What is NDI?
by Robert S. Wildin, M.D., Oregon Health Sciences University

What is NDI?
NDI stands for Nephrogenic Diabetes Insipidus.  It is a medical condition in which the kidney is unable to conserve water.

What are the symptoms?
The main symptoms are excreting large amounts of dilute urine ("polyuria"), and drinking large amounts of water ("polydipsia") to make up for the water lost in the urine. 

In infants, irritability, lethargy, fever, vomiting, constipation or diarrhea, seizures, and failure to gain weight can be seen, although they are also seen in many other conditions.

What are the complications?
Rapid and severe dehydration occurs when not enough water is drunk to make up for water lost in the urine.  The dehydration is usually "hyperosmolar," meaning that the concentration of the blood plasma gets too high.  If this happens rapidly, or if it is present for a long time, permanent brain damage can occur.  Poor nutrition and poor growth may be seen.  The great and constant flow of urine over many years can expand the ureters and the bladder, causing a variety of potential problems.  Death can occur with very severe dehydration.

Is it treatable?
Yes.  First, it is essential to provide free access to water at all times.   Water should be taken according to thirst, but infants may require a schedule of water supplements.  Of course, free access to restroom facilities is also necessary.

Beyond that, some drugs and drug combinations have been found to improve concentrating ability, reduce the rate of urine formation, and thereby decrease the requirement for drinking water.  Commonly used drugs include hydrochlorothiazide (HCTZ) and indomethacin.  HCTZ is sometimes combined with amiloride.  Other drugs with similar properties but different names have also been used.  DDAVP or desmopressin is generally NOT effective in NDI, though it is effective in a related disorder called central or neurogenic diabetes insipidus.  As with all medicines, you and your doctor should be familiar with the side effects of the drugs prescribed.  In addition, a diet high in protein and high in sodium may limit the ability of some drugs to reduce urine output.  At present, there is no cure for NDI.

What causes NDI?  Is it genetic?
There are several causes of NDI.  NDI that is present at or shortly after birth ("congenital NDI") is usually genetic.  It is due to permanent genetic changes that alter the kidney's ability to concentrate the urine.  Most commonly, the V2 receptor molecule that senses the presence of the concentrating hormone vasopressin, or AHD, is broken.  The gene that encodes this molecule is "X-linked," meaning that it is found on the "X" chromosome.  (Chromosomes are the packets of genetic instructions that are present in each of our cells.)  X-linked NDI is seen mostly in boys, who have only one X chromosome (and one Y chromosome).  Girls have two X chromosomes (and no Y), so even if they carry a broken V2 receptor gene on one of their Xs, the other is fine.  A girl who has one broken V2 receptor gene and one normal one is a "carrier" for NDI.  Carrier girls usually have no symptoms, but a normal genetic process called Lyonization means that some girls WILL have mild symptoms of NDI, and, rarely, they can be a severely affected as boys can.

A woman who carries the X-linked NDI gene has a 50:50 chance of passing it on each time she becomes pregnant.  If the baby is a boy, there is a 50:50 chance he will be affected (have NDI).  If the baby is a girl, there is a 50:50 chance that she will be a carrier like her mother.  The X-linked inheritance also means that EVERY daughter of a man with NDI will be a carrier, but none of his sons will be affected or carry the gene.

A second genetic form of NDI has been discovered, although it appears to be more rare.   In this case, the V2 receptor gene is normal, but the gene for making the kidney water channel, through which water is re-absorbed, is broken.  Since this "aquaporin 2" gene is not on the X or the Y chromosome, everyone, regardless of their sex, has exactly two copies of this gene.  In this case, an affected person has inherited a broken "aquaporin 2" gene from both of his or her carrier parents.   With this "autosomal recessive" form of NDI, girls are affected as often as boys.  A couple who has one child with this form of NDI generally will have a one-in-four chance (for each pregnancy) of having another child with NDI.

It is important to realize that a genetic form of NDI may be present even if no one else in the family has ever had it.  As you can see, the genetics of NDI is somewhat complicated.  You may wish to visit a Medical Genetics professional (a M.D. Medical Geneticist or a Genetic Counselor) to better understand the genetic issues in your case.   Your physician can refer you to one.  A blood test for carrier identification may also be available through the Medical Genetics professional.

NDI with symptoms that begin after infancy may be "acquired" (not genetic).   Several things may cause the kidney to loose its urine concentrating ability.   Certain kidney diseases and "systemic" disorders, such as amyloidosis, as well as

some medications (especially lithium) are the more common culprits.  Sometimes the NDI is reversible, at least partly, and sometimes it is not.   Like the genetic forms of NDI, people with these conditions may benefit from medical therapy for the NDI in addition to therapy directed at their primary condition.

What happens if I need hospitalization or surgery?
Whenever a person with NDI needs hospitalization or surgery, or is unconscious, or their intake is restricted in some other way, their caregivers must be aware of the NDI.   They must ensure that enough water is provided to avoid dehydration, and, as people with NDI know, this can mean A LOT of water!  Dilute I.V. fluids at high rates are necessary if the patient cannot take fluids by mouth.  Regular monitoring of the serum electrolytes is essential.  Consulting a specialist who is familiar with NDI is often helpful.  Some people feel that wearing a "MediAlert" bracelet will help alert emergency room doctors in case they are unable to express themselves in a medical emergency.

If severe dehydration does occur, extra water should be provided promptly, but the rehydration should be managed very carefully,  Serious problems can occur when the concentration of body fluids changes too rapidly.

My doctor has never had a patient with NDI.  What can I do?
NDI is rather rare: so many doctors may not see a case their entire career.   Consulting a specialist with experience with NDI, at least initially, can help you establish an effective management program and educate you and your primary care doctor about the condition.  You are likely to find NDI-knowledgeable doctors among the specialties of Nephrology, Endocrinology, and Metabolic Genetics.  Locating a physician comfortable with NDI can take some effort, but the benefits are worth it.

The Diabetes Insipidus Foundation, Inc. also publishes this brochure and provides networking with other families who have NDI.

What can I expect in the future?
With appropriate management and avoidance of situations where serious dehydration is likely to occur, most people with isolated NDI lead relatively normal lives.  By making minor adjustments, they can have friends, participate in athletics, complete school, hold down regular jobs, and even be an entrepreneur.  They can have families.   Subject to the complications mentioned above, the life span is expected to be normal.

Return to 4 Types of DI to read personal stories and articles about DI. Some of the information is common to all 4 types of DI, others are particular to a specific type of DI.