Diabetes insipidus and polyuria

• Polyuria means passing unusually large volumes of urine. In diabetes insipidus, the kidneys cannot concentrate urine, so the urine is large in volume and very dilute and thirst is intense.
• Diabetes insipidus is a water problem, not a sugar problem. Central (arginine vasopressin deficiency, AVP-D) means too little antidiuretic hormone is made. Nephrogenic (arginine vasopressin resistance, AVP-R) means the kidney ignores normal or high levels of the hormone.
• A typical adult makes 3 to 30 L a day of very dilute urine in central disease and 3 to 20 L a day in nephrogenic disease, with urine osmolality usually under 300 mOsm/kg and specific gravity usually under 1.005. ^[1][3][4]
• As long as thirst and access to water are intact, the patient drinks what is lost and serum sodium stays near normal (roughly 136 to 147 mmol/L). If thirst or access is impaired, free water is lost faster than it is replaced and hypernatraemia develops. ^[1][3]
• Diagnosis proves hypotonic polyuria, rules out solute diuresis, then uses a water deprivation test with desmopressin and, where available, plasma copeptin. Treatment is desmopressin for central disease and free water plus a low-salt, low-protein diet, thiazides, and sometimes NSAIDs or amiloride for nephrogenic disease. ^[1][3][4]

By the end of this page you should be able to:

1. Define polyuria, hypotonic polyuria, central (AVP-D) and nephrogenic (AVP-R) disease, and distinguish them from primary polydipsia and osmotic diuresis.
2. List the common central and nephrogenic causes, including lithium, hypercalcaemia and hypokalaemia.
3. Explain the osmoregulatory arc from the hypothalamus to the collecting duct, and why its failure produces polyuria, nocturia and hypernatraemia.
4. Interpret urine osmolality, serum sodium and a 24-hour urine volume in a polyuric patient.
5. Plan and interpret a water deprivation test with desmopressin, and use plasma copeptin cut-offs.
6. Manage acute and chronic hypernatraemic dehydration and choose treatment for each type of disease.
7. Recognise gestational disease, the triphasic postoperative pattern and the adipsic, high-risk form.
8. Adapt diagnosis and management when vasopressin analogues, tests or intravenous fluids are scarce.

Polyuria is approached here from the renal and general-medicine point of view. It treats polyuria as a presenting problem, names the central and nephrogenic causes of DI, and works out how to test and manage them. The endocrinology subspecialty aspects of AVP deficiency (hypothalamic and pituitary disease, its causes and imaging) are taken up in the endocrinology topic on diabetes insipidus; read that page when the cause is central. The correction of hypernatraemic dehydration itself is taken up in the renal-genitourinary topic on hypernatraemia; this page deals with the diagnosis that explains why the sodium is high.

AVP is synthesised in the supraoptic and paraventricular nuclei of the hypothalamus, stored in the posterior pituitary, and released in response to a rise in plasma osmolality (osmoreceptors) and to a fall in plasma volume or pressure (baroreceptors). At the kidney it binds the V2 receptor on principal cells of the collecting duct, activating a cAMP cascade that inserts aquaporin-2 (AQP2) water channels into the apical membrane; water then leaves the urine down the medullary osmotic gradient. ^[1] Failure anywhere in this arc gives DI. Destruction of over 90% of the vasopressinergic neurons is needed before AVP deficiency produces hypotonic polyuria. ^[2]

• Central DI (AVP-D). Deficient AVP secretion from the posterior pituitary or hypothalamus; may be complete (essentially no AVP) or partial. Only about 10% of neurosecretory neurons need remain intact to avoid deficiency. ^[3]
• Nephrogenic DI (AVP-R). AVP is present (often raised) but the renal tubule does not respond, because of defects in the V2 receptor or AQP2. ^[4]
• Gestational DI. Excess breakdown of AVP by placental vasopressinase (cysteine aminopeptidase), usually in the second or third trimester. ^[2]
• Adipsic (hypodipsic) DI. Central DI in which hypothalamic osmoreceptors are also damaged, so thirst is absent or severely blunted. This is the form with the highest mortality. ^[2]

