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Central Diabetes Insipidus

(Vasopressin-Sensitive Diabetes Insipidus)

By

Ian M. Chapman

, MBBS, PhD, University of Adelaide, Royal Adelaide Hospital

Last full review/revision Aug 2019| Content last modified Aug 2019
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Diabetes insipidus results from a deficiency of vasopressin (antidiuretic hormone [ADH]) due to a hypothalamic-pituitary disorder (central diabetes insipidus) or from resistance of the kidneys to vasopressin (nephrogenic diabetes insipidus). 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 central from nephrogenic diabetes insipidus. Treatment is with desmopressin or lypressin. Nonhormonal treatment includes use of diuretics (mainly thiazides) and vasopressin-releasing drugs, such as chlorpropamide.

Pathophysiology

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) and 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 central diabetes insipidus. The pathology of central diabetes insipidus thus always involves the supraoptic and paraventricular nuclei of the hypothalamus or a major portion of the pituitary stalk.

Central diabetes insipidus may be

  • Complete (absence of vasopressin)

  • Partial (insufficient amounts of vasopressin)

Central diabetes insipidus also may be

  • Primary, in which there is a marked decrease in the hypothalamic nuclei of the neurohypophyseal system

  • Secondary (acquired)

Etiology

Primary central diabetes insipidus

Genetic abnormalities of the vasopressin gene on chromosome 20 are responsible for autosomal dominant forms of primary central diabetes insipidus, but many cases are idiopathic.

Secondary central diabetes insipidus

Central diabetes insipidus 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

Onset of central diabetes insipidus may be insidious or abrupt, occurring at any age. The only symptoms in primary central diabetes insipidus are polydipsia and polyuria. In secondary central diabetes insipidus, 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

Diagnosis

  • Water deprivation test

  • Sometimes vasopressin levels

Central diabetes insipidus must be differentiated from other causes of polyuria, particularly psychogenic polydipsia (see table Common Causes of Polyuria) and nephrogenic diabetes insipidus. All tests for central diabetes insipidus (and for nephrogenic diabetes insipidus) are based on the principle that increasing the plasma osmolality in normal people will lead to decreased excretion of urine with increased urine osmolality.

Table
icon

Common Causes of Polyuria

Mechanism

Example

Vasopressin-sensitive polyuria

Decreased synthesis of vasopressin

Primary diabetes insipidus, hereditary (usually autosomal dominant)

Primary diabetes insipidus, hereditary associated with diabetes mellitus, optic nerve atrophy, nerve deafness, and atonia of bladder and ureters

Acquired (secondary) diabetes insipidus (causes outlined in text)

Decreased release of vasopressin

Psychogenic polydipsia (dipsogenic diabetes insipidus)

Vasopressin-resistant polyuria

Renal resistance to vasopressin

Congenital nephrogenic diabetes insipidus (usually X-linked recessive trait)

Acquired nephrogenic diabetes insipidus: Chronic kidney disease, systemic or metabolic disease (eg, myeloma, amyloidosis, hypercalcemic or hypokalemic nephropathy, sickle cell disease), certain drugs (eg, lithium, demeclocycline)

Osmotic diuresis

Hyperglycemia (in diabetes mellitus)

Poorly resorbed solutes (mannitol, sorbitol, urea)

The water deprivation test is the simplest and most reliable method for diagnosing central diabetes insipidus but should be done only while the patient is under constant supervision. Serious dehydration may result. Additionally, if psychogenic 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 >30 mOsm/L in sequentially voided specimens. Serum electrolytes and osmolality are again determined. Exogenous vasopressin is then given (5 units of aqueous vasopressin subcutaneously, 10 mcg desmopressin [DDAVP] intranasally, or 4 mcg IM or IV). Urine for specific gravity or osmolality measurement is collected one final time 60 minutes postinjection, and the test is terminated.

A normal response produces maximum urine osmolality after dehydration (often > 1.020 specific gravity or >700 mOsm/kg [700 mmol/kg]), exceeding the plasma osmolality; osmolality does not increase more than an additional 5% after injection of vasopressin. Patients with central diabetes insipidus 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 central diabetes insipidus 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 nephrogenic diabetes insipidus 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 is the most direct method of diagnosing central diabetes insipidus; levels at the end of the water deprivation test (before the vasopressin injection) are low in central diabetes insipidus and appropriately elevated in nephrogenic diabetes insipidus. However, vasopressin levels are difficult to measure, and the test is not routinely available. In addition, water deprivation is so accurate that direct measurement of vasopressin is unnecessary. Plasma vasopressin levels are diagnostic after either dehydration or infusion of hypertonic saline.

Pearls & Pitfalls

  • The water deprivation test should be done while the patient is under constant supervision because serious dehydration may occur.

Table
icon

Water Deprivation Test Results

Parameter

Normal

Complete Central Diabetes Insipidus

Partial Central Diabetes Insipidus

Complete Nephrogenic Diabetes Insipidus

Partial Nephrogenic Diabetes Insipidus

Psychogenic 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.

