Nephrogenic Diabetes Insipidus (Bichet - November 1998)
| Title: | Nephrogenic Diabetes Insipidus (Bichet - November 1998) |
|---|---|
| Author: | Bichet, Daniel G. |
| Publisher: | American Journal of Medicine |
| Date Published: | November 01, 1998 |
| Reference Number: | 198 |
In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital nephrogenic diabetes insipidus (NDI), the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In <10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations of the aquaporin-2 gene (AQP2), ie, the vasopressin-sensitive water channel, have been identified. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind with AVP or to trigger an intracellular cyclic adenosine-monophosphate (cAMP) signal. Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. The acquired form of NDI is much more common than the congenital form, is almost always less severe, and is associated with downregulation of AQP2. The advances described here are examples of "bedside physiology" and provide diagnostic tools for physicians caring for these patients.
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)
- the vasopressin-1a receptor (V1aR),
- the vasopressin-1b receptor (V1bR),
- the vasopressin-2 receptor (V2R),
- and the oxytocin receptor (OTR).
V2Rs are located in the basolateral membrane of the principal cells of the kidney collecting duct (CD). (If you imagine the principal cell as being an upright triangle, and the perimeter of the rectangle as the cell membrane, the bottom and sides of the triangle would be the basolateral membranes and the top would be the apical membrane.) V2Rs are also located outside the kidney (these are called extrarenal V2Rs), though researchers do not know exactly where they are located.
When AVP forms a weak, reversible chemical bond with the V2Rs located in the kidney CD, it initiates a molecular sequence which allows the kidneys to reabsorb the body water flowing through its CDs, leaving behind concentrated urine that is later voided. Researchers are developing a detailed knowledge of this molecular sequence, the broad strokes of which occur as follows:
- AVP binds with V2R, which is coupled to a Gs protein.
- When the binding occurs, the alpha subunit of the Gs separates from the beta/gamma subunit and stimulates the enzyme, adenylyl cyclase (AdC).
- AdC then increases the activity of a metabolic regulator called cyclic adenosine monophosphate (cAMP).
- cAMP then stimulates protein kinase A (PKA),
- which leads to the insertion of aquaporin-2s (AQPs) into the apical membrane of the principal cells of the kidney CD.
AQP2s are proteins that act as channels through which water can cross the cell membrane. In the absence of AVP they reside in little sacs called water channel vesicles (WCVs) within the cell, beneath the apical membrane. When stimulated by the AVP-initiated molecular sequence, the WCVs travel to and fuse with the apical membrane. At this point the AQP2s are inserted into the membrane, which makes the apical membrane up to 100 times more water permeable. This increased water permeability is what allows the kidneys to reabsorb the water flowing through the kidney CDs. When AVP absents itself from the cell, the AQP2s are retrieved from the apical membrane, are taken back to the interior of the cell, and the apical membrane returns to its previous state of low water permeability.
The disorder nephrogenic diabetes insipidus (NDI) is a condition wherein the kidneys are unable to respond to the antidiuretic message of AVP. Thus, they are unable to reabsorb body water flowing through the CDs. So, the NDI patient is unable to regulate his body water, cannot concentrate his urine and experiences polyuria (chronic passage of large volumes of urine) and polydipsia (chronic, excessive thirst).
NDI may be either inherited or acquired. The inherited form of NDI is rare, but its symptoms, though the same as the acquired form of NDI, are more severe. The symptoms of inherited NDI can appear in the first week of life, and in addition to polyuria and polydipsia (which may be difficult to recognize in an infant) include: failure to thrive, constipation, unexplained fever, irritability, vomiting and anorexia (showing itself as a preference for water above food or milk). If these symptoms are not recognized as indicators of NDI, the infant's high water needs may not be met, resulting in severe bouts of dehydration that could cut off oxygen to the brain, kidneys and other organs, resulting in physical and mental retardation, and even death.
