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NORD gratefully acknowledges Jeff M. Sands, MD, Juha P. Kokko Professor of Medicine, Renal Division Director, Emory University School of Medicine, for assistance in the preparation of this report.
Nephrogenic diabetes insipidus (NDI) is a rare kidney disorder that may be inherited or acquired. NDI is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin. NDI is a distinct disorder caused by complete or partial resistance of the kidneys to arginine vasopressin (AVP). Vasopressin is an antidiuretic hormone used by the kidney to manage water balance in the body. NDI causes chronic excessive urine production (polyuria). Patients must drink as much water as they excrete, leading to excessive thirst (polydipsia). Failure to do so can result in severe dehydration. If left untreated, repeated episodes of severe dehydration may develop, eventually resulting in serious complications including cognitive impairment. Most cases of hereditary NDI are due to changes (mutations or variants) in the AVPR2 gene and are inherited in an X-linked pattern. Rare cases are due to variants in the AQP2 gene and are inherited in an autosomal recessive or dominant pattern. NDI may also be acquired during life due to drugs (e.g., lithium therapy), kidney disease, obstruction of the tubes that carry urine from the kidneys to the bladder (ureters) and prolonged metabolic imbalances such as low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). NDI may also be a temporary complication associated with pregnancy.
The term nephrogenic diabetes insipidus was first used in the medical literature in 1947. In the past, the term diabetes insipidus renalis was used to denote this disorder. NDI is different from central diabetes insipidus, which is a rare disorder characterized by the inability of the body to produce vasopressin (rather than vasopressin resistance as in NDI).
The symptoms of NDI can vary from one person to another. Some individuals may be more severely affected than others. The acquired form is almost always less severe than the hereditary forms. In hereditary X-linked NDI, symptoms usually appear shortly after birth and most children are diagnosed within the first year of life. In autosomal dominant NDI, symptoms tend to appear later in life, sometimes not until adulthood. The acquired form of NDI most often occurs in adults and the onset of symptoms may be slow.
The two main symptoms of NDI are chronic excessive urine production (polyuria) leading to excessive thirst (polydipsia). Excessive urination at night (nocturia) also occurs. Some infants may present with vomiting, retching, unexplained fevers, lethargy and irritability. Constipation, diarrhea and poor feeding may also occur. As a result, some infants may fail to grow or gain weight at the expected rate (failure to thrive). In some patients, these symptoms may be mild and underappreciated.
Infants and adults with NDI may rapidly develop dehydration following low water intake, a hot environment or concurrent illness. Infants with NDI may experience repeated episodes of dehydration, which can result in weakness, confusion, dry mucous membranes, dry skin and weight loss. If left untreated, severe dehydration may develop. Repeated episodes of severe dehydration may result in significant abnormalities including seizures, brain damage, developmental delays and physical and intellectual disability. However, with proper diagnosis and prompt treatment, intelligence and development are usually normal.
Because of the chronic excretion of large amounts of urine, additional symptoms may develop as affected individuals age including bedwetting at night (nocturnal enuresis), abnormal accumulation of urine in the kidneys (hydronephrosis), swelling (distention) of the ureters with urine due to blockage (hydroureter) and an abnormally large bladder (megacystis). Some individuals develop widening (dilatation) of the urinary tract.
Adults with NDI may also develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope).
Many individuals with NDI attain an adult height that is just below normal or where would be expected otherwise. This may result from unsuccessful management or inadequate nutrition during childhood (e.g., failure to thrive).
A variety of factors can cause acquired NDI. A common cause is chronic use of the drug lithium. Less common causes include protein malnutrition, a variety of kidney diseases, obstruction of the urinary tract and prolonged metabolic imbalances, specifically low levels of potassium in the blood (hypokalemia) or high levels of calcium in the blood (hypercalcemia). Other drugs such as certain antibiotics, antivirals, antifungals or antineoplastic drugs have been reported to potentially cause acquired NDI. During pregnancy, some women may develop a temporary (transient) form of NDI.
