Diabetes insipidus

What it is

Diabetes insipidus (DI) is a rare disorder in which the kidneys cannot conserve water properly, producing 3 to 20 litres of dilute urine per day and driving an intense, unrelenting thirst. Also called arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R) depending on subtype, DI affects an estimated 1 in 25,000 people worldwide. Despite sharing the word "diabetes" with diabetes mellitus, the two conditions are entirely unrelated: DI involves the hormone vasopressin (antidiuretic hormone, ADH) and water balance, not insulin or blood glucose. In Canada, diagnosis and initial workup typically flow through endocrinology or nephrology, with desmopressin available on most provincial formularies for confirmed central DI.

The condition is classified into two main types based on where the problem originates:

Type	Former name	Core defect	Key example causes
AVP-D (central DI)	Central DI	Insufficient vasopressin production or release from the hypothalamus/pituitary	Head injury, pituitary surgery, brain tumour, autoimmune, idiopathic
AVP-R (nephrogenic DI)	Nephrogenic DI	Kidneys fail to respond to vasopressin	Lithium therapy, chronic kidney disease, hypercalcaemia, inherited receptor mutations
Gestational DI	Gestational DI	Placental enzyme degrades vasopressin faster than normal	Pregnancy (resolves postpartum)

Causes and mechanism

Vasopressin is produced in the hypothalamus and released from the posterior pituitary. It binds to receptors in the kidney's collecting ducts, triggering water reabsorption. When this signal is absent or ignored, the kidneys excrete free water continuously, regardless of hydration status.

In AVP-D (central DI), the most common identifiable causes are damage to the hypothalamus or pituitary from neurosurgery, traumatic brain injury, tumours (such as craniopharyngioma), or autoimmune inflammation. Up to 30% of central DI cases are idiopathic — no structural cause is ever found.

In AVP-R (nephrogenic DI), lithium carbonate — widely prescribed in Canada for bipolar disorder — is the single most common drug cause, affecting up to 40% of long-term lithium users to some degree. Other causes include severe hypokalaemia, hypercalcaemia, and rare X-linked or autosomal mutations in the vasopressin V2 receptor or aquaporin-2 water channel genes.

Gestational DI is a transient form driven by placental vasopressinase, an enzyme that accelerates vasopressin breakdown during the second and third trimesters.

Symptoms and diagnosis

The hallmark presentation is the combination of polyuria (urine output exceeding 50 mL/kg/day, often 3–20 L/day) and polydipsia (intense, persistent thirst). Urine appears pale or colourless. Nocturia — waking repeatedly overnight to urinate — is common and disruptive. If fluid intake cannot keep pace, dehydration develops rapidly, presenting as dry mouth, dizziness, tachycardia, and in severe cases confusion or altered consciousness.

In children, DI may appear as unexplained bedwetting, irritability, fever without infection, and poor growth — symptoms that can be mistaken for other conditions.

Diagnostic workup typically includes:

1. Urine and serum osmolality — dilute urine (osmolality below 300 mOsm/L) alongside concentrated serum (elevated sodium) is the key finding.
2. Supervised water deprivation test — assesses whether the kidneys can concentrate urine when fluid is withheld; performed in hospital given dehydration risk.
3. Desmopressin response test — administering synthetic vasopressin distinguishes AVP-D (urine concentrates in response) from AVP-R (no response).
4. Brain MRI — identifies structural causes such as pituitary tumours or hypothalamic lesions. In healthy individuals, the posterior pituitary appears as a bright spot on T1-weighted MRI; absence of this signal can support a diagnosis of central DI.
5. Serum electrolytes — hypernatraemia is common in untreated or under-treated DI.

In Canada, LifeLabs and Dynacare both process urine and serum osmolality as standard send-out tests; turnaround is typically 24–48 hours.

Treatment options

Treatment is guided by DI subtype and underlying cause.

AVP-D (central DI): Desmopressin (DDAVP), a synthetic vasopressin analogue, is the primary treatment. It is available in Canada as a nasal spray, sublingual tablet, and injectable form. Desmopressin reduces urine output and thirst effectively in most patients. Where a structural cause exists — such as a resectable pituitary tumour — treating that cause may partially or fully resolve DI.

AVP-R (nephrogenic DI): Desmopressin is generally ineffective because the receptor is unresponsive. Management focuses on:

• Removing or reducing the causative agent (e.g., adjusting lithium dose under psychiatric supervision, correcting hypercalcaemia or hypokalaemia).
• A low-sodium, low-protein diet to reduce renal solute load and urine output.
• Thiazide diuretics, which paradoxically reduce urine volume by decreasing fluid delivery to the collecting duct.
• NSAIDs (e.g., indomethacin) as an adjunct in some cases.

Gestational DI: Desmopressin is safe in pregnancy and is the treatment of choice; the condition typically resolves within weeks of delivery.

Across all types, maintaining adequate fluid intake is non-negotiable. Patients should carry water at all times and ensure any treating clinician — including surgeons, anaesthesiologists, and emergency physicians — is aware of the diagnosis before any procedure involving fluid restriction.

When to see a clinician in Canada

Seek prompt medical attention if you are producing very large volumes of pale urine and feel persistently thirsty, especially if you are also waking multiple times overnight. Dehydration from DI can escalate to a medical emergency within hours if fluid access is cut off — for example, during a gastrointestinal illness, a surgical fast, or a hospital admission for an unrelated condition.

Patients on long-term lithium therapy who develop polyuria and polydipsia should raise this with their prescriber; lithium-induced nephrogenic DI requires a careful medication review rather than abrupt discontinuation. Children with unexplained bedwetting combined with excessive thirst and poor growth warrant paediatric endocrinology referral.

In Canada, referral pathways vary by province. Most family physicians can initiate the osmolality workup and refer to endocrinology or nephrology for the water deprivation test and MRI. Telehealth platforms (Maple, Dialogue) can facilitate initial triage in remote or underserved areas, but the supervised water deprivation test requires in-person hospital monitoring.

Limitations and open questions

Research is still emerging on the long-term renal outcomes of lithium-induced nephrogenic DI after lithium is discontinued — some degree of concentrating defect appears to persist in a proportion of patients even years after stopping the drug. The optimal diagnostic threshold for the water deprivation test remains debated, and a 2021 study in the Journal of Internal Medicine noted that copeptin stimulation testing (measuring a vasopressin surrogate) may outperform the traditional water deprivation test for distinguishing DI subtypes, though this assay is not yet widely available in Canadian hospital laboratories. Health Canada has not issued specific guidance on copeptin testing, and provincial coverage for this assay is inconsistent. The renaming of DI to "arginine vasopressin deficiency/resistance" — formally proposed in a 2022 Journal of Clinical Endocrinology and Metabolism position statement — has not yet been uniformly adopted in Canadian clinical documentation or provincial formulary listings, which may cause confusion for patients reviewing their own records.