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Diabetes Insipidus and SIADH

Water Balance Physiology

Vasopressin (AVP/ADH) Regulation

Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is the central regulatory hormone of water balance. It is synthesized as a preprohormone in the magnocellular neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. The precursor molecule is proteolytically cleaved into three products: AVP itself, neurophysin II (the carrier protein), and copeptin, a C-terminal glycoprotein released in equimolar amounts with AVP. Because copeptin is considerably more stable in plasma than AVP, it has emerged as a valuable surrogate biomarker for AVP secretion in clinical diagnostics.

The primary physiological stimulus for AVP release is plasma osmolality, sensed by osmoreceptors located in the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO). The osmotic threshold for AVP release is approximately 280 to 285 mOsm/kg, above which AVP secretion increases linearly with rising osmolality. The thirst threshold is set slightly higher, at approximately 290 to 295 mOsm/kg, providing a critical safety mechanism that ensures behavioral water seeking complements the renal concentrating actions of AVP.

Non-osmotic stimuli also drive AVP release, though the volume/pressure-sensing pathway is less sensitive than the osmotic pathway, requiring a 7 to 10% decrease in blood volume before activation. However, once triggered, volume-mediated AVP release can produce much higher AVP levels than osmotic stimulation alone. Other non-osmotic stimuli include hypotension, nausea (which is a particularly potent stimulus), pain, stress, angiotensin II, and nicotine.

AVP Receptor Subtypes

AVP acts through three receptor subtypes, each with distinct tissue distributions and physiological roles. V1a receptors are located on vascular smooth muscle, platelets, and hepatocytes, where they mediate vasoconstriction and platelet aggregation. V1b receptors (also designated V3) are expressed on anterior pituitary corticotrophs, where they potentiate CRH-stimulated ACTH release. V2 receptors, the most clinically relevant subtype for water balance, are located on the principal cells of the renal collecting duct. These Gs-coupled receptors activate the cAMP-PKA signaling cascade, which triggers the insertion of aquaporin-2 (AQP2) water channels into the apical membrane and also stimulates urea transporters (UT-A1) and the epithelial sodium channel (ENaC).

The functional consequence of V2 receptor activation is the reabsorption of free water from the collecting duct lumen, enabling the kidney to concentrate urine from approximately 100 mOsm/kg (maximal dilution in the absence of AVP) to approximately 1200 mOsm/kg (maximal concentration with full AVP activity).

Renal Concentrating Mechanism

The kidney's ability to concentrate urine depends on three essential prerequisites working in concert. First, the countercurrent multiplication system in the loop of Henle generates a corticomedullary osmotic gradient ranging from 300 mOsm/kg in the cortex to 1200 mOsm/kg at the papilla. Urea recycling contributes approximately 50% of this medullary interstitial osmolality. Second, AVP must be present in adequate quantities to activate V2 receptors. Third, functional V2 receptors and intact intracellular signaling must enable AQP2 channel insertion. Disruption at any of these levels results in impaired urinary concentrating ability and polyuria.

<image>A detailed diagram of the renal concentrating mechanism showing a nephron with the loop of Henle creating the countercurrent multiplication system. On the left, show the cortex-to-medulla osmotic gradient from 300 to 1200 mOsm/kg. On the right, show a magnified view of the collecting duct principal cell with the V2 receptor on the basolateral membrane, the Gs-cAMP-PKA signaling cascade, and aquaporin-2 water channels being inserted into the apical membrane via vesicle trafficking. Show water molecules moving from the collecting duct lumen through AQP2 channels, through the cell, and out via basolateral AQP3/AQP4 channels into the interstitium. Label all components clearly.</image>

Diabetes Insipidus (DI)

Classification (Updated 2022 Nomenclature)

The classification of diabetes insipidus has undergone an important nomenclature revision, driven by documented cases of patients receiving inappropriate diabetes mellitus treatment due to the shared word "diabetes" in both conditions. The updated terminology designates the previously named "central" or "cranial" diabetes insipidus as arginine vasopressin deficiency (AVP-D), reflecting insufficient AVP production or secretion. The formerly termed "nephrogenic" diabetes insipidus is now designated arginine vasopressin resistance (AVP-R), reflecting renal resistance to AVP action. While adoption of this updated nomenclature is recommended by expert consensus, it is not yet universal in clinical practice.

