Diabetes insipidus (DI) refers to a condition characterized by complete or partial deficiency of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), or an insensitivity of the kidneys to AVP. This results in impaired water reabsorption in the renal distal tubules and collecting ducts, leading to a syndrome marked by polyuria, polydipsia, and excessive thirst. DI is relatively rare, can occur at any age, but is more commonly observed in adolescents, with a higher prevalence in males compared to females. DI due to complete or partial deficiency of AVP is classified as central diabetes insipidus (CDI), whereas DI caused by renal insensitivity to AVP is termed nephrogenic diabetes insipidus (NDI). NDI is rare; therefore, this section focuses on CDI.
Etiology and Pathogenesis
CDI arises from various factors that disrupt the synthesis, transport, storage, or release of AVP and can be categorized as acquired, hereditary, or idiopathic.
Acquired Causes
Approximately 50% of cases are caused by tumors affecting the hypothalamic-pituitary region and nearby areas, such as pituitary adenomas, craniopharyngiomas, pineal gland tumors, and metastatic tumors. About 10% are associated with head trauma, including severe traumatic brain injuries or surgeries involving the hypothalamic-pituitary region. A smaller proportion of cases result from brain infections (e.g., meningitis, tuberculosis, syphilis), Langerhans cell histiocytosis, other granulomatous diseases, or vascular lesions. During pregnancy, the placenta may produce an N-terminal aminopeptidase that accelerates the degradation of AVP, leading to AVP deficiency and clinical manifestations of polyuria and thirst (gestational DI). Symptoms are typically mild and resolve postpartum.
Hereditary Causes
A small number of CDI cases have a familial basis, following an autosomal dominant inheritance pattern due to mutations in the AVP-neurophysin II (AVP-NPⅡ) gene. Additionally, X-linked recessive hereditary DI is transmitted by female carriers, with symptoms manifesting primarily in males. Heterozygous females may have mild urine concentration defects, generally without significant symptoms of polydipsia or polyuria. Wolfram syndrome (also referred to as DIDMOAD: diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) results from mutations in the WFS1 gene and manifests as DI, diabetes mellitus, optic nerve atrophy, and hearing loss. It is inherited in an autosomal recessive manner but is extremely rare.
Idiopathic Causes
Idiopathic cases account for about 30% of CDI, with no identifiable cause. In some patients, autopsies reveal a significant reduction or almost complete loss of neurons in the hypothalamic supraoptic nucleus and paraventricular nucleus. The cause of this degenerative process remains unclear. Research has detected antibodies against the hypothalamic nuclei, specifically targeting AVP-producing cells, in the blood of these patients. The condition may also be associated with autoantibodies against thyroid, gonadal, and gastric parietal cells.
Clinical Manifestations
The primary symptoms include polyuria, polydipsia, and excessive thirst, with a preference for cold water. Nocturia is common and may disrupt sleep. The onset is often abrupt, with symptoms appearing on a clearly identifiable date. Daily urine volume typically exceeds 50 mL/kg and can range from 4 to 10 liters. Urine specific gravity is generally below 1.005, and urine osmolality is lower than plasma osmolality, often not exceeding 300 mOsm/（kg. 2O）. The urine is pale and clear, resembling water. In some cases, symptoms are milder, with daily urine volumes ranging from 2.5 to 5 liters. Under water restriction, urine specific gravity may exceed 1.010, and urine osmolality can rise above plasma osmolality, reaching 300–600 mOsm/(kg.H2O).
Hypoosmolar polyuria often causes a mild elevation in plasma osmolality, stimulating the osmoreceptors in the hypothalamic thirst center. Affected individuals experience intense thirst and consume large amounts of water. If water intake is sufficient, serum sodium, plasma osmolality, and serum creatinine generally remain within normal limits. However, when the hypothalamic thirst center is impaired (e.g., due to anterior communicating artery aneurysms or related surgeries), the sensation of thirst may be lost (a condition known as adipsic DI). In situations where consciousness is impaired due to surgery, anesthesia, or head trauma, the inability to compensate for water loss can lead to severe dehydration and hypernatremia. This may manifest as profound muscle weakness, fever, neuropsychiatric symptoms, delirium, or even death.