DI is rare: about 1 in 25,000 people, it can begin at any age, and men and women are affected equally. ^[1] Central disease is more common than nephrogenic disease in adult endocrine clinics, with hypothalamic-pituitary surgery and tumour one of the commoner causes. ^[2] Inherited nephrogenic disease is uncommon; it is an X-linked trait with variable penetrance in heterozygous females. ^[4] Because DI is a quality-of-life disease that rarely kills someone who can drink freely, prevalence data are sparse and every figure should be treated as an estimate. ^[1]

The renal question is which causes are reversible and how quickly. From the renal point of view, central and nephrogenic causes behave differently: central disease is an endocrine deficiency, nephrogenic disease is a tubular resistance.

• Tumour of the hypothalamus or pituitary region (about 10 to 15% of cases). Craniopharyngioma, germinoma, meningioma, and pituitary or hypothalamic tumours; metastases to the stalk (breast, lung); lymphoma.
• Trauma and surgery (about 10 to 25%). Transfrontal or transsphenoidal surgery; traumatic brain injury; postoperative central DI usually appears within 24 hours and resolves within 2 to 5 days if it is transient. ^[1]
• Vascular. Hypothalamic or cerebral infarction or haemorrhage, cerebral aneurysm, subarachnoid haemorrhage, Sheehan syndrome, sickle cell disease.
• Autoimmune or inflammatory. Lymphocytic hypophysitis, systemic lupus erythematosus, scleroderma, granulomatosis with polyangiitis, IgG4 disease.
• Granulomatous or infiltrative. Sarcoidosis, Langerhans cell histiocytosis, Erdheim-Chester disease.
• Infection. Meningitis, encephalitis, tuberculosis, toxoplasmosis, cerebral abscess.
• Congenital or genetic. Autosomal dominant AVP-neurophysin II gene mutations; Wolfram (DIDMOAD) syndrome.
• Other. Idiopathic or autoimmune disease (better investigation now shows many formerly "idiopathic" cases are autoimmune); pregnancy from placental vasopressinase; drugs such as phenytoin and alcohol.
• Adipsia arises from the same lesions that destroy AVP neurons, when hypothalamic osmoreceptors are also damaged. ^[2]

CDI usually appears after surgery, not before. Pituitary adenomas do not present with DI; if DI is present with a sellar mass, think of craniopharyngioma, germinoma or a granulomatous process. ^[2]

• Drugs. Lithium is the commonest drug trigger; NDI develops in 40 to 55% of lithium-treated patients and can appear as early as 8 weeks after starting. Demeclocycline, cidofovir, foscarnet, cisplatin, amphotericin B, dexamethasone, dopamine, ifosfamide, ofloxacin and orlistat are also implicated. ^[1]
• Metabolic. Severe hypokalaemia, severe hypercalcaemia, starvation and low protein intake.
• Renal and vascular. Sickle cell nephropathy, acute tubular necrosis, cystic kidney disease, medullary sponge kidney, autosomal dominant polycystic kidney disease.
• Infiltrative. Sarcoidosis, amyloidosis, Sjogren disease, multiple myeloma.
• Obstructive. Release of obstructing periureteral fibrosis.
• Congenital or genetic. X-linked V2 receptor gene mutations (most common inherited form, variable in heterozygous females); autosomal aquaporin-2 gene mutations.

Lithium-induced disease may be reversible if caught early: AQP2 expression rises within 1 to 2 weeks after stopping lithium in experimental models and some patients improve within 3 weeks, but 17 of 27 patients still had a concentrating capacity under 800 mOsm/kg a year after stopping, so prolonged use predisposes to permanent resistance. ^[1]

The kidney builds a hypertonic medulla. When AVP is present, AQP2 channels are inserted into the apical membrane of the collecting duct, allowing water to leave the urine into the hypertonic interstitium and a small volume of concentrated urine to be excreted. If AVP is absent or ineffective, the collecting duct stays impermeable to water, the filtrate stays hypotonic, and a large volume of dilute urine is produced.

