Medicine chapters
SIADH and diabetes insipidus (water deprivation test)
How ADH controls water balance, how too much ADH (SIADH) causes euvolaemic hyponatraemia and too little ADH action (diabetes insipidus) causes dilute polyuria, and how the water deprivation test separates cranial, nephrogenic and psychogenic polyuria.
- SIADH = euvolaemic hyponatraemia with low plasma osmolality, inappropriately concentrated urine (>100 mOsm/kg) and urine sodium >30 mmol/L, after excluding hypothyroidism, adrenal failure and diuretics; treat with fluid restriction and raise sodium no more than 8 mmol/L in 24 hours.
- Diabetes insipidus gives large volumes of dilute urine with high-normal sodium; cranial DI responds to desmopressin, nephrogenic DI (lithium, hypercalcaemia, hypokalaemia) does not.
- In the water deprivation test, normal people and primary polydipsia concentrate urine; cranial DI concentrates only after desmopressin (>50% rise); nephrogenic DI never does.
On this page
Overview
Antidiuretic hormone (ADH, vasopressin) decides how much water the kidney keeps. Too much ADH (SIADH) traps water and causes hyponatraemia, the commonest electrolyte problem in hospital. Too little ADH, or kidneys that ignore it (diabetes insipidus), causes large volumes of dilute urine and thirst. The water deprivation test is the classic dynamic test that separates the causes of polyuria.
ADH physiology
- Made in the supraoptic and paraventricular nuclei of the hypothalamus; carried down axons and stored in the posterior pituitary.
- Released mainly in response to rising plasma osmolality, sensed by hypothalamic osmoreceptors. ADH is switched off below about 280 mOsm/kg; maximal antidiuresis is reached near the top of the normal range (about 295 mOsm/kg); thirst starts just above this.
- Also released by low blood volume or pressure, nausea, pain, stress, surgery and drugs.
- V2 receptors in the collecting duct → cAMP → aquaporin-2 water channels inserted into the luminal membrane → water reabsorbed → concentrated urine.
- V1 receptors on vessels → vasoconstriction (used in septic shock).
- Cortisol and thyroid hormone are needed to excrete a water load; their deficiency mimics SIADH.
Syndrome of inappropriate ADH secretion (SIADH)
What happens
- ADH is released without an osmotic or volume stimulus. Water is retained, diluting sodium.
- Only a modest rise in body water occurs because the extra volume triggers natriuresis (ANP, reduced aldosterone). So the patient is clinically euvolaemic and has no oedema, but urine sodium is high.
Causes
| Group | Examples |
|---|---|
| Malignancy | Small cell lung cancer (commonest), pancreas, prostate, thymus, lymphoma |
| Lung disease | Pneumonia (including Legionella), TB, lung abscess, ventilation |
| CNS disease | Meningitis, encephalitis, head injury, subarachnoid haemorrhage, stroke, tumour, abscess, subdural haematoma |
| Drugs | Carbamazepine, SSRIs, tricyclics, antipsychotics, chlorpropamide, cyclophosphamide, vincristine, opioids, ecstasy (MDMA), PPIs |
| Other | Post-operative state, pain, nausea, alcohol withdrawal, porphyria, HIV |
Clinical features
- Often none if mild or slow.
- Nausea, headache, confusion, irritability, falls; seizures and coma with severe or rapid falls in sodium (symptoms are usual below about 125 mmol/L and serious below about 115 mmol/L, sooner in the elderly).
Diagnostic criteria
- Hyponatraemia with low plasma osmolality (below about 275 mOsm/kg).
- Urine osmolality inappropriately high (above 100 mOsm/kg, usually above plasma).
- Urine sodium above 30 mmol/L on a normal salt intake.
- Clinical euvolaemia (no dehydration, no oedema).
- Normal thyroid and adrenal function and normal renal function; no recent diuretics.
Always exclude adrenal insufficiency (including ACTH deficiency) and hypothyroidism before labelling SIADH. Secondary adrenal failure in particular produces an identical biochemical picture, especially after neurosurgery.
In a dry patient with hyponatraemia, a test infusion of 1–2 litres of 0.9% saline raises sodium if the cause is salt and water depletion, but not in SIADH (the extra salt is simply passed out in concentrated urine, and sodium may even fall).
Differential diagnosis of hyponatraemia (by volume status)
| Volume | Urine sodium | Causes |
|---|---|---|
| Hypovolaemic | Low (<20) if extra-renal loss | Vomiting, diarrhoea, burns |
| Hypovolaemic | High (>20–30) | Diuretics (thiazides), Addison disease, salt-wasting nephropathy, cerebral salt wasting |
| Euvolaemic | High | SIADH, hypothyroidism, glucocorticoid deficiency |
| Euvolaemic | Very low urine osmolality (<100) | Primary polydipsia, beer potomania, low solute diet |
| Hypervolaemic (oedema) | Low | Heart failure, cirrhosis, nephrotic syndrome |
| Hypervolaemic | High | Renal failure |
- Pseudohyponatraemia (normal osmolality): severe hyperlipidaemia or paraproteinaemia.
