What is diabetes insipidus?

Diabetes Insipidus

What is diabetes insipidus (DI) and why do we get it?
Diabetes insipidus (DI) is caused by a problem with either the production, or action, of the hormone vasopressin (AVP). If you have DI your kidneys are unable to retain water. This leads to the production of large volumes of urine and, in turn, greatly increased thirst. DI can occur at any age, but is mostly found in adults. It is a rare disorder, affecting only about 1 in 25,000 people.

To understand DI we need to understand a little about how the body regulates water balance - the difference between how much water the body takes in and how much it passes out. Water balance is very important for the body. A large proportion of what we are is made up of water. In addition, the amount of water we have in our circulation is a large factor in determining the balance of salt in our bodies. As with any function that is important, the body has a sensitive mechanism for regulating water balance. Like any good mechanism it is also simple, involving two key components:
• Vasopressin (AVP or ADH - antidiuretic hormone) - which regulates the amount of water passed out of the body in urine.
• Thirst and drinking - which determines the amount of water the body takes in.

AVP (sometimes called Anti-diuretic hormone or ADH) is a hormone released from the rear most part of the pituitary gland (the posterior pituitary). This gland is located at the base of the brain, and is about 3 to 5 centimetres behind the bridge of the nose. AVP circulates in the bloodstream and acts on the kidneys to reduce the amount of water that is passed out in urine.

How AVP and thirst work together is best described with the help of the bath tub analogy. As with a bath tub, the body likes to keep the level of water it contains at the right level for its purposes. There are only two ways the level of water can be altered:
• Water can be let in to the bath through turning the taps on; just as thirst and drinking can allow more water into the body 4 Diabetes insipidus
• Water can be let out of the bath through taking the plug out; just as the body can let more water out by reducing the amount of AVP produced and so letting more water to be passed out of the body as urine

Unlike a bath tub, the body is very good at sensing the level of water it has on board. If it does not have enough and is dehydrated, it triggers us to drink more through activating the thirst (turning on the taps). At the same time, it makes more AVP and so reduces water loss in urine (it puts the plug in). On the other hand, if the body senses the level of water is too much, it turns the thirst off (turning taps off) and makes less AVP (taking the plug out of the plug hole). The level of water is therefore maintained through a combined approach.

Together, AVP and thirst maintain water balance very effectively in both situations where water is either easy to find, or is scarce. DI occurs when this mechanism regulating water balance breaks down.

The two forms of diabetes insipidus (DI)
1. Cranial diabetes insipidus (CDI)
CDI is caused by the partial or absolute lack of AVP. The lack of AVP means that the kidneys cannot retain the amount of water that the body needs them to, and produces a lot of dilute urine. The body is therefore reliant on only one of its two mechanisms to keep the amount of water in the body at the correct level, thirst and drinking. People with CDI are thirsty all of the time; they pass large amounts of urine frequently through the day and often have to pass urine several times at night.
Sometimes CDI occurs on its own and however in many cases, it is accompanied by loss of other hormones made by the pituitary. This may be through a problem in the development of the pituitary gland; a tumour within or near the gland; or the result of an accident, or surgery to, or near to, the gland.
CDI following pituitary surgery may be temporary, only lasting a week or two. In some cases it may be permanent.

2. Nephrogenic diabetes insipidus (NDI)
NDI is a condition in which the kidneys do not respond to the normal signal (AVP) to reduce water loss. Thus, the kidneys are not able to absorb the water that passes through them.
The primary symptoms of NDI are polyuria (passage of large volumes of urine) and polydipsia (excessive thirst and drinking).

Inherited NDI may show up in the first weeks of life. Symptoms can include irritability, failure to thrive, lack of appetite and vomiting. Investigation can reveal high blood levels of sodium. Up to 90% of the cases of inherited NDI are the result of mutations affecting the AVP-receptor (V2R) that is needed for the kidney to respond to AVP and reabsorb water. The remaining cases are the result of mutations in the pore in kidney cells through which water is reabsorbed (AQP2). Though each type of inherited NDI has a different genetic cause, the symptoms of each are the same.

Males are the most likely to display symptoms of X-linked NDI, whereas males and females are equally likely to display symptoms of the autosomal recessive form of NDI. This is because the V2R gene is carried on the X-chromosome and males have only one X-chromosome. A problem with a gene on this single X-chromosome can’t be counter-balanced by another normal X-chromosome (the position in females). Autosomal recessive NDI is carried on a non-sex chromosome, so males and females are equally likely to inherit the problem.

Acquired NDI is the more common form of NDI and can occur at any time of life. Most often, acquired NDI is a result of the use of the drug lithium. Acquired NDI can also result from the use of other drugs, such as colchicine, methoxyflurane, amphotericin B, gentamicin, loop diuretics and demeclocycline. It can also occur as a result of certain diseases and physical conditions, which can result in either permanent or temporary NDI such as:
• chronic kidney failure
• other kidney diseases
• abnormally low levels of potassium
• abnormally high levels of calcium
• sickle cell disease 6 Diabetes insipidus
• And rarely, during pregnancy

Treatment of NDI
There is as yet no cure for inherited NDI. Currently, NDI is managed by:
• ensuring ready access to water
• following a low-sodium (and sometimes lowprotein) diet, and
• using thiazide diuretics, alone or in combination with a prostaglandin inhibitor or a potassium-sparing diuretic, to reduce the volume of urine output.

