Hereditary Nephrogenic Diabetes Insipidus

Clinical characteristics: Hereditary nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.

Diagnosis/testing: The diagnosis of hereditary NDI is established in a male proband with NDI by identification of a hemizygous pathogenic variant in AVPR2 or identification of a compound heterozygous or homozygous pathogenic variant in AQP2 by molecular genetic testing. The diagnosis of hereditary NDI is usually established in a female proband with NDI by identification of a heterozygous pathogenic variant in AVPR2 or identification of a compound heterozygous or homozygous pathogenic variant in AQP2 by molecular genetic testing.

Management: Treatment of manifestations: Management by a multidisciplinary team (nutritionist, pediatric nephrologist/endocrinologist, clinical geneticist); free access to drinking water and to toilet facilities; reduction of polyuria (and thus polydipsia) up to 50% without inducing hypernatremia by use of a thiazide diuretic (e.g., hydrochlorothiazide, chlorothiazide) often used in combination with either amiloride (a potassium-sparing diuretic) or indomethacin; dietary restriction of sodium; in individuals with dehydration or shock, establish whether the deficit is primarily in free water (through water deprivation or excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid extravasation) to avoid inappropriate treatment of dehydration with normal saline (0.9% NaCl); when "NPO" (nothing per ora), individuals with NDI must have intravenous replacement of their usual oral intake of water as 5% dextrose in water; treat hydronephrosis, hydroureter, and megacystis with medical management to reduce urine output and continuous or intermittent bladder catheterization when post-void urinary bladder residuals are significant.

Prevention of secondary complications: Reduction of urine production by drug therapy and voiding at two-hour intervals may prevent or reduce serious renal, ureteral, or bladder dilatation.

Surveillance: Monitor growth and development at least every three months in infants and at least every six months in older children; measurement of serum sodium concentration to identify unrecognized hyperosmolality and early dehydration at least every three months in infants, at least every six months in older children, and annually in adults or only as needed; annual kidney ultrasound examination to monitor for hydronephrosis and megacystis.

Agents/circumstances to avoid: Water intake must not be restricted.

Evaluation of relatives at risk: Evaluation of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilatation of the urinary tract.

Genetic counseling: Hereditary NDI is most commonly inherited in an X-linked manner (~90% of individuals). Hereditary NDI can also be inherited in an autosomal recessive manner (~9% of individuals) or in an autosomal dominant manner (~1% of individuals). The risks to sibs and offspring depend on the mode of inheritance and the genetic status of the parents, which can be established in most families using molecular genetic testing. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the disease-causing pathogenic variant(s) in the family have been identified.