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(see Sidebar 1: Electrolyte Disorders: Hyponatremia and see Renal Transport Abnormalities: Nephrogenic Diabetes Insipidus.)
Diabetes insipidus (DI) results from a deficiency of ADH due to a hypothalamic-pituitary disorder (central DI [CDI]) or from resistance of the kidney to ADH (nephrogenic DI [NDI]). Polyuria and polydipsia develop. Diagnosis is by water deprivation test showing failure to maximally concentrate urine; ADH levels and response to exogenous ADH help distinguish CDI from NDI. Treatment is with intranasal desmopressin or lypressin. Nonhormonal treatment includes use of diuretics (mainly thiazides) and ADH-releasing drugs, such as chlorpropamide.
Pathophysiology
Polyuria may result from CDI, a deficiency of ADH, NDI, or compulsive or habitual water drinking (psychogenic polydipsia). The posterior lobe of the pituitary is the major site of ADH storage and release, but ADH 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 CDI. The pathology of CDI thus always involves the supraoptic and paraventricular nuclei of the hypothalamus or a major portion of the pituitary stalk.
CDI may be complete (absence of ADH) or partial (insufficient amounts of ADH). CDI may be primary, in which there is a marked decrease in the hypothalamic nuclei of the neurohypophyseal system.
Etiology
Primary CDI
Genetic abnormalities of the ADH gene on chromosome 20 are responsible for autosomal dominant forms of primary CDI, but many cases are idiopathic.
Secondary CDI
CDI 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 (Hand-Schüller-Christian disease), granulomas (sarcoidosis or TB), vascular lesions (aneurysm and thrombosis), and infections (encephalitis or meningitis).
Symptoms and Signs
Onset may be insidious or abrupt, occurring at any age. The only symptoms in primary CDI are polydipsia and polyuria. In secondary CDI, 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 (sp gr usually < 1.005 and osmolality < 200 mOsm/L) are excreted. Nocturia almost always occurs. Dehydration and hypovolemia may develop rapidly if urinary losses are not continuously replaced.
Diagnosis
CDI must be differentiated from other causes of polyuria (see Table 4: Pituitary Disorders: Common Causes of Polyuria ), particularly psychogenic polydipsia and NDI. All tests for CDI (and for NDI) are based on the principle that increasing the plasma osmolality in normal people will lead to decreased excretion of urine with increased osmolality.
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Table 4
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| Common Causes of Polyuria |
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Category
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Mechanism
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Example
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Vasopressin-sensitive polyuria
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Decreased synthesis of ADH
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Primary diabetes insipidus, hereditary (usually autosomal dominant)
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Primary diabetes insipidus, associated with diabetes mellitus, optic atrophy, nerve deafness, and atonia of bladder and ureters
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Acquired diabetes insipidus (causes outlined in text)
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Decreased release of ADH
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Psychogenic polydipsia (dipsogenic diabetes insipidus)
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Vasopressin-resistant polyuria
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Renal resistance to ADH
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Congenital nephrogenic diabetes insipidus (usually X-linked recessive trait)
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Acquired nephrogenic diabetes insipidus: Chronic renal disease, systemic or metabolic disease (eg, myeloma, amyloidosis, hypercalcemic or hypokalemic nephropathy, sickle cell disease), certain drugs (eg, lithium, demeclocycline)
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Osmotic diuresis
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Hyperglycemia (in diabetes mellitus)
Poorly resorbed solutes (mannitol, sorbitol, urea)
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The water deprivation test is the simplest and most reliable method for diagnosing CDI 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 sp gr 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 sp gr or > 30 mOsm/L in sequentially voided specimens. Serum electrolytes and osmolality are again determined, and 5 units of aqueous vasopressin are injected sc. Urine for sp gr or osmolality measurement is collected one final time 60 min postinjection, and the test is terminated.
