Nephrogenic Diabetes Insipidus

If you want to learn more about:

• Normal Physiology of Vasopressin Action please click here.
• AVPR2 and AQP2 please click here.

Causes of secondary NDI include drug toxicity (most notably lithium toxicity), hypercalcemia, hypokalemia, chronic renal insufficiency, and osmotic diurectics.

If you want to learn more about Characteristic Signs of NDI please click here.

While secondary NDI typically develops later in life and is often temporary, primary NDI is present from birth and persists throughout life. Both types of NDI are characterized by polyuria, polydipsia, and nocturia. Symptoms of primary NDI also include vomiting and anorexia, failure to thrive, unexplained fevers, and constipation.

In children with NDI, unrelated illnesses, a hot environment, or the withholding of water may rapidly lead to severe dehydration and hypernatremia, which can result in seizures or even coma. Repeated episodes of hypernatremic dehydration during infancy may cause permanent brain damage, manifesting as developmental delay or mental retardation. Patients with primary NDI typically remain below average in height, possibly because the intake of large quantities of water hinders adequate food intake. Over time, polyuria can lead to hydronephrosis or megabladder, which can result in renal dysfunction, urinary reflux, or ruptures within the urinary tract after minor trauma.

In general, primary NDI shows little clinical variation; in a few cases, intrafamilial variation in the severity of NDI has been reported (6), and some AVPR2 mutations seem to cause only partial NDI (7, 8). In female carriers of an NDI-associated mutation in AVPR2, symptoms of NDI are typically very mild, and may only be unmasked in situations of water deprivation, such as the “nothing per os” requirement before a surgical procedure. In rare cases, females are as severely affected by AVPR2-related NDI as males (9).


In infants, the characteristic symptoms of NDI (polyuria, polydipsia, nocturia) are difficult to recognize. Other symptoms of primary NDI (vomiting and anorexia, failure to thrive, unexplained fevers, constipation) are more obvious, but unspecific. Therefore, primary NDI is often not diagnosed until months or sometimes years after birth. Awareness of an increased genetic risk for NDI can facilitate diagnosis in the neonatal period (9, 10).

NDI is indicated by high plasma vasopressin concentrations in the presence of high plasma osmolality and low urine osmolality. A diagnosis of NDI can be confirmed through the water deprivation challenge test (the Miller-Moses test). While this test is highly diagnostic, it requires hospitalization, repeated blood draws, and specialized lab tests, and is not without risks to the patient. In addition, the water deprivation challenge test cannot differentiate between AVPR2-related NDI and AQP2-related NDI and may be difficult to interpret in cases of mild NDI, where partial responsiveness to vasopressin is retained.

Genetic testing can allow a diagnosis of NDI based on a single blood draw. In addition, genetic testing can identify female carriers of an NDI-associated mutation in AVPR2.


NDI can be treated effectively by abundant intake of water and a very low sodium diet. To prevent injury to the urinary tract due to dilatation, urine volume can be reduced by up to 50% through drug therapy with thiazide diuretics such as hydrochlorothiazide (11). Since thiazide diuretics lead to potassium wasting, they are often combined with a potassium-sparing diuretic such as amiloride (12). Both types of diuretics are believed to lower urine output by causing renal water retention upstream of the collecting ducts. Non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethicin can also improve urine concentrating ability, but chronic use has been associated with gastric and renal tubular damage.

Dehydration due to NDI should be treated with oral intake of water, if possible. In emergency situations, intravenous fluids may be given.


Loss-of-function mutations in AVPR2 or AQP2 are believed to account for about 80% and 10%, respectively, of all cases of primary NDI (13). AVPR2-related and AQP2-related NDI differ markedly in their inheritance pattern.

AVPR2-related NDI is inherited in an X-chromosome linked manner and affects all males with a diseaseassociated loss-of-function mutation in AVPR2. In heterozygous females, AVPR2-related NDI is expressed to varying degrees, depending on which X chromosome is inactivated in most of the cells expressing AVPR2. Occurrence of severe AVPR2-related NDI in females presumably depends on heavily skewed inactivation of the non-mutated X chromosome (4, 14, 15).

About half of patients with AVPR2-related NDI have no family history at all, suggesting that the diseasecausing mutation occurred in the patient himself or his female ancestors on the maternal side (4).

AQP2 is autosomally encoded, so that AQP2-related NDI is equally common in males or females. Most (90%) of NDI-associated mutations in AQP2 are recessive and lead to the NDI phenotype only in homozygous individuals. A small number (10%) of NDI-associated mutations in AQP2 are dominant and cause NDI in heterozygous individuals.



The Nephrogenic Diabetes Insipidus (AVPR2) Evaluation detects mutations in AVPR2, which have been associated with about 80% of all cases of primary NDI. In contrast to current diagnostic methods, this test can help diagnose most cases of primary NDI based on a single blood draw and without water deprivation of the patient. Genetic testing can also be used to clarify inconclusive results from provocative testing. Furthermore, the Nephrogenic Diabetes Insipidus (AVPR2) Evaluation can identify female carriers of NDI-associated mutations in AVPR2. Knowledge of a genetic risk for AVPR2-related NDI can help to diagnose the condition in the newborn period, so that lasting consequences can be avoided.