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Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Author:
Richard H Sterns, MD
Section Editor:
Michael Emmett, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Oct 2022. | This topic last updated: Jul 29, 2021.

INTRODUCTION — The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH) [1]. If water intake exceeds the reduced urine output, the ensuing water retention leads to the development of hyponatremia.

The SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine osmolality above 100 mosmol/kg. In SIADH, the urine sodium concentration is usually above 40 mEq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the serum uric acid concentration is frequently low [1]. (See "Diagnostic evaluation of adults with hyponatremia".) (Related Pathway(s): Hyponatremia: Evaluation in adults.)

The pathophysiology and etiology of SIADH will be reviewed here. The treatment of this disorder is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)

PATHOPHYSIOLOGY

Pathogenesis of hyponatremia — The plasma sodium concentration (PNa) is a function of the ratio of the body's content of exchangeable sodium and potassium (NaE and KE) and total body water (TBW) as described by Edelman's classic equation:

 PNa  ≈  (NaE + KE)/Total body water

Antidiuretic hormone (ADH, arginine vasopressin) secretion results in a concentrated urine and therefore a reduced urine volume. The higher the plasma ADH, the more concentrated the urine. In most patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), ingestion of water does not adequately suppress ADH, and the urine remains concentrated. This leads to water retention, which increases TBW. This increase in TBW lowers the plasma sodium concentration by dilution (see above equation) [1]. In addition, the increase in TBW transiently expands the extracellular fluid volume and thereby triggers increased urinary sodium excretion, which both returns the extracellular fluid volume toward normal and further lowers the plasma sodium concentration.

Hyponatremia can occur in SIADH even if the only fluid given is isotonic saline [2]. The mechanism by which this occurs and why isotonic saline administration can lower the plasma sodium concentration in patients with SIADH and a highly concentrated urine is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous hypertonic saline'.)

Patterns of ADH secretion — In normal individuals, plasma ADH levels are very low when the plasma osmolality is below 280 mosmol /kg, thereby permitting the excretion of ingested water, and ADH levels increase progressively as the plasma osmolality rises above 280 mosmol/kg (figure 1).

ADH regulation is impaired in SIADH; five different patterns have been described [3-5]. The prevalence of these patterns differs among series:

Type A is characterized by grossly elevated levels of ADH unresponsive to osmotic deviations [5]. Plasma ADH levels are often above that required for maximum antidiuresis, so the urine osmolality is typically very high. High hormone levels above the physiologic range suggest ectopic secretion of ADH, most commonly by bronchogenic carcinoma.

Type B is characterized by an abnormally low osmotic threshold for ADH release (ie, a threshold that is below the level of plasma osmolality at which plasma ADH becomes detectable in normal individuals) and a linear increase in plasma ADH in response to a rising plasma osmolality. Such patients have been described as having a "reset osmostat." Establishing the presence of this condition is important because, unlike other forms of SIADH, there is no need to be concerned that the plasma sodium will continue to fall without therapy, because ADH secretion is suppressed when the plasma osmolality falls below the reset threshold level. This disorder is discussed in detail elsewhere. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)

Type C is characterized by ADH levels that are persistently in the physiologic range and are neither suppressed by a low plasma osmolality nor stimulated by a rising plasma osmolality. This pattern differs quantitatively from type A, in which superphysiologic levels of ADH are observed. However, like type A, it could occur in patients with ectopic ADH secretion.

Type D is characterized by normal osmoregulation (ie, ADH secretion varies appropriately with the plasma osmolality), but the urine is concentrated even if ADH release is suppressed. At least one mechanism by which this occurs is a germ cell mutation in which the vasopressin-2 (V2) receptor is constituently activated [3]. However, one study found that none of the six patients with a type D pattern had an activating mutation of the V2 receptor [5]. Other potential mechanisms include production of an antidiuretic compound other than immunoreactive arginine vasopressin and a postreceptor defect in trafficking of aquaporin-2 water channels, which mediate ADH-induced antidiuresis. (See 'Hereditary SIADH' below.)

Type E is characterized by a decline in plasma ADH as the serum sodium concentration increases during infusion of hypertonic saline. This pattern is hypothesized to be caused by altered baroreceptor signaling despite normovolemia so that a minor decrease in blood pressure or blood volume results in a large increase in ADH secretion. Similarly, a minor increase in blood pressure or blood volume caused by saline infusion results in a large decrease in ADH secretion [5].