In cases of glucocorticoid deficiency, renal water clearance is reduced. Therefore, when DI coexists with anterior pituitary insufficiency, the symptoms of DI may improve. Symptoms often recur or worsen after glucocorticoid replacement therapy.
Triphasic DI may develop following transection of the pituitary stalk (e.g., due to head trauma or surgery). The first phase (acute phase, lasting 3–5 days) is characterized by markedly increased urine output and decreased urine osmolality. The second phase lasts a few days, during which urine output sharply decreases, urine osmolality rises, and serum sodium drops. This phase is believed to result from excessive AVP release due to axonal degeneration in the posterior pituitary. The third phase represents permanent DI.
In acquired forms of DI, additional symptoms and signs related to the underlying primary condition may also be present.
Diagnosis and Differential Diagnosis
The diagnosis of typical diabetes insipidus (DI) is generally straightforward. In the presence of polyuria, thirst, and polydipsia, DI should be considered. The water deprivation test followed by administration of vasopressin can be used to establish the diagnosis. For cases where the water deprivation test cannot be conducted but clinical features are characteristic, a diagnostic trial using desmopressin may be performed.
Diagnostic Criteria
The main diagnostic criteria include:
- Excessive urine output, often exceeding 50 mL/(kg·d).
- Urine osmolality below plasma osmolality, typically less than 300 mOsm/(kg·H2O).
- Inadequate water intake may result in hypernatremia.
- The water deprivation test fails to increase urine osmolality, while administration of vasopressin increases urine osmolality by more than 10%.
- Significant clinical improvement following treatment with vasopressin or desmopressin.
Diagnostic Methods
Water Deprivation and Vasopressin Test
This test observes changes in urine osmolality before and after water deprivation and administration of vasopressin. After a set period of water deprivation, when maximal urine concentration is achieved and does not further increase, vasopressin is administered. In healthy individuals, administration of exogenous AVP does not result in an additional increase in urine osmolality. In CDI patients, due to AVP deficiency, exogenous AVP significantly increases urine osmolality.
Procedure
The duration of water deprivation depends on the degree of polyuria and generally begins at night (though it can be conducted during the day in severe cases), lasting between 6 to 16 hours. During this period, blood pressure, body weight, urine output, and urine osmolality are monitored every 1–2 hours. When a peak plateau in urine osmolality is reached (defined as two consecutive urine osmolality measurements differing by less than 30 mOsm/(kg·H2O)), plasma osmolality is measured, and vasopressin (posterior pituitary extract) 5U is administered subcutaneously. Urine osmolality is then measured 1 and 2 hours after injection.
Interpretation
Normal individuals demonstrate a significant reduction in urine output and a gradual increase in urine osmolality to levels above 800 mOsm/(kg·H2O) after water deprivation. In DI patients, urine output remains high, and urine osmolality may increase modestly but does not exceed 800 mOsm/(kg·H2O).
In healthy individuals and patients with primary polydipsia, urine osmolality changes little after vasopressin administration, with any increase rarely exceeding 10%.
CDI patients show a significant increase in urine osmolality, exceeding 10% after vasopressin administration. The more severe the AVP deficiency, the greater the percentage increase in urine osmolality. Complete CDI often demonstrates an increase greater than 50%, while partial CDI may show a post-deprivation urine osmolality exceeding plasma osmolality, with a 10–50% increase after vasopressin administration.
In nephrogenic DI, water deprivation does not result in concentrated urine, and vasopressin administration increases urine osmolality by less than 10%.
This method is simple and reliable but requires close monitoring to prevent severe dehydration during the test. If severe dehydration occurs during water deprivation (e.g., weight loss exceeding 3% or significant drops in blood pressure), the test should be immediately terminated, and the patient should be given water.
Measurement of Plasma AVP
In healthy individuals, plasma AVP levels are 2.3–7.4 pmol/L under ad-libitum water intake and increase significantly following water deprivation. In CDI patients, plasma AVP levels are low and show no significant increase or only a minimal increase after water deprivation.
Etiological Diagnosis
After confirming the diagnosis of DI, identifying the underlying cause is critical. Visual field examination and imaging studies, such as CT or MRI of the sella turcica, should be conducted to assess for pituitary or surrounding lesions. On T1-weighted MRI, the posterior pituitary typically appears as a hyperintense "bright spot," which is absent in CDI patients, indicating depletion or loss of stored AVP granules.
