Nephrogenic syndrome of inappropriate antidiuresis (ORPHA:93606)
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare genetic disorder of water balance, closely resembling the far more frequent syndrome of inappropriate antidiuretic secretion (SIAD), and characterized by euvolemic hypotonic hyponatremia due to impaired free water excretion and undetectable or low plasma arginine vasopressin (AVP) levels.
Epidemiology
NSIAD is a very rare disease with 21 cases of hyponatremia due to NSIAD having been reported to date, the majority of them coming from 5 families. NSIAD affects mainly males.
Clinical description
Age at diagnosis can range from the first day of life to more than 70 years. When disease onset occurs in childhood, it generally presents with hyponatremic seizures. Asymptomatic female carriers have also been described. Symptoms of NSIAD are the classical symptoms of hyponatremic encephalopathy (cerebral edema) such as nausea, vomiting, dizziness and gait disturbances. The life-threatening symptoms of acute and severe hyponatremia (altered consciousness, respiratory arrest and death) have never been reported in NSIAD but can theoretically occur.
Etiology
NSIAD is due to a gain of function mutation in the type 2 AVP receptor (AVPR2) gene (location Xq28), thus representing the mirror image of nephrogenic diabetes insipidus (see this term). This mutation leads to constant activation of the AVPR2 receptor on renal collecting duct cells, which causes an increase in free water reabsorption and an increase in urine concentration. Three mutations in this gene have been identified, 2 of them have been described in only one patient.
Diagnostic methods
The first step in diagnosing NSIAD is to diagnose SIAD. The diagnostic criteria are as follows: euvolemic hypotonic hyponatremia, increased urinary osmolality (> 100 mosm/kg), increased urinary sodium (> 30 mmol/l), normal thyroid, adrenal, cardiac and renal function and no use of diuretics. The circumstances in which the AVPR2 mutation should be screened are 'idiopathic' SIAD with low or undetectable plasma AVP levels, familial history of NSIAD or unexplained SIAD in childhood. A mutation in the AVPR2 gene confirms diagnosis.
Differential diagnosis
The main differential diagnosis is idiopathic SIAD.
Genetic counseling
NSIAD is an X-linked disorder, affecting mainly males, with females often being asymptomatic carriers (only 3 cases of symptomatic hyponatremic females have been reported). Genetic counseling is possible.
Management and treatment
Treatment of NSIAD is lifelong. Fluid restriction is the cornerstone of treatment. It is generally sufficient to avoid episodes of hyponatremia and is well tolerated (good compliance). There is a concern of restricting fluids in young infants due to the risk of malnutrition. Oral urea is the second step of treatment and acts by increasing free water clearance (osmotic diuresis). It is safe and well tolerated in children and adults, even over long-term use. Intermittent urea intake (non-daily) can be an option in some patients. Urea can also be used to correct an acute episode of hyponatremia. Non-peptide vasopressin receptor antagonists (vaptans), which have received market authorization for the management of SIAD, have shown inefficacy in a patient with mutant R137C - V2R but could be of interest in patients with the recently described mutant F229V-V2R on the basis of in vitro data. Patients must be monitored when increased water intake is anticipated (sports, heat wave) or in case of postoperative perfusion.
Prognosis
The prognosis of NSAID is good, if episodes of severe hyponatremia are avoided.

                            Last update: 
                            October 2012


                            - Expert reviewer(s): 
                            Dr Frederic VANDERGHEYNST