Determinants of urine output — In addition to the persistent secretion of ADH, there are two other potentially important determinants of the urine output in patients with SIADH: the rate of solute excretion and partial escape from the effect of ADH.

Solute excretion — In normal subjects, the urine output is primarily determined by water intake. Changes in water intake lead to alterations in the plasma osmolality that are sensed by the osmoreceptors in the hypothalamus that regulate both ADH release and thirst. As an example, an increase in water intake sequentially lowers the plasma osmolality, decreases ADH secretion, and reduces collecting tubule permeability to water; the net effect is the rapid excretion of the excess water in a dilute urine.

In SIADH, however, an increase in water intake does not produce an increase in water excretion because ADH release is relatively fixed. Suppose that a patient has moderately severe SIADH with a urine osmolality that cannot be reduced below 750 mosmol/kg (the normal minimum urine osmolality is 40 to 100 mosmol/kg). In this patient, the urine output is determined by the rate of excretion of solutes (primarily sodium and potassium salts and urea). Now suppose this patient consumes a typical Western diet containing approximately 750 mosmol of solute, all of which are excreted in the urine each day. With a fixed urine osmolarity of 750 mosmol/kg, the daily urine output will be only one liter (750 ÷ 750 = 1), and it will not increase in response to increased water intake.

One way to increase water excretion in this hypothetical patient with SIADH is to prescribe a high-salt and -protein diet while restricting water ingestion. If, for example, the solute intake and therefore solute excretion rose to 1200 mosmol/day, the urine output would increase to 1.6 L/day (1200 ÷ 750 = 1.6). The increase in water excretion would then tend to raise the plasma sodium concentration toward normal.

Similar considerations concerning the role of solute intake apply when ADH effect is relatively fixed at a low level in central or nephrogenic diabetes insipidus. (See "Urine output in diabetes insipidus".)

Escape from the effect of ADH — Studies in experimental animals given ADH and water have shown an initial phase of water retention and hyponatremia followed by partial escape from the antidiuresis so that, despite persistently high levels of ADH, urine osmolality decreases. When the urine osmolality falls, water excretion increases, matching water intake, and the plasma sodium concentration tends to stabilize [6,7]. A similar response appears to occur in humans [8,9].

This escape from ADH-induced antidiuresis appears to be mediated by decreased expression of aquaporin-2, the ADH-sensitive water channel in the collecting tubules [10]. The regulation of aquaporin-2 in this setting appears to be unrelated to plasma or tissue osmolality [11,12].

ETIOLOGY — One of the following causes of persistent antidiuretic hormone (ADH) release is likely to be present in patients who fulfill the clinical criteria for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) [1,13].

CNS disturbances — Any CNS disorder, including stroke, hemorrhage, infection, trauma, and psychosis, can enhance ADH release. A discussion of the disturbances in water balance that may occur in patients with mental illness and a brief review of the antidiuretic action of carbamazepine, a drug that can cause an SIADH picture, are found elsewhere. (See "Causes of hypotonic hyponatremia in adults".)

As in other causes of SIADH, hyponatremia associated with intracranial bleeding, as well as other severe neurologic events, is due to ADH-mediated water retention and to urinary sodium losses. However, with these severe neurologic conditions, there is uncertainty as to whether the sodium losses are a result of SIADH-induced expansion of the extracellular volume or whether they are caused by salt wasting (ie, cerebral salt wasting), with release of ADH that is secondary to a reduction in extracellular fluid volume. (See 'Cerebral salt wasting' below.)

Because of this uncertainty, therapy of hyponatremia in patients with CNS disorders usually requires the administration of hypertonic saline, rather than fluid restriction or isotonic saline. (See 'Cerebral salt wasting' below.)

Malignancies — Ectopic production of ADH by a tumor is most often due to a small cell carcinoma of the lung and is rarely seen with other lung tumors [1,14]. Less common causes of malignancy-associated SIADH include head and neck cancer, olfactory neuroblastoma (esthesioneuroblastoma), and extrapulmonary small cell carcinomas [15-17].

