What is Arginine Vasopressin Deficiency (AVP-D)?

AVP Deficiency, formerly known as Diabetes insipidus (DI), is caused by a problem with either the production, or action, of the hormone vasopressin (AVP). If you have AVP-D your kidneys are unable to retain water.

This leads to the production of large volumes of urine and, in turn, greatly increased thirst. AVP Deficiency can occur at any age, but is mostly found in adults. It is a rare disorder, affecting only about 1 in 25,000 people.

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. AVP Deficiency occurs when this mechanism regulating water balance breaks down.

AVP Resistance

AVP Resistance is not a pituitary condition, but it is similar to AVP Deficiency. In this condition 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 AVP Resistance are polyuria (passage of large volumes of urine) and polydipsia (excessive thirst and drinking).

Inherited AVP Resistance 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 AVP Resistance 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 AVP Resistance has a different genetic cause, the symptoms of each are the same.

Males are the most likely to display symptoms of X-linked AVP Resistance, whereas males and females are equally likely to display symptoms of the autosomal recessive form of AVP Resistance. 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 AVP Resistance is carried on a non-sex chromosome, so males and females are equally likely to inherit the problem.

Acquired AVP Resistance is the more common form of AVP Resistance and can occur at any time of life. Most often, acquired AVP Resistance is a result of the use of the drug lithium. Acquired AVP Resistance 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 AVP Resistance 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

AVP Deficiency Symptoms

What are the symptoms of AVPD?

AVP Deficiency, also known as 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.

Excessive thirst and need to pass urine.

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

Other symptoms include:

• Urine is very pale, possibly clear and doesn’t concentrate
• Preference of icy cold drinks
• Headaches (which may be due to dehydration)
• Exhaustion
• Shivering
• Nausea
• Dehydration symptoms: parched mouth, cracked lips, coated tongue, dry eyes and dry skin
• Most foods intolerable with a preference to drink fluids
• Weight loss

AVP Deficiency (diabetes insipidus) diagnosis

AVP Deficiency, also known as Diabetes insipidus (DI) is caused by a problem with either the production, or action, of the hormone vasopressin (AVP). If you have AVP Deficiency your kidneys are unable to retain water.

Diagnosis

There are a number of tests for AVP Deficiency which can lead to a diagnosis. AVP Deficiency is also known as diabetes insipidus and people with this condition often have excessive urine production.

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)

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.

AVP Deficiency Treatment

AVP deficiency, previously known as diabetes insipidus (DI) is caused by a problem with either the production, or action, of the hormone vasopressin (AVP). If you have AVP deficiency your kidneys are unable to retain water.

How is AVP deficiency treated?

AVP deficiency is treated by the drug desmopressin, also known as DDAVP®, which people usually have to take multiple times a day.

This medication mimics AVP and 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 being broken down by the body.

How should I take my medication?

A variety of different preparations of this drug are available, each of which is given by a different route. These routes include:

• Injection
• Nasal drops
• Nasal spray
• Oral tablets
• Oral lyophilisates (wafers that melt in the mouth)

All methods are effective and it is a matter of finding the best match for you, based on preference and lifestyle. The spray and the tablets are popular choices. Depending on the individual, medication is generally taken between 1 and 3 times a day. Your endocrinologist will advise you on how to dose your medication. Injections are usually given only in hospitals, for those who can’t take their usual oral or spray desmopressin.

How often you take your medication can vary depending on the severity of your symptoms. An ideal aim is for a you to pass around 2 litres of urine over 24 hours, whilst taking your 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.

What does ‘breakthrough’ mean and how does this effect me?

‘Breakthrough’ is a term that a number of people with AVP deficiency use. It is the period when your previous dose of desmopressin medication has run out and you see a return in symptoms, such as excessive passing of urine (urine colour becomes paler) and an excessive thirst starts. This means that your next desmopressin dose is due. Earlier breakthrough can sometimes occur several hours before your expected next normal dose is due.

Experiencing ‘breakthrough’ can be unpleasant but it can be very helpful for you. It offloads any excess fluid which can help manage your sodium levels, and it confirms that your next desmopressin dose is due.

Are there any side effects of treatment?

Desmopressin 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 AVP deficiency is straightforward, but if you are experiencing any difficulty controlling your condition 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 AVP deficiency.

Generic versions of desmopressin

There are generic substitutions available for the Ferring DDAVP® range of AVP deficiency medications. 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 AVP-D 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 were stabilised on, desmopressin.

Parents of children with AVP-D 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 checking urgently.

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