Nephrogenic diabetes insipidus is a disorder of water balance. The body normally balances fluid intake with the excretion of fluid in urine. However, people with nephrogenic diabetes insipidus produce too much urine (polyuria), which causes them to be excessively thirsty (polydipsia). Affected individuals can quickly become dehydrated if they do not drink enough water, especially in hot weather or when they are sick.

Nephrogenic diabetes insipidus can be either acquired or hereditary. The acquired form is brought on by certain drugs and chronic diseases and can occur at any time during life. The hereditary form is caused by genetic mutations, and its signs and symptoms usually become apparent within the first few months of life.

Infants with hereditary nephrogenic diabetes insipidus may eat poorly and fail to gain weight and grow at the expected rate (failure to thrive). They may also be irritable and experience fevers, diarrhea, and vomiting. Recurrent episodes of dehydration can lead to slow growth and delayed development. If the condition is not well-managed, over time it can damage the bladder and kidneys leading to pain, infections, and kidney failure. With appropriate treatment, affected individuals usually have few complications and a normal lifespan.

Nephrogenic diabetes insipidus should not be confused with diabetes mellitus, which is much more common. Diabetes mellitus is characterized by high blood sugar (glucose) levels resulting from a shortage of the hormone insulin or an insensitivity to this hormone. Although nephrogenic diabetes insipidus and diabetes mellitus have some features in common, they are separate disorders with different causes.

The hereditary form of nephrogenic diabetes insipidus can be caused by mutations in at least two genes. About 90 percent of all cases of hereditary nephrogenic diabetes insipidus result from mutations in the AVPR2 gene. Most of the remaining 10 percent of cases are caused by mutations in the AQP2 gene. Both of these genes provide instructions for making proteins that help determine how much water is excreted in urine.

The acquired form of nephrogenic diabetes insipidus can result from chronic kidney disease, certain medications (such as lithium), low levels of potassium in the blood (hypokalemia), high levels of calcium in the blood (hypercalcemia), or an obstruction of the urinary tract.

The kidneys filter the blood to remove waste and excess fluid, which are stored in the bladder as urine. The balance between fluid intake and urine excretion is controlled by a hormone called vasopressin or antidiuretic hormone (ADH). ADH directs the kidneys to concentrate urine by reabsorbing some of the water into the bloodstream. Normally, when a person's fluid intake is low or when a lot of fluid is lost (for example, through sweating), increased levels of ADH in the blood tell the kidneys to make less urine. When fluid intake is adequate, lower levels of ADH tell the kidneys to make more urine.

Mutations in the AVPR2 or AQP2 genes prevent the kidneys from responding to signals from ADH. Chronic kidney disease, certain drugs, and other factors can also impair the kidneys' ability to respond to this hormone. As a result, the kidneys do not reabsorb water as they should, and the body makes excessive amounts of urine. These problems with water balance are characteristic of nephrogenic diabetes insipidus.

Normal Function

The AVPR2 gene provides instructions for making a protein known as the vasopressin V2 receptor. This receptor works together with a hormone called vasopressin or antidiuretic hormone (ADH) in the kidneys. The vasopressin V2 receptor is found in structures called collecting ducts, which are a series of small tubes that reabsorb water from the kidneys into the bloodstream.

The interaction between ADH and the vasopressin V2 receptor triggers chemical reactions that control the body's water balance. When a person's fluid intake is low or when a lot of fluid is lost (for example, through sweating), the body produces more ADH. This hormone attaches (binds) to the vasopressin V2 receptor and directs the kidneys to concentrate urine by reabsorbing some of the water back into the bloodstream. When fluid intake is adequate, less ADH is available to interact with the vasopressin V2 receptor. At these times, less water is reabsorbed into the bloodstream and the urine is more dilute.

Health Conditions Related to Genetic Changes

Nephrogenic diabetes insipidus

More than 200 mutations in the AVPR2 gene have been identified in people with nephrogenic diabetes insipidus. Most of these mutations cause the vasopressin V2 receptor protein to be misfolded into an incorrect 3-dimensional shape. The misfolded protein is trapped within the cell, where it is unable to reach the cell surface to interact with ADH. Less common mutations in the AVPR2 gene prevent the production of any vasopressin V2 receptor protein or lead to a version of the protein that reaches the cell surface but cannot partner with ADH.

Without functional vasopressin V2 receptors, the kidneys are unable to respond to signals from ADH. As a result, collecting ducts do not reabsorb water as they should, and the body makes excessive amounts of urine. These problems with water balance are characteristic of nephrogenic diabetes insipidus.

Other disorders

At least two mutations in the AVPR2 gene have been found to cause another kidney disorder known as nephrogenic syndrome of inappropriate antidiuresis (NSIAD). This condition is characterized by low levels of salt in the blood (hyponatremia), which can lead to brain swelling and other serious complications. NSIAD also causes the blood to be abnormally dilute (serum hypo-osmolality).