Ectopic ADH secretion by tumor cells has been documented in vitro. In addition, some small cell lung cancer cells increase ADH secretion in response to high osmolality, suggesting a degree of regulation of the ectopic secretion [18]. This in vitro finding is compatible with the clinical observation that some patients with tumor-induced SIADH show evidence of osmoregulation of ADH release [4]. (See "Pathobiology and staging of small cell carcinoma of the lung".)

Drugs — Certain drugs can enhance ADH release or effect, including chlorpropamide, carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose intravenous cyclophosphamide, and selective serotonin reuptake inhibitors (table 1) [1,19-27]. Experimental studies suggest that chlorpropamide may increase concentrating ability both by increasing sodium chloride reabsorption in the loop of Henle (thereby enhancing the efficiency of countercurrent exchange) and by augmenting collecting tubule permeability to water [20]. The latter effect may be mediated by an increased number of ADH receptors in the collecting tubule cells. Carbamazepine and oxcarbazepine also act at least in part by increasing the sensitivity to ADH [21,22,25].

SIADH due to high-dose intravenous cyclophosphamide may be a particular problem since patients receiving this regimen are often fluid loaded to prevent hemorrhagic cystitis [26,27]. As a result, marked water retention and potentially fatal hyponatremia may ensue in selected cases [26]. This complication has been primarily described with doses in the range of 30 to 50 mg/kg used to treat malignancy, or 6 g/m2 as given in the STAMP protocol in preparation for bone marrow rescue [27]. Although less common, hyponatremia can also occur with the lower doses (10 to 15 mg/kg) that are given as pulse therapy in autoimmune diseases such as lupus nephritis. Chemotherapy-induced nausea may play a contributory role since nausea is a potent stimulus to ADH release [28]. The fall in the plasma sodium concentration in this setting can be minimized by using isotonic saline rather than free water to maintain a high urine output.

SIADH is also associated with the selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline) [29-33]. The exact prevalence is unknown; patients above age 65 years may be more susceptible to the complication [33]. The risk of developing severe hyponatremia requiring hospitalization is greatest in the first few weeks after initiating treatment with these agents [34].

Many other drugs have been associated with the SIADH. These include vincristine, vinblastine, vinorelbine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine oxidase inhibitors, melphalan, ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents, interferon-alpha, interferon-gamma, sodium valproate, bromocriptine, lorcainide, amiodarone, ciprofloxacin, high-dose imatinib, and "ecstasy" (methylenedioxymethamphetamine), a drug of abuse that may also be associated with excessive water intake [1,29,35-39].

Surgery — Surgical procedures are often associated with hypersecretion of ADH, a response that is probably mediated by pain afferents [40-42]. In addition, hyponatremia may develop after other types of interventional procedures, such as cardiac catheterization [43].

Hyponatremia is also a common late complication of transsphenoidal pituitary surgery, occurring in 21 to 35 percent of cases [44,45]. Although relative cortisol deficiency may contribute, the major cause is inappropriate ADH release from the injured posterior pituitary gland. The fall in the plasma sodium concentration is most severe on the sixth to seventh postoperative day. This form of isolated hyponatremia (or isolated second phase) appears to be a subset of the classic triphasic cycle in which initial polyuria is followed by transient SIADH and then either recovery or, in severe cases, a third phase of permanent central diabetes insipidus. (See "Clinical manifestations and causes of central diabetes insipidus", section on 'Neurosurgery or trauma'.)

Rarely, hyponatremia after pituitary surgery is due to cerebral salt wasting. (See 'Cerebral salt wasting' below.)

Pulmonary disease — Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can lead to the SIADH, although the mechanism by which this occurs is not clear [41]. A similar response may infrequently be seen with asthma, atelectasis, acute respiratory failure, and pneumothorax [1,41].

Hormone deficiency — Both hypopituitarism and hypothyroidism may be associated with hyponatremia and an SIADH picture that can be corrected by hormone replacement. (See "Hyponatremia and hyperkalemia in adrenal insufficiency" and "Causes of hypotonic hyponatremia in adults", section on 'Hypothyroidism'.)

Hormone administration — The SIADH can by induced by exogenous hormone administration, as with vasopressin (to control gastrointestinal bleeding), desmopressin (dDAVP; to treat von Willebrand disease or hemophilia or platelet dysfunction), or oxytocin (to induce labor) [46-49]. As with vasopressin and desmopressin, oxytocin acts by increasing the activity of the vasopressin-2 (V2; antidiuretic) receptor [50].