Two additional forms complete the classification. Primary polydipsia (previously termed dipsogenic diabetes insipidus) results from excessive water intake that suppresses AVP secretion, either from hypothalamic thirst center dysfunction or psychogenic causes. Gestational diabetes insipidus occurs when placental vasopressinase (cystine aminopeptidase) degrades circulating AVP at an accelerated rate, typically manifesting in the third trimester and resolving after delivery.

AVP Deficiency (Central DI) - Etiologies

The causes of AVP deficiency are diverse and span surgical, neoplastic, infiltrative, autoimmune, genetic, vascular, traumatic, and idiopathic categories. Post-surgical AVP-D is the most common identifiable cause, occurring after transsphenoidal surgery in 10 to 20% of patients transiently and 1 to 3% permanently. The "triple-phase response" is a well-recognized post-neurosurgical pattern in which initial DI (days 1 to 5, from surgical trauma to vasopressin neurons) is followed by SIADH (days 5 to 10, from uncontrolled release of stored AVP from degenerating neurons) and then either permanent DI or resolution.

Tumors affecting the hypothalamic-pituitary region include craniopharyngioma, germinoma, metastatic disease (particularly from breast and lung primaries), and less commonly pituitary macroadenomas (which rarely cause DI unless post-surgically). Infiltrative diseases, including sarcoidosis, Langerhans cell histiocytosis (which causes DI in 15 to 50% of CNS-involved cases), and Erdheim-Chester disease, represent important etiologies. Autoimmune AVP-D results from lymphocytic infundibuloneurohypophysitis, in which anti-AVP cell antibodies target vasopressin-producing neurons; MRI characteristically shows stalk thickening and loss of the posterior pituitary bright spot.

Genetic forms include autosomal dominant AVP-neurophysin II gene mutations, which cause progressive onset of DI during childhood, and autosomal recessive forms such as Wolfram syndrome (DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; caused by WFS1 gene mutations). Vascular causes include Sheehan syndrome and aneurysmal compression. Traumatic brain injury frequently causes transient DI. Importantly, 20 to 50% of cases remain idiopathic, and in young patients with idiopathic DI, occult germinoma or Langerhans cell histiocytosis should always be reconsidered during follow-up.

AVP Resistance (Nephrogenic DI) - Etiologies

Congenital AVP resistance is most commonly caused by X-linked AVPR2 mutations affecting the V2 receptor, accounting for 90% of genetic cases. Autosomal recessive AQP2 mutations affecting aquaporin-2 water channels account for the remaining 10%.

Among acquired causes, lithium is the most common, affecting up to 40% of chronic lithium users with some degree of polyuria and causing frank nephrogenic DI in approximately 12%. Lithium enters collecting duct cells via ENaC and reduces AQP2 expression through mechanisms that may persist even after lithium discontinuation. Electrolyte disorders are another important cause: hypercalcemia reduces AQP2 expression and interferes with the medullary concentration gradient, while hypokalemia downregulates AQP2 and impairs the medullary gradient. Other drug causes include demeclocycline, foscarnet, amphotericin B, cidofovir, and ifosfamide. Chronic kidney disease causes concentrating defects through loss of medullary architecture, while obstructive uropathy, sickle cell disease (through medullary ischemia from vasa recta sickling), and pregnancy represent additional etiologies.

Clinical Presentation

The cardinal symptoms of diabetes insipidus are polyuria and polydipsia. Polyuria is defined as urine output exceeding 3 liters per day in adults (or more precisely, greater than 50 mL/kg/day). In complete DI, urine output may reach 15 to 20 liters per day. Patients typically experience intense thirst with a preference for ice-cold water, along with nocturia and sleep disruption.

If the thirst mechanism is intact and water is freely available, patients can generally maintain their serum sodium in the normal to high-normal range through compensatory fluid intake. However, the situation becomes dangerous when the thirst mechanism is impaired (adipsia or hypodipsia) or when water access is restricted, as in hospitalized, sedated, or cognitively impaired patients. In these circumstances, severe hypernatremia, dehydration, and altered mental status can develop rapidly. Adipsic DI, occurring most commonly after craniopharyngioma surgery when hypothalamic damage disrupts the thirst center, represents the most dangerous variant and requires prescribed fluid intake protocols with close sodium monitoring.

