Hereditary Nephrogenic Diabetes Insipidus
| Title: | Hereditary Nephrogenic Diabetes Insipidus |
|---|---|
| Author: | Bichet, Daniel G. |
| Publisher: | Advances in Nephrology: Necker Hospital |
| Date Published: | January 01, 1991 |
| Reference Number: | 329 |
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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)
As a result of this non-response, NDI patients experience chronic passage of large volumes of urine (polyuria) and chronic, excessive urination (polydipsia). The reason HNDI is called X-linked is that the gene responsible for HNDI is located on the X-chromosome. Researchers determined this by studying the inheritance pattern of the disorder. They discovered HNDI was X-linked recessive, which meant that females carried the disorder but did not express the disorder's symptoms fully.
Males only have one X-chromosome, which they inherit from their mother. Should they inherit the NDI causing gene, they can display the full symptoms of the disorder. Though researchers do not know which of the genes on the X-chromosome is responsible for HNDI, they know a lot about the molecular sequence involved in kidney reabsorption of the body water in the CD and the accompanying urine concentration that occurs, and this may help them narrow their focus.
At one point, the researcher team of Bode and Crawford postulated that most cases of HNDI in North America could be traced to the descendants of an Ulster Scotsman who arrived in Nova Scotia in 1761. However, there has since been well documented cases of North Americans with HNDI who have no relation to the descendants of the Ulster Scotsman. HNDI has been documented in different ethnic groups worldwide. Most of these cases appeared to be transmitted in an X-linked inheritance pattern.
HNDI patients can begin manifesting symptoms of the disorder the first few days of life. In addition to polyuria and polydipsia (symptoms that may not be easily recognized in an infant), other symptoms include irritability, vomiting, constipation, failure to thrive, fever, dehydration and elevated levels of blood sodium caused by episodes of dehydration. Severe episodes of dehydration, if unrecognized and untreated, can cause physical and mental retardation, and even death. Fortunately, timely treatment of HNDI, which consists of adequate intake of water to compensate for body water lost through polyuria, can prevent dehydration-caused symptoms from occurring.
There are other disorders that result in polyuria and polydipsia. However, a diagnosis of HNDI can be quickly and accurately confirmed. Clinicians restrict patients from all liquids for a short period of time. Then the patients receive an injection of a synthetically modified form of VP called DDAVP. If the patient cannot concentrate urine in response to DDAVP, it is likely he or she has HNDI.
For VP to exert its antidiuretic effect in the kidneys, it must first bind with the vasopressin-2 receptor (V2R). In the kidney, V2R is located in the principal cells of the kidney CD. There is a body of evidence to suggest that the V2Rs in the kidneys of HNDI patients may be defective and therefore will not respond to VP. HNDI patients also do not respond to injections of DDAVP.
V2Rs also are located outside the kidney. When AVP binds with them, certain changes take place in the dynamics and chemistry of the blood: blood pressure decreases, plasma renin activity increases, and certain blood coagulation factors are released in the blood. When DDAVP is injected in HNDI patients, they show none of these responses. This indicates that the V2R outside the kidney may be faulty. This indicates that the HNDI patient may have a general defect in his or her V2Rs.
AVP also binds with a vasopressin-1 receptor (V1R) located in blood vessels, the liver and anterior portion of the hypophysis to affect changes in blood pressure, platelet aggregation and prostaglandin E2 levels. HNDI patients show normal responses in these factors when injected with DDAVP. All this leads researchers to suspect that defective V2Rs may play a role in HNDI.
As researchers understand it, the molecular sequence leading to urine concentration looks like this: VP binds with V2R, which is located in the basolateral membrane of the principal CD cells. The V2R is coupled to a Gs protein. When VP binds to the Gs-coupled V2R, it activates the adenylyl cyclase (AdC) enzyme system. AdC stimulates cAMP, an important metabolic regulator. cAMP, through a process that is not entirely clear, but likely involves protein kinase A, signals a protein called aquaporin-2 (AQP2). Upon receiving the signal, AQP2 travels to the apical membrane of the CD cell and inserts itself into it. This allows much more water than usual to travel through the membrane. And this is how the kidney is able to reabsorb the body water flowing through the CD. The remaining liquid that is not reabsorbed is concentrated urine that is shunted to the bladder.
The molecular cause for HNDI could occur anywhere along this molecular cascade, but evidence points to the defect occurring before the sequence reaches the cAMP stage. Bichet, et al., noted that DDAVP increased cAMP levels in blood plasma in normal subjects but not in HNDI patients. The molecular defect that would explain this lack of cAMP stimulation is unknown, but it seems unlikely that it is the result of an alteration in the Gs protein or an increased metabolic breakdown of cAMP.
At the time Bichet wrote this review, the gene responsible for causing HNDI had not been identified. Therefore, the best way to screen for HNDI carriers was to analyze the female's family lineage and to test the reactions of her V2Rs that are located outside the kidney to DDAVP. If she shows no hemodynamic or coagulation factor responses to DDAVP, and her family lineage indicates incidents of HNDI, there is a 60% to 70% chance that she is a carrier of HNDI.
Recently, it has become possible to detect HNDI carriers with AVPR2 sequencing.