Investigations
1st investigations to order
urine osmolality
Test
A low urine osmolality in conjunction with high serum osmolality or elevated sodium strongly suggests arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R). An ability to concentrate urine >600 mmol/kg (>600 mOsm/kg) makes AVP-D or AVP-R unlikely.
Result
low: typically <300 mmol/kg (<300 mOsm/kg)
serum osmolality
Test
The predicted serum osmolality can be calculated on the basis of the serum sodium, potassium, glucose, and blood urea nitrogen. [ Osmolality Estimator (serum) Opens in new window ] A reduced urine osmolality <300 mmol/kg (<300 mOsm/kg) in conjunction with high serum osmolality >290 mmol/kg (>290 mOsm/kg) or elevated serum sodium strongly suggests arginine vasopressin (AVP) deficiency or AVP resistance.
Result
normal or elevated
serum glucose
Test
Order as baseline investigation, and to exclude diabetes mellitus as a cause of polyuria.
Result
normal
serum sodium
Test
Serum sodium may be normal if patients have an intact thirst mechanism and have unrestricted access to fluids.
Elevated serum sodium in association with hypotonic urine (urine osmolality <300 mmol/kg [<300 mOsm/kg]) strongly suggests AVP-D or AVP-R. A low serum sodium in the context of hypotonic polyuria suggests primary polydipsia rather than AVP-D or AVP-R, as AVP suppression is appropriate.
Result
normal or elevated
serum potassium
Test
Hypokalaemia is associated with AVP-R.
Result
normal or low
serum urea nitrogen
Test
Elevated in patients with volume depletion or co-existent renal disease.
Result
normal or elevated
serum calcium
Test
Hypercalcaemia is associated with AVP-R.
Result
normal or elevated
urine dipstick
Test
Should be considered to help exclude diabetes mellitus as a cause of polyuria and to look for evidence of wider renal disease and tubulopathies.
Result
negative for glycosuria; proteinuria if underlying renal disease
24-hour urine collection for volume
Test
Polyuria is a key feature, defined as a 24-hour urine output >3 litres (or >50 mL/kg/24 hour).
Result
>3 litres per 24 hours or >50 mL/kg/24 hour
water deprivation test (WDT)
Test
Used to confirm arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R).
Patients are deprived of fluids for 8 hours or until 3% loss of their body weight is reached. Serum osmolality, urine volume, and urine osmolality are measured hourly.
Careful monitoring of water balance is essential. If the patient has severe AVP-D or AVP-R, dehydration can develop rapidly; in addition, the test should only be performed in a unit that has expertise in performing and interpreting the test.
The test should not be performed in patients with renal insufficiency, uncontrolled diabetes mellitus, or hypovolaemia, or if there is co-existing uncorrected adrenal or thyroid hormone deficiency.
A typically normal response to dehydration is a rise in urine osmolality to >700 mmol/kg (>700 mOsm/kg).
In patients with AVP-D or AVP-R, there is failure to concentrate urine in response to dehydration, such that urine remains inappropriately dilute (urine osmolality <300 mmol/kg [<300 mOsm/kg]) in the setting of a serum osmolality >290 mmol/kg (>290 mOsm/kg).
The WDT has several limitations: patient acceptability is low (the test is unpleasant for patients with primary polydipsia); the protocol is resource-intense (requiring a day in hospital, with careful supervision by experienced staff to prevent surreptitious drinking in primary polydipsia); and the sensitivity and specificity are limited by the high prevalence of partial concentrating defects, meaning many test results are indeterminate. Chronic polyuria due to longstanding primary polydipsia can also blunt maximal renal concentrating capacity by reducing the intrarenal medullary concentration gradient.[3] The diagnostic accuracy for WDT is around 70% to 75% for all polyuric states, with similar accuracy in differentiating partial AVP-D from primary polydipsia.[57][58] Furthermore, the WDT can be hazardous in patients with complete AVP-D, as they are at high risk of developing hypernatraemic dehydration.[3] Patients should be well-hydrated before the test, and if adipsia is suspected, plasma osmolality should be urgently measured to rule out existing dehydration.[3] Baseline body weight should be recorded and monitored every 2 hours; a loss of 5% or more from baseline indicates significant dehydration.[3] In such cases, serum electrolytes should be urgently checked, and the test should be stopped immediately to initiate rehydration.[3]
Result
urine osmolality <300 mmol/kg (<300 mOsm/kg) with corresponding serum osmolality >290 mmol/kg (>290 mOsm/kg)
AVP (desmopressin) stimulation test
Test
Used to distinguish between AVP-D and AVP-R following a water deprivation test.