The two AVPR2 gene mutations associated with NSIAD each change a single protein building block (amino acid) at position 137 in the vasopressin V2 receptor protein. One of these mutations replaces the amino acid arginine with the amino acid cysteine (written as Arg137Cys or R137C); the other mutation replaces arginine with the amino acid leucine (written as Arg137Leu or R137L). These mutations lead to a receptor protein that is constantly turned on (constitutively activated), even in the absence of ADH. As a result, large amounts of water are reabsorbed into the bloodstream regardless of fluid intake, and the urine is highly concentrated. These abnormalities disrupt the body's water balance, causing hyponatremia and serum hypo-osmolality.

Other Names for This Gene

• ADHR
• antidiuretic hormone receptor
• AVPR V2
• DI1
• DIR
• DIR3
• MGC126533
• MGC138386
• NDI
• renal-type arginine vasopressin receptor
• V2R
• V2R_HUMAN
• vasopressin V2 receptor

Genomic Location

Normal Function

The AQP2 gene provides instructions for making a protein called aquaporin 2. This protein forms a channel that carries water molecules across cell membranes. It is found in the kidneys in structures called collecting ducts, which are a series of small tubes that reabsorb water from the kidneys into the bloodstream.

The aquaporin 2 water channel plays an essential role in maintaining the body's water balance. The placement of these channels is controlled by a hormone called vasopressin or antidiuretic hormone (ADH). When a person's fluid intake is low or when a lot of fluid is lost (for example, through sweating), the body produces more ADH. This hormone triggers chemical reactions that ultimately insert aquaporin 2 water channels into the membrane of collecting duct cells. These channels allow water to be reabsorbed into the bloodstream, which makes the urine more concentrated. When fluid intake is adequate, less ADH is produced. Without signals from ADH, aquaporin 2 water channels are removed from the membrane of collecting duct cells. At these times, less water is reabsorbed into the bloodstream and the urine is more dilute.

Health Conditions Related to Genetic Changes

Nephrogenic diabetes insipidus

At least 40 mutations in the AQP2 gene have been identified in people with nephrogenic diabetes insipidus.

Most of the known AQP2 gene mutations cause the aquaporin 2 protein to be misfolded into an incorrect 3-dimensional shape. The misfolded protein is trapped within the cell, where it is unable to reach the cell membrane to transport water molecules. A few mutations result in the production of functional aquaporin 2 water channels, but these channels are misrouted within the cell and do not reach the cell membrane.

If aquaporin 2 water channels are not inserted into the membrane of collecting duct cells, the kidneys are unable to respond to signals from ADH. As a result, collecting ducts do not reabsorb water as they should, and the body makes excessive amounts of urine. These problems with water balance are characteristic of nephrogenic diabetes insipidus.

Other Names for This Gene

• ADH water channel
• AQP-2
• AQP-CD
• AQP2_HUMAN
• aquaporin 2 (collecting duct)
• aquaporin-2
• aquaporin-CD
• collecting duct water channel protein
• MGC34501
• water channel protein for renal collecting duct
• water-channel aquaporin 2
• WCH-CD

Genomic Location

When nephrogenic diabetes insipidus results from mutations in the AVPR2 gene, the condition has an X-linked recessive pattern of inheritance. The AVPR2 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation usually has to occur in both copies of the gene to cause the disorder. However, some females who carry a single mutated copy of the AVPR2 gene have features of nephrogenic diabetes insipidus, including polyuria and polydipsia. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

When nephrogenic diabetes insipidus is caused by mutations in the AQP2 gene, it can have either an autosomal recessive or, less commonly, an autosomal dominant pattern of inheritance. In autosomal recessive inheritance, both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In autosomal dominant inheritance, one mutated copy of the AQP2 gene in each cell is sufficient to cause the disorder.

Management is usually best accomplished by a team of physicians and other healthcare professionals. The team may include a nutritionist, a pediatric (or adult) nephrologist or endocrinologist, and a clinical geneticist.

The basis of management involves free access to drinking water and toilet facilities. The polyuria can be lowered with a low-salt (sodium), low-protein diet; thiazide diuretics: hydrochlorothiazide and chlorothiazide; other diuretics (i.e., potassium-sparing diuretic amiloride); and nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin. In babies, early recognition is very important because treatment can avoid the physical and intellectual disability that results from repeated episodes of dehydration and high levels of sodium (hypernatremia). Infants and very young children should be offered water every two hours during the day and night. In severe cases, continuous gastric feeding may be required. In adults, the decision to treat is based upon the individual patient's intolerance of the polyuria and polydipsia since, in almost all patients, the thirst mechanism is sufficient to maintain the sodium in the high-normal range. The medication desmopressin may be tried in patients who have persistent symptomatic polyuria after having the above described regimen. Several new approaches to treatment of this disorder are being investigated: V2 receptor chaperones and V2 receptor bypass.

The prevalence of nephrogenic diabetes insipidus is unknown, although the condition is thought to be rare. The acquired form occurs more frequently than the hereditary form.