FAQs

Author: Bichet, Daniel G.

Assuming you are otherwise healthy, there is no reason having either acquired or inherited NDI can prevent you from having children. If you have acquired NDI, your children are not going to get NDI from you. If you have inherited NDI, then there is a statistical probability that some of your children will inherit NDI.

One form of inherited NDI is inherited in what is called an X-linked recessive pattern. This means that the mutated gene responsible for this form of NDI, the mutated vasopressin-2 receptor gene, is carried on the X chromosome. Females have two X chromosomes; males have one, which they inherit from their mother. So, if the mother carries a mutated X chromosome on one of her two X chromosomes, and her son inherits the mutated X chromosome, then he will express the symptoms of NDI. The reason the mother often does not express the complete symptoms of NDI is that she has another X chromosome with a healthy vasopressin-2 receptor gene that helps produce healthy vasopressin-2 receptors. This often masks the effect of the mutated vasopressin-2 receptor gene on her other X chromosome.

So, if the mother is an NDI carrier and the father does not have inherited NDI, they have a 1 in 4 chance of having an unaffected boy, a 1 in 4 chance of having a boy with NDI, a 1 in 4 chance of having an unaffected girl, and a 1 in 4 chance of having a girl who carries the mutated vasopressin-2 receptor gene on one of her X chromosomes.

The other known form of inherited NDI is caused by a mutation of the aquaporin-2 gene. This gene is carried on chromosome 12, which is an autosomal chromosome. This means that the gene is carried equally by both males and females. Normally, this form of NDI is inherited in an autosomal recessive pattern, which means that one of the two chromosome 12’s carried by both the mother and the father must bear a mutated aquaporin-2 gene for their child to have a probability of being born with this form of NDI. Each of the children of the carrier mother and father stand a 1 in 4 chance of being born with NDI. And each of the children stand a 2 in 4 chance of being a NDI carrier.

X-linked NDI is rare, occurring in approximately 4 out of a million males. Autosomal recessive NDI is much more rare. And rarest of all is autosomal dominant NDI. In autosomal dominant NDI only one parent has to carry a mutated aquaporin-2 gene for their children to have a probability of being born with NDI. Each of the children of this couple stands a 1 in 2 chance of inheriting the defective aquaporin-2 gene and being born with NDI.

If your family lineage has had any sort of history of inherited NDI, you may wish to have a mutational analysis performed to see if you carry either a mutated vasopressin-2 receptor gene (females) or a mutated aquaporin-2 gene (males and females).

Author: Knoers, Nine

In infancy and early childhood, children with NDI tend to be slightly smaller and to weigh less than children their age. However, and this is especially true with those children who have received treatment early in life, NDI children tend to physically mature into adults of normal weight and of slightly below normal height. On average, NDI children grow into adults that fall within the normal weight range and slightly below the 50th percentile in the height range, the 50th percentile being where most people fall in terms of height. A simple way to put this is that the NDI child will probably fall just a little bit below the height that they normally should have reached. They tend to be just a little bit shorter than their parents.

Author: Wildin, Robert

There are many forms of DI: nephrogenic DI, neurogenic DI and primary polydipsia. Neurogenic DI is caused when the hypothalamus does not produce or secrete the antidiuretic hormone, arginine vasopressin (AVP). Primary polydipsia, a chronic intake of excessive volumes of water, remains a mystery as to its causes, which are often attributed to some type of psychological imbalance.

However, if the type of DI you are talking about is nephrogenic DI (nephrogenic diabetes insipidus or NDI), and specifically the molecular basis of inherited NDI, then researchers have to date found two genes, either of which, when mutated, can cause NDI. By far, the most common cause of inherited NDI is a mutation of the vasopressin-2 receptor(V2R) gene. This form of NDI is called X-linked NDI because the V2R gene is carried on the X chromosome.

The V2R is a receptor protein that the hormone AVP must bind with in order to start the molecular sequence which allows the kidneys to reabsorb most of the body water that flows through them and to concentrate urine. This is how the kidneysmaintain body water balance.

When the V2R is defective due to a mutated AVPR2 gene, (the AVPR2 gene makes the V2R) AVP cannot bind with it, and NDI results. The V2R gene is carried on the X chromosome. The X chromosome is known as the female sex chromosome, as females have two, and males have only one. Females, then, have a V2R gene on each of their X chromosomes, so they have a pair of V2R genes. If one of those V2R genes is mutated, they have another V2R gene on their other X chromosome that may not be mutated. V2R gene mutations are recessive, which means both the V2R genes a person inherits would have to be mutated in order for NDI to express its symptoms: chronic, excessive urination and thirst.

