Nephrogenic diabetes insipidus (NDI) is a disorder characterized by an inability of the kidneys to remove water from the urine. The main symptoms of NDI are excessive thirst (polydipsia) and excretion of large amounts of watery urine (polyuria). Individuals with NDI must drink large amounts of water to compensate for the loss of water in the urine. As a result, a person with NDI must urinate more frequently than usual.
There are two different forms of NDI, inherited and acquired. This information will focus on the inherited form of NDI. Inherited NDI is a rare disorder which is present from birth. Usually, only men have NDI. Women may have varying degrees of symptoms including increased thirst and the need for more frequent urination. If infants and young children are not treated for their NDI, they will lose too much water from their body. These periods of extreme water loss (dehydration) may lead to brain damage and, in rare cases, death. If NDI is diagnosed and treatment is started in early infancy, and if periods of severe dehydration are avoided, NDI should not affect a person’s intelligence or how long they will live.
The Cause of NDI
NDI is caused by an inability of a water-saving hormone to work properly in the kidneys. A hormone is a natural chemical made by the body that works in a different part of the body than where it was made. The hormone involved in NDI is called antidiuretic hormone (ADH), also known as vasopressin. Making ADH is one of the mechanisms which help keep water balance normal in the body. Usually, ADH allows the kidneys to save water that would otherwise be lost in the urine. The kidneys are the organs that make urine and help control the balance of water, salt, and other natural substances in the body.
ADH is made by the pituitary gland, a small organ at the base of the brain that makes many different hormones. ADH is released into the blood stream where it travels to the kidneys. The amount of ADH made by the pituitary gland depends on the body's water needs. The more water the body needs, the greater the amount of ADH made by the pituitary gland. Only when there is plenty of water does the pituitary gland make less ADH.
The nephrons are tiny tubelike structures within the kidneys that filter out waste products from the blood, and return the correct amount of water, sodium and nutrients to the body. Each kidney contains about one million nephrons. Urine forms within the nephrons and contains water and waste products that need to be removed from the body. The amount of water excreted in urine depends, in part, on how much ADH is present in the blood stream.
The way that ADH "tells" the nephron how much water to keep, and how much to excrete is through a receptor protein. A receptor protein is a natural chemical on the surface of many different types of cells. Receptor proteins will only attach to certain types of substances within the body. For example, there are receptor proteins that are specific for different types of hormones. Cells within the nephrons have receptors that are specific for ADH. When ADH attaches to these receptors, the cells respond by opening channels (tiny passageways) that allow water to return to the body. In people with NDI, the receptor for ADH does not function as it should. As a result, the water channels do not open in response to ADH, and too much water is excreted in the urine.
The receptor protein in individuals with NDI is altered due to a change in a gene. Because this gene change is permanent, NDI is a life-long condition. Thus, management, as discussed later in more detail, is also life-long.
Other Types of Diabeties Insipidus
There are different types of DI. These types are usually divided into nephrogenic (NDI) and central (CDI). Each of these two types may occur either because of a change in a gene or because of damage to cells in the body involved in water balance. If it is due to a gene change, this can be inherited. If it is due to cell damage later in life, this is usually not inherited.
Because people with NDI have a receptor protein for ADH that does not work properly, giving extra ADH as a treatment rarely works. This is different from people with central diabetes insipidus (CDI). People with CDI have the same problem that people with NDI have except that, because they do not make enough ADH but have a normal receptor for it, they can be treated with ADH.
Management of NDI
1. Adequate water intake is the main form of treatment. In adults, this requires a consistent intake of water by mouth to replace the water being lost in the urine.
2. Because sodium (salt) contributes to water loss, sodium restriction is recommended. The amount of sodium-restriction can be discussed with the doctor and/or nutritionist.
3. Diuretics, drugs that affect how much water is excreted in the urine, such as hydrochlorothiazide (HCTZ), may be helpful. HCTZ helps reduce water loss by changing the amount of sodium the kidney removes from the urine.
Use of diuretics may reduce potassium levels. Your doctor may recommend potassium-rich foods and/or potassium supplements if your potassium levels get low. Also, a second diuretic that helps the kidneys hold on to potassium, such as spironolactone or amiloride, may be considered.
4. Because protein increases the work-load on the kidneys, protein restriction is recommended. The amount of protein restriction can be discussed with the doctor and/or nutritionist.
5. Occasionally, aspirin-type drugs are used. Some studies have shown that they may decrease the amount of urine made.
All of these steps work together to help the body lose as little water as possible. Just diuretics or protein restriction by themselves is not enough.
As well, in any situation where your water losses might be more than usual, such as being under the hot summer sun, or getting a lot of exercise, it is important to have extra water available and drink more. Planning exercise or outdoor activities for the cooler times of day (morning or evening) can help.
Emergency Management of NDI
If there is inadequate intake of water for any reason, such as illness with vomiting, it is important to seek medical attention immediately to avoid serious complications.
