Nephrogenic diabetes insipidus (NDI) is a rare disorder that is caused by large amounts of dilute urine produced by the nephrons, which are found in the kidneys. Normally, the kidneys control the concentration of the urine by absorbing water and returning it to the blood in response to the body's need for water. In a healthy person, an antidiuretic (urine-limiting) hormone called arginine vasopressin (AVP) sends a signal to the kidneys to control the concentration of urine. In patients with NDI, the kidneys are unable to respond to AVP, which causes a problem with water retention. A substantial amount of water that is needed by the body is lost in large quantities as dilute urine. This leaves NDI patients continuously thirsty and in danger of dehydration.
NDI may be either acquired or inherited. Acquired NDI is more common and is usually caused by certain drugs, severe dehydration, or an electrolyte imbalance, such as elevated sodium or chlorine levels in the blood. Inherited NDI is caused by defects in the AVPR2 or AQP2 genes. NDI can be inherited in an X-linked or an autosomal fashion. X-linked mutations are carried on the X chromosome, which is one of the two sex chromosomes. Females have two X chromosomes, whereas males have one X and one Y chromosome. Males are most likely to have symptoms of inherited X-linked NDI because they receive only one X chromosome, compared to females who inherit two X chromosomes. Autosomal mutations are located on one of the 22 non-sex chromosomes. Males and females are equally likely to display symptoms of the autosomal forms of inherited NDI because this form of the disorder is not linked to a sex chromosome.
Symptoms of NDI include extreme thirst (polydipsia), excessive urination (polyuria), short stature, and a failure to develop during infancy. NDI patients require a steady supply of water to alleviate their thirst and to prevent dehydration. With early diagnosis and proper management, the quality and duration of life can be normal for patients with NDI.
NDI is different from diabetes mellitus, which involves problems with insulin and blood sugar regulation. The symptoms can be similar and may include extreme thirst and frequent urination. However, NDI is related to how the kidneys handle fluids. Urine and blood tests can determine if a patient has NDI or diabetes mellitus.
Acquired nephrogenic diabetes insipidus (NDI) is usually caused by certain drugs, such as lithium, demeclocycline, and aminoglycosides. It can also be caused by severe dehydration or an electrolyte imbalance, such as an elevated blood sodium level (hypernatremia) or elevated blood chlorine level (hyperchloremia).
Inherited NDI: Inherited NDI is caused by mutations or defects in the AVPR2 or AQP2 genes. NDI can be inherited in several ways. Most people inherit NDI as an X-linked recessive trait. About 90% of people with inherited NDI are males who have inherited the disease as an X-linked recessive trait. About 10% of people with inherited NDI inherit the disease as an autosomal recessive or autosomal dominant trait. X-linked recessive NDI is caused by mutations in the AVP receptor 2 (AVPR2) gene, which provides instructions for making the AVP V2 receptor in the kidney. Autosomal dominant and autosomal recessive forms of NDI are caused by mutations in the aquaporin-2 (AQP2), which provides instructions for making the AVP-sensitive water channel in the kidney.
X-linked inheritance: X-linked NDI is estimated to affect 1 in 200,000 males. Females have two X chromosomes while males have one X and one Y chromosome. Because males inherit an X chromosome from the mother and a Y chromosome from the father, males can only inherit X-linked diseases from the mother. In females who have one copy of the defective gene that causes NDI, the normal copy of the gene on the other X chromosome can compensate. Because males have only one X chromosome, they are more likely than females to show symptoms of X-linked NDI.
Females with one copy of the defective gene that causes NDI do not generally show symptoms but are called carriers because they may pass the defective gene to their children. If a female carrier has daughters with an unaffected male, their daughters have a 50% chance of being carriers for the disease. These daughters may show some symptoms, but are unlikely to have a serious form of the disease. If a female carrier has sons with an unaffected man, the sons have a 50% chance of getting the disease.
Autosomal recessive inheritance: To inherit NDI as an autosomal recessive trait, one must inherit two mutated alleles of the causative gene (one from each parent). A person who has only one mutated allele does not generally experience symptoms and is called a carrier. If one parent is a carrier, there is a 50% chance with each birth that the child will also be a carrier and a 0% chance that the child will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease and a 50% chance that each child will be a carrier.
Autosomal dominant inheritance: To inherit NDI as an autosomal dominant trait, one must inherit only one copy of the mutated gene for the disease to manifest. If one parent has the condition, therefore, there is a 50% chance that each of his/her children will have the disorder.