Males only have one X chromosome, which they inherit from their mother. So if the mother had a mutated V2R gene on one of her chromosomes, and that is the chromosome her son inherits from her, then he will express the symptoms of NDI because he has not inherited any other X chromosome that might carry a normal V2R gene. That is why, in X-linked NDI, the general inheritance pattern is this: females can carry the mutated V2R gene and pass it on to their sons who will express NDI. The sons, in turn, will pass on the gene to all of their daughters and none of their sons.

Females who carry the mutated V2R gene can express the symptoms of NDI to varying degrees but rarely as severely as do their sons. The reason they can express lighter symptoms is because the normal V2R gene may not be able to completely compensate for the mutated one. All of a female’s X chromosomes in the cells in excess of one are inactivated by some unknown process called X-inactivation. In some cells, the X chromosome with the NDI gene is inactivated. These cells are normal. In other cells, the X chromosome with the normal gene is inactivated. Since the NDIX chromosome remains active, and is the only active X, these cells are just like the ones in boys with NDI. Most carrier females have little to no symptoms because having half of their cells expressing the normal X chromosome is sufficient. But some females are unlucky and have, by random chance, any fewer than half of their cells expressing the normal X. These women have varying degrees of symptoms.

The other gene that, when mutated, causes NDI is the gene that produces aquaporin-2 (AQP2), a water-transporting protein that helps the kidney reabsorb water and concentrate urine. The AQP2 gene is carried on a non-sex chromosome (chromosome 12), so that it is carried by both males and females. A baby will inherit one AQP2 gene from his or her mother, and one from the father. A mutated AQP2 gene is recessive; that is, if only one of a person’s AQP2 gene pair is mutated, that person will not express the symptoms of NDI. However, if the baby inherits a mutated AQP2 gene from both mother and father, then both of the baby’s AQP2 gene pairs are mutated and the baby will express the symptoms of NDI.

The most likely explanation is that the father had X-linked NDI. He passed the gene on to his daughter, who had symptoms because more of her cells expressed the NDI X chromosome than the normal one. She passed on her NDI X chromosome to her son, who has NDI.

Alternatively, the family could have neurogenic (central) NDI, which is sometimes passed through families without regard to sex.

Author: Knoers, Nine

Children with NDI usually begin puberty within the normal age range.

Author: Robertson, Gary

To my knowledge, NDI and hydrocephalus of the brain are not related. However, NDI can cause hydronephrosis of the kidney.

Author: Wildin, Robert

NDI is predominantly seen in boys. However, it can be seen in girls under two genetic circumstances. The X-linked form generally restricted to boys can also exist in girls in varying degrees of severity, even as severe as the boys’. This apparently occurs as a result of skewed X-inactivation. You can read about this in Nomura’s Detection of Skewed X-inactivation in Two Female Carriers of Vasopressin Type 2 Receptor Gene Mutation and in van Lieburg’s Clinical Phenotype of Nephrogenic Diabetes Insipidus in Females Heterozygous for a Vasopressin Type 2 Receptor Mutation.

However, a second genetic form of NDI exists that is autosomal recessive and due to defects in Aquaporin-2, the water channel protein. In the United States, this form is rarer. Most of the cases reported in the literature so far have occurred in the context of consanguinity, i.e., parents who are genetically related.

I assume that the case you describe has no prior family history of NDI. I would say that if there is no chance that your girl’s parents are genetically related, then heterozygosity for the X-linked form (vasopressin receptor defect) is somewhat more likely, but if there is any suggestion of possible consanguinity, then one should look for Aquaporin-2 mutations.

Author: Knoers, Nine

The number of NDI patients is not exactly known. It is estimated that between one in 100,000 and one in 500,000 are born with the disease.

Author: Robertson, Gary

It is not clear if you mean two mutations in the same gene or one mutation in two different genes. The first is rare. The second is less rare but still uncommon.

Author: Bichet, Daniel G.

NDI renders the kidneys unable to reabsorb the body water flowing through their collecting ducts by disrupting their ability to balance body water. Body water that should be reabsorbed is instead voided as dilute urine. This could lead to severe dehydration, which is a life-threatening condition. Fortunately, all that is needed to prevent dehydration is ready and reliable access to water. This may require careful planning for youngsters, but it is definitely doable.

Infants born with NDI begin to manifest its symptoms in the first days of life. NDI’s two primary symptoms, polyuria and polydipsia, can be difficult to detect in an infant, and the NDI infant cannot communicate his increased need for water in words. But there are other symptoms that can alert the parent or caregiver to the possibility that their infant may have NDI and therefore need much more water intake than normal.

The NDI infant may be irritable, feverish, or constipated. He or she may fail to thrive, vomit often, be anorexic, and prefer water to milk. Should the infant’s polyuria go unnoticed and untreated, he or she may suffer severe bouts of dehydration, which result in excessively high plasma sodium levels. This could cause mental and physical retardation, and even death. Extreme as these conditions are, Dr. Bichet, one of the world’s leading NDI researchers and treatment specialists, has observed that as long as the NDI infant has adequate and timely access to water, he or she can experience normal development and a normal life span.

