Diabetes Insipidus (DI)
Summary
Diabetes insipidus (DI) is a condition characterised by the production of large volumes of dilute urine (polyuria) due to either a deficiency of antidiuretic hormone (ADH/vasopressin) — Cranial DI, or renal insensitivity to ADH — Nephrogenic DI. Patients present with polyuria (>3 L/day, often >5-10 L), polydipsia, and nocturia. The diagnosis is confirmed by demonstrating an inability to concentrate urine despite high plasma osmolality, using the water deprivation test. The response to desmopressin (synthetic ADH) distinguishes cranial from nephrogenic DI. Cranial DI is treated with desmopressin replacement; nephrogenic DI is treated by addressing the underlying cause and using paradoxical thiazide diuretics or NSAIDs.
Key Facts
- Definition: Polyuria (>3 L/day) with dilute urine despite normal or high serum osmolality
- Cranial DI: Due to ADH deficiency (pituitary/hypothalamic pathology)
- Nephrogenic DI: Due to renal resistance to ADH
- Biochemistry: High plasma osmolality (>295 mOsm/kg) + Low urine osmolality (<300 mOsm/kg)
- Differentiation: Water deprivation test with desmopressin
- Treatment (Cranial): Desmopressin (DDAVP)
- Treatment (Nephrogenic): Treat cause; Thiazides; NSAIDs; Amiloride (lithium-induced)
Clinical Pearls
"Serum Concentrated, Urine Dilute = DI": In DI, the kidneys fail to concentrate urine. Serum osmolality rises (concentrated) while urine osmolality remains low (dilute).
"Water Deprivation Test Differentiates the Types": Withhold water; if urine concentrates after desmopressin → Cranial DI. If no response → Nephrogenic DI. If urine concentrates during water deprivation before desmopressin → Primary polydipsia.
"Lithium Is the Commonest Cause of Nephrogenic DI": Lithium damages the collecting duct's ability to respond to ADH. It can be irreversible.
"Post-Pituitary Surgery DI Is Usually Transient": Following transsphenoidal surgery, transient DI is common (days to weeks). Rarely permanent. Monitor fluid balance and sodium closely.
"Desmopressin Requires Dose Titration": Too much desmopressin causes hyponatraemia and water intoxication. Titrate based on symptoms and sodium levels.
Why This Matters Clinically
DI can cause severe dehydration and hypernatraemia if not recognised. In the post-operative neurosurgical setting, monitoring for DI is critical. Understanding the distinction between cranial and nephrogenic DI guides treatment.[1,2]
Incidence & Prevalence
| Parameter | Data |
|---|---|
| Prevalence | ~1 in 25,000 |
| Cranial DI | ~50% of cases |
| Nephrogenic DI | ~50% (includes drug-induced) |
| Post-surgical | Common after pituitary surgery (usually transient) |
Causes
Cranial (Central) DI:
| Cause | Notes |
|---|---|
| Idiopathic | Most common (~30%) |
| Post-neurosurgical | Pituitary surgery; Often transient |
| Trauma | Head injury |
| Tumours | Craniopharyngioma; Germinoma; Metastases |
| Inflammatory | Sarcoidosis; Langerhans cell histiocytosis |
| Hypoxic brain injury | Sheehan's syndrome |
| Genetic | Rare; Autosomal dominant |
Nephrogenic DI:
| Cause | Notes |
|---|---|
| Lithium | Most common drug cause; May be irreversible |
| Hypercalcaemia | Reduces aquaporin-2 expression |
| Hypokalaemia | Impairs concentrating ability |
| Chronic kidney disease | Loss of medullary gradient |
| Drugs | Demeclocycline, Foscarnet |
| Genetic | X-linked (AVPR2), Autosomal recessive (AQP2) |
Normal ADH Physiology
| Step | Details |
|---|---|
| 1 | Osmoreceptors in hypothalamus detect high plasma osmolality |
| 2 | Posterior pituitary releases ADH (vasopressin) |
| 3 | ADH binds V2 receptors on collecting duct principal cells |
| 4 | Aquaporin-2 water channels inserted into apical membrane |
| 5 | Water reabsorbed → Concentrated urine |
Pathophysiology by Type
Cranial DI:
- Failure of ADH synthesis/secretion
- Causes: Pituitary/hypothalamic damage (tumour, surgery, trauma, infiltration)
- Result: Dilute urine; Polyuria; Hypernatraemia
Nephrogenic DI:
- ADH is present but kidneys do not respond
- Causes: V2 receptor mutations; Aquaporin-2 defects; Lithium toxicity
- Result: Same clinical picture; Does NOT respond to desmopressin
Symptoms
| Symptom | Notes |
