vasopressin (antidiuretic hormone [ADH]) due to a hypothalamic-pituitary disorder. Polyuria and polydipsia develop. Diagnosis is by water deprivation test showing failure to maximally concentrate urine; vasopressin levels and response to exogenous vasopressin help distinguish argininevasopressin deficiency from argininevasopressinvasopressin-releasing medications, such as chlorpropamide.
(See also Syndrome of Inappropriate ADH Secretion and Nephrogenic Diabetes Insipidus [ArginineVasopressin Resistance].)
Pathophysiology of ArginineVasopressin Deficiency
Vasopressin acts primarily to promote water conservation by the kidneys by increasing the permeability of the distal tubular epithelium to water. At high concentrations, vasopressin also causes vasoconstriction. Like aldosterone, vasopressin plays an important role in maintaining fluid homeostasis and vascular and cellular hydration. The main stimuli for vasopressin release are
Increased osmotic pressure of water in the body (sensed by osmoreceptors in the hypothalamus)
Volume depletion (sensed by vascular baroreceptors)
The posterior lobe of the pituitary is the primary site of vasopressin storage and release, but vasopressin is synthesized within the hypothalamus. Newly synthesized hormone can still be released into the circulation as long as the hypothalamic nuclei and part of the neurohypophyseal tract are intact. Only about 10% of neurosecretory neurons must remain intact to avoid argininevasopressin deficiency. The pathology of argininevasopressin deficiency thus always involves the supraoptic and paraventricular nuclei of the hypothalamus or a major portion of the pituitary stalk.
Arginine vasopressin deficiency may be
Complete (absence of vasopressin)
Partial (insufficient amounts of vasopressin)
Argininevasopressin deficiency also may be
Primary, in which there is a marked decrease in the hypothalamic nuclei of the neurohypophyseal system
Secondary (acquired)
Etiology of ArginineVasopressin Deficiency
Primary argininevasopressin deficiency
Genetic abnormalities of the vasopressin gene on chromosome 20 are responsible for autosomal dominant forms of primary argininevasopressin deficiency, but many cases are idiopathic.
Secondary argininevasopressin deficiency
Argininevasopressin deficiency may also be secondary (acquired), caused by various lesions, including hypophysectomy, cranial injuries (particularly basal skull fractures), suprasellar and intrasellar tumors (primary or metastatic), Langerhans cell histiocytosis, lymphocytic hypophysitis, granulomas (sarcoidosis or tuberculosis), vascular lesions (aneurysm, thrombosis), and infections (encephalitis, meningitis).
Symptoms and Signs of ArginineVasopressin Deficiency
Onset of argininevasopressin deficiency may be insidious or abrupt, occurring at any age.
The only symptoms in primary argininevasopressin deficiency are polydipsia and polyuria. In secondary argininevasopressin deficiency, symptoms and signs of the associated lesions are also present.
Enormous quantities of fluid may be ingested, and large volumes (3 to 30 L/day) of very dilute urine (specific gravity usually < 1.005 and osmolality < 200 mOsm/kg [200 mmol/kg]) are excreted. Nocturia almost always occurs. Dehydration and hypovolemia may develop rapidly if urinary losses are not continuously replaced.
Common causes of polyuria include
Diabetes mellitus (most common)
Argininevasopressin deficiency
Argininevasopressin resistance (nephrogenic diabetes insipidus)
Compulsive or habitual water drinking (primary polydipsia)
Diagnosis of ArginineVasopressin Deficiency
Water deprivation test
Sometimes vasopressin or copeptin levels
Argininevasopressin deficiency must be differentiated from other causes of polyuria, particularly primary polydipsia (see table Common Causes of Polyuria) and argininevasopressin resistance. All tests for argininevasopressin deficiency (and for argininevasopressin resistance) are based on the principle that increasing the plasma osmolality in normal people will lead to decreased excretion of urine with increased urine osmolality.
Common Causes of Polyuria
Mechanism | Example |
|---|---|
Vasopressin-sensitive polyuria | |
Decreased synthesis of vasopressin | Primary argininevasopressin deficiency, hereditary (usually autosomal dominant) Acquired (secondary) argininevasopressin deficiency (causes outlined in text) Primary diabetes insipidus, hereditary associated with diabetes mellitus, optic nerve atrophy, nerve deafness, and atonia of bladder and ureters (Wolfram syndrome) |
Decreased release of vasopressin | Primary polydipsia (dipsogenic diabetes insipidus) |
Vasopressin-resistant polyuria | |
Renal resistance to vasopressin | Congenital (usually X-linked recessive trait) Acquired argininevasopressin resistance: Chronic kidney disease, systemic or metabolic disease (eg, myeloma, amyloidosis, hypercalcemic or hypokalemic nephropathy, sickle cell disease |
Osmotic diuresis | Hyperglycemia (in diabetes mellitus) |
The water deprivation test is the simplest and most reliable method for diagnosing argininevasopressin deficiency but should be done only while the patient is under constant supervision. Serious dehydration may result. Additionally, if primary polydipsia is suspected, the patient must be observed to prevent surreptitious drinking.
The test is started in the morning by weighing the patient, obtaining venous blood to determine electrolyte concentrations and osmolality, and measuring urinary osmolality. Voided urine is collected hourly, and its specific gravity or, preferably, osmolality is measured. Dehydration is continued until orthostatic hypotension and postural tachycardia appear, ≥ 5% of the initial body weight has been lost, or the urinary concentration does not increase > 0.001 specific gravity or >
A normal response produces maximum urine osmolality after dehydration (often > 1.020 specific gravity or > argininevasopressin deficiency are generally unable to concentrate urine to greater than the plasma osmolality but are able to increase their urine osmolality by > 50 to > 100% after exogenous vasopressin administration. Patients with partial argininevasopressin deficiency are often able to concentrate urine to above the plasma osmolality but show a rise in urine osmolality of 15 to 50% after vasopressin administration. Patients with argininevasopressin resistance are unable to concentrate urine to greater than the plasma osmolality and show no additional response to vasopressin administration (see table Water Deprivation Test Results).