- Hyperosmolar hyponatraemia: hyperglycaemia or mannitol pull water out of cells.
- Cerebral salt wasting (after subarachnoid haemorrhage) looks like SIADH but the patient is volume depleted: treat with saline, not fluid restriction.
Management
Treat the cause (stop the drug, treat pneumonia or tumour).
Chronic or mild–moderate symptoms
- Fluid restriction to about 500–1000 mL/day: first line; works if the patient complies.
- Demeclocycline (600–1200 mg daily): induces a reversible nephrogenic DI; causes photosensitivity and can harm the kidneys.
- Vasopressin V2 receptor antagonists ("vaptans", e.g. tolvaptan): cause loss of water without salt (aquaresis); start in hospital because sodium can rise too fast; liver toxicity with long use.
- Urea tablets and loop diuretics with salt are other options.
Severe symptoms (seizures, coma, vomiting, very low GCS)
- Hypertonic (3%) saline given in small boluses or slowly (for example 1 mL/kg over an hour, repeated as needed) in HDU or ICU, with sodium checked every 1–2 hours.
- Aim to raise sodium by about 4–6 mmol/L in the first few hours, which is usually enough to stop symptoms.
Rate of correction
- In chronic hyponatraemia (present more than 48 hours, or unknown), the brain has adapted by losing solutes. Raise sodium by no more than 8 mmol/L in 24 hours (and about 18 mmol/L in 48 hours).
- Over-rapid correction causes osmotic demyelination syndrome (central pontine myelinolysis): days later, dysarthria, dysphagia, quadriparesis, "locked-in" state. Highest risk with alcohol excess, malnutrition, liver disease and hypokalaemia.
- If sodium rises too fast, give water (5% dextrose) and/or desmopressin to bring it back down.
Calculated osmolality = 2 × Na + glucose + urea (all mmol/L)
Na 120, glucose 5, urea 4 → 2 × 120 + 5 + 4 = 249 mOsm/kg (low)
Rough rule: 1 mL/kg of 3% saline raises Na by about 1 mmol/L
70 kg patient → 70 mL of 3% saline ≈ +1 mmol/L
"From low to high, your pons will die": correcting low sodium too fast damages the pons.
Diabetes insipidus (DI)
Definition and features
- Passage of large volumes (usually over 3 L/day) of dilute urine because of lack of ADH (cranial) or renal resistance to ADH (nephrogenic).
- Polyuria, nocturia, intense thirst, preference for cold water.
- Plasma sodium and osmolality are high-normal or high; dangerous hypernatraemia if the patient cannot drink (unconscious, infant, damaged thirst centre).
- Urine output below 2 L/day makes DI very unlikely.
Causes
| Cranial (central) DI | Nephrogenic DI |
|---|---|
| Pituitary or hypothalamic surgery (commonest; often temporary) | Lithium (commonest drug cause) |
| Head injury | Hypercalcaemia, hypokalaemia |
| Tumours: craniopharyngioma, germinoma, metastases (breast, lung), pituitary macroadenoma with suprasellar spread | Demeclocycline, amphotericin, glibenclamide |
| Infiltration: sarcoidosis, Langerhans cell histiocytosis, hypophysitis | Chronic kidney disease, sickle cell disease, obstructive uropathy, renal tubular acidosis |
| Infection: TB meningitis, encephalitis | Inherited: V2 receptor mutation (X-linked), aquaporin-2 mutation |
| Vascular: Sheehan syndrome, aneurysm | Prolonged polyuria of any cause ("medullary washout") |
| Familial (AVP gene), Wolfram (DIDMOAD), idiopathic (often autoimmune) | – |
- Gestational DI: the placenta makes vasopressinase, which breaks down ADH; responds to desmopressin (resistant to the enzyme) but not to natural vasopressin.
- Masked DI: cortisol deficiency hides DI; it appears when hydrocortisone is started.
After pituitary surgery: the triphasic response
- DI for a few days (axon shock).
- SIADH phase (stored ADH leaks from dying nerve endings) → risk of hyponatraemia.
- Permanent DI if most hypothalamic neurones are lost.
Monitor fluid balance and sodium daily; avoid fixed desmopressin doses in the early days.
The water deprivation test
Before the test
- Exclude diabetes mellitus, hypokalaemia, hypercalcaemia and renal failure.
- Replace cortisol and thyroid hormone if deficient.
- Confirm polyuria with a 24-hour urine volume.
- Stop the test early if the patient may be in danger.
Procedure
- No fluids from early morning (overnight only if polyuria is mild); supervise to stop secret drinking.
- Measure weight, urine volume, urine osmolality and plasma osmolality and sodium hourly, for up to 8 hours.
- Stop the deprivation if weight falls by more than 3% or plasma osmolality rises above about 300 mOsm/kg (or sodium is clearly high).
