Investigations
1st investigations to order
urine osmolality
Test
A low urine osmolality in conjunction with high serum osmolality or elevated sodium strongly suggests AVP-D or AVP-R.
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 ]
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, with volumes ranging from 3 litres to >20 litres per day.
Result
>3 litres per 24 hours or >50 mL/kg/24h
water deprivation test
Test
Used to confirm AVP-D or 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).
Result may be indeterminate secondary to partial defects in the arginine vasopressin axis.
Long-standing chronic polyuria secondary to primary polydipsia can limit maximal renal concentrating ability as it reduces intra-renal electrolyte gradients.
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 AVP-D, AVP-R, and primary polydipsia.
A baseline (without water deprivation or hypertonic saline-stimulation) copeptin level >21.4 pmol/L differentiates AVP-R from primary polydipsia and AVP-D.[58] A copeptin level >4.9 pmol/L during graded hyperosmolar stimulation with a 3% sodium chloride infusion has a diagnostic accuracy of 96% in differentiating AVP-D from primary polydipsia.[57]
Should be performed only in specialised units. Arginine stimulation test may be considered but is less accurate than hypertonic saline test.[59]
Result
baseline copeptin level >21.4 pmol/L is diagnostic of AVP-R; copeptin level >4.9 pmol/L differentiates AVP-D from primary polydipsia
Investigations to consider
pituitary MRI (contrast-enhanced)
Test
The posterior pituitary normally shows as a bright spot on T1-weighted MRI. This bright spot is absent in nearly all patients with AVP-D.[1]
Follow-up imaging is recommended, 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
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 should prompt consideration of WFS1 gene studies.[39]
AVP-neurophysin gene studies can be used predictively within a kindred with autosomal dominant familial AVP-D.[37]
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][37]
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.[29]
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; however, tumour markers lack sensitivity.[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 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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