HIV infection — A common cause of hyponatremia is symptomatic HIV infection, either the acquired immune deficiency syndrome (AIDS) or early symptomatic HIV infection [51]. Although volume depletion (due, for example, to gastrointestinal losses) or adrenal insufficiency may be responsible, many patients have the SIADH. Pneumonia, due to Pneumocystis carinii or other organisms, central nervous system infections, and malignant disease, are most often responsible in this setting [51]. (See "Electrolyte disturbances with HIV infection".)

Hereditary SIADH — The clinical picture of SIADH may result from genetic disorders that result in antidiuresis. A mutation affecting the gene for the renal V2 receptor, which some investigators have named nephrogenic syndrome of inappropriate antidiuresis, has been found to cause clinically significant hyponatremia.

In the initial description of the nephrogenic syndrome, two male infants were described who presented with hyponatremia, hypoosmolality, increased urine osmolality, and a high urine sodium concentration consistent with SIADH, but with no detectable circulating ADH [52,53]. Gain-of-function mutations were found in the gene encoding the V2 receptor that mediates the antidiuretic response to ADH; persistent activation of the receptor was responsible for the persistent antidiuretic state [54]. The gene for the V2 receptor is located on the X chromosome, and loss-of-function mutations of the gene are responsible for X-linked nephrogenic diabetes insipidus. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hereditary nephrogenic DI'.)

The nephrogenic syndrome of inappropriate antidiuresis has also been found in adult men and women. In one study, a 74-year-old man with an initial diagnosis of SIADH was unresponsive to oral inhibitors of the V2 receptor; he was subsequently discovered to have a gain-of-function mutation of the gene for this receptor [55]. After screening of family members, two additional hemizygous males and four heterozygous females were identified. Spontaneous episodes of hyponatremia and/or an abnormal water load test were observed in all but one woman with the genetic defect, who had preferential inactivation of the X chromosome harboring the mutated allele.

Most patients with the nephrogenic syndrome of inappropriate antidiuresis harbor a mutation that "locks" the V2 receptor in the open position and thereby makes it unresponsive to vasopressin antagonists [56]. Gain-of-function mutations involving other regions of the gene have been reported in which response to vasopressin antagonists is preserved [57].

An activating mutation affecting the signaling pathway between the V2 receptor and cyclic adenosine monophosphate has been identified as another cause of the nephrogenic syndrome of antidiuresis in children with hyponatremia [58]. The mutation is located in the gene encoding the guanine-nucleotide alpha subunit (GNAS), which is involved in transmitting signals via the G protein-coupled V2 receptor.

Polymorphisms in the genes encoding the hypothalamic osmoreceptor, transient receptor potential vanilloid type 4 (TRPV4), may also cause mild hyponatremia [59]. Population studies show that men but, for reasons unknown, not women with a proline to serine substitution at residue 19 are two to six times more likely to have a serum sodium ≤135 mEq/L than men with the wild-type allele [59]. The mean serum sodium concentrations among men with one copy of the variant allele are lower by approximately 2 mEq/L. In vitro, TRPV4 channels with the variant allele are hyporesponsive to mild hypotonic stress but respond normally to severe osmotic stress. Thus, affected individuals would be expected to behave as if they have a reset osmostat, with a lower-than-normal serum sodium concentration that regulates normally around that value. Based upon what has been observed in genetically engineered mice that lack a functioning TRVPV4 channel, it has been postulated that humans with the variant hypofunctioning allele would exhibit unrestricted drinking, and therefore, more severe hyponatremia, if they were to develop SIADH for another reason. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)

Idiopathic — Idiopathic SIADH has been described primarily in older adult patients [60-63]. However, some cases of apparently idiopathic disease were later found to be caused by an occult tumor (most often small cell carcinoma or olfactory neuroblastoma) and, in older patients, giant cell (temporal) arteritis [1,61,64,65].

CEREBRAL SALT WASTING — A rare syndrome has been described in patients with cerebral disease (particularly subarachnoid hemorrhage) that mimics all of the findings in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) except that salt wasting is thought to be the primary defect, with the ensuing volume depletion causing a secondary rise in antidiuretic hormone (ADH) release. This distinction is not easy to make since the true volume status of the patient is often difficult to ascertain. The pathogenesis, manifestations, and treatment of cerebral salt wasting are discussed separately. (See "Cerebral salt wasting".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) (The Basics)")

SUMMARY

Definition – The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH). (See 'Introduction' above.)

SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine osmolality above 100 mosmol/kg (algorithm 1). In SIADH, the urine sodium concentration is usually above 40 mEq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the serum uric acid concentration is frequently low. (See 'Introduction' above.) (Related Pathway(s): Hyponatremia: Evaluation in adults.)

Pathogenesis – ADH secretion results in a concentrated urine and therefore a reduced urine volume. In most patients with SIADH, ingestion of water does not adequately suppress ADH, and the urine remains concentrated. This leads to water retention, which increases total body water (TBW). This increase in TBW lowers the plasma sodium concentration by dilution. In addition, the increase in TBW transiently expands the extracellular fluid volume and thereby triggers increased urinary sodium excretion, which both returns the extracellular fluid volume toward normal and further lowers the plasma sodium concentration. (See 'Pathophysiology' above.)

Etiology – One of the following causes of persistent ADH release is likely to be present in patients who fulfill the clinical criteria for the SIADH (see 'Etiology' above):

Any CNS disorder, including stroke, hemorrhage, infection, trauma, and psychosis can enhance ADH release. There is uncertainty as to whether hyponatremia in patients with severe neurologic disorders (such as hemorrhage or trauma) is due to SIADH or salt wasting (ie, cerebral salt wasting). (See 'CNS disturbances' above and 'Cerebral salt wasting' above.)

Ectopic production of ADH by a tumor is most often due to a small cell carcinoma of the lung and is rarely seen with other lung tumors. Less common causes of malignancy-associated SIADH include head and neck cancer, olfactory neuroblastoma (esthesioneuroblastoma), and extrapulmonary small cell carcinomas. (See 'Malignancies' above.)

Certain drugs can enhance ADH release or effect, including chlorpropamide, carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose intravenous cyclophosphamide, and selective serotonin reuptake inhibitors (table 1). Many other drugs have been associated with the SIADH. These include vincristine, vinblastine, vinorelbine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine oxidase inhibitors, melphalan, ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents, interferon-alpha, interferon-gamma, sodium valproate, bromocriptine, lorcainide, amiodarone, ciprofloxacin, and high-dose imatinib. "Ecstasy" (methylenedioxymethamphetamine) is a drug of abuse that may also be associated with both SIADH and excessive water intake. (See 'Drugs' above.)

Surgical procedures are often associated with hypersecretion of ADH, a response that is probably mediated by pain afferents. In addition, hyponatremia may develop after other interventional medical procedures, such as cardiac catheterization. (See 'Surgery' above.)

Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can lead to the SIADH, although the mechanism by which this occurs is not clear. A similar response may infrequently be seen with asthma, atelectasis, acute respiratory failure, and pneumothorax. (See 'Pulmonary disease' above.)

Both hypopituitarism and hypothyroidism may be associated with hyponatremia and clinical findings identical to SIADH, but these abnormalities are corrected by hormone replacement. (See 'Hormone deficiency' above.)

SIADH can by induced by exogenous administration of hormones: vasopressin (to control gastrointestinal bleeding); ADH analogs, such as desmopressin (dDAVP; to treat von Willebrand disease, hemophilia, other forms of platelet dysfunction, or enuresis); or other hormones with antidiuretic effects, such as oxytocin (to induce labor). (See 'Hormone administration' above.)

Symptomatic HIV infection is associated with SIADH. (See 'HIV infection' above.)

The clinical picture of SIADH may result from genetic disorders that result in antidiuresis. (See 'Hereditary SIADH' above.)

