Arginine vasopressin disorders

Arginine vasopressin (AVP) disorders are a group of conditions in which the kidneys cannot effectively concentrate urine, resulting in hypotonic polyuria. Arginine vasopressin deficiency (AVP-D), previously known as central DI, is the most common AVP disorder and is caused by decreased hypothalamic production or pituitary release of AVP, resulting in insufficient levels of circulating AVP. AVP-D can be primary (e.g., idiopathic, hereditary) or secondary (e.g., due to brain lesions, injury, infection). Arginine vasopressin resistance (AVP-R), previously known as nephrogenic DI, results from renal unresponsiveness to AVP and may be hereditary or acquired (e.g., medication-induced, renal disease). Most individuals with AVP disorders develop polydipsia and polyuria in response to excessive fluid loss. Individuals with nocturia may have sleep deprivation and/or daytime sleepiness. Children may present with nonspecific symptoms (e.g., irritability, fever), clinical signs of significant dehydration, and/or clinical features of hypernatremia. Initial diagnosis in adults is based on the presence of hypotonic polyuria on a 24-hour urine collection. Confirmatory testing (e.g., water deprivation test) can differentiate between AVP disorders and primary polydipsia. Management includes oral fluids to compensate for urinary loss. For AVP-D, pharmacological therapy with desmopressin may be used; surgical intervention may be required for patients with AVP-D due to a brain mass. Management of acquired AVP-R involves treating the underlying cause; the condition is typically reversible within weeks to months, although lithium-induced AVP-R may be irreversible. Pharmacotherapy with thiazide diuretics, NSAIDs, or amiloride is indicated in some patients.

• Prevalence in the US (adults and children): 1:25,000 ^[1][2]
• Sex: ♀ = ♂

Epidemiological data refers to the US, unless otherwise specified.

Arginine vasopressin deficiency (central diabetes insipidus) ^[2][3]

• Most common form: caused by insufficient or absent hypothalamic synthesis or posterior pituitary secretion of AVP
• Types
  • Primary (∼ ⅓ of cases)
    • Most cases are idiopathic.
    • The hereditary form is rare.
    • An autoimmune etiology of primary AVP-D has been suggested. ^[4][5]
  • Secondary (∼ ⅔ of cases)
    • Brain tumors (especially craniopharyngioma) and cerebral metastasis (most common: lung cancer and leukemia/lymphoma)
    • Neurosurgery: usually after the removal of large adenomas
    • Traumatic brain injury, pituitary bleeding, subarachnoid hemorrhage
    • Pituitary ischemia (e.g., Sheehan syndrome, ischemic stroke)
    • Infection (e.g., meningitis)
    • Granulomatous disease affecting the hypothalamus (e.g., sarcoidosis, Langerhans cell histiocytosis)
• Subtype: adipsic arginine vasopressin deficiency
  • Hypothalamic osmoreceptor defects lead to loss of thirst despite decreased AVP secretion.
  • Associated with an increased risk of hypernatremia

AVP-D following neurosurgery is usually transient.

Arginine vasopressin resistance (nephrogenic diabetes insipidus) ^[2][3]

• Rare: caused by defective AVP receptors in the distal tubules and collecting ducts
• Types
  • Hereditary (mutation in AVP receptor): very rare
  • Acquired: typically reversible if the underlying cause is resolved
    • Adverse effect of medications (lithium, demeclocycline)
    • Hypokalemia, hypercalcemia
    • Renal disease (e.g., autosomal dominant polycystic kidney disease, renal amyloidosis, obstructive uropathy)
    • Pregnancy

• AVP enables the integration of aquaporins into the plasma membrane of collecting duct cells → reabsorption of free water
• Either ↓ AVP (AVP-D) or defective renal AVP receptors (AVP-R) → impaired ability of the kidneys to concentrate urine (hypotonic collecting ducts) → dilute urine (low urine osmolarity)
• Hyperosmotic volume contraction ^[6]
  • Loss of fluid with urine → increased extracellular fluid osmolarity → passage of fluid from the intracellular to the extracellular space → equalization of the osmolarities of the extracellular and intracellular fluid
  • Due to the loss of fluid, the osmolarities of intracellular and extracellular compartments are now higher (hyperosmotic) than the initial values.
  • The fluid volume is redistributed between the two compartments to equalize the osmolarities and remains lower than the initial values in each of them (volume contraction)

Note that in AVP-D, AVP levels are decreased, while in AVP-R, they are normal or increased to compensate for the high urine output.

• Polyuria with dilute urine
• Nocturia → restless sleep, daytime sleepiness
• Polydipsia (excessive thirst)
• In cases of low water intake → severe dehydration (altered mental status, lethargy, seizures, coma) and hypotension
• Symptoms may worsen during pregnancy.

In the absence of nocturia, AVP disorders are very unlikely.