Elderly people with NDI also require careful monitoring. They may not be able to communicate their need for water either. And sometimes they become less sensitive to their thirst. Elderly patients suffering from dehydration can be more prone to infection, kidney failure, confusion, lethargy, constipation and decreased skin turgor.

Whether the patient is an infant or an elderly person, clinicians can check the patient’s plasma sodium level. If it is abnormally high, it may indicate dehydration.

Author: Knoers, Nine

The disorder and its symptoms remain the same, but NDI may seem easier for adults to manage simply because they have finished physically developing and their physiology remains relatively more stable. Also, a child may have more difficulty managing their diet, medication and fluid balance simply because they are children and have many distractions, so their parents, of course, will be the ones to keep track of their child’s medication and fluid balance.

Author: Knoers, Nine

If a woman is certain she is an NDI carrier, then, unfortunately, the only certain way of not passing on the NDI gene is to not have children. If a woman is certain she is an NDI carrier and she is pregnant, she can have a prenatal diagnosis to determine if her unborn child is carrying the NDI gene. It is also suggested that the mother seek family counseling to help her prepare for a child born with NDI.

Author: Bichet, Daniel G.

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 ureaare 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.

Most generally, the nature of the defect in the AQP2 gene (whether inherited in the recessive or dominant mode) results in AQP2’s that are not allowed out of the endoplasmic reticulum (ER) because they are improperly folded. Since the defective AQP2’s cannot leave the ER, they cannot travel to the apical membrane. Since they cannot get to the apical membrane, they cannot insert themselves into it in order to increase the apical membrane’s water permeability. Please refer to the information on our site dealing with AQP2 for further details.

Author: Knoers, Nine

It is estimated that between one in 100,000 and one in 500,000 infants will be born with NDI.

Author: Robertson, Gary

A male with the x-linked type of NDI cannot pass it to any of his sons, but he can pass it to his daughters who will be carriers but probably will have little or no sign of the disease. A male with the autosomal recessive type of NDI can pass the mutant gene to either a son or daughter but neither is likely to get the disease. If he has the dominant type (very rare), he can pass the gene and the disease to either a daughter or son.

Author: Bichet, Daniel G.

Nephrogenic diabetes insipidus (NDI) can either be acquired or inherited. If a person has inherited NDI, that means one of two genes, either his vasopressin-2 gene or his aquaporin-2 gene, is mutated and as a result his kidneys cannot reabsorb the body water flowing through his kidney collecting ducts. This type of NDI will not go away because the mutated gene responsible for disrupting the water reabsorption process will not go away. Most acquired forms of NDI, however, can be healed.

Researchers have learned a great deal about the molecular sequence underlying the water reabsorption process and a great deal about the nature of the mutations that result in NDI. Their knowledge gives them ground to speculate that the means for reversing NDI – making it go away – might be discovered one day in the next decade. The cure may come through genetic therapy, manipulating the mutated gene responsible for inherited NDI so that the protein it encodes and helps create will be able to function properly. Or the cure may come through a more complete knowledge of the molecular sequence involved in the water reabsorption process and the cellular mechanics supporting it. Some researchers suggest there may be other molecular sequences involved in the water reabsorption process. If this proves true, then one day researchers might be able to discover how the alternative molecular sequence can more fully take over for the disrupted molecular process that results in NDI. But for now, inherited NDI can only be managed, not cured.

Sometimes NDI occurs as a result of a more basic, underlying systemic disorder such as sickle cell anemia. If the systemic disorder or disease cannot be reversed, then the resulting NDI cannot be expected to stop.

Acquired NDI, however, can go away. Lithium-induced NDI, the most common form of acquired NDI, can slowly reverse itself once lithium is discontinued. This may take many weeks or months, and in some cases, does not go away at all. But in most cases, the NDI does stop. The benefits of lithium to control certain psychiatric diseases might be superior to the symptoms and signs of lithium-induced nephrogenic diabetes insipidus.

Sometimes the NDI-inducing underlying systemic disorder may be an electrolyte disturbance such as abnormally high levels of plasma calcium (hypercalcemia) or abnormally low levels of plasma potassium (hypokalemia). These disorders are sometimes more easily correctable. And as they are corrected, the NDI is reversed.

NDI that occurs after unilateral or bilateral ureteral obstructions have been reversed will also go away on its own after several weeks. Occasionally, NDI occurs during pregnancy. This too, is transient and will reverse itself after the pregnancy. NDI caused by dietary abnormalities is reversible once the diet becomes balanced again.