Key Facts

The water deprivation test with desmopressin challenge distinguishes cranial from nephrogenic DI. Cranial DI responds to desmopressin; nephrogenic does not. Over-treatment with desmopressin risks hyponatraemia.

Epidemiology

Cranial DI: incidence ~3 per 100,000. Most cases follow pituitary surgery. Nephrogenic DI: lithium-induced is commonest acquired cause.

Aetiology

Cranial: pituitary/hypothalamic surgery (~50%), tumours (craniopharyngioma, metastases), trauma, infiltrative (sarcoidosis, Langerhans cell histiocytosis), idiopathic (~30%), autoimmune hypophysitis. Nephrogenic: lithium (~20-40% of chronic users develop concentrating defect), hypercalcaemia, hypokalaemia, chronic kidney disease, genetic (X-linked AVPR2 mutations — most common inherited form).

Pathophysiology

Cranial: reduced/absent ADH secretion from posterior pituitary → collecting ducts remain impermeable to water → dilute urine → polyuria → compensatory polydipsia. Nephrogenic: ADH levels are normal/high but collecting duct cells are resistant (downregulated aquaporin-2 channels) → same result.

Symptoms

• Polyuria: >3L/day (often 5-15L; can be >20L in severe cranial DI)
• Polydipsia: intense thirst, craving for cold water
• Nocturia: often >3 times per night
• Dehydration if water access limited (confusion, hypotension — especially post-operative patients)

Signs

• Usually well if adequate water access
• Dehydration if water restricted: dry mucous membranes, tachycardia, hypotension
• Features of underlying cause (pituitary surgery scar, visual field defect)

Biochemistry

• Raised/high-normal serum osmolality (>290 mOsm/kg)
• Raised serum sodium (may be >145 mmol/L if water-restricted)
• Dilute urine: osmolality <300 mOsm/kg (often <100)

Red Flags

• Post-neurosurgical polyuria → cranial DI until proven otherwise
• Severe hypernatraemia with altered consciousness → medical emergency
• Triphasic response after pituitary surgery: DI → SIADH → permanent DI (days 1-3 → days 4-7 → after day 7)

Baseline

• Paired serum and urine osmolality: serum >290 with urine <300 suggests DI
• U&Es: Na⁺ (high-normal or raised), K⁺, renal function
• Blood glucose, calcium (exclude other causes)

Water Deprivation Test (Gold Standard)

1. Fluid restriction for 8 hours (supervised; weigh hourly — stop if >3% body weight lost)
2. Measure urine osmolality hourly and serum osmolality
3. Normal response: urine osmolality >600 mOsm/kg (excludes DI)
4. If urine remains dilute (<300) with rising serum osmolality: give IM desmopressin 2μg
5. Cranial DI: urine osmolality rises >50% (or >600) after desmopressin
6. Nephrogenic DI: urine osmolality remains <300 despite desmopressin
7. Primary polydipsia: urine concentrates partially with water deprivation (medullary washout may limit concentration)

Copeptin

• Copeptin (C-terminal fragment of AVP precursor): more stable than ADH measurement; emerging diagnostic test; basal copeptin low in cranial DI; may replace WDT in future

Imaging

• Pituitary MRI: loss of posterior pituitary bright spot on T1 (cranial DI); pituitary/hypothalamic lesion
• Renal USS: if nephrogenic DI

Cranial DI

• Desmopressin (DDAVP): synthetic ADH analogue
  • Intranasal: 10-40μg OD-BD
  • Oral: 100-400μg BD-TDS
  • Sublingual: 60-240μg BD
• Titrate to control polyuria while avoiding hyponatraemia
• Monitor: fluid balance, serum Na⁺, urine output
• Advise on fluid intake: drink to thirst (avoid excess → hyponatraemia)

Nephrogenic DI

• Treat underlying cause: stop lithium if possible (effects may be partially reversible); correct hypercalcaemia, hypokalaemia
• Thiazide diuretics: bendroflumethiazide 2.5-5mg OD (paradoxically reduces urine volume by ~50% via sodium depletion → increased proximal reabsorption)
• Amiloride 5-10mg BD: particularly useful in lithium-induced DI (blocks lithium entry into collecting duct via ENaC)
• Low-sodium, low-protein diet: reduces solute load
• High-dose desmopressin: occasionally partially effective in partial nephrogenic DI

Monitoring

• Serum Na⁺: regularly (over-treatment → hyponatraemia; under-treatment → hypernatraemia)
• Fluid balance, body weight
• Annual pituitary function if cranial DI

Referral Criteria

• Endocrinology: all DI
• Neurosurgery: if pituitary lesion identified

Cranial DI: excellent with desmopressin; most require lifelong treatment (unless transient post-surgical — ~50% post-surgical DI resolves within days-weeks). Nephrogenic DI: depends on cause; lithium-induced may be partially irreversible even after lithium cessation. Risk of severe hypernatraemia if water access is limited (elderly, post-operative, altered consciousness). Quality of life generally good with appropriate treatment.

Water Deprivation Test Interpretation

Cranial vs Nephrogenic DI