Most of the fluid in the body is comprised of water. Maintaining the proper amount of fluid throughout the body is referred to as maintaining body water balance. There are many water balance disorders, and nephrogenic diabetes insipidus (NDI) is one of them. In lay terms, NDI can be described as a condition in which the kidneys do not respond to a signal from the antidiuretic hormone, arginine vasopressin (AVP). Thus, the kidneys are unable to reabsorb the water that passes through a part of them called the collecting duct, and therefore they cannot balance body water. This results in the NDI patient voiding large amounts of dilute urine, while leaving the body short of water.
Normally, body water flows through the kidneys, and the vast majority of it is reabsorbed from the kidneys’ nephrons into their inner tissue. (The nephron is a combination of a filter and tube. There are about a million of them in each kidney.) The liquid that is not reabsorbed becomes the concentrated urine that is shunted to the bladder and out the urethra.
The primary symptoms of NDI are polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst). Inherited NDI may show up in the first weeks of life with symptoms that include fever, irritability, constipation, failure to thrive, lack of appetite, vomiting and high blood levels of sodium.
Robert Wildin of the Oregon Health Sciences University in Portland, Oregon, USA, explains that “The kidney’s water reabsorbing mechanism can malfunction due to the effects of other diseases, drugs or toxic substances. This is called acquired NDI. It may begin at any time in life. Alternatively, NDI may occur due to a genetic deficiency of one of the essential components of the water reabsorbing mechanism. People with these inherited forms of NDI usually have symptoms beginning within weeks of birth, though their significance may be missed for months or even years.”
For a hormone to transmit its hormonal message, it must first link with a hormone receptor specific to it. Normally, the hormone arginine vasopressin (AVP) links up to a hormone receptor called the vasopressin-2 receptor (V2R) that is located in the principal cells of a part of the kidney called the collecting duct. This linking of AVP and V2R initiates a molecular sequence that makes the cells of the kidney collecting duct more water permeable. This enables the kidneys to reabsorb the water flowing through the collecting duct. It is this sequence that breaks down when a person has NDI.
The V2R receptor, like all receptors, is a protein. Cells synthesize proteins using instructions encoded in genes. When a gene is mutated, it is likely to produce defective proteins incapable of carrying out their function in the body. The transmission of mutated genes from parents to child forms the basis of inherited disorders. To date, researchers have identified the genetic basis of three forms of inherited NDI:
X-linked NDI is caused by mutations of the V2R gene (technically AVPR2) that result in defective V2Rs.
Both autosomal recessive NDI and autosomal dominant NDI are caused by mutations of the aquaporin-2 (AQP2) gene that result in defective AQP2s.
Up to 90% of the cases of inherited NDI are the result of mutations of the V2R gene. The remaining cases are the result of mutations of the AQP2 gene. Though each type of inherited NDI has a different genetic cause, the symptoms of each are identical.
What is different about the two forms of inherited NDI is that males are the most likely to display symptoms of X-linked NDI, whereas males and females are equally likely to display symptoms of the autosomal recessive form of NDI. This is because the V2R gene is carried on the X-chromosome. Males have one X-chromosome, and females have two X-chromosomes. Therefore, if a male inherits a mutated V2R gene from his mother, he will most likely have NDI, whereas the female, should she carry a mutated V2R gene on one of her X-chromosomes, has a good chance of having a normal V2R gene on her other X-chromosome. Her normal V2R gene will mask the effects of her mutated V2R gene. Autosomal recessive NDI is carried on a non-sex chromosome, so males and females are equally likely to inherit it, though a mutated AQP2 gene must be inherited from both parents for NDI to express itself in their child.
In 1969 Bode and Crawford hypothesized in “Nephrogenic diabetes insipidus in North America–The Hopewell hypothesis” that all inherited NDI originated from a common carrier (which implied a common genetic mutation the same for all NDI patients). Since then, researchers have disproved this hypothesisby discovering over 70 different mutations of the V2R gene. Many of these mutations are located at different points on the V2R gene and disable the V2Rsproduced by these genes in different ways. Researchers have also discovered more than 13 different AQP2 gene mutations, located at different points on the AQP2 gene, that disrupt AQP2s in different ways. Inherited NDI has been identified in different ethnic groups worldwide.
Acquired NDI is the more common form of NDI and can occur at any time of life. Most often, acquired NDI is a result of the use of the drug, lithium. Dr. David Marples of the University of Leeds in England, demonstrated the changes in AQP2 due to lithium use for the first time in 1995 in Lithium-induced Down regulation of Aquaporin-2 Water Channel Expression in Rat Kidney Medulla. Acquired NDI can also result from the use of other drugs, such as colchicine, methoxyflurane, amphotericin B, gentamicin, loop diuretics and demeclocycline. In Diabetes Insipidus [Bell], Tally Bell, a registered nurse from Wesley Medical Center in Wichita, Kansas, USA, points out that in addition to the use of certain drugs, acquired NDI can also occur as a result of certain diseases and physical conditions, which can result in either permanent or temporary NDI. Bell notes that acquired NDI can also occur as a consequence of a more fundamental disorder such as:
- chronic kidney failure,
- other kidney diseases,
- abnormally low levels of potassium,
- abnormally high levels of calcium,
- sickle cell disease,
- one or more of the ureters (the fibromuscular tubes shunting urine from the kidney to the bladder) being blocked,
as the result of protein starvation,or
- on a transient basis during pregnancy.