Diabetes Insipidus

Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). In CDI, the amount of antidiuretic hormone (ADH) produced by the hypothalamus or released from the pituitary gland is decreased. In nephrogenic DI, the kidneys fail to respond to circulating ADH. Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Central and NDI are differentiated based on measured ADH levels and response to a water deprivation test. Central DI is treated with desmopressin, while nephrogenic DI is treated with diuretics and dietary salt restriction.

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  • Total prevalence: 1 in 25,000 people
  • Central diabetes insipidus (CDI) is more common than nephrogenic diabetes insipidus (NDI). 
  • Only 1 in 10 cases of DI is congenital.
  • Men and women are equally affected.
  • 20% of patients undergoing neurosurgery will develop some degree of DI.


Role of antidiuretic hormone (ADH)

Antidiuretic hormone is also called vasopressin.


Antidiuretic hormone regulates serum osmolarity and blood pressure.

  • Increased free water absorption resulting in:
    • ↓ Serum osmolarity
    • ↑ Urine osmolarity 
    • ↑ Intravascular volume 
  • Vasoconstriction


  • Synthesized in the supraoptic nuclei of the hypothalamus
  • Stored and secreted by the posterior pituitary 
  • Secreted in response to:
    • Increased plasma osmolarity (detected by osmoreceptors (vasopressin type 2 (V₂)) in the hypothalamus)
    • Hypovolemia (detected by baroreceptors (vasopressin type 1 (V₁)) in the carotid sinus and aortic arch)
Adh regulation and production

Regulation and pathway of ADH production

Image by Lecturio.

Central DI

Central diabetes insipidus is caused by the insufficient production of ADH from the hypothalamus or insufficient release from the posterior pituitary gland.

  • Idiopathic
    • Most common (30%50%)
    • Assumed to be caused by autoimmune damage to ADH-producing cells
  • Acquired
    • Autoimmune 
    • Pituitary or secondary tumors
      • Craniopharyngioma 
      • Adenoma
    • Neurosurgery or head trauma
    • Infiltrative disease 
      • Sarcoidosis
      • Langerhans cell histiocytosis
    • Hypoxic encephalopathy 
    • Meningitis
    • Alcohol intoxication
  • Congenital (rare)
    • Congenital hypopituitarism 
    • Wolfram syndrome

Nephrogenic DI

Nephrogenic diabetes insipidus is caused by an insufficient response of the kidneys to ADH.

  • Acquired
    • Long-term lithium therapy (most common)
    • Hypercalcemia (2nd most common)
    • Pregnancy
    • Hypokalemia
    • Other drugs (antivirals, antifungals, antibiotics, antineoplastic drugs) 
    • Acute or chronic kidney disease
      • Autosomal dominant polycystic kidney disease (ADPKD)
      • Renal amyloidosis
      • Bardet-Biedl syndrome
      • Bartter syndrome
      • Sjögren’s syndrome
    • Mild form is often found in elderly individuals (decline in kidney function with age).
  • Congenital (rare)
    • Likely cause if NDI presents in childhood
    • Most common: mutations in the gene encoding V2
      • X-linked inheritance
    • Less common: mutations in the gene encoding the aquaporin (AQP) channels
      • Autosomal recessive/autosomal dominant inheritance

Clinical Presentation and Diagnosis

Clinical presentation

Central diabetes insipidus and NDI present with the same symptoms:

  • Polyuria
    • Defined as > 3 L urine output/day
  • Nocturia (leading to daytime sleepiness)
  • Polydipsia (secondary to increased serum sodium and plasma osmolality)
  • Neurologic symptoms may occur secondary to hypernatremia.
    • Irritability
    • Coma, if severe


  • Water deprivation test
    • Plasma and urine osmolality are measured before water restriction.
    • No water intake for 2–3 hours.
    • Plasma and urine osmolality are measured after this interval. 
    • Hourly measurements of plasma and urine osmolality
    • If there is no increase in urine osmolarity, an ADH analog (desmopressin) is administered.
      • If urine osmolarity increases → CDI (= lack of central ADH secretion is compensated through desmopressin)
      • If urine osmolarity stays low → NDI (= defect in kidneys prevents the ADH-mimicking effect of desmopressin)
  • Additional testing:
    • Head computed tomography (CT) or magnetic resonance imaging (MRI) (if CDI is suspected)
    • Review of current medications (lithium salts, foscarnet, clozapine)
Table: Diagnostics
ADH level Urine specific gravity Serum osmolarity Water deprivation test (after ADH analog administration)
CDI ↓ ADH < 1.006 > 290 mOsm/kg Good response (> 50% increase in urine osmolarity)
NDI Normal or ↑ ADH No or minimal change in urine osmolarity

Head CT of a craniopharyngioma (calcified cystic mass): Diabetes insipidus is estimated to occur in up to 35% of patients before surgery and 70%–90% after surgery.

Image: “Craniopharyngioma1” by Matthew R Garnett, Stéphanie Puget, Jacques Grill, Christian Sainte-Rose. Craniopharyngioma. Orphanet Journal of Rare Diseases.. License: CC BY 2.0


Central DI

  • Medical therapy:
    • Desmopressin (1st line)
    • Drugs with antidiuretic effect (rarely used)
      • Nonsteroidal anti-inflammatory drugs (NSAIDs), thiazide diuretics, carbamazepine
      • Less effective and more side effects than desmopressin
  • Nutritional:
    • Low-sodium, reduced-protein diet
    • Hydration
    • If electrolyte abnormalities do not normalize through oral water intake: IV dextrose plus water or IV hypo-osmolar fluids
    • Special consideration in children: 
      • Early treatment important due to harmful effects of hypernatremia
      • Give water every 2 hours (day and night).
      • Monitor food intake and growth.
      • Low-protein diet not recommended

Nephrogenic DI

  • Medical therapy:
    • Hydrochlorothiazide
    • Indomethacin
    • Amiloride
    • Avoidance of offending agent (most commonly lithium) → kidney function may return to normal after discontinuation.
  • Nutritional: same as for central DI

Differential Diagnosis

  • Diabetes mellitus: a chronic metabolic disorder characterized by resistance to insulin (type 2) or insufficient production of insulin (type 1) resulting in hyperglycemia and resultant polyuria due to osmotic diuresis. Also presents with polydipsia due to increased diuresis. Patients would be expected to have elevated serum glucose and glucosuria. 
  • Psychogenic polydipsia: excessive fluid intake without an identifiable organic cause, often seen in individuals with schizophrenia, anxiety disorders, or anorexia nervosa. This excessive drinking of fluids results in polyuria and, in severe cases, hyponatremia. Water deprivation test would show an increase in urine osmolarity after fluid restriction, which differentiates it from DI.


  1. Tabibzadeh N. et al. (2019). Complications métaboliques et rénales chroniques du traitement par sels de lithium [Chronic metabolic and renal disorders related to lithium salts treatment]. Rev Med Interne.
  2. Ghirardello, S. et al. (2006). Diabetes insipidus in craniopharyngioma: postoperative management of water and electrolyte disorders. Journal of pediatric endocrinology & metabolism: JPEM, 19 Suppl 1, 413–421. 
  3. Hui C., Radbel J.M. Diabetes Insipidus. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved Oct 8, 2020, from https://www.ncbi.nlm.nih.gov/books/NBK470458/
  4. Bendz, H., Aurell, M. (1999). Drug-Induced Diabetes Insipidus. Drug-Safety, 449–456.

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