• Polyuria. Central disease produces 3 to 30 L a day; nephrogenic disease 3 to 20 L a day of very dilute urine. ^[3]
• Dilute urine. Urine osmolality usually under 200 to 300 mOsm/kg; specific gravity usually under 1.005. It is often under 200 mOsm/kg in nephrogenic disease. ^[3][4]
• Nocturia. AVP would normally peak at night; without its action the patient wakes repeatedly to void. Nocturia is almost always present in both types. ^[3]
• Thirst is the safety valve. Most patients have an intact thirst mechanism and drink to match losses, so serum sodium stays near normal (roughly 136 to 147 mmol/L). ^[1]
• Hypernatraemia when thirst fails. Infants, older adults, patients with altered consciousness, those with adipsic DI, and anyone without free access to water cannot keep pace. Free water is then lost faster than it is replaced, serum sodium rises, well above 145 mmol/L and sometimes dramatically, and neurological symptoms (excitability, confusion, seizures, coma) may follow. ^[4]
• Chronic washout. Long-standing polyuria depletes the medullary osmotic gradient and down-regulates AQP2, so even normal kidneys become partially resistant to AVP. This is why a water deprivation test can be hard to interpret in chronic primary polydipsia. ^[1]
• Partial disease. Most central disease is partial; some residual secretion means the urine is not maximally dilute and the response to desmopressin is smaller. ^[2]

• "I pass huge amounts of very pale, almost water-clear urine" - volume and dilution. ^[1][3]
• "I drink all the time and carry water with me"; waking at night both to drink and to void. ^[3][4]
• Most patients feel well if they can drink freely. The illness is discovered when they cannot: during travel, surgery, intercurrent illness, or if water is not offered. ^[3]
• Thirst is usually for plain water, not sweet drinks. ^[3]
• In central disease, associated posterior-pituitary problems may appear: headache, visual field defect, other hormone deficiencies. ^[3]
• Crucial distinction from primary polydipsia: those patients usually do not have nocturia and tend to wake to drink rather than to void; about 20% of patients with schizophrenia have polydipsia. ^[2]

• Volume status. Often clinically euvolaemic if drinking freely; hypovolaemia and hypernatraemia if not.
• Signs of an underlying cause in central disease. Visual fields, cranial-nerve findings, signs of a sellar mass (refer to the endocrinology topic for detail).
• Infants and children. Severe dehydration, vomiting, constipation, failure to thrive, growth retardation. Inherited disease often presents in childhood, but timing varies from infancy to later childhood. ^[1][4]
• Older adults and patients with cognitive impairment. May not complain of thirst; dehydration may be the first sign. ^[4]
• Postoperative patients. Polyuria within hours of pituitary surgery, especially with intact consciousness and unrestricted fluid access. ^[2]
• In severe congenital disease, high urine output can produce ureteric and pelvic dilatation. ^[4]

The main question is whether a polyuric patient has DI (central or nephrogenic), primary polydipsia, or solute/osmotic diuresis. Each is separated by urine osmolality, serum sodium, and the response to water deprivation and desmopressin. ^[2][4]

Two quick clinical anchors, worth memorising: ^[1][2][4]

• Serum sodium. In hypotonic polyuria, a value above 147 mmol/L strongly suggests DI, while a value under 135 mmol/L suggests primary polydipsia. Most patients present between 136 and 147 mmol/L and need dynamic testing. Serum sodium is mildly elevated (142 to 145 mmol/L) in nephrogenic disease with good water access. ^[1][4]
• Urine osmolality. Under 300 mOsm/kg defines hypotonic polyuria; over 300 mOsm/kg suggests a solute diuresis. A value over 700 mOsm/kg indicates significant AVP activity and effectively excludes DI. ^[1][2]
• Osmotic diuresis, most often uncontrolled diabetes mellitus, is the commonest cause of polyuria overall. Always check plasma glucose and exclude glucosuria before labelling a patient with DI. ^[1]

Cross-check with endocrinology and hypernatraemia. For the endocrine causes of central disease, posterior-pituitary disorders and imaging, read the endocrinology topic on diabetes insipidus. For correction of the water and sodium deficit itself, see the renal-genitourinary topic on hypernatraemia; that page deals with the sodium problem, this page with its cause.

