Nephrogenic Diabetes Insipidus: Causes Revealed

Title: Nephrogenic Diabetes Insipidus: Causes Revealed
Authors: Holtzman, M.D., Eliezer J.; Ausiello, M.D., Dennis A.
Publisher: Hospital Practice (Office Edition)
Date Published: March 15, 1994
Reference Number: 109
In congenital NDI, the failure of the renal tubules to respond to antidiuretic hormone is caused by mutation of the arginine vasopressin receptor gene. Two dozen different mutations have been identified to date--all with the same clinical consequences. Several causes of acquired NDI, of which lithium is the most common, are also discussed.

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

In this article, Holtzman and Ausiello summarize the cellular and molecular biology of the antidiuretic hormone, arginine vasopressin (AVP). They also describe nephrogenic diabetes insipidus (NDI), a disorder that occurs when the kidneys do not respond to AVP. NDI is characterized by polyuria (chronic, excessive passage of large volumes of urine) and polydipsia (chronic, excessive thirst). It can either be acquired or inherited.

Normally, the molecular sequence that results in the kidney being able to reabsorb body water and concentrate urine, and thus maintain body water, runs like this: AVP binds with the vasopressin-2 receptor (V2R), which is located in the bottom and sides of the membranes of the principal cells in the kidney collecting duct. The V2R is already coupled to a stimulatory G protein and when AVP binds with the V2R this configuration activates the enzyme, adenlylate cyclase (AdC). AdC then generates the important metabolic regulator, cAMP. This causes a process (that is not fully understood but probably involves protein kinase A) which activates transport vessels inside the cell that deliver water-transporting proteins to the apex of the membranes of the principal cells of the kidney collecting duct. When these water-transporting proteins are inserted into the cell membranes they form channels through which much more water can flow through the cells than usual. This is what allows the kidney collecting duct to reabsorb a significant amount of water that flows through it. The remaining liquid is the concentrated urine that is later excreted.

The water transporting proteins, as signaled by the process that is initiated when AVP binds with V2R, shuttle back and forth from the holding place within the cell to the cell membranes that they make more water permeable.

In congenital NDI, patients have an adequate to high level of AVP, but the kidney collecting duct cells do not respond to it and, therefore, the kidneys cannot reabsorb the water flowing through them. Congenital NDI can manifest in the first days of life and, if unrecognized and untreated, can cause severe dehydration, failure to thrive, fever, irritability, constipation, vomiting and high blood sodium, all of which can combine to cause physical and mental retardation and even death.

The most common form of inherited NDI by far is X-linked NDI. It is called this because the gene mutation responsible for NDI is located on the long arm of the X chromosome. Because females have two X chromosomes and males have one, males who inherit the mutated gene responsible for NDI from their mothers are much more likely to express the disorder than females who, if they inherit the gene, will generally carry, but not express, NDI.

Further analysis revealed that the V2R gene is located on the long arm of the X chromosome, right at the location previous analysis pinpointed as the NDI locus. Since the V2R is an essential part of the AVP-mediated urine concentration process, researchers analyzed the V2R genes of NDI patients and found them to be mutated. Mutated genes can produce proteins with structural abnormalities that lead to functional defects. Such is the case with mutated V2R genes and the proteins they produce: V2Rs.

Imagine a V2R as a long string of beads (the beads are amino acids). The majority of the V2R lies in seven folded bunches, called transmembrane domains, that lie within the cell membrane, a thin strip of tissue that encircles the cell, separating its insides from the outside. Part of the V2R snakes outside the cell to form three curves called extracellular loops 1, 2 and 3. Part of it snakes inside the cell to form intracellular loops 1, 2 and 3. One end of the V2R, called the amino terminus is outside the cell with the extracellular loops; one end, called the carboxy terminus, is inside the cell with the intracellular loops. (You can look at a diagram of a V2R here.)

To date, over 24 different mutations of the V2R gene resulting in NDI have been reported worldwide. Each of these mutation occur at different points on the V2R gene; each alters the structure of the V2Rs they produce in different ways; each results in either a nonfunctional or functionally impaired V2R; all produce the same clinical symptoms.

The authors believe that the functional lapses will fall under four possible categories and that a defective V2R can possess one or a combination of them:
It is hoped that the precise mapping between V2R structure and function will lead to a deeper understanding of how the V2R changes one form of energy into another as it participates in the molecular urine concentrating process and that such knowledge will lead to development of pharmacological agents to better treat NDI.
Of the acquired causes of NDI, long term lithium use (a drug often prescribed for certain psychological disorders such as manic depression) is the most common. From 12% to 20% of all patients on lithium develop NDI. Lithium-induced NDI was always thought to be fully reversible but it is now considered plausible that lithium use may cause long-term kidney damage. Though it is still debated as to how lithium induces NDI, many researchers think lithium impairs adenylate cyclase activation which results in a decrease in cAMP formation. Other things that induce NDI include the drug demeclocycline, low levels of blood potassium, and too high levels of blood calcium.