General: The body naturally produces an antidiuretic or urine-limiting hormone called arginine vasopressin (AVP). AVP signals the kidneys to return water to the blood and helps to control the concentration of the urine. In people with nephrogenic diabetes insipidus (NDI), the kidneys cannot properly respond to this hormonal signal and produce abnormally high amounts of dilute urine. NDI may be either acquired or inherited.
Acquired NDI: Acquired NDI is usually caused by certain drugs, such as lithium and certain antibiotic, antifungal, chemotherapy, and antiviral drugs. It can also be caused by severe dehydration, urinary blockage, or an electrolyte imbalance, such as an elevated blood sodium level (hypernatremia) or an elevated blood chlorine level (hyperchloremia). When NDI is induced by a drug, the drug damages the kidneys in such a way that they are unable to respond to AVP. Disturbance of the aquaporin-2 shuttle, a channel that makes the kidneys collect more water, is the cause of acquired NDI.
Inherited NDI: Inherited NDI is caused by defects in either the AVPR2 or the AQP2 gene. About 90% of patients with inherited NDI are males with X-linked recessive NDI who have mutations in the AVP receptor 2 (AVPR2) gene, which provides instructions for making the AVP V2 receptor in the kidney. Other modes of inheritance are autosomal recessive (9%) or autosomal dominant (1%). These forms of the disease are caused by mutations in the aquaporin-2 (AQP2) gene, which provides instructions for making the vasopressin-sensitive water channel in the kidney. Males are more likely than females to be affected by inherited X-linked NDI, whereas males and females are equally likely to display symptoms of NDI that is inherited as an autosomal recessive or an autosomal dominant trait.
SIGNS AND SYMPTOMS
General: The main symptoms of nephrogenic diabetes insipidus (NDI) are extreme thirst (polydipsia) and excretion of large amounts of dilute urine (polyuria). The symptoms are similar for both the acquired and the inherited forms of the disease. When NDI is inherited, these symptoms appear at birth and are usually diagnosed before one year of age. When the condition is acquired, symptoms may not occur until adulthood.
Inherited NDI: Infants born with NDI may become dehydrated if they do not receive enough fluids to replace the water lost through the urine. If left untreated, NDI can cause brain damage and stunted growth. Symptoms in infants may include poor feeding and development, rapid onset of severe dehydration, and a swollen bladder caused by the high urine volume. Some infants also have vomiting, gagging, constipation or diarrhea, unexplained fevers, weakness, and irritability.
Acquired NDI: The initial symptoms of acquired NDI may include rapid onset of severe dehydration, vomiting, diarrhea, fever, seizures, or coma. Other symptoms may include a swollen kidney (hydronephrosis), a swollen ureter (hydroureter), and an abnormally large bladder (megalocystis). If a person has normal thirst mechanisms and drinks enough fluids, NDI may have no significant effects on the fluid and electrolyte balance of the body. If the person does not drink enough fluids, the high urine output may cause high blood sodium levels, dry skin, sunken eyes, fatigue, headache, irritability, low body temperature, muscle pains, rapid heart rate, weight loss, and shock.
TYPES OF THE DISEASE
Acquired NDI: Acquired nephrogenic diabetes insipidus (NDI) occurs more frequently than inherited NDI but is still a rare disorder. It is usually less severe than inherited NDI and can occur at any time during the life cycle. Acquired NDI is usually caused by certain drugs, such as lithium and certain antibiotic, antifungal, chemotherapy, and antiviral drugs. It can also be caused by severe dehydration, urinary blockage, or an electrolyte imbalance, such as an elevated blood sodium level (hypernatremia) or an elevated blood chlorine level (hyperchloremia). When NDI is induced by a drug, the kidneys become damaged in such a way that they are unable to respond to anti-diuretic hormone. Disturbance of the aquaporin-2 shuttle, a channel that makes the kidneys collect more water, is the cause of acquired NDI.
Acquired NDI can also occur as a consequence of more fundamental disorders, such as kidney disease, abnormally low levels of potassium, abnormally high levels of calcium, or sickle cell disease. Acquired NDI may also be caused by one or more of the ureters becoming blocked during pregnancy or as a result of protein starvation. Acquired NDI can be either permanent or temporary, depending on the length of exposure to the drug or condition that caused the symptoms to occur.
