Nephrogenic diabetes insipidus (NDI)

The hallmark clinical features of NDI are polyuria and polydipsia. Symptoms appear within the first few weeks of life and can be dangerous if unrecognied. Clinical features include poor feeding, poor weight gain, irritability, and recurrent hypernatraemic dehydration with intermittent high fever. Prolonged or recurrent episodes of hypernatraemic dehydration may cause seizures, permanent brain damage, developmental delay, and cognitive impairment; with early diagnosis and proper management, intelligence and life span are usually normal. Chronic excretion of large urine volumes can result in hydronephrosis, hydroureter, and megacystis, with potential complications including urinary tract rupture, infection, intractable pain, impaired bladder function, and kidney failure.

Incidence of X-linked NDI in the general population of Quebec was determined at approximately 8.8 per million male live births. However, the incidence of NDI is elevated in certain regions due to founder effects.

NDI is caused by germline pathogenic variants in AVPR2 (~90%) or AQP2 (~10%). The AVPR2 gene encodes the type 2 vasopressin receptor, which is expressed on the basolateral side of collecting duct cells. After activation of the receptor by vasopressin, translation of the water channel aquaporin 2 and its incorporation into the apical membrane of the collecting duct cells is amplified, so that the uptake of water from the primary urine is increased. A loss of function of the receptor prevents the vasopressin-induced incorporation of aquaporin 2 and impairs the reabsorption of water; resulting in increased excretion of hypotonic urine (polyuria).

NDI associated with AVPR2 shows X-linked inheritance, while AQP2-associated NDI is typically inherited in an autosomal recessive manner, although dominant inheritance has also been observed in rare cases. Predictive testing of at-risk relatives is possible once a familial pathogenic variant has been identified. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis rests on demonstration of hypotonic polyuria with hypernatraemia and an inadequate renal response to desmopressin. Serum sodium >145 mEq/L with low urine specific gravity supports the diagnosis; failure to increase urinary osmolality above 200 mOsm/kg H₂O after parenteral DDAVP with elevated plasma AVP confirms renal vasopressin resistance. Copeptin, a stable surrogate for AVP, reliably discriminates AVP resistance from AVP deficiency and primary polydipsia.

Main differential diagnoses include:

• Central diabetes insipidus (AVP-D): deficient AVP synthesis or secretion; urine concentrates after DDAVP; pathogenic variants in AVP.
• Acquired NDI: more common; triggers include lithium therapy, hypokalaemia, hypercalcaemia, urinary tract obstruction, and chronic kidney disease.
• Primary polydipsia: excess fluid intake suppresses AVP secretion; plasma osmolality >295 mOsm/kg excludes it.

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for informed clinical decision-making.
• Knowledge of the underlying pathogenic variant enables specific and individualised surveillance and is the prerequisite for any targeted medical care.
• Once the familial pathogenic variant is known, targeted testing of at-risk relatives can identify those who may benefit from clinical evaluation and earlier intervention.

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