Thiazide diureticscan reduce an NDI patient's polyuria, but they may also deplete the body's stores of potassium. This depletion can cause other symptoms and may be dangerous. When taking thiazide diuretics, the patient's potassium levels must be monitored. To maintain sufficient potassium in the body, the addition of potassium supplements or amiloride (but not both) to the treatment regime may be required.

DI is not related to diabetes mellitus
It is very important to point out that DI is not related to the type of diabetes most people have heard of - diabetes mellitus which is very common and can also cause symptoms of passing a lot of urine and being thirsty. In DI, there is NO problem with the level of sugar in the blood or urine. This is very important as friends, relatives and health care workers may make assumptions about the condition you have, based on the more common condition.

What does it feel like to have DI?
The main symptoms that you will feel are thirst (no matter how much you drink) and the need to pass urine very frequently, even during the night. You will pass large volumes of urine; you may pass as much as 4 - 10 litres of urine a day. It is important that you do not try to prevent this by ignoring your thirst and drinking less, or you will disturb the balance of water in your body.

You may well have symptoms of dehydration, for example feeling shivery and nauseous with headaches. People with DI have mentioned that their excessive thirst can be compared with eating 4 or 5 dry cream crackers one after the other, without any drinks.

Most patients do have a thirst mechanism, but a few patients don’t. This is called HYPODIPSIA. The combination of DI and hypodipsia is unusual and requires special attention from patients, carers and doctors.

How is it diagnosed?
What tests are carried out and how will these feel?
Investigation methods for patients with excessive urine production would be:
• Measurement of 24 hour urine output
• Measurement of plasma osmolality from a blood test (a measure of sodium and glucose circulating in the blood)
• Water deprivation test (described below)
• Therapeutic trial of desmopressin (DDAVP®)

The water deprivation test deprives you of fluid for 6-8 hours to see if there is a reduction in the volume of urine. You can expect to feel quite thirsty during this test. The next stage is to give you a small quantity of desmopressin, usually as an injection. If you have CDI, you should notice a reduction in the amount of urine you pass. This shows that your kidneys are responding to the hormone.

 If you have NDI, this response does not occur or is impaired, as the kidneys don't recognise the effect of the hormone in small doses. Once you are allowed to drink again, you will begin to feel better. If you need other hormone treatments, you will need to continue taking them during the test. This test can be performed as a day case.

How is DI treated?
CDI is treated with an AVP-like like drug called desmopressin or DDAVP®. This medication acts specifically on the kidneys in the same way as natural AVP, though it lasts longer than natural AVP as it is more resistant to breakdown.

 A variety of different preparations are available, each of which is given by a different route: injection, nasal drops, nasal spray, tablets to be taken and swallowed, or oral lyophilisates (wafers that melt in the mouth). All are effective and it is a matter of finding the best match for each individual, based on preference and lifestyle. The spray and the tablets are popular choices. Depending on the severity of the DI, these are generally taken between 1 - 3 times a day; some people have to take the medication 4 times a day. Doses vary between people, again based partly on degree of their symptoms. An ideal aim is for a patient to pass around 2 litres of urine over 24 hours whilst taking their desmopressin. A good test of satisfactory management of fluid levels is to weigh yourself each morning. A varying body weight on a day to day basis can help you monitor fluid balance when you start treatment. Remember that 1 litre of water weighs 1 kilogram.

Treatment has remarkably few side effects. Those who use the nasal spray may find some problems with the drug working when they have a heavy cold. Some people who use the tablets, find they work less well when they have an upset stomach. Some people can run into problems if the balance of treatment means that they are taking in more water than they are passing out; this can lead to the gradual development of water overload and a drop in the level of sodium in the blood stream (hyponatraemia). This is best addressed by re-balancing treatment by looking at how much desmopressin is given and how much fluid is being taken in. You will gradually feel better once you are taking desmopressin. Overall, the treatment of DI is straightforward, but if you are experiencing any difficulty controlling your DI please do talk to your endocrinologist.

Please note that DesmoMelt®, although of the same preparation as DDAVP® Melt, is the product brand name for children or adults who have enuresis, not diabetes insipidus.

Generic Versions of desmopressin It has come to our notice that there are generic substitutions available for the Ferring DDAVP® range of diabetes insipidus medication. These generic Diabetes insipidus 9 Aftercare substitutions might present some differences in patients than their usual DDAVP® brand, especially for those who have no thirst mechanism, or for children.

Adults with DI may find that they ‘break through’ earlier, (with more thirst and urine output) or perhaps later (with less thirst and urine output) than they did when taking, and stabilised, on desmopressin.

 Parents with children with DI should look out for any change in behaviour (more/less thirst/ urine or simply a personality change - tiredness, grumpiness etc.) which might represent a change in total water balance and a change in serum sodium which will need urgent checking.

Many will find no difference, but some might. If your prescription (or your child’s prescription) is changed to a generic version, and you/your child experience less stability with the medication, then we encourage you to contact your GP or endocrinologist for advice.