Differential Diagnosis
Nephrogenic Diabetes Insipidus (NDI)
NDI results from renal insensitivity to AVP and may have hereditary or acquired causes:
Hereditary NDI: About 90% of cases are associated with mutations in the AVP receptor (V2R) gene, an X-linked recessive disorder. Mutations in the gene encoding aquaporin-2 (AQP-2), which is involved in post-receptor signaling, can also cause NDI and follow an autosomal recessive inheritance pattern.
Acquired NDI
This is secondary to tubular damage (e.g., from medications such as lithium or gentamicin). Patients with NDI also present with polyuria, thirst, and polydipsia. The water deprivation test fails to reduce urine output or increase urine osmolality significantly, and vasopressin administration increases urine osmolality by less than 10%. Baseline and post-deprivation plasma AVP levels are elevated.
Primary Polydipsia
This is often associated with psychiatric factors (psychogenic polydipsia) or, in some cases, medications and hypothalamic lesions. It arises due to excessive water intake, leading to polyuria and dilute urine, mimicking DI. However, relevant clinical history and accompanying neuropsychiatric symptoms aid differentiation. Symptoms are typically more pronounced during the day, with no nocturia or impact on sleep. AVP secretion is intact, and the results of the water deprivation-vasopressin test resemble those of healthy individuals.
Diabetes Mellitus
Polyuria, thirst, and polydipsia may occur. Blood glucose and urine glucose monitoring facilitate differentiation.
Chronic Kidney Disease
Especially in cases involving tubular injury, hypokalemia, or hypercalcemia, renal concentrating ability may be impaired, causing polyuria and thirst. These conditions typically have characteristic primary disease features, and the degree of polyuria tends to be milder.
Treatment
Hormone Replacement Therapy
Desmopressin
Desmopressin (DDAVP), also known as 1-desamino-8-D-arginine vasopressin, is a synthetic vasopressin analogue. It has a potent antidiuretic effect without vasopressor activity and minimal adverse effects, making it the first-line treatment for central diabetes insipidus.
Oral tablets are administered at 0.1–0.4 mg per dose, 2–3 times daily. For some patients, a single dose taken before bedtime may reduce nighttime urination and drinking frequency, ensuring adequate sleep and rest. Since the effective dose varies significantly between individuals, treatment must be individualized to avoid water intoxication. DDAVP is also effective for gestational diabetes insipidus due to its resistance to degradation by AVP-degrading enzymes. Other formulations include subcutaneous injections (1–4 μg) or intranasal spray (10–20 μg), administered 1–2 times daily.
Pituitary Extract
Pituitary extract, derived from the posterior pituitary glands of pigs or cows, contains AVP. Its effect lasts for 3–6 hours, requiring multiple daily injections, which makes its long-term use inconvenient. It is primarily used for DI caused by brain trauma or during surgery, administered as 5–10 U subcutaneously per dose.
Other Antidiuretic Medications
Hydrochlorothiazide
Hydrochlorothiazide, at a dose of 25 mg 2–3 times daily, can reduce urine volume by about half. The mechanism may involve inhibition of sodium reabsorption in the distal tubules, leading to reduced blood volume and increased reabsorption of sodium and water in the proximal tubules, thus decreasing the amount of water delivered to the AVP-sensitive collecting ducts and reducing urine volume. It is also effective for nephrogenic diabetes insipidus. However, long-term use may cause hypokalemia and hyperuricemia, necessitating appropriate potassium supplementation.
Carbamazepine
Carbamazepine can stimulate AVP secretion, resulting in reduced urine output. The dosage is 0.2 g per dose, taken 2–3 times daily. Adverse effects include peripheral granulocytopenia, liver damage, fatigue, and dizziness.
Etiological Treatment
For acquired diabetes insipidus, treating the underlying primary disease should be prioritized whenever possible.
Prognosis
The prognosis depends on the cause and severity of the condition. DI caused by mild brain trauma or infections may resolve completely. Idiopathic diabetes insipidus is often permanent, but with adequate water intake and appropriate antidiuretic treatment, patients can generally maintain a normal lifestyle with little impact on life expectancy.