Diabetes Insipidus (DI)

How to Cite This Chapter: Khan T, Rodríguez-Gutiérrez R, Brito JP, Prebtani APH, Kunert-Radek J, Płaczkiewicz-Jankowska E. Diabetes Insipidus (DI). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.8.1. Accessed July 18, 2024.
Last Updated: January 1, 2021
Last Reviewed: January 1, 2021
Chapter Information

Definition, Etiology, PathogenesisTop

Diabetes insipidus (DI) is a condition characterized by increased water loss (polyuria >50 mL/kg/d) resulting from excretion of a large volume of diluted urine and usually by compensatory increased thirst (polydipsia) due to:

1) Central DI (neurohypophyseal): Arginine vasopressin (antidiuretic hormone) (ADH) deficiency. This may result from:

a) Damage to the vasopressin-secreting neurons located in the supraoptic and paraventricular nuclei in the hypothalamus or to the pituitary stalk or posterior pituitary gland (vasopressin transport and storage sites, respectively). The most common cause of central DI is idiopathic (autoimmune process) followed by tumors (germinoma, metastatic lesions, craniopharyngioma), hypophysitis (inflammation of the pituitary gland), infiltrative diseases (sarcoidosis, Langerhans cell histiocytosis), hypoxic encephalopathy, and head trauma.

b) Genetic defects, such as familial central DI (autosomal dominant gene defect encoding ADH), Wolfram syndrome (DIDMOAD syndrome [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness]), congenital hypopituitarism, and septo-optic dysplasia.

2) Nephrogenic DI: Loss of sensitivity of the renal tubules to ADH (ADH resistance), which may result from mutations in the vasopressin V2-receptor gene (X-linked inheritance with males mostly affected; heterozygous females may be asymptomatic but at risk of polyuria during pregnancy) and in the aquaporin 2 (AQP2) gene (encodes the ADH-sensitive water channels in the collecting tubule cells). Nephrogenic DI may also occur in hypercalcemia, hypokalemia, renal diseases (eg, bilateral urinary tract obstruction, polycystic kidney disease, renal amyloidosis), and it can be caused by drugs (eg, lithium [most common], amphotericin B, cidofovir, and foscarnet).

Clinical FeaturesTop

DI manifests as polyuria (>50 mL/kg/d) and polydipsia that usually prevents hypovolemia and hypernatremia. Patients characteristically report nocturia (sometimes voiding several times throughout the night) and polydipsia at night. In individuals unable to have adequate fluid intake, life-threatening hypovolemia and hypernatremia may occur. Signs and symptoms due to hypernatremia or an underlying hypothalamic-pituitary tumor may also be present.

Onset of polyuria:

1) Children: Familiar central DI and hereditary nephrogenic DI manifest with severe polyuria in the first week of life.

2) Adults: Central DI may manifest in an abrupt manner. Nephrogenic DI has a gradual onset.


Diagnostic Tests

1. Laboratory studies:

1) Plasma sodium concentration, plasma osmolality: High-normal or high.

2) Urine osmolality, specific gravity: Low and characteristically lower than plasma osmolality.

3) Urinary sodium: Usually <20 mmol/L.

4) Water deprivation test (combined with the desmopressin/1-deamino-8-D-arginine vasopressin [DDAVP] stimulation test): The test is performed usually in an inpatient setting only after polyuria due to diabetes mellitus, hypokalemia, and hypercalcemia have been excluded. The patient should stop drinking water in the morning before arriving at the clinic (or preferably, if safe, from dinner on the day before). Urine volume, urine osmolality, serum creatinine, plasma sodium concentration, plasma osmolality, blood pressure (BP), pulse, and body weight should be measured at baseline. Thereafter, measure urine specific gravity, urine osmolality, plasma osmolality, serum sodium, BP, pulse, and body weight every 2 hours. Serum copeptin level is also measured at the start and end of the test. Copeptin is the C-terminal segment of the precursor for ADH. While direct measurement of ADH is difficult, copeptin can be easily measured and provides a reliable surrogate marker for ADH. Terminate the test when: (1) body weight decreases ≥3%; (2) urine osmolality is stable (difference <10%) in 2 or 3 samples despite rising plasma osmolality; (3) serum sodium levels are above the upper limit of normal (≥145 mmol/L) with plasma osmolality >295 to 300 mOsm/kg (in patients with DI, this usually occurs within a few hours); or (4) urine osmolality reaches a normal value, which excludes DI (>600 mOsm/kg). If the criteria for termination of the test are not met, it should be continued for 18 hours to exclude DI. Interpretation of test results: Table 1.

