What causes NDI?

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Topic: NDI: An Overview
Author: Bichet, Daniel G.
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Inherited mutations of either the vasopressin-2 gene or the aquaporin-2 gene are one, though rare, cause of NDI. More frequently NDI is caused by use of certain prescription drugs or an underlying physical condition or systemic disease or disorder.

Long-term lithium use is the most common cause of acquired NDI. Lithium is widely used to help manage certain psychological bi-polar disorders such as manic depression. Approximately one American per thousand is on lithium treatment. Of these, between 20 to 40% develop polyuria (the chronic passage of large volumes of urine that is one of the two main symptoms of NDI), and up to 12% develop NDI.

Other drugs which can also result in NDI are: colchicine, methoxyflurate, amphotericin B, gentamicin, loop diuretics, methicillin, vinblastine, furosemide, foscarnet, cidofovir, certain anticancer drugs, angiographic dyes and demeclocycline.

Electrolyte disturbances such as excessively low plasma levels of potassium or abnormally high plasma calcium levels can result in NDI. Other systemic disorders that can cause NDI include sickle cell anemia, sarcoidosis, amyloidosis, Franconi syndrome, Sjogrens syndrome, chronic kidney failure and kidney diseases.

Pregnancy can sometimes induce a temporary case of NDI.

The ureters are fibromuscular tubes that extend from the kidney to the bladder. Urine from the kidneys flows through them to the bladder. There are two of them, one for each kidney, and sometimes one or both of them can become blocked. Once the blockage(s) are removed, a patient will often experience transient NDI.

Compulsive water drinking can cause NDI, as can a low protein and/or low-sodium diet. This last statement requires some explanation because a low-sodium and, sometimes, low-protein diet is recommended to help reduce an NDI patient's polyuria. Dr. David Marples explains how a low-sodium and low-protein diet can be both a cause of, and a treatment for, NDI.

Marples says that people on low-protein diets generally are not able to concentrate their urine as much as people with more protein in their diet. This is because they have lower levels of urea, a by-product of protein metabolism, stored in their kidneys. Since urea stored in the inner portion of the kidney helps create the proper osmotic conditions for the kidney to be able to concentrate urine, less urea means less concentrated urine. People on low protein diets also produce less AQP2s, the water channel in the kidney collecting ducts that helps produce concentrated urine by allowing the kidney to reabsorb the body water flowing through the collecting ducts.

However, NDI caused by a low-protein diet is not a big problem because the osmotic conditions partially created by urea are used to generate the excretion of urea. So if the person on a low-protein diet has little urea to get rid of, the weakening of the osmotic conditions needed to excrete urea is not that important. If a person's NDI is caused by something other than a low-protein diet, then he or she will produce lots of dilute urine. This will wash away urea anyway, preventing it from helping generate the osmotic conditions for urine concentration. In this case, eating a low-protein diet will not cause any additional problems. In fact, by eating a low-protein diet, the patient will produce less urea and therefore will need less water to carry it from the body. Though this probably has only a minor effect, it does reduce the NDI patient's urine volume a little. The primary beneficial effect of reducing protein intake is that it can reduce the demands placed on other parts of the kidney (mainly the proximal tubule), and this may help extend the kidney's functional ability.

Salt is the other major solute (along with urea) used to generate the osmotic conditions in the inner portion of the kidney necessary for urine concentration. Thus a low-sodium diet could prevent the generation of the required osmotic conditions. However, if a patient has NDI from some other cause, his or her excessive dilute urine will wash out the osmotic gradient needed for urine concentration anyway, so it would not make any difference, as far as generating the required osmotic conditions goes, if the NDI patient was on a low-sodium diet or not. But researchers and clinicians agree that a low sodium diet can help modify the NDI patient's abnormally high urine because less salt in the body translates to less salt in the urine. Since salt requires water (urine) to be carried from the body, a lower salt intake means a reduction in urine flow.

More importantly, if the NDI patient reduces his sodium intake, he will be relatively salt-depleted, and his body will try harder to retain what salt he has by absorbing it more actively in another part of the kidney. This results in more body water being reabsorbed at this part of the kidney, which means less body water will reach the collecting duct - the place in the kidney where the misfunction occurs that results in NDI. Therefore, there will be less urine.