Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management

Abstract

Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.

Keywords: empagliflozin; fluid restriction; hyponatremia; sodium-glucose cotransporter 2 inhibitors (SGLT2i); syndrome of inappropriate antidiuresis (SIAD); tolvaptan; urea.

Graphical Abstract

Figure 1.

Classification of hyponatremia according to tonicity. Syndrome of inappropriate antidiuresis (SIAD) is the most common cause of hypotonic hyponatremia. Adapted from Sahay 2014 with permission (343), with reference to Spasovski 2014 (15).

Figure 2.

Useful formulae in the management of hyponatremia. Cr, creatinine; FEUA, fractional excretion of uric acid; mOsm, milliosmoles; Na⁺ , sodium; UA, uric acid. References (in order): Hiller 1999 (9), Adrogué 1997 (344), Maesaka 1998 (207), and Fürst 2000 (276).

Figure 3.

Schematic diagram of the development of acute vs chronic onset of hyponatremia, explaining typical difference in symptom severity. Intensity of shading is a visual representation of osmolality. Acute hyponatremia results in relatively hypotonic serum/cerebrospinal fluid (CSF) compared to brain tissue, leading to osmotic influx of water into glial cells to equalise osmolar gradient, which may cause cerebral edema and potential seizure, coma, and death. Chronic hyponatremia often occurs more gradually. As serum/CSF osmolality falls, water enters the brain more slowly and is matched by export or deactivation of brain osmolytes including sodium, potassium, and organic osmolytes (eg, myoinositol, glycerophosphorylcholine, creatine, glutamate, glutamine, taurine) to equalize the osmolar gradient (116). The resulting hypotonic brain is vulnerable to rapid correction if the reverse process happens too rapidly, which may cause osmotic demyelination syndrome (see Fig. 7).

Figure 4.

Causes of syndrome of inappropriate antidiuresis (SIAD). Malignancy (solid organ (particularly lung and nasopharyngeal), lymphoma). Pulmonary disorders (infection, asthma, cystic fibrosis, respiratory failure). Central nervous system disorders (infection, hemorrhage, thrombosis, trauma, tumour, hydrocephalus, autoimmune (multiple sclerosis, Guillain-Barré syndrome), multiple system atrophy, delirium tremens). Transient stimuli (nausea, pain, stress, prolonged endurance exercise, general anesthesia, pituitary surgery). Drugs (see Table 5). Idiopathic (“reset osmostat,” cause not yet apparent). Hereditary (nephrogenic SIAD). AVP, arginine vasopressin. Original figure created with BioRender, with reference to Spasovski 2014 (15).

Figure 5.

Mechanism of arginine vasopressin (AVP) action at renal V2 receptors. AVP interacts with the vasopressin V2 receptor on the principal cells of the renal collecting duct. When the G protein-coupled receptor V2 receptor is activated, cyclic adenosine monophosphate signaling leads to increased synthesis and deployment of aquaporins, which are stored in intracellular vesicles which then merge with the luminal cell wall. Aquaporins allow the resorption of solute-free water out of the filtrate and into serum, resulting in more concentrated urine excretion. AVP also acts on epithelial sodium channel (ENaC) urea transporters to increase sodium and urea resorption to increase medullary interstitial osmolality and hence urinary concentrating gradient. Persistent AVP stimulation “inappropriate” with respect to serum osmolality will lead to excessive water retention and a fall in serum osmolality and serum sodium concentration. Original figure created with BioRender, with reference to Christ-Crain 2019.

Figure 6.

Biochemical subtypes of syndrome of inappropriate antidiuresis (SIAD), categorized according to 5 patterns of copeptin (types A-E), based on copeptin measurement when hyponatremic, and after infusion of hypertonic saline to normalized serum sodium. This illustrates distinct phenotypes of SIAD based on arginine vasopressin response—the clinical significance of which is not clear. Upper graph is an original figure, adapted from A-E below. A-E are reproduced from Fenske 2014 (96) with permission.

Figure 7.