1. Confirm polyuria with a 24-hour urine collection: output over 3 L a day or over 50 mL/kg in adults (over 2 L/m2 in children). If daily urine is under 2.5 L, further investigation for DI is usually not required.
2. Exclude common confounders. Diabetes mellitus, renal impairment, hypercalcaemia, hypokalaemia, drugs (diuretics, lithium, SGLT2 inhibitors), infection, prostate or bladder problems.
3. Baseline tests. 24-hour urine volume and osmolality, serum electrolytes and osmolality, glucose. A urine osmolality over 700 mOsm/kg indicates significant AVP activity and effectively excludes DI. ^[2]
4. Hypotonic polyuria (urine osmolality under 300 mOsm/kg) in the absence of solute diuresis is the trigger for dynamic testing. ^[1]

This is the standard test. It is run as an inpatient in an endocrine unit because it can cause dangerous dehydration and because primary polydipsia patients must be supervised to prevent surreptitious drinking.

• Preparation. Baseline weight, blood pressure, heart rate, plasma osmolality and electrolytes, urine osmolality. Correct electrolytes such as potassium and calcium first. Hold drugs that alter urine output (diuretics, SGLT2 inhibitors, glucocorticoids, NSAIDs) for 24 hours.
• Deprivation. Nothing by mouth, usually for up to 8 hours (some protocols up to 17 hours). Monitor weight, blood pressure and heart rate every hour, urine output and osmolality every 2 hours, and plasma osmolality and sodium every 2 hours.
• Endpoints (stop and test). Completed 8 hours of dehydration (up to 17 in some protocols); two consecutive urine osmolalities within 10% of each other plus 2% weight loss; weight loss over 3% (or 5% in some older protocols); serum sodium above the upper limit of normal (preferably above 150 mmol/L); orthostatic hypotension; intractable thirst. ^[1][3]
• Desmopressin phase. If urine remains dilute, give desmopressin (2 to 4 mcg subcutaneously or intravenously; intranasal is not preferred because absorption is unpredictable; some protocols use 10 mcg intranasally) and collect urine hourly for 1 to 2 hours with modest food and drink. ^[1][3]
• Adipsic patients need urgent measurement of plasma osmolality to exclude dehydration before the test begins. ^[2]

Interpretation tips from specialist centres: ^[1][2][3]

• Some apply a simple rule: normal kidneys reach over 800 mOsm/kg when water-deprived according to Flynn (Ref 1), while Tomkins (Ref 2) and Merck (Ref 3) state the maximum is often 700 to 800 mOsm/kg; DI stays under 300 mOsm/kg. ^[1][2][3]
• An intermediate result (300 to 800 mOsm/kg) suggests partial DI or primary polydipsia; after desmopressin a rise of under 50% points to partial DI.
• Maximal urine osmolality reached during the test depends on the final plasma osmolality and the strength of the osmotic stimulus; semi-qualitative clinical judgement is often needed rather than a single binary cut-off.
• Chronic polyuria of any cause can wash out the medulla and blunt responses.
• Doubling of urine osmolality after desmopressin is often accepted as evidence of intact renal response when the baseline is very low, though this can be misleading.
• Overall, the WDT has been reported to have sensitivity 80 to 100% and specificity 67 to 100%; one large prospective study found overall diagnostic accuracy of only 70%, falling to 40% in primary polydipsia. ^{[5] [1]}
• The diagnostic criteria for the WDT were based on only 36 patients, which partly explains this imprecision. ^[5]

Copeptin is the C-terminal peptide of provasopressin, secreted in equimolar amounts with AVP but much more stable in blood. It is a practical surrogate for AVP and is not yet routine in every laboratory.