Diagnostic Workup

Initial Assessment

The diagnostic workup begins with confirmation of true polyuria through a 24-hour urine collection demonstrating output exceeding 50 mL/kg/day. Baseline laboratory studies should include serum sodium, plasma osmolality, urine osmolality, urine specific gravity, serum glucose (to exclude osmotic diuresis from diabetes mellitus), calcium, potassium, and creatinine. If the serum sodium is already elevated above 147 mEq/L with a urine osmolality below 300 mOsm/kg, DI is virtually confirmed, and the workup should proceed directly to distinguishing central from nephrogenic causes.

Water Deprivation Test (Miller-Moses Test)

The water deprivation test is indicated when the diagnosis remains uncertain, particularly when the serum sodium is in the normal range. The protocol involves withholding fluids under close monitoring, with hourly measurements of body weight, serum osmolality, urine osmolality, and serum sodium. The test is terminated when urine osmolality plateaus (defined as less than 30 mOsm/kg increase over two consecutive hours), body weight decreases by more than 3%, serum sodium exceeds 145 mEq/L, or serum osmolality exceeds 295 mOsm/kg. At the point of maximal dehydration, desmopressin is administered (2 mcg intravenously or intramuscularly, or 10 mcg intranasally), and the urine osmolality response is measured.

In complete AVP-D, urine osmolality remains below 300 mOsm/kg after dehydration but rises by more than 50% (often more than 100%) after desmopressin administration. Partial AVP-D produces intermediate urine concentration of 300 to 600 mOsm/kg that rises 10 to 50% with desmopressin. In AVP-R, urine remains dilute (below 300 mOsm/kg) with minimal or no response to desmopressin (less than 10% increase). Primary polydipsia produces appropriately concentrated urine (above 600 to 800 mOsm/kg) after dehydration, with no significant additional rise with desmopressin. A significant limitation of this test is that partial forms are often difficult to distinguish, and medullary washout from chronic water loading in primary polydipsia may mimic DI.

Copeptin-Based Diagnostics (Emerging Standard)

Copeptin-based testing has emerged as a superior diagnostic approach in expert centers. The hypertonic saline-stimulated copeptin test involves infusing 3% NaCl to raise serum sodium to 150 mEq/L while measuring copeptin levels. A copeptin concentration above 4.9 pmol/L excludes AVP-D with greater than 95% sensitivity and specificity, identifying the patient as having either primary polydipsia or AVP-R. A copeptin below 4.9 pmol/L confirms AVP-D. This test has been shown to be superior to the traditional water deprivation test for distinguishing AVP-D from primary polydipsia. An arginine-stimulated copeptin test has been developed to avoid the need for hypernatremia, using a copeptin cutoff of 3.8 pmol/L, though it is less well validated. A baseline copeptin above 21.4 pmol/L in the setting of hyperosmolality confirms AVP-R.

MRI Findings

MRI of the hypothalamic-pituitary region provides important diagnostic information. The posterior pituitary bright spot, a T1 hyperintensity reflecting stored AVP in neurosecretory granules, is typically absent in AVP-D but present in AVP-R and primary polydipsia. Pituitary stalk thickening suggests an infiltrative or inflammatory cause such as sarcoidosis, Langerhans cell histiocytosis, germinoma, or lymphocytic hypophysitis. However, the absence of the bright spot should not be considered diagnostic in isolation, as it is absent in 10 to 20% of normal individuals.

<image>A side-by-side comparison table and diagram illustrating the water deprivation test results for four conditions: Complete AVP deficiency, Partial AVP deficiency, AVP resistance, and Primary polydipsia. For each condition, show: baseline urine osmolality, urine osmolality after maximal dehydration (with bar graph), percentage increase after desmopressin administration (with arrow showing change), and expected serum copeptin level. Include a row for posterior pituitary bright spot on MRI (present/absent). Use a clean tabular format with color-coded columns (blue for AVP-D, orange for AVP-R, green for primary polydipsia) and bar charts showing the osmolality values.</image>

Treatment

AVP Deficiency (Central DI)

Desmopressin (DDAVP), a synthetic AVP analog with selective V2 receptor agonist activity and minimal V1 activity, is the treatment of choice for AVP-D. Multiple formulations are available: intranasal (5 to 20 mcg twice daily, with 10 mcg intranasal approximately equivalent to 0.1 mg oral), oral tablets (0.1 to 0.4 mg two to three times daily), sublingual (NOCDURNA, available as 27.7 mcg and 55.3 mcg with faster absorption), and subcutaneous or intravenous (1 to 4 mcg daily, primarily for perioperative use).

