. A recent randomized controlled trial evaluated the efficacy of fluid restriction in comparison to no treatment showing a modest early rise in serum sodium of 3mmol/L in fluid restricted patients compared to 1mmol/L with no treatment. Similar results were seen in other recent trials (158).

Of note, fluid restriction is not always effective, and a clinically useful response is only seen in around half of hyponatremic patients. In a large hyponatremia registry fluid restriction was unsuccessful in 55% of cases (159). Factors predicting a poor response to fluid restriction include high urine osmolality (>500 mosm/L), and high urine sodium concentration (or high urine/serum electrolyte ratio i.e. (UNa + UK)/pNa > 1, i.e., ‘Furst equation’) (150, 160, 161).

Drug treatment in SIAD: If patients do not respond to fluid restriction, a second-line treatment has to be initiated. There are several different possibilities, which are discussed in the following.

Urea is a product of hepatic nitrogen metabolism which is renally excreted and has an osmotic effect to promote free water excretion. It is recommended as a second line treatment in the European and US guidelines(140, 150). The evidence base for the use of urea is limited due to the retrospective observational nature of most current studies. In fact, there are several observational studies of urea, but no randomized trials to date. A retrospective observational trial reported a mean increase in sodium levels of 7 mmol/L over 4 days, with no instances of rapid correction (162). Another retrospective study reported that the majority of patients normalized sodium levels within 48 hours despite fluid intake >2 L/d (163). Finally, in patients with SIAD in the context of subarachnoid hemorrhage urea treatment led to sodium normalization within a mean time of 3 days (164).

Although overcorrection has been described, there have been no published cases of ODS due to urea therapy. The main limitations are the difficult access and poor palatability due to bitter taste, which can be ameliorated by combining it with a small volume of orange juice. Urea therapy can cause an increase in serum urea concentration and blood urea nitrogen, but this does not necessarily represent deterioration in renal function or hypovolemia (162).

Tolvaptan is an oral vasopressin V2-receptor antagonist that blocks AVP action in the kidney, inducing water diuresis and thereby raising sodium levels. An intravenous alternative conivaptan is also approved, but its use is limited to a maximum duration of 4 days because of drug interaction effects with other agents metabolized by the CYP3A4 hepatic isoenzyme. The efficacy of tolvaptan versus placebo was investigated in the randomized placebo-controlled SALT-1 and SALT-2 trials in patients with chronic eu- or hypervolemic hyponatremia (165). The results showed that tolvaptan increased sodium levels within 4 days by 4 mmol/L compared to only 1 mmol/L in the placebo group and an even higher increase within 30 days. The American expert panel recommends its use as a second-line treatment, whereas the European clinical practice guidelines recommend against the use of tolvaptan in moderate to profound hyponatremia, mainly due to lack of proven outcome benefit aside from increase in sodium levels and the concern of overcorrection. Importantly, discontinuing fluid restriction when vaptans are started, initiation of treatment in the hospital and regular sodium monitoring limit the risk for overcorrection. A lower initial dose of tolvaptan, 7.5 mg, which has been associated with lower rates of overcorrection, should also be considered (166). Common side effects of tolvaptan include dry mouth, thirst, and urinary frequency.

Sodium-glucose co-transporter 2 inhibitors are approved for treatment of diabetes and heart failure, but may also be beneficial in SIAD. The sodium-glucose co-transporter 2 in the proximal renal tubule is responsible for 90% of renal glucose resorption (167). Inhibition of SGLT2 leads to glycosuria, accompanied by an osmotic diuresis. A randomized trial of inpatients with SIAD compared 4 days of empagliflozin 25mg or placebo, in addition to fluid restriction (168). Plasma sodium increased by 10mmol/L over 4 days in the empagliflozin group, compared to 7mmol/L with placebo (p = 0.04). There was no hypotension or hypoglycemia observed. The relatively high sodium increment in the placebo group suggests that at least in some patients, reversible stimuli to AVP secretion may have been present. A second, randomized controlled cross-over study in 14 patients’ outpatients with chronic SIAD compared a 4-week treatment with empagliflozin 25mg/day to placebo, without concomitant fluid restriction. Empagliflozin treatment resulted in a serum sodium increase of 4.1mmol/L (p=0.004) under empagliflozin as compared to placebo. Treatment with empagliflozin was generally well tolerated with no events of sodium overcorrection, hypoglycemia, hypotension, urinary tract or genital infection occurring during the observation period (169). Future larger studies are needed to validate these findings.

Loop diuretics block the Na+-K+-2CL- cotransporter in the thick ascending limb of the loop of Henle and decrease delivery of sodium and chloride to the kidney medulla, decreasing the medullary gradient necessary for water reabsorption in the collecting duct. Salt tablets are added to replace loop diuretic-induced sodium losses. They are listed in the European practice guidelines as a second line therapy for SIAD in combination with salt tablets. However, a recent randomized controlled trial comparing the effect of FR alone versus FR plus loop diuretics versus FR plus loop diuretics plus salt tablets did not show a significant additive effect of loop diuretics or salt tablets (158). Acute kidney injury and hypokalemia were more common in patients receiving furosemide, therefore caution should be taken when adopting this strategy.

Demeclocycline has been used for many years in management of hyponatremia of SIAD. It produces a form of NDI and so increases renal water loss even in the presence of AVP. There is a lag time of some 3–4 days in onset of action and the effect is unpredictable occurring in 33-60% of patients. Photosensitive skin reactions are a significant additional adverse effect. There are very limited data to support long-term efficacy and a systematic review did not find good quality evidence for its use (170).

Lithium also induces nephrogenic diabetes insipidus and has therefore been tried as treatment for SIAD, however, due to adverse effects and questionable efficacy it is not recommended in European guidelines.