• Baseline copeptin over 21.4 pmol/L diagnoses nephrogenic DI with 100% sensitivity and specificity. ^[1][5]
• If below that, give hypertonic saline to raise plasma sodium above 150 mmol/L (some centres aim above 147 mmol/L) and repeat: copeptin under 4.9 pmol/L = central DI; at least 4.9 pmol/L = primary polydipsia. This osmotic approach showed 96.5% diagnostic accuracy (93.2% sensitivity, 100% specificity) in a multicentre prospective study (Flynn reports 96.5%, Christ-Crain reports 97%; the difference is rounding of the same study). Guidelines differ on the sodium target, which is a reminder to interpret cut-offs locally rather than as fixed dogma. ^[1][5]
• Arginine infusion testing. A copeptin level of 3.8 pmol/L taken 60 minutes after the start of an arginine infusion distinguished central DI from primary polydipsia with 93% accuracy; it is better tolerated, with nausea the main side effect. ^[5]
• After pituitary surgery, a copeptin under 2.5 pmol/L on the first postoperative day predicts central DI with 97% specificity (positive predictive value 81%). ^[2][5]
• In hospitalised hypernatraemia, a copeptin cut-off of at most 4.4 pmol/L identified central DI with 100% sensitivity and 99% specificity among patients with plasma sodium over 155 mmol/L. ^[5]

Assay matters: the cut-offs above were developed with the KRYPTOR or LIA assays; ELISA platforms give much lower diagnostic accuracy and should not use the same cut-offs. ^[5]

• MRI of the sella and suprasellar regions: look for loss of the posterior-pituitary bright spot, pituitary-stalk thickening, or a mass. Pituitary adenoma does not present with DI; a mass with DI suggests craniopharyngioma, germinoma or granulomatous disease.
• Idiopathic or autoimmune disease with a thickened stalk warrants repeat imaging in 6 to 12 months in adults (every 6 months in younger patients) to exclude germinoma.
• Always test anterior-pituitary function in central disease, because hypothalamic-pituitary lesions bring other deficits with them.
• Patients with an abrupt onset of polyuria and polydipsia, or a family history of autoimmune disease, may have autoimmune central disease.

There is no staging system. Severity is described as: ^[3][4]

• Complete versus partial deficiency or resistance, based on how much AVP is secreted or how much the kidney responds.
• Whether thirst is intact. Adipsic DI (no thirst) is life-threatening and carries a high mortality; patients with an intact thirst mechanism are in much safer territory.
• Acute versus chronic. Acute polyuria can be severe, but if the cause is reversible (for example a transient postoperative insult), it may resolve within days.
• Particular risk groups: infants, children and older adults, because they cannot reliably recognise or communicate thirst.

Hospitalise any patient with hypernatraemic dehydration, altered consciousness, or no reliable thirst or access to water. Seek endocrinology and nephrology input.

• If not in hypovolaemic shock, use a hypotonic intravenous fluid, usually 5% dextrose in water, because fluids with higher osmolality than the urine (such as half-isotonic saline) can worsen hypernatraemia in DI. Give only as much as needed, with close monitoring.
  • Acute hypernatraemia (48 hours or less): lower serum sodium by 1 to 2 mmol/L per hour and restore normal within 24 hours; 5% dextrose in water at 3 to 6 mL/kg/hour if needed. ^[1]
  • Chronic hypernatraemia (more than 48 hours): limit correction to no more than 0.5 mmol/L per hour. A practical estimate of safe time is to double the difference between starting sodium and target sodium. Correcting faster risks cerebral oedema. ^[1]
  • Free water deficit: for men, body weight in kg times 0.6 times (serum sodium minus 140) divided by 140; for women, body weight in kg times 0.5 times (serum sodium minus 140) divided by 140. Divide by the safe time in hours for the hourly rate. ^[1]
  • Check a basic metabolic panel about every 4 hours until stable; high rates of dextrose can cause glucosuria and osmotic diuresis, needing insulin or a different hypotonic fluid. Transition to oral water as soon as possible. ^[1]
• Hypovolaemic shock is treated first with isotonic saline, then the free-water deficit is corrected.
• If anterior hypopituitarism is present after surgery, treat it at the same time (for example, cortisol deficiency).

