Nephrogenic diabetes insipidus

Other Names: Diabetes insipidus nephrogenic; Diabetes insipidus nephrogenic type 1; Vasopressin-resistant diabetes insipidus; ADH resistant diabetes insipidus; Diabetes insipidus nephrogenic X-linked

Nephrogenic diabetes insipidus is a disorder in which a defect in the small tubes (tubules) in the kidneys causes a person to produce a large amount of urine. Nephrogenic diabetes insipidus occurs when the kidney tubules, which allow water to be removed from the body or reabsorbed, do not respond to a chemical in the body called antidiuretic hormone (ADH) or vasopressin. ADH normally tells the kidneys to make the urine more concentrated. As a result of the defect, the kidneys release an excessive amount of water into the urine, producing a large quantity of very dilute urine. Nephrogenic diabetes insipidus should not be confused with diabetes mellitus, which is much more common. Diabetes mellitus is characterized by high blood sugar 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.

Forms

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.

Epidemiology

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.

Cause

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.

Inheritance

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.

Signs and symptoms

The most common symptoms are frequent urination (polyuria), especially during nighttime (nocturia), and drinking too much liquids (polydipsia).Affected individuals can quickly become dehydrated if they do not drink enough water, especially in hot weather or when they are sick. 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 100% of people have these symptoms

• Nephrogenic diabetes insipidus

80%-99% of people have these symptoms

• Hypernatremia(High blood sodium levels)
• Hypernatremic dehydration
• Hyposthenuria

30%-79% of people have these symptoms

• Anorexia
• Constipation
• Failure to thrive(Faltering weight)
• Fever
• Nausea and vomiting
• Polydipsia(Extreme thirst)

5%-29% of people have these symptoms

• Feeding difficulties(Feeding problems)
• Hydroureter
• Hypovolemia(Depleted blood volume
• Renal insufficiency(Renal failure)
• Seizure
• Short stature(Decreased body height)

1%-4% of people have these symptoms

• Enuresis nocturna
• Global developmental delay
• Polyhydramnios(High levels of amniotic fluid)

Diagnosis

Yes. GeneTests lists laboratories offering clinical genetic testing for both X-linked and autosomal types of nephrogenic diabetes insipidus. Clinical genetic tests are ordered to help diagnose a person or family and to aid in decisions regarding medical care or reproductive issues. Talk to your health care provider or a genetic professional to learn more about your testing options.

Treatment

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.

NIH genetic and rare disease info

• NIH info on Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus is a rare disease.

Nephrogenic diabetes insipidus Resources
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