Diabetes Insipidus
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Diabetes Insipidus (DI) is a condition characterised by the passage of large volumes (>3L/day) of dilute urine due to impaired water resorption by the kidney, because of reduced ADH secretion from the posterior pituitary (cranial DI) or impaired response of the kidney to ADH (nephrogenic DI).

It is important to distinguish diabetes insipidus from primary polydipsia, which is a psychiatric condition characterised by excessive water consumption. Other causes of polyuria and polydipsia, such as hyperglycaemia, are not to be confused with DI.

In health, ADH acts to increase the volume of blood intravascularly, and also to decrease the volume of urine produced. Therefore, a lack of it causes increased urine production and internal volume depletion.

  • The most common type of DI in humans is cranial DI, involving a deficiency of ADH.
  • DI can also be gestational, or present as an iatrogenic effect of alcohol or some types of drug abuse.
  • Despite the name, there is no overlap with the pathophysiology of DM; in DI urine does not contain glucose.
  • Incidence in the general population is 3/100,000.



  • Polyuria – excessive urination unaffected by reduction of fluid intake.
  • Polydipsia – can be uncontrollable and all consuming with patients drinking anything and everything to hand.
  • Dehydration since the body cannot conserve much, if any, of the water it takes in.
  • Symptoms of hypokalaemia:
    • Muscle weakness
    • Hypotonia
    • Hyporeflexia
    • Cramps
    • Tetany
    • Palpitations
    • Light-headedness (arrhythmias)
  • Symptoms of hypernatraemia:
    • Lethargy
    • Thirst
    • Weakness
    • Irritability
    • Confusion
    • Coma
    • Fits
    • Signs of dehydration.

Other causes of hypernatraemia:
Water loss in excess of sodium loss…

  • Fluid loss without water replacement (e.g. diarrhoea, vomit, burns)
  • Incorrect IV fluid replacement (Excessive saline)
  • Diabetes insipidus – suspect if large urine volume. This may follow head injury or CNS surgery, especially pituitary.
  • Osmotic dieresis for diabetic coma
  • Primary aldosteronism – suspect if hypertension, hypokalaemia and alkalosis due to high bicarbonate.



Cranial DINephrogenic DI
  • Disease of the hypothalamus
  • Neurosurgery
  • Trauma
  • Primary/ secondary tumours
  • Infiltrative disease (sarcoidosis, histiocytosis)
  • Idiopathic
  • Hypokalaemia
  • Hypercalcaemia
  • Drugs: lithium chloride, dimeclocycline, glibenclamide
  • Renal tubular acidosis
  • Sickle cell disease
  • Prolonged polyuria of any cause
  • Familial (mutation in ADH receptors)

Damage to the hypothalamo-neurohypophysial tract or the posterior pituitary with an intact hypothalamus does not lead to ADH deficiency, and therefore does not cause CDI. This is because ADH is still able to ‘leak’ from the damaged end of the intact neurone.

Neurogenic Causes

  • Cranial/ neurogenic DI is caused by insufficient levels of ADH due to lack of its production in the brain.
  • Idiopathic =<50%
  • Also due to damage of the hypothalamus, pituitary stalk, posterior pituitary, or head trauma. Vasopressin is released by the posterior pituitary, but unlike most other pituitary hormones, it is produced by the hypothalamus. Cranial DI can therefore be a failure of production at the hypothalamus or a failure of release at the pituitary.
  • Congenital: Defects in ADH gene, such as in DIDMOAD. DIDMOAD is a rare autosomal recessive disorder: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (also known as Wolfram’s syndrome). Familial neurogenic diabetes insipidus is the rarest cause of cranial DI.
  • Tumour (may present with DI and hypopituitarism) – craniopharyngioma, metastases, pituitary tumour.
  • Trauma: temporary if distal to pituitary stalk as proximal nerve endings frow out to find capillaries in scar tissue and begin direct secretion again.
  • Hypophysectomy
  • Autoimmune hypophysitis
  • Inflammation: histiocytosis, sarcoidosis (suspect neurosarcoidosis if CSF protein high, facial nerve palsy, CSF pleocytosis, DI, hemiparesis, psychosis, papilloedema, ataxia, seizures, optic atrophy, hearing loss or nystagmus)
  • Vascular: haemorrhage
  • Infection: meningoencephalitis. Sheehan’s syndrome is pituitary infarction from shock, e.g. postpartum haemorrhage. It is rare.


Nephrogenic Causes

  • Nephrogenic DI is a form of diabetes insipidus primarily due to pathology of the kidney which results in its improper response to ADH, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.
  • Most common in its acquired forms, meaning that that the defect was not present at birth.
  • The most obvious cause is a systemic or renal disorder such as amyloidosis, polycystic kidney disease or electrolyte imbalance.
  • There are some inherited causes of nephrogenic DI. These come in the form of type 1, affecting the AVPR2 gene (x-linked defect causing the V2 vasopressin receptor in the kidney to stop functioning properly), and type 2, affecting the AQP2 gene (a mutation in the aquaporin 2 gene impedes normal functionality of the kidney water channel, impeding the kidney’s ability to absorb water; autosomal recessive).
  • Metabolic causes include low potassium and high calcium. Hypercalcaemia causes natriuresis (increased sodium loss in urine) and water diuresis.
  • Drugs such as lithium and demeclocycline can cause DI. Chronic lithium ingestion affects the tubules by entering the collecting tubule cells through sodium channels, accumulating and interfering with the normal response to ADH, causing ADH resistance.
  • Chronic renal disease and post-obstructive uropathy are two other causes of DI.