Principles of management of acute vs chronic hyponatremia, and potential risks. Intensity of shading is a visual representation of osmolality. In acute hyponatremia, cerebral osmolar adaptation has not yet occurred so it is acceptable to allow (or induce) rapid correction of serum sodium, with low risk of ODS. We advocate a cutoff of hyponatremia duration less than 24 hours rather than 48 hours to maximize the safety of this approach. In hyponatremia with severe symptoms of any (or unknown) duration, emergency management with bolus hypertonic saline is indicated to prevent progression of potentially life-threatening cerebral edema (see “Emergency Management of Severe Hyponatremia”). Once the target initial increment of serum sodium rise is achieved (eg, 4-6 mmol/L) and/or if symptoms improve, ongoing correction is determined by duration of hyponatremia. If duration is unknown, it is safest to assume it to be chronic and aim for gradual correction. In chronic hyponatremia, gradual correction of serum sodium allows for restoration of brain tissue osmolality toward the normal range with the import or synthesis of osmolytes (sodium, potassium, organic osmolytes as discussed in Fig. 3), and slow exit of excess intracellular water. The typical target rate of correction is 5 to 8 mmol/L per 24 hours, or lower for those with risk factors for ODS. If rapid correction of serum sodium above the target rate occurs (overcorrection, eg, > 10 mmol/L within 24 hours), it is advised to relower serum sodium (eg, with IV dextrose 5%, and/or desmopressin (DDAVP), see “In Case of Overcorrection: Relowering of Plasma Sodium” below) to prevent the rare complication of ODS. ODS can occur as a consequence of rapid exit of intracellular water damaging the myelin sheath, particularly in the pons, and can cause devastating neurological outcomes or death. Onset of symptoms of ODS is often delayed. Subsequent correction after relowering should be gradual. H₂O, water; DDAVP, desmopressin (arginine vasopressin analogue); IV, intravenous; ODS, osmotic demyelination syndrome.

Figure 8.

Diagnosis and initial management of nonmild hyponatremia while confirming a diagnosis of SIAD. CT, computed tomography; IV, intravenous; Na⁺, sodium; NaCl, sodium chloride; ODS, osmotic demyelination syndrome; pNa, plasma sodium concentration; SIAD, syndrome of inappropriate antidiuresis; subcut, subcutaneous. Original figure, with reference to guidelines by Spasovski 2014 and Verbalis 2013 (3, 15).

Figure 9.

Identifying a urine sodium threshold for diagnosis of syndrome of inappropriate antidiuresis (SIAD) vs hypovolemic hyponatremia: urine sodium concentrations (UNa) in a prospective assessment of 58 patients with plasma sodium concentration less than 130 mmol/L, classified according to response to intravenous 0.9% saline rehydration (gold standard assessment of volume status). This study recommended a threshold of UNa greater than 30 mmol/L to differentiate hypovolemia (saline responders) from SIAD (saline nonresponders). Spot UNa in saline responders and nonresponders. All individual values as well as the mean ± 1 SEM are included. Figure reproduced from Chung 1987 with permission (199).

Figure 10.

An approach to management of syndrome of inappropriate antidiuresis (SIAD), based on current limited evidence base. pNa, plasma sodium concentration.

Figure 11.

Renal physiology in SIAD, and mechanisms of action of tolvaptan, urea, and SGLT2i at the nephron. SIAD: Nonosmotic increase in circulating AVP leads to increased water resorption in the collecting duct via aquaporins, plus reduced sodium resorption in the proximal convoluted tubule, ascending limb, and distal convoluted tubule, resulting in concentrated urine production and decreased serum sodium concentration (see Fig. 5). AVP also promotes water retention by upregulating expression of UT-A1s to increase reabsorption of urea, augmenting medullary interstitial osmolality and hence urinary concentrating ability. Tolvaptan: blockade of AVP V2 receptor leads to reduced water resorption in the context of reduced aquaporins, resulting in a free water diuresis leading to a rise in serum sodium. Urea: Administration of urea leads to increased concentration of urea both in the filtrate and the renal interstitium. This leads to A, increased water resorption in the descending limb due to the osmotic effect of urea, initially leading to an elevated sodium concentration in the filtrate in the descending limb. This leads to increased sodium resorption by passive diffusion in the ascending limb, reducing sodium loss. Later, the osmotic draw of urea in the filtrate leads to B, reduced water resorption in the collecting duct, resulting in an osmotic diuresis and rise in serum sodium. SGLT2i: SGLT2i inhibitors act at the sodium-glucose cotransporter in the proximal tubule to reduce resorption of glucose and sodium. The primary effect is glycosuria (even in those without diabetes mellitus), accompanied by increased water excretion due to an osmotic diuresis. There is a transient increase in sodium excretion as well; however, the net effect on plasma sodium level is to increment when used in hyponatremia. AVP, arginine vasopressin; SIAD, syndrome of inappropriate diuresis; SGLT2i, sodium-glucose cotransporter 2 inhibitor. Original figure created with biorender.com, with reference to Decaux 1980 regarding urea physiology (306).