Nephrogenic diabetes insipidus

Definition

Nephrogenic diabetes insipidus (NDI) is a kidney disorder characterized by the organ's inability to respond to the antidiuretic hormone (ADH), also called arginine vasopressin (AVP), produced in the hypothalamus, a structure of the brain. NDI involves an abnormality in the kidney tubules which prevents the proper amount of water from being reabsorbed from the kidneys back into the body. Instead, the water is excreted in large amounts as diluted urine.

Description

There are two categories of nephrogenic diabetes insipidus: inherited and acquired. Within the inherited group, there are three types of NDI: X-linked, autosomal recessive, and autosomal dominant. Unlike the more common diabetic disorder diabetes mellitus , NDI is not related to insulin production or levels of sugar in the blood and urine.

Ninety percent of inherited NDI is X-linked, meaning it is caused by an alteration in a gene carried on the X chromosome. Since women have two X chromosomes and men have only one, an X-linked recessive condition is expected to effect men since they do not have a second X chromosome with a normal copy of the gene to produce the needed substance. Autosomal recessive NDI is rarer and equally affects males and females. Autosomal dominant NDI is the most rare of the three and affects both males and females.

Inherited NDI is present from birth and symptoms usually manifest within the first several days of life. If the disorder is not diagnosed and treated early, it will cause the body to lose too much water. This dehydration can lead to brain damage and eventually death. But, with early diagnosis and treatment to avoid severe dehydration, the person can live a normal life span without any mental impairment.

Acquired NDI is the most common type of the disease and can be acquired at any age. It is most frequently acquired through the long-term use of certain prescription medicine, including demeclocycline, methicillin, foscarnet, and some anticancer drugs. In rare instances, it can be caused by an underlying disease or disorder, such as sickle cell anemia , chronic kidney failure, sarcoidosis, amyloidosis, Fanconi syndrome, and Sjögrens syndrome. Other rare causes of acquired NDI are low blood levels of potassium and abnormally high blood calcium levels. Pregnancy can also result in temporary acquired NDI. However, most cases of acquired NDI are caused by long-term use of the prescription drug lithium, used to treat bipolar disorder (manic depression ).

NDI, also called gypsy's curse, is caused by the kidneys inability to respond to the water-saving hormone (ADH), a natural chemical manufactured in the brain but works in the kidneys. The body's two kidneys make urine, which is then sent to the bladder, and help to maintain the balance of water, salt, and minerals. A majority of the water is reabsorbed from nephrons in the kidneys into surrounding inner tissue. Each kidney contains hundreds of thousands of nephrons, microscopic-size tubes that filter the water flowing into the kidneys. The water that is not absorbed becomes urine.

The first references to NDI appeared in medical literature in the 1880s, but it wasn't until the 1940s that detailed observations and studies were done. In a landmark 1946 study published in the American Journal of the Diseases of Children, authors A. J. Waring, L. Kajdi, and V. Tappan, summarized the main clinical and pathophysiological aspects of the disorder. "The presenting complaints were unexplained fever, failure to gain weight, and constipation. The bouts of dehydration are usually not associated with acidosis. The thirst of one of the patients studied was satisfied only when five to six times the normal requirement of fluid was offered. The levels of (blood) serum sodium and chloride decreased to normal and the infant remained free from fever on this high fluid intake."

Genetic profile

Genes are the blueprint for the human body that directs the development of cells and tissue. Mutations in some genes can cause genetic disorders such as inherited nephrogenic diabetes insipidus. Every cell in the body has 23 pairs of chromosomes, 22 pairs of which are called autosomes and contain two copies of individual genes. The 23rd pair of chromosomes is called the sex chromosome because it determines a person's sex. Men have an X and a Y chromosome while women have two X chromosomes. X-linked nephrogenic diabetes insipidus is caused by a defect in the vasopressin-2 receptor (AVPR2) gene in the X chromosome which renders the kidneys unreceptive to ADH.

Since inherited NDI is usually inherited as an X-linked condition, almost all persons with the disorder are male. Females have two X chromosomes, which means they have two copies of each gene. Males have only one X chromosome and one copy of each gene. If a male has an altered AVPR2 gene, he will have NDI. If a female has one altered gene, she will be a carrier and will be at risk to pass the altered gene on to her children. If her son inherits the altered gene, he will be affected. If her daughter inherits the affected gene, she will be a carrier like her mother. If her son does not inherit the altered gene, he will not be affected and will not pass the altered gene on to his children. If a daughter does not inherit the altered gene, she will not pass it on to her children. If an affected male has children, all of his daughters will be carriers but none of his sons will be affected.