In most cases of hereditary NDI inheritance is X-linked recessive. In rare cases, inheritance is autosomal recessive or dominant. Some cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation).
X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest almost exclusively in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Although most females who carry the mutated gene usually do not develop the clinical symptoms (asymptomatic) of NDI, some females do develop certain symptoms such as varying degrees of excessive urination and excessive thirst. This occurs because of a process known as marked skewing of X chromosome inactivation. In this process, the X chromosome carrying the normal gene is inactivated instead of the X chromosome with the mutated gene.
The X-linked recessive form of NDI, which account for approximately 90% of cases, is caused by disruptions or changes (mutations) of the AVPR2 gene on the X chromosome.
Approximately 10% of cases of hereditary NDI are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Less than 1% of cases hereditary NDI are inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Most (but not all) patients with autosomal recessive or dominant NDI are caused by mutations of the aquaporin-2 (AQP2) gene.
The symptoms of NDI result from the inability of the kidneys to reabsorb water. Water within the body normally flows through the kidneys where it is reabsorbed through structures called nephrons – tubular filters that collect urine containing water and waste products. The water is filtered out and eventually returned the body. The amount of water retained is determined by the antidiuretic hormone, arginine vasopressin. This hormone works with a protein coating the cells of nephrons called a vasopressin-2 receptor (V2R). The V2R protein recognizes vasopressin in the body. Vasopressin and V2Rs bind together to begin a complex chemical process that manages water intake by the kidneys. As part of this process, another protein known as aquaporin-2 (AQP2) is activated to serve as a passageway or water channel through which water crosses the cell membrane.
The V2R protein is encoded by the AVPR2 gene, which is abnormal in individuals with the X-linked form of this disorder. An abnormal AVPR2 gene results in abnormal V2Rs that are trapped within cells (intracellular) and do not reach the cell surface. A few abnormal V2Rs do reach the cell surface, but they fail to recognize or bind with vasopressin, thereby preventing the proper reabsorption of water.
Individuals with autosomal recessive or dominant NDI generally have variants in the AQP2 gene, which encodes the water channel protein aquaporin-2. An abnormal AQP2 gene results in abnormal aquaporin-2. Abnormal aquaporin-2 proteins result in abnormal water channels that prevent enough water from passing through the cell membranes.
If the kidneys do not properly reabsorb water, the water is lost through frequent urination. The urine of individuals with NDI is dilute or weak, meaning that the urine has too much water in it.
The X-linked inherited form of NDI usually affects males. Females can be carriers of the X-linked type, may develop mild symptoms and can pass it on to their male offspring. The autosomal dominant, autosomal recessive and acquired forms of NDI affect males and females in equal numbers. The symptoms of NDI may begin at any age, usually rapidly and without warning. The incidence of NDI is not known; the X-linked form is estimated to affect 4 males out of every 1,000,000.
The acquired form of NDI is more common than the inherited forms. Approximately 55% of individuals on long-term lithium therapy develop NDI. The exact, overall incidence of acquired NDI is unknown.
A diagnosis of NDI may be suspected based upon the identification of characteristic findings, specifically excessive urination and excessive thirst. A thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests may be used to confirm a diagnosis. NDI may be suspected in children and adults who present with polyuria and polydipsia. Genetic testing can be done to look for variants in the V2R or AQP2 genes.
Clinical Testing and Workup
Physicians may take blood and urine samples to determine the concentration of particles or solids (e.g., salts, minerals, sugar) within those samples. The ratio of particles to water within the blood or urine is known as osmolality. Individuals with NDI have a high proportion of solids in relation to water (high osmolality) in their blood and a low proportion of solids in relation to water (low osmolality) in their urine.
Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Affected individuals may also receive injections of the hormones vasopressin or desmopressin (DDAVP). Desmopressin is a synthetic derivative of vasopressin. Individuals with NDI do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin.