Measurement of circulating vasopressin or copeptin, the C-terminal peptide end of vasopressin, is the most direct method of diagnosing argininevasopressin deficiency; levels of vasopressin and copeptin at the end of the water deprivation test (before the vasopressin injection) are low in argininevasopressin deficiency and appropriately elevated in argininevasopressin resistance. However, vasopressin and copeptin levels are difficult to measure, and the tests are not routinely available. In addition, the physiologic response to water deprivation is so accurate that direct measurement of vasopressin or copeptin is unnecessary. Plasma vasopressin or copeptin levels are only diagnostic after either dehydration or infusion of hypertonic saline.
Pearls & Pitfalls
|
Water Deprivation Test Results
Parameter | Normal | Complete ArginineVasopressin Deficiency | Partial ArginineVasopressin Deficiency | Complete ArginineVasopressin Resistance | Partial ArginineVasopressin Resistance | Primary Polydipsia |
|---|---|---|---|---|---|---|
Uosm after dehydration (step 1) | Very high (> 700–800 mOsm/kg [> 700–800 mmol/kg]) | Very low (less than plasma osmolality) | Low (≥ 300 mOsm/kg [≥ 300 mmol/kg]) | Very low (less than plasma osmolality) | Very low (less than plasma osmolality) | High (500–600 mOsm/kg [500–600 mmol/kg]) |
Uosm increase after vasopressin (step 2) | Minimal (< 5%) | 50 to > 100% | 15–50% | < 50 mOsm/kg (<50 mmol/kg) | Up to 45% | No change |
Uosm = urine osmolality. | ||||||
Primary polydipsia
Primary polydipsia (sometimes referred to as psychogenic polydipsia) may present a difficult problem in differential diagnosis. Patients may ingest and excrete up to 6 L of fluid/day and may have a mental health disorder. Unlike patients with argininevasopressin deficiency and argininevasopressin resistance, patients with primary polydipsia usually do not have nocturia, nor does their thirst wake them at night. Continued ingestion of large volumes of water in this situation can lead to life-threatening hyponatremia.
Patients with acute excessive water drinking are able to concentrate their urine during water deprivation. However, because chronic water intake diminishes medullary tonicity in the kidneys, patients with long-standing polydipsia are not able to concentrate their urine to maximal levels during water deprivation, a response similar to that of patients with partial argininevasopressin deficiency. However, unlike argininevasopressin deficiency, patients with primary polydipsia show no response to exogenous vasopressin after water deprivation. This response resembles that of argininevasopressin resistance, except that basal vasopressin levels are low compared with the elevated levels present in argininevasopressin resistance. After prolonged restriction of fluid intake to ≤ 2 L/day, normal concentrating ability returns within several weeks.
Treatment of ArginineVasopressin Deficiency
Nonhormonal medications, eg, diuretics
Argininevasopressin deficiency can be treated with hormone replacement and treatment of any correctable cause. In the absence of appropriate management, permanent renal damage can result.
Restricting salt intake may also help because it reduces urine output by reducing solute load.
Hormonal medications
vasopressin
For each patient, the duration of action of a given dose must be established because variation among individuals is great. The duration of action can be established by following timed urine volumes and osmolality. The nightly dose is the lowest dose required to prevent nocturia. The morning and evening doses should be adjusted separately. The usual dosage range in individuals > 12 years is 10 to 40 mcg, with most requiring 10 mcg twice a day. For children age 3 months to 12 years, the usual dosage range is 2.5 to 10 mcg twice a day.
argininevasopressin
Pearls & Pitfalls
Nonhormonal medications
At least 3 groups of nonhormonal medications are useful in reducing polyuria:
Diuretics, primarily thiazides
Vasopressin
Prostaglandin inhibitors
These medications have been particularly useful in partial argininevasopressin deficiency and do not cause the adverse effects of exogenous vasopressin.
Thiazide diuretics paradoxically reduce urine volume in partial and complete argininevasopressin deficiency (and argininevasopressin
Vasopressin-releasing medications can reduce or eliminate the need for vasopressin in some patients with partial central argininevasopressin deficiency. None is effective in argininevasopressin resistance. Chlorpropamide 3 to 5 mg/kg orally once or twice a day causes some release of vasopressin and also potentiates the action of vasopressin
argininevasopressin resistance.
Key Points
Argininevasopressin deficiency is caused by a deficiency of vasopressin, which decreases the kidneys' ability to reabsorb water, resulting in massive polyuria (3 to 30 L/day).
The cause may be a primary genetic disorder or various tumors, infiltrative lesions, injuries, or infections that affect the hypothalamic-pituitary system.
Diagnose using a water deprivation test; patients cannot maximally concentrate urine following dehydration but can concentrate urine after receiving exogenous vasopressin.
Low vasopressin or copeptin levels are diagnostic, but vasopressin and copeptin levels are difficult to measure, and the tests are not routinely available.
vasopressin.
More Information
Working Group for Renaming Diabetes Insipidus, Arima H, Cheetham T, et al. Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus. Endocr J 69(11):1281-1284, 2022. doi:10.1507/endocrj.EJ20220831