Dosing should be titrated to control symptoms while avoiding the most significant complication of treatment: dilutional hyponatremia from excessive free water retention. A deliberate daily "escape" period, achieved by skipping one dose and allowing breakthrough polyuria, is an important strategy to prevent progressive water overloading. This is particularly important when the thirst mechanism is intact, as patients will continue drinking despite adequate antidiuresis. Serum sodium should be monitored weekly during initial titration and every 3 to 6 months once stable.

Adipsic DI represents the most challenging management scenario, requiring prescribed fluid intake (typically 1.5 to 2 liters daily), fixed desmopressin dosing, and close sodium monitoring on a weekly or more frequent basis. Without an intact thirst mechanism, these patients cannot self-regulate their fluid intake and are at risk of both dangerous hypernatremia and hyponatremia.

AVP Resistance (Nephrogenic DI)

The management of AVP-R begins with treating any identifiable underlying cause, including discontinuation of offending medications, correction of hypercalcemia, and repletion of hypokalemia. Ensuring adequate free water access is fundamental. Pharmacological strategies, while unable to fully correct the concentrating defect, can substantially reduce urine output.

Thiazide diuretics, particularly hydrochlorothiazide at 25 to 50 mg daily, produce a paradoxical antidiuretic effect in nephrogenic DI by inducing mild volume contraction that stimulates increased proximal tubular sodium and water reabsorption, thereby reducing distal fluid delivery and urine output by 25 to 50%. Amiloride at 5 to 20 mg daily is particularly useful in lithium-induced nephrogenic DI because it blocks lithium entry into collecting duct cells via ENaC, addressing the mechanism of lithium toxicity directly. NSAIDs such as indomethacin (25 to 50 mg two to three times daily) reduce prostaglandin-mediated antagonism of AVP action but are limited by gastrointestinal and renal side effects. A low-sodium, low-protein diet reduces the solute load and obligatory water excretion. Combination therapy with thiazide plus amiloride is often the most effective approach. High-dose desmopressin may partially overcome resistance in some acquired forms.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Pathophysiology

SIADH is characterized by persistent AVP secretion (or AVP-like action) despite normal or low plasma osmolality and clinical euvolemia or mild hypervolemia. The inappropriate antidiuresis leads to impaired free water excretion, progressive water retention, and dilutional hyponatremia with relatively concentrated urine. An important adaptive mechanism, termed "escape from antidiuresis," partially limits the degree of hyponatremia through compensatory natriuresis, downregulation of AQP2 expression, and release of atrial and brain natriuretic peptides.

Diagnostic Criteria (Bartter and Schwartz)

The classic diagnostic criteria for SIADH, established by Bartter and Schwartz, require the simultaneous presence of seven findings: hyponatremia with serum sodium below 135 mEq/L; decreased serum osmolality below 275 mOsm/kg; inappropriately concentrated urine with osmolality above 100 mOsm/kg (typically above 300); elevated urine sodium above 30 mEq/L on normal salt intake; clinical euvolemia without edema, orthostasis, or signs of volume depletion; normal thyroid and adrenal function (which must be specifically excluded); and the absence of recent diuretic use.

Etiologies

The causes of SIADH span four major categories. Malignancy is an important cause, with small cell lung cancer being the most common neoplastic etiology, producing ectopic AVP in 10 to 15% of cases. Other malignant associations include head and neck cancers, lymphoma, mesothelioma, pancreatic cancer, and olfactory neuroblastoma.

Central nervous system disorders, including stroke, hemorrhage, meningitis, encephalitis, head trauma, neurosurgery, Guillain-Barre syndrome, multiple sclerosis, and hydrocephalus, represent a broad category of neurogenic causes. Pulmonary diseases such as pneumonia (bacterial, viral, or tuberculous), positive pressure ventilation, asthma exacerbations, COPD exacerbations, and empyema can all trigger SIADH.