In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken and studied. A water deprivation test studies body weight and both urine output and composition and can determine the levels of vasopressin in the body. This test may be used to distinguish between the various causes of diabetes insipidus. A water deprivation test can also differentiate between individuals with complete or partial NDI.
Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of central diabetes insipidus.
An ultrasound may be used to detect whether any kidney (renal) abnormalities (e.g., hydronephrosis, dilation) are present. During an ultrasound, reflected sound waves are used to create an image of internal organs or structures.
The treatment of NDI is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), endocrinologists, nutritionists and other health care professionals may need to plan an individual’s treatment systematically and comprehensively.
The mainstay of therapy is ensuring proper fluid intake and reducing urine output. Specific treatments include dietary modifications and the administration of certain drugs. Adequate water intake is essential for individuals with NDI to prevent dehydration. Infants may require periodic offerings of water. If the child cannot consume enough water to match their urine output, they may require a feeding tube to be placed into the stomach or intestine.
Children, parents and adults should take precautions to ensure affected individuals have access to drinking water and toilet facilities. Heavy sleepers may need to be awakened during the night to drink water and to urinate. Parents should work with school officials and teachers to ensure that proper provisions are in place for their children. Affected individuals are encouraged to wear medic alert bracelets or some similar form of identification that indicates that they have NDI.
Dietary modifications and drug therapy are used to decrease urine output. Individuals with NDI may be placed on a very low sodium diet (0.5 g/d) because sodium contributes to water loss. Drugs that affect how much water is excreted in the urine (diuretics) may also be used. Diuretics, which include hydrochlorthiazide or chlorothiazide, inhibit the amount of salt absorbed by the kidneys, thereby reducing water loss. These drugs may be used alone or in combination with other drugs such as indomethacin or amiloride. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that can increase urine concentration and reduce urine output. Indomethacin, which may also be used alone, may be associated with adverse side effects such as gastrointestinal bleeding. Amiloride is a diuretic that helps the body maintain potassium levels, which may drop with hydrochlorthiazide therapy.
For individuals with acquired NDI treating the underlying cause (e.g., correcting metabolic imbalances or discontinuing drug use) can reverse the kidneys resistance to vasopressin. However, this reversal may take weeks. In some cases, caused by the use of drugs such as lithium, it may take years for the kidneys to respond to vasopressin again or it can become irreversible.
Individuals with NDI undergoing surgery that requires no food or drink for a period of time preceding the surgery should consult with their physicians. Affected individuals will require proper hydration, usually via an IV, before and/or during surgery.
Genetic counseling is recommended for affected individuals and their families with the inherited forms of the disorder. Other treatment is symptomatic and supportive.
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Researchers are studying the use of pharmacological chaperones as potential treatments for individuals with X-linked nephrogenic diabetes insipidus. In this form of NDI, defective vasopressin 2 receptors are misshapen (misfolded) and become trapped within the cell where they breakdown (degrade). These defective receptors do not reach the cell’s plasma membrane where they promote water reabsorption. Researchers are studying the use of drugs that may be able to guide (chaperone) these receptors to the cell membrane. Researchers believe these pharmacological chaperones can bind with receptor proteins preserving enough of the natural shape and function of the proteins so that they do not become trapped within the cells and can travel to their proper destination and perform their intended function.
Researchers are also studying the use of medications that can activate alternative pathways that result in an increase in aquaporin-2 water channels in the cell membrane. This approach attempts to by-pass the defective vasopressin 2 receptor. Since in X-linked nephrogenic diabetes insipidus, the aquaporin-2 water channel is thought to be normal, finding an alternative pathway to activate it may promote water reabsorption. More research is necessary to determine the long-term safety and efficacy of these potential treatments for individuals with X-linked NDI.
Contact for additional information about nephrogenic diabetes insipidus:
Jeff M. Sands, MD
Juha P. Kokko Professor of Medicine
Renal Division Director
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