Inherited NDI: Inherited NDI is caused by defects in either the AVP receptor 2 gene (AVPR2) or the
aquaporin-2 gene (AQP2). Approximately 90% of patients with inherited NDI are males with X-linked recessive NDI who have mutations in the AVPR2 gene, which provides instructions for making the AVP V2 receptor in the kidney. Other modes of inheritance are autosomal recessive (9%) or autosomal dominant (1%), in which the defective gene is AQP2, which provides instructions for making the vasopressin-sensitive water channel in the kidney. Males are more likely than females to be affected by X-linked NDI, whereas males and females are equally likely to display symptoms of the autosomal forms of inherited NDI.
Other: Some doctors have described a third type of NDI called partial NDI. Individuals with partial NDI are diagnosed later in childhood. These individuals usually do not have delayed growth or development, and they are able to concentrate the urine in response to dehydration but not as well as unaffected individuals.
General: Nephrogenic diabetes insipidus (NDI) should be considered in people with polyuria (excessive urine production) and/or polydipsia (excessive thirst). Blood and urine tests are performed to test for abnormal levels of water, sodium, and arginine vasopressin (AVP).
Blood test: Blood is tested for sodium levels and plasma concentration, which is the ratio of plasma solutes to plasma solvent. Increased blood sodium or blood plasma concentration indicate NDI.
Urine test: Because output of a large volume of dilute urine is the main symptom of NDI, many types of urine testing are performed when diagnosing NDI. These include testing the total amount of urine produced in a 24-hour period and the concentration of the urine, which is measured by testing the urine specific gravity. In patients with NDI, the volume of urine is higher than normal, and the urine has a low concentration and specific gravity. Although an overnight urinary concentration test in female relatives has been proposed as a method of carrier detection, it has been proven unreliable. Failure to concentrate the urine normally in the presence of high blood AVP levels or when given desmopressin (DDAVP), a synthetic antidiuretic hormone, indicates NDI.
Water deprivation test: Patients with NDI tend to produce urine that has a low concentration despite being deprived of water. On administration of AVP, patients with NDI will show little or no increase in urine concentration. During the water deprivation test, the patient is carefully monitored to make sure his or her body weight and blood plasma concentration stay within a safe range. The patient goes without water for less than six hours while the blood plasma concentrations and urine volume are measured. If the patient has NDI, he or she will be resistant to the antidiuretic action of AVP. Immediately following the water deprivation period, a patient with NDI will still have concentrated blood plasma and dilute urine despite the fact that he or she will be fairly dehydrated at that point. At the end of the water fast, the patient's response to an infusion of DDAVP is measured. If the patient does not respond to DDAVP, he or she may have NDI. If the patient shows highly concentrated urine in response to DDAVP, he or she may have a different form of diabetes insipidus called pituitary diabetes insipidus, which is also called central or neurogenic diabetes insipidus. Following DDAVP administration, a patient with NDI caused by a mutant AQP2 gene will display an increased heart rate and blood pressure, whereas the patient who has NDI caused by a mutated V2R gene will not.
Ultrasound: An ultrasound may be performed to examine for swelling of the kidney, the urinary tract, and the bladder to establish the extent of disease in an individual diagnosed with NDI. Some degree of urinary tract swelling may be seen on ultrasound examination even in infants.
DNA test: If a person has a family history of NDI, a sample of the patient's blood is analyzed in a laboratory for the mutated AVPR2 or AQP2 genes. If a mutation is present, a positive diagnosis is made. Although a carrier does not have NDI disease, he or she may pass a copy of the mutated gene to his or her children. Molecular genetic testing of the AVPR2 gene detects approximately 95% of disease-causing mutations in individuals with X-linked NDI. Molecular genetic testing of the AQP2 gene detects about 95% of disease-causing mutations in individuals with autosomal recessive NDI.
Dehydration: Rapid and severe dehydration occurs when not enough water is consumed to make up for water lost in the urine. If this happens rapidly or if it is present for a long time, permanent brain damage and poor growth may occur. Dehydrated individuals may be treated with intravenous (IV) administration of normal saline, especially in emergency situations. However, saline infusion may elevate sodium in the blood to dangerous levels. Repeated or prolonged episodes of severe dehydration may result in seizures, shock, developmental delay, mental decline, and death.
Urinary tract swelling: The large and constant flow of urine over many years can expand the urinary tract and the bladder. This may cause a variety of potential problems, including rupture of the urinary tract, infection, pain, improper bladder function, and/or kidney failure. In addition, reversible NDI may progress to irreversible NDI in these patients.