Hypertonic encephalopathy is the most severe complication of NDI. Hypertonic refers to the abnormal concentrated plasma (body fluid) that results from extreme water loss. Encephalopathy refers to the changes in the brain that occur as a result of the high sodium that also results from extreme water loss. Symptoms of encephalopathy may include sleepiness, irritability, trembling, confusion and unsteadiness, and may progress to seizures and coma. Water loss can be replaced intravenously and continued until water intake by mouth can be resumed. Medical staff can replace lost fluid quickly but, if the blood sodium level is very high, the sodium level must be returned to normal gradually to prevent additional complications.
Other Medical Management Issues in NDI
It is recommended that persons with NDI wear a medic alert bracelet, necklace, or other item that indicates that you have NDI. This will help to ensure that appropriate treatment, including intravenous fluids, are started as soon as possible in an emergency even if you are unable to provide a medical history.
For any medical procedures requiring sedation or anesthesia, the medical staff should be informed that you have NDI so that adequate fluids can be provided during and after the procedure until you are able to take water by mouth again.
Studies have shown that people with NDI have a risk of the ureters (the tubes that connect each kidney to the bladder) and the bladder becoming abnormally large. It is believed that this enlargement is due to the build-up of urine that occurs when the kidneys make urine faster than the body can get rid of it. Adults who have not been treated for NDI typically have enlargement of these structures which can lead to kidney failure by 40 to 50 years of age. Thus, even though frequent urination can be very inconvenient, those with NDI are encouraged to urinate as soon as possible when the urge is felt and avoid prolonged "holding it in." You should void every two hours.
The Genetics of NDI
Genes are the basic unit of hereditary material. Every cell of our body contains approximately 80,000 genes. Genes contain the instruction code or "blueprint" that directs the development and function of each cell and tissue in the human body. Genes, in turn, are packaged on larger structures called chromosomes. Each chromosome contains several thousand genes.
Genes and chromosomes exist in pairs. Every cell has 23 pairs of chromosomes containing two copies of every gene. Each person received one copy of every gene from their mother in the egg cell, and one from their father in the sperm cell. The 23rd pair of chromosomes are known as the sex chromosomes because the genes on those chromosomes determine if a person is a man or a woman. Men have an X and a Y chromosome while women have two X chromosomes. Women receive an X chromosome from both their mother and father while men receive a Y from their father, and an X from their mother.
Most often, genes function properly. In some cases however, a change, or mutation in a gene can cause it to not function. Mutations in certain genes can cause inherited, or genetic disorders. Some inherited disorders are caused by non-functioning genes on the X chromosome, and these are called X-linked disorders. NDI is inherited in what is called an X-linked pattern because the non-functioning gene that causes NDI is located on the X chromosome. This non-functioning gene results in an altered receptor protein that doesn’t work as it should, causing the kidneys to be insensitive to ADH.
In X-linked recessive disorders, usually women are unaffected because they possess two copies of all the genes on the X chromosome. If one gene copy is not functioning, the other copy is able to compensate. Men, however, only have one copy of genes on the X chromosome. If a gene on the X chromosome is not functioning, then a man will have the disorder. Women are called "carriers" of the disorder because they themselves are not affected, but can have sons who are affected and daughters who are carriers. Women who are carriers can show some symptoms of NDI, however these symptoms will be milder than those of men who are affected with NDI.
There is a 50% chance with each pregnancy that a woman who is a carrier will pass on her X chromosome that contains the non-functioning gene. The chance that a mother who is a carrier and a father who is unaffected with NDI will have a son with the disorder is one in two, or 50%, since men receive an X chromosome from their mother. Daughters of a carrier woman have a 50% chance of being a carrier like their mother. In contrast, all daughters of men with an X-linked recessive disorder will be carriers, while all sons will be unaffected since they receive a Y chromosome from their father. Therefore, men with NDI can only have sons who are not affected with NDI and daughters who are carriers of the disorder.
NDI can result from a number of different mutations within the gene on the X chromosome. More than 50 mutations have been identified, and most unrelated families with NDI have a different mutation. In 1969, it was thought that the majority of individuals with NDI in North America were descendants of a common ancestor, an Ulster Scot who immigrated to Nova Scotia in 1761 on the ship "Hopewell". This "Hopewell hypothesis" was shown to be false when the gene for NDI was discovered. Known descendants of the Ulster Scot ancestor do have the same disease-causing mutation in the NDI gene, yet other families have different mutations, and are unrelated to the Hopewell kindred. In addition, the Hopewell hypothesis is not true because people of many different races can have NDI.
Dietary Management of NDI
Goals: 1. Limit the amount of sodium and nutrients in the diet.
