Diabetes insipidus (DI) is a condition in which the kidneys cannot effectively concentrate urine, resulting in hypotonic polyuria. Central DI (CDI), the most common form of DI, is caused by decreased hypothalamic production or pituitary release of antidiuretic hormone (ADH), resulting in insufficient levels of circulating ADH. CDI can be primary (idiopathic) or secondary to brain lesions or injury. Nephrogenic DI (NDI) is characterized by ADH resistance and may be hereditary or acquired. Patients with DI typically develop polydipsia in response to excessive fluid loss. Most patients also experience nocturia, which can lead to sleep deprivation and daytime sleepiness. DI is initially diagnosed based on the presence of hypotonic polyuria on a 24-hour urine collection. Subsequently, confirmatory testing (e.g., water deprivation test) can differentiate between CDI, NDI, and primary polydipsia. Patients with DI should be encouraged to compensate for urinary fluid losses with oral fluids. For CDI, pharmacotherapy with desmopressin (a synthetic ADH analogue) may be used. For acquired NDI, management involves treating the underlying cause (e.g., correcting metabolic derangement, relieving obstructive uropathy, or discontinuing the causative drug); the condition is typically reversible within weeks to months, although lithium-induced NDI may be irreversible. In some cases, pharmacotherapy with thiazide diuretics, NSAIDs, or amiloride may be indicated.
- Prevalence in the US: 3:100,000 
- Sex: ♀=♂
Epidemiological data refers to the US, unless otherwise specified.
Central diabetes insipidus (CDI) 
- Most common form: caused by insufficient or absent hypothalamic synthesis or posterior pituitary secretion of ADH
Primary (∼ ⅓ of cases)
- Most cases are idiopathic.
- The hereditary form is rare.
- Autoimmune etiology of primary CDI has been suggested 
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)
- Primary (∼ ⅓ of cases)
- Subtype: adipsic diabetes insipidus
- Hypothalamic osmoreceptor defects lead to loss of thirst despite decreased ADH secretion.
- Associated with an increased risk of hypernatremia
DI following neurosurgery (e.g., transsphenoidal surgery) is usually transient.
Nephrogenic diabetes insipidus (NDI) 
- Rare: caused by defective ADH receptors in the distal tubules and collecting ducts
- Hereditary (mutation in ADH 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)
- ADH enables the integration of aquaporins into the plasma membrane of collecting duct cells → reabsorption of free water
- Either ↓ ADH (central DI) or defective renal ADH receptors (nephrogenic DI) → impaired ability of the kidneys to concentrate urine (hypotonic collecting ducts) → dilute urine (low urine osmolarity)
Hyperosmotic volume contraction 
- 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 central DI, ADH levels are decreased, while in nephrogenic DI, 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, diabetes insipidus is very unlikely.
- Obtain a thorough patient history and perform a physical examination to assess for possible causes of diabetes insipidus.
- Obtain initial studies including serum sodium, plasma osmolality, and urine osmolality.
- Obtain subsequent studies (e.g., water deprivation test) to distinguish between primary polydipsia, CDI, and NDI.
- See also “Differential diagnosis of polyuria-polydipsia syndromes” for expected laboratory findings.
- Obtain imaging to rule out brain tumors in patients with CDI.
Initial laboratory studies 
Routine studies: BMP, urinalysis
- To rule out causes of osmotic diuresis, e.g., hyperglycemia with glucosuria
- To assess for acquired causes of NDI, 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 unclear; obtain subsequent studies to differentiate between polyuria-polydipsia syndromes.
- ↑ Na+ and/ or ↑ plasma osmolality: Diabetes insipidus likely; obtain subsequent studies to differentiate between CDI and NDI.
Subsequent laboratory studies 
- To distinguish between polyuria-polydipsia syndromes, ADH activity can be assessed directly or indirectly.
- Consult endocrinology for guidance and follow local testing protocols if available.
Water deprivation test (indirect assessment of ADH activity)
Urine concentrating capacity is assessed during a period of dehydration; desmopressin is then administered to assess response to a synthetic ADH analogue. 
- 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
- Urine osmolality increases to > 800 mOsm/kg: Primary polydipsia is confirmed.
- Urine osmolality remains ≤ 800 mOsm/kg: Administer desmopressin (a synthetic ADH analogue).
Interpretation after desmopressin administration
Urine osmolality (300–800 mOsm/kg) and:
- Significant increase (≥ 10%) after desmopressin: partial CDI
- No or minimal increase (< 10%) after desmopressin: primary polydipsia
Urine osmolality (< 300 mOsm/kg) and:
- Significant increase (> 50%) after desmopressin: complete CDI (indicating intact renal ADH receptors)
- No or moderate increase (< 50%) after desmopressin: NDI (indicating defective renal ADH receptors)
- Urine osmolality (300–800 mOsm/kg) and:
Plasma copeptin (direct assessment of ADH activity) 
- Circulating plasma copeptin levels reflect circulating ADH levels.
- Measure random plasma copeptin levels.
- ≥ 21.4 pmol/L: NDI 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: CDI
Plasma ADH measurement is not routinely utilized because results are unreliable, as ADH is unstable and has a short half-life ex vivo.
Brain imaging 
- Indications: suspected or confirmed CDI 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.”
|Primary polydipsia vs. central DI vs. nephrogenic DI |
|Central diabetes insipidus||Nephrogenic diabetes insipidus||Primary polydipsia (psychogenic polydipsia)|
|Mechanism|| || |
|Etiology|| || || |
|ADH|| || || |
|Initial studies||Serum sodium|| |
|Plasma osmolality|| || |
|Urine osmolality|| || |
Indirect assessment of ADH activity
|Water deprivation test|| || |
|After desmopressin administration|| || || |
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 
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 
- 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 diabetes insipidus, and those who are hospitalized or cannot access water because of mobility impairment. 
Central diabetes insipidus 
- 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
Desmopressin (preferred): synthetic ADH 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 ADH and increases its secretion
- Desmopressin (preferred): synthetic ADH analogue without vasoconstrictive effects
Most patients with CDI 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. 
Nephrogenic diabetes insipidus 
- 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
- NSAIDs (e.g., indomethacin)
- Amiloride: indicated in patients with lithium-induced NDI who continue lithium therapy
In patients with renal disease, NSAID treatment must be used with caution because of the potential nephrotoxic effects.
Special patient groups
Gestational diabetes insipidus 
- Definition: transient diabetes insipidus 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., HELLP, AFLP, hemochromatosis)
- ↓ Peripheral vascular resistance and blood pressure → ↓ threshold for ADH secretion
- ↑ Vasopressinase secretion from placental trophoblasts after 8 weeks' gestation
- ↑ Compensatory ADH production
- Clinical features: same as in non-pregnant individuals
- 24-hour urine collection to confirm polyuria (urine output > 3 L/day)
- Desmopressin challenge test
- Treatment: desmopressin
- Complications: preeclampsia, oligohydramnios