Differential Diagnosis and Pathophysiology of Diabetes Insipidus
|Title:||Differential Diagnosis and Pathophysiology of Diabetes Insipidus|
|Publisher:||Nippon Jinzo Gakkai Shi. Japanese Journal of Nephrology|
|Date Published:||November 01, 1995|
We have not yet received the publisher's permission
to reproduce the full-text version of this article.
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)
Diabetes insipidus (DI) is a disease in which large amounts of dilute urine are passed over any given stretch of time. Dilute urine is urine with a low percentage of solutes (the particle portion of a solution) in the urine. There are two recognized types of DI:
- neurogenic DI, wherein the body fails to produce the antidiuretic hormone, arginine vasopressin (AVP). (AVP, when it binds with the vasopressin-2 receptor (V2R), initiates a cascade of molecule sequences that results in the kidneys being able to concentrate urine and maintain body water balance.)
- nephrogenic DI, in which the body produces enough AVP, but the kidneys cannot respond to it. To this Valtin maintains that medicine should add a third type of DI, called dipsogenic DI.
Dispsogenic DI (sometimes referred to as primary polydipsia (PP)) refers to a condition wherein the patient chronically consumes large amounts of water. Generally PP is attributed to an emotional or psychological cause. However, Valtin states that since PP's symptoms are the same as nephrogenic and neurogenic DI, and since it is diagnosed using the same physiological variables as the other DI types, it is logical to call it a type of DI. This has the advantage of not automatically committing clinicians to ascribing an emotional cause for PP, or, as Valtin would prefer to call it, dipsogenic diabetes insipidus.
Each type of DI produces the same symptoms polyuria (the chronic passage of large amounts of urine). How then, can clinicians distinguish among the types? How can they determine the cause and therefore the type of DI so they can administer the appropriate treatment?
Clinicians submit patients suspected of having DI to a water deprivation test. A water fast ordinarily leads to an increase in the patient's plasma osmolality. That is, the concentration of the particles in the plasma -- as expressed in terms of units of solute (particles) per kilogram of solvent (in this case, plasma) -- increases. Normally, this increase will stimulate the release of AVP, upon which the urine concentrating process depends. If, after adequate dehydration, the patient's urine osmolality has risen to a certain level, then it may be concluded that the patient can produce AVP and the kidneys can respond to it. If, after adequate dehydration, the urine osmolality does not rise substantially, then either enough AVP is not being produced, or enough is being produced, but the kidneys cannot respond to it. The next step taken by the clinician is to administer a synthetic analog of AVP. If this markedly reduces the patients polyuria, then the patient has neurogenic DI. He cannot produce AVP, but he can respond to it. Thus, the therapeutic effect of synthetic AVP. If the patient does not respond to AVP, then it may be concluded that he has nephrogenic DI.
Valtin emphasizes, however, that the water deprivation test is inconclusive in around 25% of DI patients. Generally, the problem lies in trying to distinguish partial neurogenic DI from dipsogenic DI. In these cases several measurements of urine osmolality over a longer period of time can clarify the diagnosis, though this is beyond the constraints of most medical centers.
Science has penetrated deeply into the molecular processes by which AVP is synthesized. It has mapped the AVP gene, (the gene that synthesizes AVP) as well as various mutations of the gene that interferes with the synthesis of AVP. Valtin's belief is that further research will enable scientists to pinpoint the exact point in the molecular process where a given mutation interferes with the production of vasopressin. They will then be able to develop a highly specific therapy for each mutation of the AVP gene that results in neurogenic DI.
Similarly, medical science now has a good insight into the molecular sequence, initiated by the binding of AVP with the V2 receptor, that allows the kidney to concentrate urine and maintain body water balance. It has a clear working model of the specific gene that, when mutated, interrupts this sequence and results in nephrogenic DI. Valtin predicts that since the molecular sequence which results in urine concentration and body water balance has many steps, there are likely to be other mutations discovered that interfere with the process. And he predicts that eventually specific therapies will be available for each of them.