|---|---|
| Polyuria | >3 L/day; Often 5-20 L; "Like a tap" |
| Polydipsia | Compensatory intense thirst |
| Nocturia | Frequent waking to urinate |
| Dehydration symptoms | If access to water is limited |
| Weight loss | If prolonged fluid loss |
Signs
| Sign | Notes |
|---|---|
| Dehydration | Dry mucous membranes; Reduced skin turgor; Hypotension (if severe) |
| Normal examination | Often if fluid intake matches output |
| Hypernatraemia | Only if access to water is restricted |
Biochemistry
| Parameter | DI | Primary Polydipsia |
|---|---|---|
| Plasma sodium | High normal or ↑ | Low normal or ↓ |
| Plasma osmolality | High (>295 mOsm/kg) | Low-normal |
| Urine osmolality | Low (<300 mOsm/kg) | Low (<300 mOsm/kg) |
Red Flags
[!CAUTION] Red Flags — Urgent Assessment:
- Severe hypernatraemia (Na >155 mmol/L)
- Altered consciousness
- Rapid onset polyuria post-pituitary surgery
- Continued polyuria with signs of dehydration (hypotension, tachycardia)
Hydration Status
| Finding | Significance |
|---|---|
| Skin turgor | Reduced in dehydration |
| Mucous membranes | Dry |
| Capillary refill | Delayed |
| Blood pressure | Low if hypovolaemic |
| Heart rate | Raised if hypovolaemic |
Neurological
- GCS (hypernatraemia causes confusion)
- Visual fields (may indicate pituitary tumour)
- Cranial nerves
Blood Tests
| Test | Finding |
|---|---|
| Serum sodium | Normal or high (>145 mmol/L) |
| Plasma osmolality | High (>295 mOsm/kg) |
| Urea | May be elevated (dehydration) |
| Calcium | Check for hypercalcaemia (nephrogenic cause) |
| Potassium | Check for hypokalaemia (nephrogenic cause) |
| Lithium level | If on lithium |
Urine Tests
| Test | Finding |
|---|---|
| Urine volume | >3 L/24 hours |
| Urine osmolality | <300 mOsm/kg (dilute) |
| Urine specific gravity | <1.005 |
Water Deprivation Test
| Phase | Procedure | Interpretation |
|---|---|---|
| Water deprivation (8 hours) | Withhold fluids; Measure urine osmolality, body weight, plasma osmolality hourly | Normal: Urine concentrates >600 mOsm/kg |
| Stop if | Weight loss >3%; Severe thirst; Hypernatraemia | Safety measure |
| Desmopressin challenge | Give desmopressin 2 mcg IM | |
| Cranial DI | Urine concentrates >50% after desmopressin | |
| Nephrogenic DI | No urine concentration after desmopressin | |
| Primary polydipsia | Urine concentrates during water deprivation (before desmopressin) |
Imaging
| Modality | Purpose |
|---|---|
| MRI Pituitary | All cranial DI cases; Identify tumour, infiltration |
| Normal posterior bright spot | May be absent in cranial DI (T1 hyperintensity) |
Management Algorithm
DIABETES INSIPIDUS MANAGEMENT
↓
┌─────────────────────────────────────────────────────────────┐
│ DIAGNOSIS │
├─────────────────────────────────────────────────────────────┤
│ ➤ Confirm polyuria (>3 L/24h or 50 mL/kg/day) │
│ ➤ Check paired plasma + urine osmolality │
│ ➤ High plasma osm + Low urine osm = DI │
│ ➤ Exclude diabetes mellitus (glucose) │
│ ➤ Water deprivation test if diagnosis uncertain │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ DIFFERENTIATE CRANIAL VS NEPHROGENIC │
├─────────────────────────────────────────────────────────────┤
│ WATER DEPRIVATION + DESMOPRESSIN TEST: │
│ │
│ CRANIAL DI: │
│ ➤ Urine does NOT concentrate during water deprivation │
│ ➤ Urine DOES concentrate after desmopressin (>50% rise) │
│ │
│ NEPHROGENIC DI: │
│ ➤ Urine does NOT concentrate during water deprivation │
│ ➤ Urine does NOT concentrate after desmopressin │
│ │
│ PRIMARY POLYDIPSIA: │
│ ➤ Urine concentrates normally during water deprivation │
│ ➤ No need for desmopressin │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ CRANIAL DI TREATMENT │
├─────────────────────────────────────────────────────────────┤
│ ➤ Desmopressin (DDAVP) — synthetic ADH analogue │
│ • Nasal spray: 10-40 mcg daily in 1-2 doses │
│ • Oral tablet: 100-600 mcg daily in 2-3 doses │
│ • Sublingual: 60-360 mcg daily │
│ • Titrate to control symptoms and avoid hyponatraemia │
│ │
│ ⚠️ RISK: Hyponatraemia from overcorrection │
│ ➤ Monitor sodium regularly │
│ ➤ Allow 1 day/week without desmopressin for "breakthrough"│
│ polyuria (prevents hyponatraemia) │
│ │