The drug of choice is desmopressin (DDAVP), a synthetic vasopressin analogue. Its half-life is prolonged (6 to 8 hours in Flynn [Ref 1] and Tomkins [Ref 2]; Merck [Ref 3] states antidiuretic activity lasting 12 to 24 hours in most patients) by removing the amino group of cysteine, so it can be given twice or three times daily; the pressor activity is abolished by substituting D-arginine for L-arginine. ^[1][2][3]

Formulations reported in the literature (mostly adult data; doses differ greatly by route; titrate to urine output and serum sodium):

• Usually a low dose at night is started first, to control nocturia, and titrated weekly until symptoms are stable over a month. ^[1]
• The drug starts working within an hour and lasts 6 to 8 hours (Flynn; Tomkins) or 12 to 24 hours (Merck) by formulation; inter-individual variation is large, especially by age and sex. ^[1][2][3]
• Hyponatraemia is the main hazard. After each dose, allow aquaresis so excess water is excreted without electrolyte loss; reduce the dose if hyponatraemia persists. Practical options: delay or omit a dose once or twice a week until 2 to 3 voids occur; or delay each dose slightly. ^[1]
• Parenteral doses are much smaller than oral doses because bioavailability differs markedly. ^[3]
• If desmopressin is unavailable, second-line central options include thiazide diuretics, carbamazepine, chlorpropamide, clofibrate and indapamide, but each carries significant side effects. ^[1]

In infants and young children, thiazides deserve special mention. They paradoxically reduce urine volume by 25 to 50% (by creating mild extracellular volume contraction that increases proximal tubular reabsorption) and are effective and safe early in life; treatment is usually switched to desmopressin once the diet moves to solids. ^[1][3] Dosing from the literature (for example hydrochlorothiazide 1 to 4 mg/kg/day divided into 1 to 2 doses; chlorothiazide liquid in infants) should be supervised by a paediatric specialist. ^[1]

1. Reverse the cause where possible. Stop or adjust the offending drug (lithium may take weeks to improve and sometimes never fully recovers), correct hypercalcaemia and hypokalaemia, relieve obstruction.
2. Ensure free water intake sufficient to match losses. Serious sequelae are rare if patients can drink at will.
3. Reduce the solute load with a low-salt, low-protein diet: protein no more than about 1.0 g/kg/day and sodium no more than 2.3 g/day (under 100 mEq/day), aiming at an osmotic load of about 15 mOsm/kg/day. This can be hard in growing children, where it may compromise nutrition. ^[1][4]
4. Medications to cut urine output:
   • Thiazide diuretics: hydrochlorothiazide 25 mg orally once or twice daily in adults, or 1 to 4 mg/kg/day divided into one or two doses in children; chlorothiazide liquid is useful in infants. In a classic low-sodium study, hydrochlorothiazide cut urine output to roughly half of baseline after 3 days. ^[1][4]
   • Potassium-sparing diuretics such as amiloride, often combined with a thiazide; amiloride is also used specifically with lithium. ^[4]
   • NSAIDs such as indomethacin, modestly reducing urine volume by 10 to 25%, perhaps by reducing renal blood flow and glomerular filtration rate. Use carefully (renal, gastric, cardiovascular risks). ^[3]
   • Together, sodium restriction plus a thiazide plus an NSAID can further reduce urine volume in AVP-R.
5. Partial nephrogenic DI may respond to supraphysiologic doses of desmopressin (for example 80 mcg intravenously 3 to 4 times daily, 20 mcg intranasally 4 times daily, or 720 mcg daily by mouth). Only about a quarter of patients with congenital NDI respond, so this is reserved for patients with inadequate response or contraindications to diuretics. ^[1]

Thiazides, NSAIDs, sodium restriction and restriction of dietary protein all modestly reduce urine volume in partial central disease as well (25 to 50% with a thiazide), and these drugs do not carry the fluid-retention risk of exogenous vasopressin. Chlorpropamide, carbamazepine and clofibrate can stimulate vasopressin release and are occasionally useful, but are inferior to desmopressin and seldom used. ^[3]

