Nephrogenic Syndrome of Inappropriate Antidiuresis

Nephrogenic syndrome of inappropriate antidiuresis is an X-linked disorder in which activating variants of the vasopressin V2 receptor gene (AVPR2) cause water retention, hyponatraemia and concentrated urine, with undetectable arginine vasopressin.

It is rare. The commonest variants are R137C and R137L, and males are more severely affected. Heterozygous females vary from normal sodium to marked hyponatraemia because of skewed X inactivation. Presentation is in infancy with seizures, or later with chronic mild hyponatraemia found by chance.

A late onset form with F229V and I130N variants has been described in adults.

Pathophysiology.

The mutated V2 receptor signals without vasopressin, so aquaporin 2 channels insert in the collecting duct and water is reabsorbed. Plasma osmolality falls but urine remains concentrated.

Plasma vasopressin is low or undetectable, which separates the disorder from the syndrome of inappropriate antidiuresis of other causes.

• Infants: irritability, vomiting, poor feeding, hypotonia, seizures and growth failure, often after a large fluid intake.
• Older children and adults: headache, nausea, fatigue, cognitive problems and attention difficulty, often few symptoms despite sodium of 125 to 130 mmol/L.
• Normal blood pressure and no oedema.

Red flags.

• Seizure, drowsiness or coma with sodium under 120 mmol/L.
• Rapid correction of sodium causing osmotic demyelination.

• Plasma sodium low (often 120 to 130 mmol/L) with plasma osmolality under 275 mOsm/kg, urine osmolality over 100 mOsm/kg and urine sodium over 30 mmol/L, in a patient who is euvolaemic with normal thyroid, adrenal and kidney function.
• Undetectable or low plasma copeptin or arginine vasopressin. Raised copeptin points to the syndrome of inappropriate antidiuresis of other causes instead.
• AVPR2 sequencing confirms the diagnosis. Test the mother and relatives.

Differential diagnosis.

• Syndrome of inappropriate antidiuresis from drugs, lung or brain disease and cancer.
• Cerebral salt wasting, adrenal insufficiency, hypothyroidism and heart, liver or kidney failure.
• Psychogenic polydipsia and reset osmostat.

• Fluid restriction to 800 to 1000 mL daily in adults (in infants, about 80% of maintenance needs) is the first measure, with a high solute diet.
• Urea 0.25 to 0.5 g/kg daily (adults 15 to 30 g daily) in divided doses with flavouring to mask the taste, is the most useful long term drug.
• Loop diuretic (furosemide 20 to 40 mg daily) with salt tablets can be added. Tolvaptan does not work reliably because the mutated receptor is active without vasopressin.
• Acute severe hyponatraemia with seizures: hypertonic sodium chloride 3% 150 mL (2 mL/kg in children) over 20 minutes, repeated once if symptoms persist, aiming to raise sodium by 5 mmol/L in the first hours and no more than 10 mmol/L in 24 hours.
• Avoid desmopressin, excess fluids and drugs that cause hyponatraemia.

Special groups. Infants and children: dietitian supervision to meet growth needs. Pregnancy: carrier women need sodium monitoring and fluid advice. Genetic counselling: 50% risk to children of carrier women.

Monitoring. Sodium weekly at first, then every 3 to 6 months, and urine osmolality, growth and development yearly.

Referral and escalation. Paediatric or adult endocrinology; urgent admission for seizures or sodium under 120 mmol/L.