Arginine Vasopressin (AVP, also called vasopressin; originally known as antidiuretic hormone or ADH) has been mentioned as one regulator of plasma volume by its ability to concentrate urine via its action on renal distal tubule water reabsorption. It is produced by the posterior pituitary under the influence of centers in the anterior hypothalamus. Several factors influence production: blood osmotic changes (concentration and dilution, acting on osmoreceptors in the hypothalamus), blood volume changes, certain neural influences such as pain, and certain drugs such as morphine and alcohol. The two most important syndromes associated with abnormal AVP (ADH) are diabetes insipidus and the “inappropriate ADH” syndrome.

Diabetes Insipidus (DI) is a syndrome manifested by hypotonic polyuria. In spite of the name “diabetes,” it is not associated with diabetes mellitus, which produces a hypertonic polyuria (due to overexcretion of glucose). In general, there are three major etiologies of DI: neurogenic (hypothalamus unable to produce AVP [ADH] normally), renal (end-organ inability to respond normally to AVP [ADH], and temporary overpowering of the vasopressin system (ingestion of large quantities of water; sometimes called primary DI). Patients with DI are usually thirsty.

Before starting a test sequence to determine etiology, it has been recommended that the following preliminary tests be done—24-hour urine collection for volume, osmolality, and solute excretion and serum sodium, potassium, calcium, and osmolality—all under basal conditions (unrestricted diet and water intake). The goals are to determine if polyuria exists (urine output over 2000 ml/day); if so, whether the urine is hypotonic (urine osmolality below 300 mosm/kg; literature range, 200-300 mosm/kg). If results show excess urine output that is hypotonic, the patient could have DI. Then the solute content per day should be measured. If the solute excretion is not increased (i.e., is less than 20 mosm/kg/day) the patient does not have a solute-induced diuresis and definitely qualifies for the diagnosis of DI. However, other relatively common etiologies for polyuria should be excluded, such as osmotic diuresis (glucose, NaC1, mannitol,) diuretics, hypokalemia, hypercalcemia, drug-induced (lithium, chlorpromazine, thioridazide), sickle cell disease, pregnancy-induced DI, severe chronic renal disease, or after acute tubular necrosis or renal transplantation. If the serum sodium or calcium level is high, this condition should be corrected before doing provocative tests. It is also necessary to stop any medications affecting AVP (ADH) secretion, all tobacco or alcohol use, and all caffeine-containing beverages at least 24 hours before and during the test. One investigator recommends blood osmolality measurement be done on plasma collected with heparin anticoagulant and tested using the freezing point depression method for best accuracy.

The standard diagnostic procedure in DI is the water deprivation (dehydration) test. Although the basic procedure is followed throughout the literature, some details vary (such as the exact criteria for maximum dehydration, the minimum urine osmolality value acceptable as a response to maximal fluid-restriction dehydration, and the details of preparation for and starting the test. There are other test protocols in the literature to disclose etiology of DI; two of these will be presented, as well as the water deprivation test.

1. Baseline serum osmolality and sodium levels that are high normal or elevated—serum osmolality over 295 mosm/kg (some investigators use 288 or 290) or sodium level over 143 mEq/L (mmol/L), with low urine osmolality (less than 300 mOsm/kg; literature range, 200-300)—are strong evidence against primary water-intake DI. The next step recommended is to inject subcutaneously either 1 µg of DDAVP (desmopressin, a synthetic analog of AVP) or 5 IU of AVP (vasopressin or ADH) and collect urine samples 30, 60, and 120 minutes afterward. If the highest urine osmolality after vasopressin is less than 50% higher than the baseline urine osmolality value, this suggests nephrogenic DI. If the result shows increase equal to or greater than 50%, this suggests neurogenic DI.

2. It is also possible to differentiate between neurogenic, nephrogenic, and primary water intake etiologies for DI using administration of DDAVP for 2-3 days in a hospital with close observation. In patients with hypothalamic (neurogenic) DI there should be substantial decrease in thirst and urine output. In renal (nephrogenic) DI (primary polydipsia), there should be substantial decrease in urine output but increasing hyponatremia and body weight (due to continued high fluid intake). Although the simplicity of this test is attractive, it may be hazardous (especially in patients with primary polydipsia) and results are not always clear-cut.

3. In the water deprivation test, the duration of water restriction is based on the degree of polyuria. The greater the output, the greater need for close supervision of the patient to prevent overdehydration. Patients with urine output less than 4000 ml/24 hours undergo restricted fluid after midnight; those with output greater than 4000 ml/24 hours begin fluid restriction at the time the test begins. Body weight and urine osmolality are measured hourly from 6 A.M. to noon or until three consecutive hourly determinations show urine osmolality increase of less than 30 mosm/kg (of H2O). The procedure should be terminated if body weight loss becomes more than 2 kg. When urine osmolality becomes stable, plasma osmolality is obtained. Osmolality should be greater than 288 mosm/kg for adequate dehydration. If this has occurred, 5 units of aqueous vasopressin (or 1 µg DDAVP) is administered subcutaneously. A urine specimen for osmolality is obtained 30-60 minutes after the injection. In central DI, there should be a rise in urine osmolality more than 9% of the last value before administration of vasopressin. In polyuria from nephrogenic DI, hypokalemia, or severe chronic renal disease, there is usually little increase in osmolality either during the dehydration test or after vasopressin administration. Patients with primary polydipsia frequently take longer than usual to dehydrate to a serum osmolality over 288, and urine osmolality rises less than 9% after vasopressin administration.