• Gestational DI is caused by placental vasopressinase degrading AVP, usually in the second or third trimester. Serum sodium in pregnancy normally runs lower than outside pregnancy, which can mask the diagnosis. Desmopressin is the treatment because it is not broken down by placental vasopressinase; it is pregnancy category B. Small studies do not show a signal of major fetal risk, but the numbers are small. Doses are usually standard or slightly higher; placental enzyme activity disappears postpartum, so treatment can usually be withdrawn within weeks to months. Desmopressin has minimal transfer into breast milk and does not affect infant water balance. ^[2]
• Infants and children with inherited disease may develop permanent brain damage and intellectual disability if recognition is delayed; growth failure can need gastrostomy feeding. Monitor growth, development and sodium, with careful titration to avoid water intoxication. ^[1][4]
• Adipsic DI. No thirst means fixed fluid targets: a common approach uses a target weight, fixes a daily urine-output target, takes daily weights and calculates daily water intake from urine losses, with plasma sodium checked weekly. Thrombosis risk during hypernatraemic dehydration is high; screen for sleep apnoea. ^[2]

This fully reversible sequence is seen after pituitary or suprasellar surgery and after traumatic brain injury:

1. Phase 1 - central DI. Abrupt polyuria from sudden loss of AVP, lasting several days.
2. Phase 2 - SIADH. Unregulated AVP release from degenerating posterior-pituitary tissue causes antidiuresis and typically hyponatraemia, lasting days to weeks.
3. Phase 3 - permanent central DI. When most AVP-secreting neurons have degenerated, DI returns.

The two polyuric phases look like central DI (dilute polyuria responding to desmopressin); the middle phase looks like syndrome of inappropriate antidiuresis and needs fluid restriction rather than more desmopressin. Correctly identifying the phase matters because the treatment changes. Other postoperative causes of polyuria (mobilisation of intraoperative fluids, hyperglycaemia, diuretics, growth-hormone-related diuresis after acromegaly surgery) must be excluded. Recovery occurs over weeks to months in many patients; permanent DI is more likely after craniopharyngioma surgery. ^[2]

• Hypernatraemic dehydration and brain injury. Especially in infants, older adults, adipsic patients and anyone without free access to water.
• Seizures, coma and intracranial bleeding can occur with acute, severe hypernatraemia because the brain cannot adapt. ^[1]
• Renal and urological. Ureteric and pelvic dilatation in severe congenital disease with very high output. ^[4]
• Growth failure in infants with inherited disease, sometimes needing gastrostomy feeding. ^[4]
• Hyponatraemia from treatment. Over-treatment with desmopressin without aquaresis can cause water intoxication and seizures in small children; furosemide can be used to induce diuresis. ^{[3] [1]}
• Poor quality of life. Nocturia, interrupted sleep, interrupted work and travel; high fluid intake can itself be harmful (hydronephrosis, hydroureter, fluorosis from excessive intake have been reported in children). ^[1]

Most patients who understand the disease and can drink freely lead normal lives. Central DI is generally well controlled once the right desmopressin dose and schedule are found; disease often becomes apparent only when the patient cannot drink (travel, surgery, vomiting illness). Nephrogenic disease is harder: urine output falls only partly, and high fluid intake is burdensome. Reversibility depends on cause and duration - early lithium disease may resolve within weeks, but prolonged exposure often leaves permanent concentrating defects. Infants with inherited disease do worst if recognition is delayed, because dehydration in the first years can permanently injure the developing brain. ^[1][4]

• Infants and children. Early diagnosis is essential; consider inherited disease in any infant with polyuria, failure to thrive or affected relatives. ^[4]
• Pregnancy. Gestational DI usually appears in the second or third trimester and responds to desmopressin, which placental vasopressinase does not degrade. ^[2]
• Older adults and those with cognitive impairment. Dehydration may be the presenting sign rather than thirst. ^[4]
• Patients after pituitary or suprasellar surgery. Expect the triphasic pattern; use the criteria above (hypotonic urine with output over 3.5 L/day and plasma sodium over 143 mmol/L is a common simplified cut-off) and avoid letting the phase-2 antidiuresis be treated with more desmopressin. ^[2]