Women who have the abnormal AVPR2 gene may have milder symptoms of NDI than males. This is because early in development, one X-chromosome in each cell of a female is "turned off" at random. If by chance a woman has more than half of the X chromosomes that carry the normal AVPR2 gene turned off, she may have mild symptoms of NDI. Approximately 90% of people with inherited NDI have it as a result of this X-linked gene.

The gene that produces aquaporin-2 (AQP2) can cause autosomal recessive and autosomal dominant NDI when altered. The AQP2 gene produces a protein that helps the kidneys reabsorb water into the body and concentrate urine. Since the AQP2 gene is carried on chromosome 12, a non-sex chromosome, it is carried in both males and females. Also, an abnormal AQP2 gene is recessive, meaning if only one of the person's two AQP2 genes is abnormal, it will not cause NDI. If both genes are abnormal, then that person will have NDI. A child born to a couple who are both carriers of autosomal recessive NDI has a 25% chance to be affected since the child is at risk to receive a copy of the altered gene from its mother and father. In autosomal dominant NDI, either parent may be affected and may pass the altered gene to the child. Also, only one altered gene is necessary to be present for the condition to manifest. Acquired NDI is not hereditary and can not be genetically passed on from parents to their offspring.

Demographics

In general, the various types of NDI appear to affect people regardless of age, race, or ethnicity. However, in X-linked NDI, the predominance of cases is among males. The exact number of people with NDI is not known. Estimates range from one in every 500,000 to five in every 100,000. In acquired NDI, one of the diseases that can cause it is sickle cell anemia, which occurs primarily in people of African descent.

Signs and symptoms

The primary symptoms for all types of NDI are generally the same: polyuria (excreting large amounts of dilute urine), and polydipsia, drinking excessive amounts of water, from 3-10 gal (12-38 L) per day. In infants born with NDI, symptoms begin to occur within a few days after birth. But since a child cannot verbally communicate its need for larger than normal amounts of water, parents, physicians, and other caregivers must be alert to other signs of the disorder. Overt signs include fever, irritability, and constipation, all of which may indicate dehydration. The child may also vomit often, be anorexic, and prefer water to milk. Other signs include rapid and severe dehydration if fluids are restricted or withheld, high levels of sodium and chloride in the blood, and urine that does not have a high specific gravity.

Elderly people, usually those with acquired NDI, may need close monitoring for symptoms especially if they are unable to communicate their need for lots of water, such as patients with Alzheimer disease or other mental deterioration. Also, elderly persons may be less sensitive to their need for water. Because of this, elderly persons with NDI can be more prone to dehydration, leading to such problems as infection, kidney failure, confusion, lethargy, and constipation.

For acquired NDI, close medical monitoring should be done for people at high risk for the disorder. These include people undergoing long-term treatment with lithium, and people with sickle cell anemia, chronic kidney failure, other kidney problems, very low blood levels of potassium and protein, and high blood levels of calcium.

Diagnosis

NDI is one of four types of diabetes insipidus (DI). In all four types, the basic symptoms are extreme thirst and excessive urination. Depending on other symptoms and conditions present in the patient, it can often be easy for a physician to suspect NDI. But additional tests are required to confirm it. These include a test of urine concentration to measure the ratio of osmotically active particles (such as sodium) to body water, a blood test to determine plasma concentrations, measuring urine volume, and a test to determine the level of the antidiuretic hormone AVP in blood plasma.

Sometimes physicians will have the patient take a water deprivation test to help determine the type of NDI present. In this test, the patient goes without water or other liquids for up to six hours. The blood plasma concentrations and urine volume are then measured. Even though a patient with NDI will become dehydrated during this test, the doctor monitors the patient's body weight and blood plasma osmolarity levels to insure they remain within safe parameters. At the end of the test, the patient is generally diagnosed with NDI if he or she has high levels of osmotically active particles in the blood and low levels of osmotically active particles in the urine.