  1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.703.
  2. Steele A, Gowrishankar M, Abrahamson S, et al. Postoperative hyponatremia despite near-isotonic saline infusion: a phenomenon of desalination. Ann Intern Med 1997; 126:20.
  3. Robertson GL. Regulation of arginine vasopressin in the syndrome of inappropriate antidiuresis. Am J Med 2006; 119:S36.
  4. Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int 1976; 10:25.
  5. Fenske WK, Christ-Crain M, Hörning A, et al. A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis. J Am Soc Nephrol 2014; 25:2376.
  6. Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988; 34:351.
  7. Gross PA, Anderson RJ. Effects of DDAVP and AVP on sodium and water balance in conscious rat. Am J Physiol 1982; 243:R512.
  8. LEAF A, BARTTER FC, SANTOS RF, WRONG O. Evidence in man that urinary electrolyte loss induced by pitressin is a function of water retention. J Clin Invest 1953; 32:868.
  9. JAENIKE JR, WATERHOUSE C. The renal response to sustained administration of vasopressin and water in man. J Clin Endocrinol Metab 1961; 21:231.
  10. Ecelbarger CA, Nielsen S, Olson BR, et al. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J Clin Invest 1997; 99:1852.
  11. Murase T, Ecelbarger CA, Baker EA, et al. Kidney aquaporin-2 expression during escape from antidiuresis is not related to plasma or tissue osmolality. J Am Soc Nephrol 1999; 10:2067.
  12. Saito T, Higashiyama M, Nagasaka S, et al. Role of aquaporin-2 gene expression in hyponatremic rats with chronic vasopressin-induced antidiuresis. Kidney Int 2001; 60:1266.
  13. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007; 356:2064.
  14. Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997; 156:1669.
  15. Ferlito A, Rinaldo A, Devaney KO. Syndrome of inappropriate antidiuretic hormone secretion associated with head neck cancers: review of the literature. Ann Otol Rhinol Laryngol 1997; 106:878.
  16. Talmi YP, Wolf GT, Hoffman HT, Krause CJ. Elevated arginine vasopressin levels in squamous cell cancer of the head and neck. Laryngoscope 1996; 106:317.
  17. Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238:97.
  18. Kim JK, Summer SN, Wood WM, Schrier RW. Osmotic and non-osmotic regulation of arginine vasopressin (AVP) release, mRNA, and promoter activity in small cell lung carcinoma (SCLC) cells. Mol Cell Endocrinol 1996; 123:179.
  19. Weissman PN, Shenkman L, Gregerman RI. Chlorpropamide hyponatremia: drug-induced inappropriate antidiuretic-hormone activity. N Engl J Med 1971; 284:65.
  20. Hensen J, Haenelt M, Gross P. Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptors. Eur J Endocrinol 1995; 132:459.
  21. Gold PW, Robertson GL, Ballenger JC, et al. Carbamazepine diminishes the sensitivity of the plasma arginine vasopressin response to osmotic stimulation. J Clin Endocrinol Metab 1983; 57:952.
  22. Kamiyama T, Iseki K, Kawazoe N, et al. Carbamazepine-induced hyponatremia in a patient with partial central diabetes insipidus. Nephron 1993; 64:142.
  23. Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994; 35:181.
  24. Nielsen OA, Johannessen AC, Bardrum B. Oxcarbazepine-induced hyponatremia, a cross-sectional study. Epilepsy Res 1988; 2:269.
  25. Sachdeo RC, Wasserstein A, Mesenbrink PJ, D'Souza J. Effects of oxcarbazepine on sodium concentration and water handling. Ann Neurol 2002; 51:613.
  26. Bressler RB, Huston DP. Water intoxication following moderate-dose intravenous cyclophosphamide. Arch Intern Med 1985; 145:548.
  27. Salido M, Macarron P, Hernández-García C, et al. Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus. Lupus 2003; 12:636.
  28. Nausea and vasopressin. Lancet 1991; 337:1133.
  29. ten Holt WL, van Iperen CE, Schrijver G, Bartelink AK. Severe hyponatremia during therapy with fluoxetine. Arch Intern Med 1996; 156:681.
  30. Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports. CMAJ 1996; 155:519.
  31. Covyeou JA, Jackson CW. Hyponatremia associated with escitalopram. N Engl J Med 2007; 356:94.
  32. Ozturk S, Ozsenel EB, Kazancioglu R, Turkmen A. A case of fluoxetine-induced syndrome of inappropriate antidiuretic hormone secretion. Nat Clin Pract Nephrol 2008; 4:278.
  33. Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study. Arch Intern Med 2004; 164:327.
