EndocrinologyTier 2Disease (DEADMAN)

Diabetes insipidus - nephrogenic

Description

Collecting duct resistance to ADH -> failure to concentrate urine -> hypotonic polyuria
*Renamed 2022: "arginine vasopressin resistance" (AVP-R)*, with cranial DI now "AVP deficiency" (AVP-D)
- Driven by fatal medication errors from confusion with diabetes mellitus. Not yet in ICD-11 - both names in use

Defining features

Polyuria >3 L/day (>50 mL/kg/day) with urine osmolality <300 mOsm/kg
Serum sodium normal or high if access to water is intact - rises fast the moment access is lost
Complete vs partial (residual concentrating capacity)

Differential of hypotonic polyuria

	Plasma Na	Response to desmopressin
AVP-R (nephrogenic)	High-normal/high	<15% rise in urine osm (partial: up to ~45%)
AVP-D (cranial)	High-normal/high	>50% rise
Primary polydipsia	Low-normal	Intermediate; urine osm rises with fluid restriction alone

Acquired forms vastly outnumber congenital
Lithium is the commonest cause - nephrogenic DI in ~20-40% of long-term users; some impairment of concentrating ability in most
Congenital: ~1:250,000 births
- ~90% X-linked AVPR2 (males affected, carrier females variably symptomatic)
- ~10% autosomal AQP2 (recessive > dominant)

Normal physiology

Osmoreceptor -> ADH -> V2 receptor (basolateral, Gs/cAMP) -> aquaporin-2 trafficked to the apical membrane -> water reabsorption
Requires an intact medullary concentration gradient (loop of Henle, urea recycling)

Acquired

Drugs - lithium (commonest), amphotericin B, aminoglycosides, cidofovir, foscarnet, cisplatin, demeclocycline, ifosfamide, rifampicin
- Lithium enters principal cells via ENaC, inhibits GSK3-beta -> dec AQP2 expression and causes tubulointerstitial nephritis
Electrolyte - *hypercalcaemia and hypokalaemia* (the two to name)
- Both dec AQP2 expression and impair NaCl reabsorption in the thick ascending limb -> the medullary gradient is also lost
Renal - post-obstructive uropathy, chronic kidney disease, sickle cell disease/trait (medullary infarction), amyloid, Sjogren, polycystic kidney disease, recovery phase of ATN
Pregnancy - placental vasopressinase degrades AVP (technically increased clearance; responds to desmopressin, which resists vasopressinase)
Osmotic diuresis, high protein/salt load

Congenital

AVPR2 (X-linked) - loss-of-function V2 receptor; presents in infancy with vomiting, failure to thrive, fever, hypernatraemia, developmental delay
AQP2 - the water channel itself

Confirm polyuria: 24-hour volume >3 L (>50 mL/kg) and exclude osmotic diuresis (glucose, urea, mannitol)
Paired serum and urine osmolality + serum sodium
- Serum osm >295 with urine osm <300 -> diagnosis is already made; no water deprivation test needed
Copeptin (a stable AVP surrogate) has largely replaced the water deprivation test
- Baseline copeptin >21.4 pmol/L diagnoses AVP-R without any stimulation, and separates it from AVP-D and primary polydipsia
- Arginine- or hypertonic saline-stimulated copeptin where baseline is not diagnostic
- The classical water deprivation test misclassifies partial forms and primary polydipsia in ~25-30%
Desmopressin challenge after water deprivation: rise in urine osmolality <15% (complete) or up to 45% (partial) confirms renal resistance
Then find the cause: calcium, potassium, UEC, lithium level, urinalysis, renal ultrasound
Genetic testing (AVPR2, AQP2) in congenital/paediatric or familial cases

1. Treat the cause - the highest-yield step

Correct hypercalcaemia and hypokalaemia - usually fully reversible
Relieve obstruction
Withdraw the offending drug where possible
- Lithium: discuss with psychiatry - after >10-15 years of exposure the defect is often only partly reversible, and psychiatric relapse may outweigh it

2. Reduce the solute load

Low sodium and low protein diet - dec obligate solute excretion -> dec urine volume
Free access to water at all times
- *Never fluid-restrict a patient with AVP-R* - they cannot concentrate, so restriction produces rapid hypernatraemia

3. Pharmacological

Thiazide diuretic (hydrochlorothiazide) - paradoxical antidiuresis
- Mild volume depletion -> inc proximal Na and water reabsorption -> less water delivered distally
- Add a low-salt diet or the effect is lost; watch for hypokalaemia (which worsens the DI)
Amiloride - the treatment of choice in lithium-induced AVP-R
- Blocks ENaC, the channel lithium uses to enter principal cells -> prevents further accumulation and toxicity
- Combines well with a thiazide and offsets its hypokalaemia
NSAID (indomethacin) - prostaglandins antagonise ADH action; adjunct in refractory or congenital disease
- Nephrotoxicity limits long-term use
High-dose desmopressin may help partial acquired forms; useless in complete congenital disease

Congenital

Early diagnosis, unrestricted water, thiazide + amiloride +/- indomethacin, high-calorie low-solute feeds
Growth and neurodevelopment depend on avoiding repeated hypernatraemic episodes

Lithium - also causes chronic tubulointerstitial nephritis, CKD, hypothyroidism, hyperparathyroidism/hypercalcaemia (which then worsens the DI)
Hypercalcaemia of any cause - primary hyperparathyroidism, malignancy, sarcoid
Sickle cell disease and trait; obstructive uropathy; medullary cystic disease
Sjogren syndrome, amyloidosis
X-linked AVPR2 in males - family history of affected maternal uncles
Bartter and Gitelman syndromes (via hypokalaemia)

Reversible if the cause is corrected early - electrolytes, obstruction, short-duration drug exposure
Lithium-induced disease becomes irreversible with duration and can persist for years after cessation
Congenital disease is lifelong; repeated infantile hypernatraemic dehydration -> seizures, intellectual disability, cerebral calcification
Complications of chronic high urine output: hydronephrosis and a large atonic bladder, nocturia, growth failure in children
The lethal scenario: any patient with AVP-R who loses access to water - intercurrent illness, anaesthesia, intubation, dementia. Flag it in the notes and on the drug chart

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