Patients are given the synthetic AVP analogue desmopressin (also known as DDAVP) subcutaneously, and serum osmolality, urine osmolality, and urine volumes are measured hourly over the next 4 hours.
Patients with AVP-D respond to desmopressin with a reduction in urine output and an increase in urine osmolality to >750 mmol/kg (>750 mOsm/kg).
Patients with AVP-R do not respond to desmopressin, with no or little reduction in urine output and no increase in urine osmolality.
Result
AVP-D: reduction in urine output and increase in urine osmolality to >750 mmol/kg (>750 mOsm/kg); AVP-R: little or no reduction in urine output and no increase in urine osmolality
hypertonic saline-stimulated test with measurement of copeptin
Test
Used to differentiate arginine vasopressin deficiency (AVP-D), arginine vasopressin resistance (AVP-R), and primary polydipsia. Should be performed only in specialised units due to potential side effects, including intense thirst, nausea, and headache. Arginine stimulation test may be a safer alternative, but is less accurate than the hypertonic saline test (74% vs. 96%).[60]
Copeptin is the c-terminal fragment of the larger AVP-precursor synthesised within the magnocellular neurons of the supraoptic and paraventricular nuclei. It is cleaved from the precursor as one of the final steps in post-translational processing within secretory granules at the nerve terminals in the posterior pituitary. Copeptin is released in equimolar amounts to AVP.[3] Importantly, it is much more stable and much easier to develop as a sustainable direct measure of the AVP axis.[3]
In AVP-R, impaired kidney response to AVP leads to compensatory high AVP (and copeptin) levels. Conversely, baseline copeptin remains low in AVP-D (due to deficient AVP production), as well as in primary polydipsia (because excessive water intake suppresses AVP secretion by lowering osmolar stimulus). A baseline (without water deprivation or hypertonic saline-stimulation) copeptin level >21.4 pmol/L differentiates AVP-R from primary polydipsia and AVP-D.[59]
During hyperosmolar stimulation, in which a 3% sodium chloride infusion is used to artificially raise plasma osmolality, a copeptin level greater than 4.9 pmol/L can differentiate primary polydipsia from AVP-D with 96% diagnostic accuracy.[58] Patients with AVP-D fail to mount an adequate AVP/copeptin response, so copeptin remains below the threshold.
Result
baseline copeptin level >21.4 pmol/L is diagnostic of AVP-R; copeptin level >4.9 pmol/L differentiates primary polydipsia from AVP-D
Investigations to consider
pituitary MRI (contrast-enhanced)
Test
Should be ordered in all patients with arginine vasopressin deficiency (AVP-D). The posterior pituitary normally shows as a bright spot on T1-weighted MRI (reflecting the extent of stored AVP within neurosecretory granules). This bright spot is absent in nearly all patients with AVP-D.[1] However, its specificity is limited. The bright spot can also be absent in healthy individuals, particularly in older adults, due to an age-related decline in AVP storage, and in a small number of younger people.[3] Additionally, up to 40% of patients with primary polydipsia may lack the bright spot, possibly due to suppressed AVP synthesis from chronic hypo-osmolality.[3] Conversely, modern imaging studies show that up to 20% of patients with confirmed complete AVP-D and 40% with partial AVP-D may still retain the bright spot, likely due to residual AVP or oxytocin granules.[3] Thus, while the absence of the bright spot is a useful diagnostic clue, it should always be interpreted alongside clinical and biochemical findings.[3]
Evidence of pituitary enlargement, including increased pituitary stalk thickness or a pituitary mass, may suggest the underlying pathology of AVP-D (e.g., pituitary stalk thickening may suggest an autoimmune cause, while a pituitary mass should raise the possibility of craniopharyngioma, granulomatous disease, or other inflammatory conditions).[3][4][24][61]
If initial imaging is normal, follow-up imaging is recommended at 6 months and 12-18 months, as causal pituitary or para-pituitary lesions may not manifest on initial scans.