Drug-induced SIADH is increasingly common, with SSRIs being the most frequent pharmacological cause, affecting up to 12% of elderly patients. Carbamazepine and oxcarbazepine, intravenous cyclophosphamide, vincristine, opioids, ecstasy/MDMA, NSAIDs, exogenous desmopressin, chlorpropamide, and thiazide diuretics are additional drug causes. Post-surgical SIADH is particularly common after transsphenoidal and other neurosurgical procedures, characteristically occurring on days 5 to 10. Other causes include pain, nausea, HIV infection, and idiopathic SIADH (especially in the elderly). A rare genetic form, nephrogenic syndrome of inappropriate antidiuresis (NSIAD), results from gain-of-function V2 receptor mutations causing constitutive receptor activation with low or undetectable AVP levels.

Differential Diagnosis of Hyponatremia

Accurate diagnosis of SIADH requires systematic exclusion of other causes of hyponatremia. Hypovolemic hyponatremia from gastrointestinal losses, diuretics, cerebral salt wasting, or adrenal insufficiency is distinguished by clinical signs of volume depletion and, in extrarenal losses, low urine sodium below 20 mEq/L. Hypervolemic hyponatremia from heart failure, cirrhosis, or nephrotic syndrome presents with clinical edema or ascites. Pseudohyponatremia from hyperproteinemia or hyperlipidemia occurs only with indirect ion-selective electrode methods. Hypertonic hyponatremia from hyperglycemia, mannitol, or intravenous contrast requires correction of the measured sodium (adding 1.6 to 2.4 mEq/L per 100 mg/dL glucose above 100 mg/dL).

Cerebral Salt Wasting (CSW) vs. SIADH

The distinction between cerebral salt wasting and SIADH is among the most challenging differential diagnoses in clinical medicine, as both conditions present with hyponatremia, elevated urine sodium, and concentrated urine. The critical differentiating feature is volume status: CSW produces hypovolemia (manifested by tachycardia, orthostasis, negative fluid balance, and elevated BUN-to-creatinine ratio) caused by natriuretic peptide release following CNS injury, while SIADH maintains euvolemia. This distinction has direct therapeutic implications: CSW requires sodium and volume replacement, whereas fluid restriction, the mainstay of SIADH treatment, would worsen CSW. The fractional excretion of urate can be a helpful adjunctive test, as it is elevated in both conditions during hyponatremia but normalizes after sodium correction in CSW while remaining elevated in SIADH.

SIADH Management

Acute Symptomatic Hyponatremia (Na <120 mEq/L with seizures/severe symptoms)

Severe symptomatic hyponatremia with seizures, obtundation, or signs of cerebral herniation constitutes a medical emergency requiring urgent treatment with hypertonic saline. The recommended approach is a 100 to 150 mL bolus of 3% NaCl administered intravenously over 10 to 20 minutes, which may be repeated up to two additional times if symptoms persist. The immediate goal is to raise serum sodium by 4 to 6 mEq/L within the first 1 to 2 hours, which is typically sufficient to arrest seizure activity and reduce cerebral edema.

The maximum correction rate must not exceed 8 mEq/L in any 24-hour period (some experts allow up to 10 mEq/L, with more conservative targets in high-risk patients). Overcorrection carries the devastating risk of osmotic demyelination syndrome (ODS), formerly termed central pontine myelinolysis, which involves demyelination of pontine and extrapontine structures. Patients at highest risk for ODS include those with chronic hyponatremia (present for more than 48 hours), alcoholism, liver disease, hypokalemia, malnutrition, and serum sodium below 105 mEq/L.

Moderate Symptoms / Subacute

For patients with moderate symptoms or subacute SIADH, fluid restriction to 500 to 1000 mL daily is the first-line therapy. However, several factors predict failure of fluid restriction: urine osmolality exceeding 500 mOsm/kg, a urine-to-plasma electrolyte ratio (urine sodium plus potassium divided by plasma sodium) greater than 1, and urine output below 1500 mL per day. When fluid restriction is insufficient, solute loading with oral salt tablets (3 to 9 grams daily) with or without oral urea (15 to 60 grams daily dissolved in water) can promote free water excretion, though urea's palatability poses adherence challenges.