│ ➤ Treat underlying cause if identified (tumour, etc.) │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ NEPHROGENIC DI TREATMENT │
├─────────────────────────────────────────────────────────────┤
│ ➤ Treat underlying cause: │
│ • Stop lithium (if possible) │
│ • Correct hypercalcaemia |
│ • Correct hypokalaemia │
│ │
│ ➤ Thiazide diuretics (paradoxical effect): │
│ • Reduce urine volume by inducing mild hypovolaemia │
│ • Bendroflumethiazide 2.5 mg daily │
│ │
│ ➤ Amiloride (lithium-induced): │
│ • Blocks lithium entry to collecting duct │
│ • 5-20 mg daily │
│ │
│ ➤ NSAIDs (e.g., Indomethacin): │
│ • Reduce prostaglandin-mediated antagonism of ADH │
│ │
│ ➤ Low sodium diet │
│ ➤ Adequate hydration (allow free water access) │
└─────────────────────────────────────────────────────────────┘
Medication Summary
| Drug | Indication | Dose |
|---|---|---|
| Desmopressin nasal | Cranial DI | 10-40 mcg daily |
| Desmopressin oral | Cranial DI | 100-600 mcg daily in 2-3 doses |
| Thiazide | Nephrogenic DI | Bendroflumethiazide 2.5 mg daily |
| Amiloride | Lithium-induced DI | 5-20 mg daily |
| Complication | Notes |
|---|---|
| Hypernatraemia | If water access limited; Can cause confusion, seizures |
| Dehydration | Volume depletion |
| Hyponatraemia | If desmopressin overdose or excess water intake |
| Nocturnal enuresis | Especially in children |
| Quality of life | Frequent urination; Sleep disturbance |
| Factor | Outcome |
|---|---|
| Cranial DI + Treatment | Excellent symptom control with desmopressin |
| Post-surgical DI | Often transient (days to weeks) |
| Nephrogenic DI | More difficult to treat; May be permanent (lithium) |
| Untreated | Risk of severe dehydration and hypernatraemia |
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| Endocrine Society Guidelines | Endocrine Society | Various | Diagnosis and management |
What is diabetes insipidus?
Diabetes insipidus is a condition where your kidneys produce large amounts of very dilute urine. This makes you extremely thirsty and causes you to urinate frequently. It's not related to diabetes mellitus (sugar diabetes) despite the similar name.
What causes it?
- Cranial DI: The brain doesn't make enough of a hormone called ADH (antidiuretic hormone) that tells your kidneys to hold on to water
- Nephrogenic DI: The kidneys don't respond properly to ADH
What are the symptoms?
- Passing large amounts of urine (many litres a day)
- Feeling very thirsty
- Waking frequently at night to urinate
How is it treated?
- Cranial DI: A medicine called desmopressin (a synthetic form of ADH), usually taken as a nasal spray or tablet
- Nephrogenic DI: Treating the underlying cause; sometimes water tablets (thiazides) help paradoxically
Is it dangerous?
If you have access to enough water and take your medication, it's usually well controlled. Without treatment, severe dehydration can occur.
- Garrahy A, Moran C, Thompson CJ. Diagnosis and management of central diabetes insipidus in adults. Clin Endocrinol. 2019;90(1):23-30. PMID: 30269342
High-Yield Exam Topics
| Topic | Key Points |
|---|---|
| Differentiation | Water deprivation test + Desmopressin response |
| Cranial DI causes | Pituitary surgery; Tumour; Trauma; Idiopathic |
| Nephrogenic DI causes | Lithium; Hypercalcaemia; Hypokalaemia |
| Treatment Cranial | Desmopressin (nasal/oral) |
| Treatment Nephrogenic | Thiazides (paradoxical); Amiloride; NSAIDs |
| Biochemistry | High plasma osm + Low urine osm |
Sample Viva Question
Q: How do you differentiate cranial from nephrogenic diabetes insipidus?
Model Answer: I would use the water deprivation test with desmopressin challenge. First, confirm DI: high plasma osmolality (>295 mOsm/kg) with dilute urine (<300 mOsm/kg). Then:
- Water deprivation phase: Withhold fluids for 8 hours; Monitor weight, plasma and urine osmolality. In DI, urine remains dilute; in primary polydipsia, urine concentrates normally.
- Desmopressin challenge: Give desmopressin 2 mcg IM.
- Cranial DI: Urine concentrates >50% after desmopressin (ADH-deficient but kidneys work)
- Nephrogenic DI: Urine does NOT concentrate after desmopressin (kidneys cannot respond to ADH)
Last Reviewed: 2025-12-24 | MedVellum Editorial Team