However, if the infant's NDI is recognized in time and treated with adequate supplies of water to replace that which is lost through polyuria, the infant can experience normal mental and physical development. Currently, NDI cannot be cured, only managed. This is done by ensuring an adequate intake of water, adhering to a low sodium diet, and treating with drugs that include hydrochlorothiazide and indomethacin. These drugs can reduce polyuria sometimes by almost half, but they have side effects which must be taken into consideration. For example, thiazides can rob the body of potassium; indomethacin can cause gastrointestinal symptoms.
NDI may be caused by mutations in one of two different genes. Ninety percent of the cases of inherited NDI are caused by mutations in the V2R gene, which result in defective V2Rs unable to perform their functions. To date, there have been 72 distinct mutations of the V2R gene that are known to result in NDI. Most of these mutations result in V2Rs that are unable to leave their holding site (the endoplasmic reticulum) within the principal cell in order to travel to the cell surface where they must be if they are to bind with AVP. Some of the V2R gene mutations result in V2Rs that are able to travel to the cell surface, but once there they are unable to bind with AVP or are unable to trigger cAMP. In all cases, the molecular sequence that results in apical cell permeability being increased by the insertion of AQP2s cannot take place.
The inheritance pattern for this type of NDI is called X-linked recessive because the V2R gene is located in the Xq28 region of the X chromosome. Only males express this form of NDI because they have only one X chromosome (which they inherit from their mother). And should they inherit an X chromosome from their mother that carries a mutated V2R gene, they do not have another X chromosome which might carry a normal V2R gene to balance the effects of the mutated gene. Females do have two X chromosomes, so even if they do inherit one X chromosome with a mutated V2R gene, chances are extremely good that their other X chromosome will carry a normal V2R gene.
Females who carry one X chromosome with a mutated V2R gene are called carriers. They may express some of the symptoms of NDI, but rarely as severely as males. Sometimes, due to a process called X-inactivation, a female carrier may have her healthy X chromosomes inactivated. Then she will have all the symptoms of NDI.
The other type of inherited NDI is caused by mutations of the AQP2 gene located on chromosome 12. The inheritance pattern for this form of NDI is autosomal recessive, which means that either males or females can inherit it, and that to do so, both the chromosome 12 from the mother and father must bear a mutated AQP2 gene.
Direct mutational analysis can determine whether an infant's NDI is due to either an AQP2 or V2R gene defect. But another way to distinguish between the two is to monitor the infant's extrarenal responses to DDAVP, a synthetic derivative of AVP. Since an infant with X-linked NDI has a general V2 defect, DDAVP will not be able to bind with V2Rs outside the kidney either, and will not show any signs of doing so in his blood chemistry. An infant with autosomal recessive NDI will.
Both forms of inherited NDI are found in different ethnic groups worldwide, but are always rare. X-linked NDI is estimated to occur to four males per million. Autosomal NDI is much rarer still. About thirty percent of the cases of NDI are the result of new mutations where there is no family history of NDI.
NDI can also be acquired, which is the more common form. It is usually less severe, and is associated with lower numbers of AQP2. Three of the most common causes of acquired NDI are:
- long-term use of the drug, lithium,
- low amounts of potassium in the blood, and
- obstruction of the ureters, which are the fibromuscular tubes running from the kidneys to the bladder.
Because both the V2R gene and the AQP2 gene have been cloned, researchers have been able to discover and study the structure and function of normal V2Rs and AQP2s and compare them to the structure and function of their defective counterparts. This has given researchers a detailed understanding of the proteins, an understanding which could lead to some form of genetic therapy for NDI patients. Currently, such molecular knowledge as researchers have discovered has enabled clinicians to test females with a history of NDI in their lineage to see if they are carrying a mutated V2R gene. It also enables them to test fetuses prenatally or infants immediately postnatally in families with a known NDI history. Also, infants who show signs of NDI, even though there is no family history of NDI, can be immediately tested for the disorder. This is vital because early detection and treatment of NDI is important if the infant is to avoid severe bouts of dehydration.