The patient is also given desmopressin acetate (DDAVP), a synthetic version of AVP, to determine if the patient has a different form of DI called pituitary diabetes insipidus, also known as central diabetes insipidus. In addition, the physician measures heart rate and diastolic blood pressure to help determine whether the NDI is caused by defective AVPR2 genes or defective AQP2 genes.

Treatment and management

Although there is no cure for NDI, all forms of the disorder are treatable. Drinking plenty of water is the first and foremost treatment. Regardless of age of the patient, water must be available at all times. However, it is important for a child to maintain control of their NDI with medication so that they can eat, drink, and grow normally.

Medications used to treat NDI include one or a combination of indomethacin (Indocin), amiloride (Midamor), the thiazide diuretics hydrochlorothiazide (Hydrodiuril) or Chlorothiazide (Diuril), and occasionally desmopressin.

Management of NDI is also accomplished through restricting the intake of sodium and sometimes protein. Thiazide diuretics can reduce a patient's urine output, but they may also cause potassium depletion. Potassium supplements may be required. NDI that occurs during pregnancy usually goes away after delivery of the child. NDI caused by diet abnormalities are usually reversible once the diet becomes balanced. Acquired NDI caused by electrolyte imbalances such as low levels of calcium in the blood plasma or high levels of potassium in the blood plasma can be reversed once the imbalance is corrected.

In patients with lithium-induced NDI, thiazide diuretics are used cautiously since they reduce the kidneys' ability to excrete lithium. In many, but not all cases, people with lithium-induced NDI can improve when the dosage is decreased or stopped. In some cases, the lithium-induced NDI is irreversible.

Prognosis

Infants and children with inherited NDI can live a normal life span providing they are diagnosed correctly, treated early, and properly manage the disorder. Without early diagnosis and treatment in infancy, NDI can lead to mental retardation and even death. Infants and children with NDI tend to be slightly smaller and weigh less than children without NDI. As children with NDI mature into adults, they tend to be slightly shorter than their parents, but with a normal weight. With appropriate treatment and management, NDI should not interfere with activities such as school, work, or sports.

Resources

BOOKS

Czernichow, P. Diabetes Insipidus in Man. S. Karger Publishing, Basel, Switzerland, 1985.

Narins, Robert G. Maxwell and Kleeman's Clinical Disorders of Fluid and Electrolyte Metabolism, Fifth Edition. McGraw-Hill Publishing, Inc., New York, 1994.

Scriver, Charles R., et al. The Metabolic Basis of Inherited Disease, Eighth Edition. McGraw-Hill Publishing, Inc., New York, 2000.

PERIODICALS

Arthus, M. F., et al. "Report of 33 Novel AVPR2 Mutations and Analysis of 117 Families with X-linked Nephrogenic Diabetes Insipidus." Journal of the American Society of Nephrology (June 2000): 1044-1054.

Bichet, D. G. "Nephrogenic Diabetes Insipidus." American Journal of Medicine (November 1998): 431-442.

Stone, Dr. Kurt A. "Lithium-induced Nephrogenic Diabetes Insipidus." Journal of the American Board of Family Practice (January/February 1999): 43-47.

Oksche, A., and W. Rosenthal. "The Molecular Basis of Nephrogenic Diabetes Insipidus." Journal of Molecular Medicine (April 1998): 326-337.

Schulz, Pasel K., et al. "Functional Characterization of the Molecular Defects Causing Nephrogenic Diabetes Insipidus in Eight Families." Journal of Clinical Endocrinology and Metabolism (April 2000): 1703-1710.

Van Lieburg, Angenita F., et al. "Clinical Presentation and Follow-up of 30 Patients with Congenital Nephrogenic Diabetes Insipidus." Journal of the American Society of Nephrology (October 1999): 1958-1964.

Wildin, R. S., and D. E. Cogdell. "Clinical Utility of Direct Mutation Testing for Congenital Nephrogenic Diabetes Insipidus in Families." Pediatrics (March 1999): 632-639.

ORGANIZATIONS

Nephrogenic Diabetes Insipidus Foundation. PO Box 1390, Eastsound, WA 98245. (888) 376-6343. Fax: (888) 376-3842. <http://www.Ndi.org>.

WEBSITES

Diabetes Insipidus Foundation.<http://diabetesinsipidus.maxinter.net>.

Ken R. Wells