Pathogenesis

The ability to concentrate urine (and thus absorb water) requires the presence of an intact concentrating gradient in the renal medulla and the ability to modulate water permeability in the collecting tubule. The latter is mediated by ADH (also called arginine vasopressin [AVP]), which is synthesized in the hypothalamus and stored in the posterior pituitary. Under basal situations, the collecting tubule is impermeable to water. However, in response to increased serum osmolarity (as detected by osmoreceptors in the hypothalamus) and/or severe volume depletion, ADH is released into the systemic circulation. It then binds to its receptor, vasopressin V₂ (AVPR2), on the basolateral membrane of the collecting tubule cell. Binding of the hormone to its receptor activates a cyclic adenosine monophosphate(cAMP)-dependent cascade that results in movement of preformed water channels (aquaporin 2 [AQP2]) to the luminal membrane of the collecting duct, rendering it permeable to water.

Defects in the AVPR2 gene cause the more common X-linked form of NDI. Mutations in the AQP2 gene have been identified in patients with the rarer autosomal dominant and recessive forms. Prenatal testing is available for families at risk for X-linked NDI. Patients with secondary forms of NDI can have ADH resistance owing to defective aquaporin expression (lithium intoxication). Secondary ADH resistance usually occurs as the result of loss of the hypertonic medullary gradient due to solute diuresis or tubular damage, resulting in the inability to absorb sodium or urea.

Clinical Manifestations

Patients with congenital NDI typically present in the newborn period with massive polyuria, volume depletion, hypernatremia, and hyperthermia. Irritability and crying are common features. Constipation and poor weight gain are also seen. After multiple episodes of hypernatremic dehydration, patients can have developmental delay and mental retardation. Enuresis, caused by large urine volumes, is common. Because of the need to consume large volumes of water during the day, patients often have diminished appetite and poor food intake. However, even with adequate caloric supplementation, patients still exhibit growth abnormalities. Patients with congenital NDI also exhibit behavioral problems, including hyperactivity and short-term memory problems. Patients with the secondary form generally present later in life, primarily with hypernatremia and polyuria. Associated symptoms such as developmental delay and behavioral abnormalities are less common in this latter group.

Diagnosis

The diagnosis is suggested in a male infant with polyuria, hypernatremia, and diluted urine. Simultaneous serum and urine osmolality measurements should be obtained. If the serum osmolality value is 290 mOsm/kg or higher with a simultaneous urine osmolality value of <290 mOsm/kg, a formal water deprivation test is not necessary. Because the differential diagnosis includes causes of central diabetes insipidus, the inability to respond to ADH (and thus the presence of NDI) should then be confirmed by the administration of vasopressin (10-20 µg intranasally) followed by serial urine and serum osmolality measurements hourly for 4 hr. In patients with possible “partial” or secondary diabetes insipidus, in whom the initial serum osmolality value may be <290 mOsm/kg, a water deprivation test should be considered. Fluids should be withheld and urine and serum osmolalities measured periodically until the serum osmolality value is >290 mOsm/kg; vasopressin is then given as before. Criteria for premature termination of a water deprivation test include a decrease in body weight of >3%. If NDI is confirmed or suspected, additional evaluation should include a detailed history to assess possible toxic exposures, determination of renal function by serum creatinine and blood urea nitrogen levels, and renal ultrasonography to identify obstructive uropathies or cystic disease. Because of massive urine output, patients with congenital NDI can have nonobstructive hydronephrosis of varying severity.

Treatment and Prognosis

Treatment of NDI includes maintenance of adequate fluid intake and access to free water, minimizing urine output by limiting solute load with a low-osmolar, low-sodium diet, and administering medications directed at decreasing urine output. For infants, human milk or a low-solute formula, such as Similac PM 60/40, is preferred. Most infants with congenital NDI require gastrostomy or nasogastric feedings to ensure adequate fluid administration throughout the day and night. Sodium intake in older patients should be <0.7 mEq/kg/24 hr. Thiazide diuretics (2-3 mg/kg/24 hr of hydrochlorothiazide) effectively induce sodium loss and stimulate proximal tubule reabsorption of water. Potassium-sparing diuretics, in particular, amiloride (0.3 mg/kg/24 hr in 3 divided doses), are often indicated. Patients who have an inadequate response to diuretics alone might benefit from the addition of indomethacin (2 mg/kg/24 hr), which has an additive effect in reducing water excretion in some patients. Renal function must be monitored closely in such patients because indomethacin can cause deterioration in renal function over time. Patients with secondary NDI might not require medications but should have access to free water. Such patients should have serum electrolytes and volume status monitored closely, particularly during periods of superimposed acute illnesses.

Prevention of recurrent dehydration and hypernatremia in patients with congenital NDI has significantly improved the neurodevelopmental outcome of these patients. However, behavioral issues remain a significant problem. In addition, chronic use of nonsteroidal anti-inflammatory drugs can predispose patients to renal insufficiency. Prognosis of patients with secondary NDI generally depends on the nature of the underlying disease.