Endocrine dynamic function tests - water deprivation test

Three causes of polyuria

Separates the three causes of hypotonic polyuria-polydipsia:
- AVP deficiency (AVP-D) - formerly cranial/central DI
- AVP resistance (AVP-R) - formerly nephrogenic DI
- Primary polydipsia
Two parts, and both are needed:

1. Water deprivation - can the patient concentrate urine endogenously?

2. Desmopressin at the end - if not, is it the hormone or the kidney?

*Superseded as the reference test by hypertonic saline-stimulated copeptin* where available - the water deprivation test misclassifies partial AVP-D and primary polydipsia in ~30% of cases

Rarely needed: most polyuria is drug-induced, osmotic (glucose), or obviously psychogenic
Primary polydipsia is the commonest of the three in practice

Rising plasma osmolality -> hypothalamic osmoreceptors -> AVP release from the posterior pituitary
AVP -> V2 receptor on collecting duct principal cells -> cAMP -> aquaporin-2 insertion into the apical membrane -> water reabsorption
At plasma osmolality ~295 mOsm/kg (Na ~145), endogenous AVP is already maximal
- -> *in a normal person, giving desmopressin at this point produces NO further rise in urine osmolality*
- -> any further rise at that point means endogenous AVP was deficient

Confirm true hypotonic polyuria: >3 L/day (>50 mL/kg/day) with urine osmolality <300
Exclude osmotic diuresis - glucose, urea, mannitol
Exclude and correct: hypercalcaemia, hypokalaemia, renal impairment
Review drugs: lithium, demeclocycline, diuretics, SGLT2 inhibitors, tolvaptan
Stop desmopressin >=24 h beforehand
*Do not perform if the patient is already hypernatraemic - the answer is already AVP-D or AVP-R, and the test is dangerous*

Fluid restriction from ~0700, typically to 17 hours (some protocols 8 h)
2-hourly: weight, BP/HR, urine volume and osmolality, plasma osmolality and sodium
*Supervised - patients drink surreptitiously, and this is the commonest reason the test fails*

### Stop the deprivation phase early if:

Then give desmopressin (2 microg IM/IV, or 20 microg intranasal) and measure urine osmolality at 1, 2 and 4 hours

Deprivation phase	After desmopressin	Diagnosis
Urine osm >700-800	No further rise	Normal / primary polydipsia
Urine osm remains <300	>750, or a rise >100% (more than doubles)	Complete AVP-D
Urine osm 300-750	Rise of ~10-50%	Partial AVP-D or primary polydipsia - the grey zone the test cannot resolve
Urine osm remains <300	*No rise (<10%)*	AVP-R (nephrogenic)

The interpretive rule in one line: fails to concentrate -> responds to desmopressin = hormone problem; fails to concentrate -> no response = kidney problem

Copeptin is the C-terminal fragment of the AVP precursor, secreted equimolar with AVP but stable and assayable
Baseline copeptin >21.4 pmol/L (no fluid restriction) = AVP-R - diagnosis made, no deprivation needed
Hypertonic saline-stimulated copeptin (3% NaCl to Na >=150): >=4.9 pmol/L = primary polydipsia; <4.9 = AVP-D (accuracy ~96%)
Arginine-stimulated copeptin is safer but less accurate head-to-head
Plasma sodium <135 or copeptin >5.6 pmol/L at baseline strongly favours primary polydipsia

MRI pituitary/hypothalamus in every confirmed AVP-D (posterior bright spot, stalk thickening)
Anterior pituitary screen; cortisol deficiency masks AVP-D

Medical staff must be immediately available; nurse-supervised throughout
Weigh accurately on the same scales; a 3% fall is the hard stop
Free access to water immediately after the desmopressin phase, but limit intake in the first few hours to avoid iatrogenic hyponatraemia (desmopressin is still acting)
*Do not perform in uncorrected adrenal insufficiency* - untreated cortisol deficiency both impairs free water excretion (masking AVP-D) and risks an adrenal crisis under the stress of dehydration
Avoid in pregnancy, hypovolaemia, uncontrolled diabetes, and in children without paediatric endocrinology supervision

AVP-D -> desmopressin, titrated to symptoms with a scheduled break to allow dilute urine; find the cause on MRI
AVP-R -> stop the offending drug where possible (lithium), thiazide + low-sodium diet, amiloride for lithium-induced disease, NSAID in selected cases
Primary polydipsia -> gradual fluid restriction, address the psychiatric or behavioural driver; *desmopressin is contraindicated - it causes severe hyponatraemia*

AVP-D: pituitary surgery, trauma, craniopharyngioma, germinoma, hypophysitis, sarcoidosis, Langerhans cell histiocytosis, metastases, Wolfram syndrome (DIDMOAD)
AVP-R: lithium, chronic hypokalaemia, hypercalcaemia, post-obstructive uropathy, sickle cell, AQP2/V2 receptor mutations, demeclocycline, tolvaptan
Primary polydipsia: schizophrenia, anxiety, anticholinergic dry mouth, hypothalamic thirst-centre lesions

Hypernatraemia is the hazard of the deprivation phase; hyponatraemia is the hazard of the desmopressin phase - both are iatrogenic and both are avoidable with monitoring
An indeterminate result is common - plan for it: proceed to copeptin testing or a supervised therapeutic trial of desmopressin with sodium monitoring rather than repeating the same test
A therapeutic trial (desmopressin with close sodium monitoring, expecting improvement in AVP-D and hyponatraemia in primary polydipsia) is a legitimate alternative in ambiguous cases
If the sodium is already high with dilute urine, the deprivation phase adds nothing but risk - go straight to desmopressin

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