- If urine is still dilute at the end (urine osmolality below about 600 mOsm/kg), give desmopressin 2 µg IM, allow drinking, and measure urine osmolality over the next 2–4 hours.
Interpretation
| Result | Plasma osmolality during deprivation | Urine osmolality after deprivation | Urine osmolality after desmopressin |
|---|---|---|---|
| Normal | Stays normal (about 275–295) | Above 600 | No further change needed |
| Primary (psychogenic) polydipsia | Low at start, stays normal | Rises (may be a little below 600 from medullary washout) | Little extra change |
| Cranial DI | Rises above 300 | Stays below 300 (dilute) | Rises by more than 50% |
| Nephrogenic DI | Rises above 300 | Stays dilute | No significant rise (below about 50%) |
| Partial cranial DI | Rises | 300–600 | Moderate rise |
Patient A: urine osmolality 250 → 600 mOsm/kg after desmopressin
Rise = (600 − 250) / 250 × 100 = 140% → cranial DI
Patient B: urine osmolality 250 → 290 mOsm/kg after desmopressin
Rise = (290 − 250) / 250 × 100 = 16% → nephrogenic DI
Primary polydipsia starts the test with a low plasma sodium and osmolality (the patient is water-loaded), whereas DI starts high-normal. This single starting value is a frequent MCQ clue.
- Newer alternative: copeptin (a stable fragment made with ADH) measured after hypertonic saline or arginine stimulation; more accurate than the classic test in specialist centres.
Treatment of DI
- Cranial DI: desmopressin (synthetic V2 agonist, long-acting, no pressor effect) by nasal spray, tablets or injection. Main danger: water intoxication and hyponatraemia, especially in the elderly or if drinking continues; teach patients to drink only to thirst and allow a daily "breakthrough" period of diuresis. Treat the cause (tumour, sarcoid).
- Nephrogenic DI: treat the cause (stop lithium if possible, correct calcium and potassium); thiazide diuretics (paradoxically reduce urine volume by causing mild volume depletion and more proximal reabsorption); low-salt, low-protein diet; NSAIDs help some; for lithium-induced DI, amiloride blocks lithium entry into collecting duct cells.
- Primary polydipsia: reduce fluid intake gradually; psychiatric care; do not give desmopressin (severe hyponatraemia).
Desmopressin in a patient with primary polydipsia or in an elderly patient drinking freely for nocturia can cause severe hyponatraemia and seizures.
Expect: ADH physiology (V2, aquaporin-2, osmotic thresholds); the SIADH criteria (euvolaemia, urine osmolality >100, urine sodium >30, normal thyroid and adrenal function); causes (small cell lung cancer, pneumonia, meningitis, carbamazepine, SSRIs, chlorpropamide, cyclophosphamide, vincristine); fluid restriction first, demeclocycline, tolvaptan, 3% saline for severe symptoms; maximum correction of 8 mmol/L per 24 hours and osmotic demyelination; cerebral salt wasting versus SIADH; causes of cranial and nephrogenic DI (lithium, hypercalcaemia, V2 mutation); triphasic response after pituitary surgery; the water deprivation test procedure, stop rules and the result table; primary polydipsia clues; desmopressin and thiazide treatment.
Quick revision
- SIADH: euvolaemic low Na, low plasma osm, urine osm >100, urine Na >30; exclude hypothyroid, adrenal, diuretics.
- Causes: small cell lung cancer, pneumonia, TB, meningitis, head injury, carbamazepine, SSRIs, vincristine.
- Treatment: fluid restriction; demeclocycline; tolvaptan; 3% saline if seizures.
- Correct chronic hyponatraemia by ≤8 mmol/L in 24 h → avoid osmotic demyelination.
- DI: >3 L/day dilute urine, high-normal Na; cranial (surgery, trauma, tumours) vs nephrogenic (lithium, high Ca, low K).
- Water deprivation: stop at 3% weight loss or osm >300; desmopressin 2 µg IM.
- Normal and psychogenic: urine concentrates; cranial: >50% rise after desmopressin; nephrogenic: no rise.
- Treat cranial DI with desmopressin; nephrogenic with thiazide (amiloride for lithium).
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Why is there no oedema in SIADH?
The water gain is limited because the expanded volume switches on sodium excretion, so the patient stays clinically euvolaemic with a high urine sodium.
Why is pituitary disease alone an uncommon cause of diabetes insipidus?
ADH is made in the hypothalamus; when the pituitary is damaged the hormone can still be released from the cut ends of the nerve fibres, so DI needs hypothalamic or high stalk damage.
Why does lithium cause polyuria?
Lithium enters collecting duct principal cells and blocks the ADH signal and aquaporin-2 production, producing nephrogenic diabetes insipidus.
What is the danger of correcting low sodium too quickly?
Brain cells that have adapted to low sodium shrink when sodium rises fast, damaging myelin in the pons and elsewhere (osmotic demyelination), which may cause permanent paralysis.