Approach

• Obtain a thorough patient history and perform a physical examination to assess for possible causes of AVP disorders.
• Obtain initial studies including serum sodium, plasma osmolality, and urine osmolality.
• Obtain subsequent studies (e.g., water deprivation test) to distinguish between primary polydipsia, AVP-D, and AVP-R.
• See also “Polyuria-polydipsia syndromes” for expected laboratory findings.
• Obtain imaging to rule out brain tumors in patients with AVP-D.

Initial laboratory studies ^[2][7]

• Routine studies: BMP, urinalysis
  • To rule out causes of osmotic diuresis, e.g., hyperglycemia with glucosuria
  • To assess for acquired causes of AVP-R, e.g., hypercalcemia, hypokalemia
• 24-hour urine collection: to confirm hypotonic polyuria, i.e., urine volume > 50 mL/kg/24 hours with urine osmolality < 800 mOsm/kg
• Serum sodium and plasma osmolality
  • ↓ Na⁺ and/or ↓ plasma osmolality: primary polydipsia likely
  • Normal values: Diagnosis is unclear; obtain subsequent studies to differentiate between polyuria-polydipsia syndromes.
  • ↑ Na⁺ and/or ↑ plasma osmolality: An AVP disorder is likely; obtain subsequent studies to differentiate between AVP-D and AVP-R.

Subsequent laboratory studies ^[2][7][8]

• To distinguish between polyuria-polydipsia syndromes, AVP activity can be assessed directly or indirectly.
• Consult endocrinology for guidance and follow local testing protocols if available.

Water deprivation test (indirect assessment of AVP activity)

Urine concentrating capacity is assessed during a period of dehydration; desmopressin is then administered to assess response to a synthetic AVP analogue. ^[2]

• Procedure
  • Keep the patient NPO.
  • Assess the following at baseline, then every 1–2 hours:
    • Plasma sodium and osmolality
    • Urine sodium and osmolality
    • Vital signs
• Interpretation after period of water deprivation ^[2]
  • Urine osmolality increases to > 800 mOsm/kg: Primary polydipsia is confirmed.
  • Urine osmolality remains ≤ 800 mOsm/kg: AVP disorders are likely; ; administer desmopressin (a synthetic AVP analogue).
• Interpretation after desmopressin administration
  • Initial urine osmolality 300–800 mOsm/kg and:
    • Significant increase (≥ 10%) after desmopressin: partial AVP-D
    • No or minimal increase (< 10%) after desmopressin: primary polydipsia
  • Initial urine osmolality < 300 mOsm/kg and:
    • Significant increase (> 50%) after desmopressin: complete AVP-D (indicating intact renal AVP receptors)
    • No or moderate increase (< 50%) after desmopressin: AVP-R (indicating defective renal AVP receptors)

Plasma copeptin (direct assessment of AVP activity) ^[2][8]

• Circulating plasma copeptin levels reflect circulating AVP levels.
• Measure random plasma copeptin levels.
  • ≥ 21.4 pmol/L: AVP-R is confirmed.
  • < 21.4 pmol/L: Obtain stimulated plasma copeptin testing, e.g., hypertonic saline infusion test.
    • > 4.9 pmol/L: primary polydipsia
    • ≤ 4.9 pmol/L: AVP-D

Plasma AVP measurement is not routinely utilized because results are unreliable, as AVP is unstable and has a short half-life ex vivo.

Brain imaging ^[7][9]

• Indications: suspected or confirmed AVP-D to determine the underlying cause
• Preferred modality: pituitary or sella protocol MRI
• Supportive findings: may reveal a tumor, inflammation, or infiltrative changes in the posterior pituitary gland

Differential diagnosis of polyuria-polydipsia syndromes

See also “Gestational diabetes insipidus.”

Other causes of polyuria and/or polydipsia

• Untreated diabetes mellitus
• Other causes of osmotic diuresis
• Beer potomania: dilutional hyponatremia secondary to limited renal free water excretion caused by intake of large amounts of beer ^[10]

The differential diagnoses listed here are not exhaustive.

The goals of management are to reduce polyuria and polydipsia to improve the patient's quality of life and maintain eunatremia.

General principles ^[2]

• Encourage adequate fluid intake and a low-sodium, low-protein diet.
• Initiate management of hypernatremia (i.e., replace free water deficit) as needed.
• Treat according to the underlying mechanism and cause.

