Bradley P. Dixon
Nephrogenic diabetes insipidus (NDI) is a rare congenital or, more commonly, acquired, disorder of water metabolism characterized by an inability to concentrate urine, even in the presence of antidiuretic hormone (ADH). The most common pattern of inheritance in congenital NDI is as an X-linked recessive disorder. Rarely, affected females are seen, presumably secondary to nonrandom X-chromosome inactivation. Approximately 10% of cases of congenital NDI are inherited as autosomal dominant or recessive disorders, with males and females affected equally. The clinical phenotype of autosomal recessive forms is similar to that of the X-linked form. Secondary (acquired), either partial or complete, forms of NDI are not uncommon. They may be seen in many disorders affecting renal tubular function, including obstructive uropathies, acute or chronic renal failure, renal cystic diseases, interstitial nephritis, nephrocalcinosis, or toxic nephropathy caused by hypokalemia, hypercalcemia, lithium, or amphotericin B.
The ability to concentrate urine (and thus absorb water) requires the delivery of urine to the collecting tubule; an intact concentrating gradient in the renal medulla; and the ability to modulate water permeability in the collecting tubule by ADH. ADH (also called arginine vasopressin [AVP]), 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 osmolality (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 R (AVPR2), on the basolateral membrane of the collecting tubule cell. Binding of the hormone to its receptor activates a cyclic adenosine monophosphate–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 (as seen in lithium intoxication). Secondary ADH resistance usually occurs as the result of loss of the hypertonic medullary gradient as a result of solute diuresis or tubular damage, resulting in the inability to absorb sodium or urea.
Patients with congenital NDI typically present in the newborn period with massive polyuria, volume depletion, hypernatremia, and hyperthermia. Irritability and inconsolability are common features. Constipation and poor weight gain are also seen. After multiple episodes of hypernatremic dehydration in infancy, patients can have developmental delay and mental retardation, although this has become less common with cautious fluid resuscitation and gradual correction of hypernatremia. 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.
The diagnosis is suggested in a male infant with polyuria, hypernatremia, and dilute 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, an 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 the massive urine output, patients with congenital NDI can have nonobstructive hydronephrosis of varying severity.
Treatment of NDI includes maintenance of adequate fluid intake and access to free water, minimizing the urine output by limiting the solute load with a low-osmolar, low-sodium diet, and administering medications directed at decreasing the 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 additionally 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 may not require medications but should have access to free water. Such patients should have the 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 antiinflammatory drugs can predispose patients to renal insufficiency. The prognosis of patients with secondary NDI generally depends on the nature of the underlying disease.