Pharmacological Therapy

Tolvaptan, an oral selective V2 receptor antagonist, is an effective pharmacological option dosed at 15 to 60 mg daily. It must be initiated in a hospital setting with frequent sodium monitoring due to the risk of overcorrection. Importantly, fluid restriction should not be imposed during tolvaptan initiation for the same reason. Tolvaptan is contraindicated in liver disease due to hepatotoxicity concerns. Urea, administered at 15 to 60 grams daily orally, functions as an osmotic diuretic promoting free water excretion and is used as first-line pharmacotherapy in some European centers. It is inexpensive and associated with fewer overcorrection events than tolvaptan. Loop diuretics combined with salt tablets (furosemide 20 to 40 mg plus sodium chloride tablets) disrupt the medullary concentration gradient and reduce concentrating ability, though this approach is less effective than tolvaptan. Demeclocycline, which induces nephrogenic DI at 600 to 1200 mg daily, is now rarely used due to its unpredictable onset of action (3 to 7 days), nephrotoxicity risk, and the availability of superior alternatives.

Overcorrection Management

If serum sodium rises too rapidly, exceeding 8 to 10 mEq/L in 24 hours, immediate intervention is required to re-lower sodium and prevent osmotic demyelination. Desmopressin at 2 to 4 mcg intravenously or subcutaneously every 6 to 8 hours halts ongoing free water excretion, while administration of 5% dextrose in water (D5W) intravenously at 3 to 6 mL/kg/hour lowers sodium back to the target range. The proactive "DDAVP clamp" strategy, combining scheduled desmopressin with hypertonic saline, allows controlled and predictable sodium correction and is increasingly employed in high-risk patients to prevent inadvertent overcorrection.

<image>A clinical management algorithm for hyponatremia. Start with serum sodium <135 mEq/L. First branch: assess osmolality (hypertonic, isotonic, hypotonic). For hypotonic: assess volume status (hypovolemic, euvolemic, hypervolemic). Euvolemic branch leads to SIADH workup (confirm urine Osm >100, urine Na >30, normal thyroid/adrenal). Then assess severity: Severe symptoms (seizures, obtundation) leads to 3% NaCl 100-150 mL bolus with correction limits (8 mEq/L/24h). Moderate symptoms leads to fluid restriction first-line, then tolvaptan or urea if refractory. Include a red warning box about osmotic demyelination syndrome risk factors and overcorrection rescue protocol (DDAVP + D5W). Use emergency-style red/yellow/green color coding for severity.</image>

Key Clinical Pearls

• The updated nomenclature (AVP-D and AVP-R) replaces "central DI" and "nephrogenic DI" to prevent confusion with diabetes mellitus; adoption is recommended but not yet universal
• Copeptin-stimulated testing (hypertonic saline stimulation with copeptin >4.9 pmol/L cutoff) has largely replaced the water deprivation test for distinguishing AVP-D from primary polydipsia in expert centers
• In post-neurosurgical patients, the "triple-phase response" (DI, then SIADH, then DI) occurs in a minority; isolated transient DI or isolated SIADH are more common than the full triple phase
• Always exclude adrenal insufficiency before diagnosing SIADH; cortisol deficiency causes impaired free water excretion that mimics SIADH; cortisol replacement corrects the hyponatremia
• Lithium-induced NDI may be irreversible even after lithium discontinuation; amiloride (blocks lithium entry via ENaC) is the preferred adjunctive therapy
• In SIADH overcorrection, act immediately with DDAVP and D5W; the window to prevent osmotic demyelination is narrow; proactive "DDAVP clamp" strategies are increasingly used in high-risk patients

References

1. Christ-Crain M, et al. "Diabetes Insipidus." Nat Rev Dis Primers. 2019;5(1):54.
2. Garrahy A, et al. "Diagnosis and Management of Central Diabetes Insipidus in Adults." Clin Endocrinol. 2019;90(1):23-30.
3. Verbalis JG, et al. "Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations." Am J Med. 2013;126(10 Suppl 1):S1-S42.
4. Refardt J, et al. "A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus." N Engl J Med. 2019;381(7):616-625.
5. Spasovski G, et al. "Clinical Practice Guideline on Diagnosis and Treatment of Hyponatraemia." Eur J Endocrinol. 2014;170(3):G1-G47.

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