Hypernatremia is rare in the ambulatory setting but may be present in patients with cognitive impairment, adipsic AVP-D, and those who are hospitalized or cannot access water because of mobility impairment. ^[11]

Arginine vasopressin deficiency ^[2]

• Management should be guided by an endocrinologist.
• Most patients are able to maintain eunatremia through increased oral fluid intake alone.
• Initiate pharmacotherapy in patients with either:
  • Polyuria and/or polydipsia
  • Hypernatremia
• Agents
  • Desmopressin (preferred): synthetic AVP analogue without vasoconstrictive effects
    • Intranasal administration is preferred.
    • Typically at bedtime to relieve nocturia
    • Start at a low dose to reduce the risk of overcorrection.
  • Chlorpropamide (alternative): enhances the effect of AVP and increases its secretion

Most patients with AVP-D are able to increase their oral fluid intake to maintain eunatremia without pharmacotherapy. However, desmopressin is typically required to relieve bothersome symptoms of polyuria and polydipsia. ^[7]

Arginine vasopressin resistance ^[2]

• Consult nephrology as needed for guidance on management.
• Treat the underlying cause, if applicable, e.g.:
  • Discontinue the causative agent (e.g., lithium, demeclocycline).
  • Correct electrolyte imbalances (e.g., hypercalcemia, hypokalemia).
  • Relieve urinary tract obstruction.
• Consider pharmacotherapy to manage polyuria and hypernatremia.
  • Thiazide diuretics
    • Lead to sodium depletion, which increases sodium and water reabsorption in the proximal tubules
    • As a result, less water reaches the distal collecting tubules and urine volume decreases
  • NSAIDs (e.g., indomethacin)
  • Amiloride: indicated in patients with lithium-induced AVP-R who continue lithium therapy

In patients with renal disease, NSAIDs must be used with caution because of the potential nephrotoxic effects.

Gestational AVP disorder (gestational diabetes insipidus) ^[12]

• Definition: transient AVP disorder caused by increased activity and/or circulating levels of vasopressinase during pregnancy that typically resolves after delivery
• Etiology: decreased metabolization of vasopressinase due to impairment in hepatic function (e.g., due to HELLP, AFLP, hemochromatosis)
• Pathophysiology
  • ↓ Peripheral vascular resistance and blood pressure → ↓ threshold for AVP secretion.
  • ↑ Vasopressinase secretion from placental trophoblasts after 8 weeks' gestation
  • ↑ Compensatory AVP production
• Clinical features: same as in nonpregnant individuals
• Diagnostics
  • 24-hour urine collection to confirm polyuria (urine output > 3 L/day)
  • Desmopressin challenge test
• Treatment: desmopressin
• Complications: preeclampsia, oligohydramnios

AVP disorders in children ^[1][13][14]

Etiology ^[1]

The etiology of AVP disorders in children is similar to that in adults.

• AVP-D is most common (∼90% of cases); AVP-R is rare. ^[1]
• Secondary causes are more common and include:
  • Congenital causes (e.g., septo-optic dysplasia, holoprosencephaly)
  • Acquired causes (same as those in adults; see “Etiology of AVP disorders”)
• Hereditary causes are rare (mostly X-linked AVP-receptor mutations).

Clinical features ^[1][13]

• The age of onset depends on the underlying cause. ^[13]
• Clinical features of AVP disorders are similar in adults and children.
• Additional manifestations in infants and children include: ^[1][13]
  • Cold water cravings
  • Primary or secondary enuresis
  • Fever
  • Irritability
  • Headache
  • Vomiting
  • Constipation
  • Growth faltering ^[1]
• Manifestations suggestive of secondary AVP-D include: ^[13]
  • Brain tumor: visual defect, diplopia, precocious puberty
  • Langerhans cell histiocytosis: rash, recurrent otitis media, bone pain

Children with AVP disorders, especially if nonverbal and/or adipsic, are at high risk for hypernatremic dehydration. ^[1]

Diagnostics ^[1]

Diagnostics for AVP disorders are similar in adults and children.

• Confirm hypotonic polyuria on 24-hour urine collection.
  • Polyuria in children:
    • Neonates: > 150 mL/kg/day ^[1]
    • Infants and children aged ≤ 2 years: > 100–110 mL/kg/day ^[1]
    • Older children: > 40–50 mL/kg/day ^[1]
  • Urine osmolality < 300 mOsm/kg and serum osmolality > 300 mOsm/kg suggests an AVP disorder. ^[1]
• Obtain BMP to:
  • Assess for hypernatremia ^[15]
  • Exclude mimics of AVP disorders (e.g., diabetes mellitus)
  • Assess for causes of acquired AVP-R (e.g., hypercalcemia, hypokalemia)
• Findings suggestive of an AVP disorder: Refer to pediatric endocrinology for further diagnostics, including
  • Water deprivation test
  • Evaluation for an underlying etiology (e.g., brain imaging, tumor markers, genetic testing)

Management ^[1][14]

Management of AVP disorders is similar in children and adults.

• Refer to a pediatric specialist (e.g, endocrinologist or nephrologist) for management.
• Provide the following dietary recommendations:
  • Free access to water
  • Low-sodium diet
  • Adequate caloric intake (specialist consultation is recommended) ^[14]
• Specialist treatment may include:
  • Management of reversible causes (e.g., hypercalcemia, hypokalemia, obstructive uropathy)
  • Pharmacologic therapy (e.g., desmopressin, thiazide diuretics, NSAIDs, and/or amiloride)