Differential Diagnoses

  • Diabetes mellitus
  • Diuretics or lithium use
  • Primary polydipsia: this causes symptoms of polydipsia and polyuria with dilute urine. Its cause is poorly understood; it may be associated with schizophrenia or mania (+/- lithium therapy) or, rarely hypothalamic disease (neurosarcoid; tumour; encephalitis; brain injury; HIV encephalopathy) As part of this syndrome, the kidneys lose their ability to fully concentrate urine, due to a wash out of the normal concentration gradient in the renal medulla.



  • Urine volume must be measured to confirm polyuria (>3L in 24h)
  • U&E: normal to high Na+.
  • Ca2+
  • Glucose (exclude DM)
  • Measure urine and serum osmolality:
    • In DI, urine osmolality is inappropriately low for the high plasma osmolality.
    • Serum osmolality is usually 285-295 Osmol/kg and urine can be concentrated to more than twice this concentration.
    • Significant DI is excluded if urine: plasma ratio is >2:1 (as is the normal situation in health), provided plasma osmolality is no greater than 295mOsmol/kg.
    • In DI, despite raised plasma osmolality, urine is dilute with a U:P ratio of <2.
    • In primary polydipsia, there may be dilutional hyponatraemia.



The 8 Hour Water Deprivation Test
This test is indicated for polyiuric patients with normal blood glucose and serum electrolytes, to determine whether diabetes insipidus accounts for their problems.

  • The purpose of this test is to see if the kidneys persist in producing dilute urine despite dehydration, and then to localise the cause.
  • Do not do the test before establishing that urine volume is >3L/d (output <3 with normal plasma Na+ and osmolality excludes significant disturbance of water balance).
  • Stop test if urine osmolality >600mOsmol/kg in Stage 1 (DI is excluded).
  • Free fluids until 07:30. Light breakfast at 06:30, no tea, coffee, smoking.

Stage 1

  • See if the kidneys continue to produce dilute urine despite dehydration, i.e. test for DI.
  • Fluid deprivation 0-8h for diagnosis of DI.
  • Start at 08:00.
  • Empty bladder, then no drinks and only dry food.
  • Weigh hourly. If >3% weight lost during test, order urgent serum osmolality. If >300mOsmol/kg, proceed to Stage 2. If <300, continue test.
  • Collect urine every 2 hours; measure its volume and osmolality.
  • Venous sample for osmolality every 4 hours.
  • Stop test after 8h (16:00) if urine osmolality >600mOsmol/kg (i.e. normal).

Stage 2

  • Differentiate cranial from nephrogenic DI.
  • Proceed if urine still dilute, i.e. urine osmolality <600mOsmol/kg.
  • Give desmopressin 2ug IM. Water can be drunk now.
  • Measure urine osmolality hourly for the next 4 hours.

This diagnostic investigation should be stopped if the patient loses >3% bodyweight, as this indicates significant and dehydration.

Interpretation of results

  • Urine osmolality >600mOsmol/kg in Stage 1.
  • U: P ratio >2 (normal concentrating ability).

Primary polydipsia

  • Urine concentrates, but less than normal, e.g. >400-600mOsmol/kg.

Cranial DI

  • Urine osmolality increases to >600mOsmol/kg after desmopressin (if equivocal an extended water deprivation test may be tried – no drinking from 18:00 the night before).

Nephrogenic DI

  • No increase in urine osmolality after desmopressin.



Cranial DI

  • Find the cause – MRI (head); test anterior pituitary function.
  • Give desmopressin, a synthetic analogue of ADH.
  • Unfortunately, treatment of the underlying condition seldom improves established cranial diabetes insipidus.

Nephrogenic DI

  • Treat the cause.
  • If it persists, try bendroflumethiazide 5mg PO/24h. Thiazide diuretics sensitise the renal tubules to endogenous vasopressin.
  • NSAIDs lower urine volume and plasma Na+ by inhibiting prostaglandin synthase: prostaglandins locally inhibit the action of ADH.
  • Treatment of the cause usually does improve nephrogenic diabetes insipidus.

Emergency management

  • Do urgent plasma U&E, and serum and urine osmolalities. Monitor U/O carefully and check U&E twice daily initially.
  • IVI to keep up with U/O. If severe hypernatraemia, do not lower Na+ rapidly as this may cause central oedema and brain injury. If Na+ is >170, use 0.9% saline initially – this contains 150mmol/L of sodium. Aim to reduce Na+ at a rate of <12mmol/L per day. Use of 0.45% saline can be dangerous.
  • Desmopressin 2ug IM (lasts 12-24h) may be used as a therapeutic trial.


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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

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