Psychogenic polydipsia

Psychogenic polydipsia may present a difficult problem in differential diagnosis. Patients may ingest and excrete up to 6 L of fluid/day and are often emotionally disturbed. Unlike patients with central diabetes insipidus and nephrogenic diabetes insipidus, they 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 psychogenic 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 central diabetes insipidus. However, unlike central diabetes insipidus, patients with psychogenic polydipsia show no response to exogenous vasopressin after water deprivation. This response resembles nephrogenic diabetes insipidus, except that basal vasopressin levels are low compared with the elevated levels present in nephrogenic diabetes insipidus. After prolonged restriction of fluid intake to 2 L/day, normal concentrating ability returns within several weeks.

Treatment

  • Hormonal drugs, eg, desmopressin

  • Nonhormonal drugs, eg, diuretics

Central diabetes insipidus 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 drugs

Desmopressin, a synthetic analog of vasopressin with minimal vasoconstrictive properties, has prolonged antidiuretic activity, lasting for 12 to 24 hours in most patients, and may be administered intranasally, subcutaneously, IV, or orally. Desmopressin is the preparation of choice for both adults and children and is available as an intranasal solution in 2 forms. A dropper bottle with a calibrated nasal catheter has the advantage of delivering incremental doses from 5 to 20 mcg but is awkward to use. A spray bottle that delivers 10 mcg of desmopressin in 0.1 mL of fluid is easier to use but delivers a fixed quantity.

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.

Overdosage can lead to fluid retention and decreased plasma osmolality, possibly resulting in seizures in small children. In such instances, furosemide can be given to induce diuresis. Headache may be a troublesome adverse effect but generally disappears if the dosage is reduced. Infrequently, desmopressin causes a slight increase in blood pressure. Absorption from the nasal mucosa may be erratic, especially when an upper respiratory infection or allergic rhinitis occurs. When intranasal delivery of desmopressin is inappropriate, it may be administered subcutaneously using about one tenth of the intranasal dose. Desmopressin may be used IV if a rapid effect is necessary (eg, for hypovolemia). With oral desmopressin, dose equivalence with the intranasal formulation is unpredictable, so individual dose titration is needed. The initial dose is 0.1 mg orally 3 times a day, and the maintenance dose is usually 0.1 to 0.2 mg 3 times a day.

Pearls & Pitfalls

  • The duration of action of a given dose of desmopressin varies greatly among individuals and must be established for each patient.

Lypressin (lysine-8- vasopressin), a synthetic agent, is given by nasal spray at doses of 2 to 4 units (7.5 to 15 mcg) every 3 to 8 hours but, because of its short duration of action, has been largely replaced by desmopressin.

Aqueous vasopressin 5 to 10 units subcutaneously or IM can be given to provide an antidiuretic response that usually lasts 6 hours. Thus, this drug has little use in long-term treatment but can be used in the initial therapy of unconscious patients and in patients with central diabetes insipidus who are undergoing surgery. Synthetic vasopressin can also be administered twice a day to 4 times a day as a nasal spray, with the dosage and interval tailored to each patient. Vasopressin tannate in oil 0.3 to 1 mL (1.5 to 5 units) IM may control symptoms for up to 96 hours.

Nonhormonal drugs

At least 3 groups of nonhormonal drugs are useful in reducing polyuria:

  • Diuretics, primarily thiazides

  • Vasopressin-releasing drugs (eg, chlorpropamide, carbamazepine, clofibrate)

  • Prostaglandin inhibitors

These drugs have been particularly useful in partial central diabetes insipidus and do not cause the adverse effects of exogenous vasopressin.

Thiazide diuretics paradoxically reduce urine volume in partial and complete central diabetes insipidus (and nephrogenic diabetes insipidus), primarily as a consequence of reducing extracellular fluid (ECF) volume and increasing proximal tubular resorption. Urine volumes may fall by 25 to 50% with 15 to 25 mg/kg of chlorothiazide.

Chlorpropamide, carbamazepine, and clofibrate can reduce or eliminate the need for vasopressin in some patients with partial central diabetes insipidus. None are effective in nephrogenic diabetes insipidus. Chlorpropamide 3 to 5 mg/kg orally once or twice a day causes some release of vasopressin and also potentiates the action of vasopressin on the kidneys. Clofibrate 500 to 1000 mg orally twice a day or carbamazepine 100 to 400 mg orally twice a day is recommended for adults only. These drugs may be used synergistically with a diuretic. However, significant hypoglycemia may result from chlorpropamide.

Prostaglandin inhibitors (eg, indomethacin 0.5 to 1.0 mg/kg orally 3 times a day, although most nonsteroidal anti-inflammatory drugs [NSAIDs] are effective) are modestly effective. They may reduce urine volume, but generally by no more than 10 to 25%, perhaps by decreasing renal blood flow and glomerular filtration rate (GFR). Together with indomethacin, restriction of sodium intake and a thiazide diuretic help further reduce urine volume in nephrogenic diabetes insipidus.

Key Points

  • Central diabetes insipidus 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 levels are diagnostic, but vasopressin levels are difficult to measure and the test is not routinely available.

  • Address any treatable causes and give desmopressin, a synthetic analog of vasopressin.

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
DIABINESE
DIURIL
TEGRETOL
INDOCIN
DDAVP, STIMATE
VASOSTRICT
LASIX
OSMITROL, RESECTISOL
LITHOBID
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