Result
may show pituitary or para-pituitary mass, congenital abnormalities, abnormal pituitary stalk; evidence of previous surgery; absence of posterior pituitary bright spot
pituitary CT
Test
CT of the sella is less sensitive than MRI for detecting pituitary pathology and is not recommended as a first-line imaging modality.[64] However, CT features of selected suprasellar masses may aid in their characterisation. For example, in suspected craniopharyngioma, CT may be useful if MRI alone is not sufficient, or if there is a specific need to visualise calcifications that might be missed on MRI.[3]
Result
may show calcification of suprasellar mass, suggestive of craniopharyngioma
CT chest and/or abdomen
Test
In patients with strong clinical suspicion of tumour, tuberculosis, or sarcoid, further cross-sectional imaging (e.g., chest and/or abdominal CT) should be ordered to assess for disease elsewhere.[3]
Result
may show evidence of metastatic cancer or widespread systemic disease
genetic testing
Test
Evidence of familial AVP-D or AVP-R should prompt consideration of focused genetic testing.
The presence of wider features of Wolfram syndrome (also called DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness] syndrome) should prompt consideration of WFS1 gene studies.[41]
AVP-neurophysin gene studies can be used predictively within a kindred with autosomal dominant familial AVP-D.[39]
In familial AVP-R, the most common mutation is a loss-of-function mutation in the AVPR2 receptor, inherited in an X-linked recessive pattern. Aquaporin-2 water channel gene mutations (autosomal recessive), and urea transporter-B mutations, also produce AVP-R.[5][10][39]
Result
WFSI mutation; AVP-neurophysin gene mutation; AVPR2 receptor gene mutation; aquaporin-2 gene mutation
antithyroid peroxidase autoantibodies
Test
AVP-D is associated with autoimmune disorders, including Hashimoto's thyroiditis.[28]
Result
positive in Hashimoto's thyroiditis
serum and cerebrospinal fluid alpha-fetoprotein and beta-human chorionic gonadotrophin
Test
Should be considered in children and adolescents (peak age of incidence of germinoma is 10-24 years) presenting with AVP-D and pituitary stalk thickening. These tumour markers may support the diagnosis of germ cell tumours and can occasionally precede radiological evidence of germinoma. However, because they lack sensitivity and may be negative in pure germinomas, all patients with AVP-D and pituitary stalk thickening require regular neuroimaging to monitor for disease progression or emergence, regardless of tumour marker results.[3]
Result
may be elevated in cases of germinoma
serum growth hormone (GH)
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Result
variable; commonly depressed if associated hypopituitarism present
serum insulin-like growth factor 1 (IGF-1)
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose GH deficiency.
Result
variable; commonly depressed if associated hypopituitarism present
provocative growth hormone (GH) tests
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Provocative agents (e.g., levodopa, insulin, glucagon) are given to stimulate pituitary to release GH.
Used to diagnose GH deficiency; may be required if other screening tests (radiography, thyroid function tests, IGF-1) are equivocal.
Result
variable; commonly, may show failure to induce GH if associated hypopituitarism present
serum LH
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose gonadotrophin hormone deficiency.
Result
variable; depressed if associated hypopituitarism present
serum follicle-stimulating hormone
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose gonadotrophin hormone deficiency.
Result
variable; depressed if associated hypopituitarism present
morning serum testosterone
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose gonadotrophin hormone deficiency in males.
Blood should be drawn between 8 a.m. and 9 a.m.
Result
variable; depressed if associated hypopituitarism present
serum thyroid-stimulating hormone (TSH) and triiodothyronine/thyroxine (T3/T4)
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose thyroid hormone deficiency.
Result
variable; commonly depressed if associated hypopituitarism present
morning serum cortisol and adrenocorticotrophic hormone (ACTH)
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction. In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.
Used to diagnose adrenal insufficiency.
Blood should be drawn between 8 a.m. and 9 a.m., when cortisol levels peak.
It is important to realise that polyuria cannot occur in the presence of chronic low mineralocorticoids; administration of corticosteroids can unmask low vasopressin and result in the onset of severe polyuria.
Result
variable; low cortisol levels in association with non-elevated levels of ACTH if hypopituitarism present
tetracosactide stimulation test
Test
If 9 a.m. cortisol is equivocal, the cortisol response to a synthetic derivative of ACTH is a useful test. Tetracosactide (a synthetic formulation of ACTH) is administered intramuscularly or intravenously; serum cortisol levels are measured at 30 and 60 minutes.
Result
variable; inadequate cortisol response if hypopituitarism present
serum prolactin
Test
Pituitary function testing should be considered in all patients diagnosed with AVP-D, looking for evidence of wider pituitary dysfunction.
Increased secretion is due to tumour compression of the pituitary stalk.
Result
variable; may be elevated if sellar or parasellar mass compressing pituitary stalk
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