· Low protein food intake pattern
· Low sodium food intake pattern
· Drink enough water to prevent dehydration
2. Consume adequate nutrients to meet your nutritional needs
Principles: 1. Decrease the amount of sodium and nutrients and maintain normal "water balance" by:
· Limit sodium intake to 500mg/day
· Restrict protein intake to 2 gm/kg
· Normalize water intake
· Monitor potassium intake and supplementation, if necessary.
2. Nutrients of main concern are: Energy, protein, potassium, sodium, iron and calcium.
Support Group for NDI
The NDI Network
Contact Person: Mary Evans-Lee
201 Jay Street A8
Stowe, PA 19464
(610) 326-7955
Informational Resources
Disclaimer for Medical Information:
The following informational resources and support groups are listed for your information. We have included resources that are believed to be reliable in their efforts to provide information that is accurate and complete. However, in view of the possibility of human error or changes in medical sciences, neither the authors of this site nor the University of Washington Medical Center guarantee that any information obtained from these organizations is in every respect accurate or complete. We are not responsible for any errors or omissions, or for the results obtained from the use of such information. We encourage you to confirm any information obtained from these organizations with other sources.
Metabolic Information Network (MIN)
P.O. Box 0847
Dallas, TX 75367-0847
1-800-945-2188
(214) 696-2188
FAX: (800) 955-3258
e-mail: mizesg@1x.netcom.com
The MIN’s mission is to facilitate research and enhance care of patients with inborn errors of metabolism. MIN provides physician referrals and other related information for both professionals and lay persons. MIN maintains a database for information on selected metabolic disorders and has an annual newsletter. Patients/parents are encouraged to complete information form to establish location and specialist seen.
National Center for Youth with Disabilities (NCYD)
University of Minnesota
General Pediatrics and Adolescent Health
D-115 Mayo
P.O. Box 721
420 Delaware St. SE
Minneapolis, MN 55455-0374
1-800-333-6293
(612) 626-2825
e-mail: okino001@maroon.tc.umn.edu
Executive Director: Nancy Okinow, MSW
NCYD is an information, policy and resource center focusing on adolescents with chronic illnesses and disabilities and the issues surrounding their transition to adult life.
PACER Center
4826 Chicago Ave. South
Minneapolis, MN 55417-1098
(612) 827-2966
FAX: (612) 827-3065
PACER Center is a coalition of (20) disability organizations founded on the concept of Parents Helping Parents. PACER strives to improve and expand opportunities that enhance the quality of life for children and young adults with disabilities and their families. This parent-run resource system is designed to further the goals of family-centered community-based comprehensive and coordinated systems of health care for children and adolescents with special needs and their families, providing technical assistance to parents and parent groups. It includes programs for parents and families, students, schools, professionals, technical assistance projects, newsletters and publications.
Selected Medical and Scientific References
Articles from Journals:
Wilden RS, Antush MJ, Bennett RL, Schoof JM, Scott CR (1994) Heterogeneous AVPR2 Gene Mutations in Congenital Nephrogenic Diabetes Insipidus. American Journal of Human Genetics, vol. 55, pp. 266-277.
This paper describes some of the different mutations that have been identified in the gene that encodes the ADH-receptor protein. Many people and families with NDI followed through our clinic participated in this study, thus, you may recognize your mutation in this paper! This study helped show that there does not appear to be a common mutation among people with NDI--that is, each family’s mutation is unique.
Robertson GL (1995) Diabetes Insipidus. Endocrinology and Metabolism Clinics of North America. vol. 24, pp. 549-572.
This paper reviews the different types of diabetes insipidus and includes an overview of the general aspects of NDI. It shows the similarities and differences of NDI and the other types of DI. It does not give much information about NDI treatment.
Uribarri J, Kaskas M (1993) Hereditary Nephrogenic Diabetes insipidus and Bilateral Nonobstructive Hydronephrosis. Nephron. vol. 65, pp. 346-349.
The potential long-term complication of enlargement of the bladder and other urinary tract structures is described in this short article.
Chapters from books:
Reeves W, Andreoli T. "Nephrogenic Diabetes Insipidus" in The Metabolic and Molecular Bases of Inherited Disease. 7th edition (1995). Edited by Scriver C, Beaudet A, Sly W, Valle D., pp. 3045-3071.
A detailed review of the biochemical, physiological and molecular aspects of NDI.
It may be helpful to you to make a card and laminate this emergency treatment, and carry it in your wallet.
I have nephrogenic diabetes insipidus. My kidneys are unable to retain normal amounts of free water because they are unable to respond to antidiuretic hormone (vasopressin). Thus, I must take in large amounts of water to keep up with my urinary losses of 3-5 times normal. If my consciousness is impaired, I must receive free water at 250 ml/kg/day. If this does not occur, I may develop hypernatremic encephalopathy. If my sodium level is high, it should be corrected cautiously.
For further information, contact the Metabolic Genetics clinic at the University of Washington Medical Center, where my case and diagnosis are well known, at 206-548-4030 (there is a physician on-call).