• Free water access is the cornerstone of survival. Guarantee unlimited oral water, teach families, and use fixed daily fluid targets where thirst is absent. ^[3][4]
• Bedside recognition. Very large volumes of very pale urine (over 3 L/day), specific gravity under 1.005 and nocturia; urine osmolality and serum sodium refine the diagnosis when available. Even without them, pattern recognition plus a supervised desmopressin trial can help, but it must be supervised because of hyponatraemia risk. ^[3]
• When desmopressin is unavailable, central DI can be managed with second-line agents (thiazides, carbamazepine, chlorpropamide, clofibrate, indapamide) plus strict water access; nephrogenic DI with thiazides, NSAIDs, amiloride, low salt and low protein, and water access. ^[1][3]
• Avoid dangerous correction. If intravenous fluids are limited, correct chronic hypernatraemia slowly (no more than 0.5 mmol/L per hour) using the simplest hypotonic fluid available, and use oral water whenever possible. ^[1]
• Prevent brain injury in infants. Feed on demand, monitor growth, identify inherited disease in families with infant polyuria. ^[4]
• Education. Sick-day rules, recognising dehydration, and early help-seeking during vomiting illnesses, to prevent death in adipsic or paediatric DI. ^[2]

• Diabetes insipidus is a water disorder: failed AVP action, not sugar. Urine is large in volume and dilute, and thirst is intense.
• Central (AVP-D) and nephrogenic (AVP-R) disease have different causes and treatments; telling them apart drives management.
• Polyuria definitions: over 3 L/day or over 50 mL/kg/day in adults; children over 2 L/m2/day.
• Hypotonic polyuria is a urine osmolality under 300 mOsm/kg; normal kidneys concentrate over 800 mOsm/kg by Flynn (Ref 1) or often 700 to 800 mOsm/kg by Tomkins (Ref 2) and Merck (Ref 3) when water-deprived; a value over 700 mOsm/kg effectively excludes DI.
• Serum sodium above 147 mmol/L (with hypotonic polyuria) suggests DI; under 135 mmol/L suggests primary polydipsia; in nephrogenic disease with good water access it is usually 142 to 145 mmol/L.
• The water deprivation test with desmopressin separates complete and partial central DI, nephrogenic DI and primary polydipsia; copeptin adds accuracy (baseline over 21.4 pmol/L = NDI; after hypertonic saline under 4.9 pmol/L = central DI; arginine stimulation at 3.8 pmol/L).
• Desmopressin is first-line for central DI in oral, nasal, sublingual and parenteral forms. Doses differ greatly by route; titrate slowly; watch for hyponatraemia and allow aquaresis.
• Nephrogenic DI is treated with free water, a low-salt low-protein diet, thiazides, amiloride and sometimes NSAIDs; reverse lithium, hypercalcaemia and hypokalaemia.
• Thiazides paradoxically reduce urine volume (about 25 to 50%) by mild extracellular volume depletion and increased proximal reabsorption; NSAIDs reduce it by about 10 to 25%. ^[3]
• Lithium causes NDI in 40 to 55% of treated patients, sometimes within 8 weeks; early stopping may reverse it, prolonged use often leaves permanent resistance. ^[1]
• The triphasic pattern after pituitary surgery is DI, then SIADH, then DI again; fluid restriction, not more desmopressin, treats the middle phase.
• Gestational DI responds to desmopressin because placental vasopressinase does not degrade it.
• Adipsic DI is the dangerous extreme: fixed fluid targets and close monitoring, with high thrombosis risk.
• Hypernatraemia correction itself is handled in the renal-genitourinary topic on hypernatraemia; this topic concerns the cause.

• Endocrinology: diabetes insipidus (central causes, hypothalamic and posterior-pituitary disease, imaging and anterior-pituitary function).
• Renal-genitourinary: hypernatraemia (correction of water and sodium deficit); hypercalcaemia; hypokalaemia; tubulointerstitial disease; polycystic kidney disease.
• Neurosurgery: pituitary and suprasellar surgery, traumatic brain injury, postoperative water-balance disorders.
• Obstetrics: gestational diabetes insipidus; pregnancy and endocrine disorders.
• Psychiatry: primary (psychogenic) polydipsia.