General: There is currently no known cure for nephrogenic diabetes insipidus (NDI). Treatment involves preventing dehydration by drinking water on a regular basis and especially at the first signs of thirst. In infants and children who may not readily communicate their thirst, water must be offered frequently, even during the night. Reducing or stopping medications that can cause NDI may improve symptoms. Friends, teachers, and neighbors should be educated about the condition. Infants and children should be monitored for abnormal growth and blood sodium concentrations and should have a yearly ultrasound evaluation to monitor for a swollen urinary tract. Continuous or intermittent bladder catheterization may be necessary when the bladder does not completely empty on its own.
Intravenous (IV) hydration: Healthcare providers generally treat dehydration with normal saline, which can be dangerous to individuals with NDI because of the sodium content. Acute blood loss or shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 2.5% dextrose in water is the preferred solution. Whenever possible, rehydration should occur through drinking water.
Drinking: The goal of treatment is to regulate fluid levels in the body. Treatment should involve regular intake of a high volume of fluid. The volume of fluids consumed should be about equal to the volume of urine produced.
Lifestyle changes: NDI patients require constant access to drinking water and toilet facilities, which may disrupt school and other social or group activities.
Patients with NDI are advised to adopt a low-sodium diet. A low-sodium diet maximizes the effectiveness of thiazide diuretics in reducing urine output. Although previously a diet low in protein was recommended for NDI patients, severe limitation of dietary protein may introduce nutritional deficiencies.
Diuretics: Thiazide (hydrochlorothiazide and chlorothiazide) and amiloride diuretics deplete total body salt, allowing the kidneys to more readily absorb water and decrease urine output. This improved water absorption can be reversed by consuming a high-salt diet. Therefore, low-sodium diets are prescribed for NDI patients. Thiazide diuretics may also deplete the body's stores of potassium. When taking thiazide diuretics, the patient's potassium levels must be monitored. To maintain sufficient potassium in the body, the addition of potassium supplements may be required. Combining a thiazide diuretic with a potassium-sparing diuretic (such as amiloride) may be more effective than using a thiazide alone. Sometimes thiazides are used in combination with the prostaglandin inhibitor, indomethacin, which treats pain.
Acquired NDI may be caused by taking lithium. Thiazide diuretics should be used with care in cases of lithium-induced NDI because they reduce the degree to which the kidney can excrete lithium. Amiloride is more widely used in these cases because it inhibits the accumulation of lithium while blunting lithium's inhibiting action on water reabsorption.
Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDS, such as indomethacin, are often prescribed to improve the ability to concentrate urine and to reduce urine output in individuals with NDI. NSAIDs have been used individually and in combination with thiazide diuretics (with or without amiloride). Because NSAIDs have undesirable effects, such as gastric and renal tubular damage, and because the incidence of complications has not been studied in individuals with NDI, caution is warranted in the chronic use of NSAIDs for treatment of NDI. Indomethacin often causes headaches and dizziness and may increase the risk of gastrointestinal disorders. If administered in the first year of life, indomethacin increases the risk of kidney disease.
Traditional or theoretical uses lacking sufficient evidence:
Low sodium diet: Patients with nephrogenic diabetes insipidus (NDI) are advised to adopt a low-sodium diet. A low-sodium diet maximizes the effectiveness of thiazide diuretics in reducing urine output. Although previously a diet low in protein was recommended for NDI patients, severe limitation of dietary protein may introduce nutritional deficiencies.
Psychomotor therapy, physical therapy: Children with a history of severe dehydration, delayed development, or a delay in establishing the correct diagnosis and management of NDI should be considered for behavioral and physical therapy before school age.
General: Prevention of nephrogenic diabetes insipidus (NDI) includes taking measures such as drinking water on a regular basis and especially at the first signs of thirst. In infants and children who may not communicate their thirst, water must be offered frequently, even during the night. Medications that could cause acquired NDI should be avoided in families at risk for the disease. Friends, teachers, and neighbors should be educated about the condition. Infants and children should be monitored for abnormal growth and blood sodium concentrations and should have a yearly ultrasound evaluation to monitor for a swollen urinary tract to prevent symptom development.
Genetic testing: Genetic testing may be performed to determine if a person carries the mutated genes that cause NDI. Although carriers do not have the disease, they may pass a copy of their mutated genes to their children. Genetic testing of children or newborns with NDI symptoms is valuable because early diagnosis and treatment can prevent the physical and mental decline associated with repeated episodes of dehydration.
Prenatal DNA testing may be performed if there is a family history of NDI. However, there are health risks associated with prenatal testing, including miscarriage. Therefore, patients should discuss the potential health risks and benefits with their healthcare provider before making any health-related decisions. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits. These counselors can help patients understand the results and limitations of these tests.
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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