  34. Mannheimer B, Falhammar H, Calissendorff J, et al. Time-dependent association between selective serotonin reuptake inhibitors and hospitalization due to hyponatremia. J Psychopharmacol 2021; 35:928.
  35. Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-secretion after "ecstasy" (3,4-MDMA). Lancet 1996; 347:1052.
  36. Wilkins B. Cerebral oedema after MDMA ("ecstasy") and unrestricted water intake. Hyponatraemia must be treated with low water input. BMJ 1996; 313:689.
  37. Adler D, Voide C, Thorens JB, Desmeules J. SIADH consecutive to ciprofloxacin intake. Eur J Intern Med 2004; 15:463.
  38. Liapis K, Apostolidis J, Charitaki E, et al. Syndrome of inappropriate secretion of antidiuretic hormone associated with imatinib. Ann Pharmacother 2008; 42:1882.
  39. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52:144.
  40. Fieldman NR, Forsling ML, Le Quesne LP. The effect of vasopressin on solute and water excretion during and after surgical operations. Ann Surg 1985; 201:383.
  41. Anderson RJ. Hospital-associated hyponatremia. Kidney Int 1986; 29:1237.
  42. Gowrishankar M, Lin SH, Mallie JP, et al. Acute hyponatremia in the perioperative period: insights into its pathophysiology and recommendations for management. Clin Nephrol 1998; 50:352.
  43. Aronson D, Dragu RE, Nakhoul F, et al. Hyponatremia as a complication of cardiac catheterization: a prospective study. Am J Kidney Dis 2002; 40:940.
  44. Sane T, Rantakari K, Poranen A, et al. Hyponatremia after transsphenoidal surgery for pituitary tumors. J Clin Endocrinol Metab 1994; 79:1395.
  45. Olson BR, Rubino D, Gumowski J, Oldfield EH. Isolated hyponatremia after transsphenoidal pituitary surgery. J Clin Endocrinol Metab 1995; 80:85.
  46. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia 2000; 6:11.
  47. Shepherd LL, Hutchinson RJ, Worden EK, et al. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989; 114:470.
  48. Humphries JE, Siragy H. Significant hyponatremia following DDAVP administration in a healthy adult. Am J Hematol 1993; 44:12.
  49. Feeney JG. Water intoxication and oxytocin. Br Med J (Clin Res Ed) 1982; 285:243.
  50. Li C, Wang W, Summer SN, et al. Molecular mechanisms of antidiuretic effect of oxytocin. J Am Soc Nephrol 2008; 19:225.
  51. Vitting KE, Gardenswartz MH, Zabetakis PM, et al. Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome. JAMA 1990; 263:973.
  52. Gitelman SE, Feldman BJ, Rosenthal SM. Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in water balance in pediatric patients. Am J Med 2006; 119:S54.
  53. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005; 352:1884.
  54. Carpentier E, Greenbaum LA, Rochdi D, et al. Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD. J Am Soc Nephrol 2012; 23:1635.
  55. Decaux G, Vandergheynst F, Bouko Y, et al. Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol 2007; 18:606.
  56. Powlson AS, Challis BG, Halsall DJ, et al. Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2. Clin Endocrinol (Oxf) 2016; 85:306.
  57. Erdélyi LS, Mann WA, Morris-Rosendahl DJ, et al. Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis. Kidney Int 2015; 88:1070.
  58. Miyado M, Fukami M, Takada S, et al. Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis. J Am Soc Nephrol 2019; 30:877.
  59. Tian W, Fu Y, Garcia-Elias A, et al. A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia. Proc Natl Acad Sci U S A 2009; 106:14034.
  60. Goldstein CS, Braunstein S, Goldfarb S. Idiopathic syndrome of inappropriate antidiuretic hormone secretion possibly related to advanced age. Ann Intern Med 1983; 99:185.
  61. Sterns RH. The syndrome of inappropriate antidiuretic hormone secretion of unknown origin. Am J Kidney Dis 1999; 33:161.
  62. Miller M, Hecker MS, Friedlander DA, Carter JM. Apparent idiopathic hyponatremia in an ambulatory geriatric population. J Am Geriatr Soc 1996; 44:404.
  63. Anpalahan M. Chronic idiopathic hyponatremia in older people due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) possibly related to aging. J Am Geriatr Soc 2001; 49:788.
  64. Inappropriate antidiuretic hormone secretion of unknown origin. Kidney Int 1980; 17:554.
  65. Gentric A, Baccino E, Mottier D, et al. Temporal arteritis revealed by a syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 1988; 85:559.
Topic 2384 Version 23.0

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