A normal response produces maximum urine osmolality after dehydration (often > 1.020 sp gr or > 700 mOsm/L), exceeding the plasma osmolality; osmolality does not increase more than an additional 5% after injection of vasopressin. Patients with CDI are generally unable to concentrate urine to greater than the plasma osmolality but are able to increase their urine osmolality by > 50% after vasopressin administration. Patients with partial CDI are often able to concentrate urine to above the plasma osmolality but show a rise in urine osmolality of > 9% after vasopressin administration. Patients with NDI are unable to concentrate urine to greater than the plasma osmolality and show no additional response to vasopressin administration.
Measurement of circulating ADH is the most direct method of diagnosing CDI; levels at the end of the water deprivation test (before the vasopressin injection) are low in CDI and appropriately elevated in NDI. However, ADH levels are difficult to measure, and the test is not routinely available. In addition, water deprivation is so accurate that direct measurement of ADH is unnecessary. Plasma ADH levels are diagnostic after either dehydration or infusion of hypertonic saline.
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 CDI and NDI, 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 (see Electrolyte Disorders: 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 kidney, 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 CDI. However, unlike CDI, patients with psychogenic polydipsia show no response to exogenous ADH after water deprivation. This response resembles NDI, except that basal ADH levels are low compared with the elevated levels present in NDI. After prolonged restriction of fluid intake to ≤ 2 L/day, normal concentrating ability returns within several weeks.
Treatment
CDI can be treated with hormone replacement and treatment of any correctable cause. In the absence of appropriate management, permanent renal damage can result.
Desmopressin, a synthetic analog of ADH with minimal vasoconstrictive properties, has prolonged antidiuretic activity lasting for 12 to 24 h in most patients and may be administered intranasally, sc, 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 μg but is awkward to use. A spray bottle that delivers 10 μg 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 adults is 10 to 40 μg, with most adults requiring 10 μg bid. For children age 3 mo to 12 yr, the usual dosage range is 2.5 to 10 μg bid. 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 BP. Absorption from the nasal mucosa may be erratic, especially when URI or allergic rhinitis occurs. When intranasal delivery of desmopressin is inappropriate, it may be administered sc using about one tenth 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 po tid, and the maintenance dose is usually 0.1 to 0.2 mg tid.
Lypressin (lysine-8-vasopressin), a synthetic agent, is given by nasal spray at doses of 2 to 4 units (7.5 to 15 μg) q 3 to 8 h but, because of its short duration of action, has been largely replaced by desmopressin.
Aqueous vasopressin 5 to 10 units sc or IM can be given to provide an antidiuretic response that usually lasts ≤ 6 h. 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 CDI who are undergoing surgery. Synthetic vasopressin can also be administered bid to qid 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 h.
At least 3 groups of nonhormonal drugs are useful in reducing polyuria: various diuretics, primarily thiazides; ADH-releasing drugs, such as chlorpropamide, carbamazepine, and clofibrate; and prostaglandin inhibitors, which are modestly effective. These drugs have been particularly useful in partial CDI and do not cause the adverse effects of exogenous ADH.
The thiazides paradoxically reduce urine volume in partial and complete CDI (and NDI), primarily as a consequence of reducing ECF volume and increasing proximal tubular resorption. Urine volumes may fall by 25 to 50% with 15 to 25 mg/kg of chlorothiazide. Restricting salt intake may also help because it reduces urine output by reducing solute load.
Chlorpropamide, carbamazepine, and clofibrate can reduce or eliminate the need for vasopressin in some patients with partial CDI. None are effective in NDI. Chlorpropamide (3 to 5 mg/kg po once/day or bid) causes some release of ADH and also potentiates the action of ADH on the kidney. Clofibrate (500 to 1000 mg po bid) or carbamazepine (100 to 400 mg po bid) is recommended for adults only. These drugs may be used synergistically with a diuretic. However, significant hypoglycemia may result from chlorpropamide.
Prostaglandin inhibitors (such as indomethacin 0.5 to 1.0 mg/kg po tid, although most NSAIDs are effective) may reduce urine volume, but generally by no more than 10 to 25%, perhaps by decreasing renal blood flow and GFR. Together with indomethacin, restriction of Na intake and a thiazide diuretic help further reduce urine volume in NDI.
Last full review/revision February 2007 by Ian M. Chapman, MBBS, PhD
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