5) Desmopressin stimulation test (second phase of the water deprivation test) is performed to differentiate central DI from nephrogenic DI. Administer desmopressin/DDAVP 1 microg subcutaneously or IV at the end of the fluid deprivation test. Measure the volume, specific gravity, and osmolality every 30 minutes for the next 2 hours. Interpretation of test results: Table 1.

2. Imaging studies: A confirmed diagnosis of central DI is an absolute indication for magnetic resonance imaging (MRI) of the sellar (hypothalamic-pituitary) region. The absence of T1 hyperintensity (bright spot) in the posterior pituitary lobe is seen in many patients with central DI.

Diagnostic Criteria and Differential Diagnosis

Table 1.


1. Central DI: Replacement therapy with a long-acting ADH analogue desmopressin (DDAVP). Usually desmopressin is administered intranasally (10-20 microg once a day or bid), orally (starting with 50 microg at bedtime, which can be increased up to 200 microg [0.2 mg] tid), or, where available, sublingually (60-120 microg tid). In patients with altered mental status or in the case of nothing per mouth or inability to use nasal route, IV or subcutaneous administration of 0.5 to 2 microg once daily to bid may be used. Adjust the dosage individually on the basis of resolution of clinical symptoms, polyuria, and polydipsia and normalization of plasma osmolality and serum sodium levels. Avoid hyponatremia.

2. Nephrogenic DI: Management depends on the causative factor:

1) Acquired renal injury: Symptomatic treatment involving appropriate fluid replacement and management of the underlying condition.

2) Electrolyte disturbances: Signs and symptoms of DI improve with normalization of electrolyte levels.

3) Genetic defects of ADH receptors or irreversible causative factor (eg, lithium): Consider a low-sodium diet as initial therapy. In case of partial response, that is, in case of improvement in polyuria/DI but without resolution, sequential therapy should be added to the preexisting therapy. In case of no improvement, the earlier therapy should be stopped and subsequent therapy tried. The following subsequent therapies could be used in this order: a thiazide diuretic (starting with hydrochlorothiazide [HCTZ] 25 mg once daily, which can be increased to bid as needed), followed by amiloride (starting with a 5-mg dose once daily, which can be increased to 10 mg bid). In symptomatic DI/polyuria due to lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin, can be added to the above in the absence of contraindications. Electrolytes and renal function need to be monitored carefully with the above-mentioned therapies. Consider high-dose desmopressin in patients with a partial ADH-receptor response.


Prognosis depends on the cause of central DI (tumor, trauma, metastases, inflammation, idiopathic). If the patient maintains appropriate fluid intake, untreated DI is not life threatening. Special attention to fluid balance is warranted in the case of unconscious trauma patients, patients after central nervous system surgery, and patients with an altered sense of thirst due to the damaged hypothalamic thirst center. Advise the patients to carry information about their DI at all times. Patients with DI treated with hormone replacement may lead normal lives. Desmopressin overdose may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (water retention and severe hyponatremia). To avoid this, the rate of correction for chronic hypernatremia should not be >10 to 12 mEq/L/d. It is also important to avoid hyponatremia.


Table 6.3-1. Differential diagnosis of central DI, nephrogenic DI, and primary polydipsia using water deprivation and desmopressin stimulation


Primary polydipsiaa

Central (neurohypophyseal) DI

Nephrogenic DI

Water restriction test (fluid deprivation test)

Urine specific gravity




Urine osmolality

>500-600 mOsm/kg

<250 mOsm/kg

<250 mOsm/kg

Plasma copeptin level

Initially low, then increasing



Desmopressin stimulation test (desmopressin 1 microg SC or IV)

Urine specific gravity

No indication for the testb

Increased by ≥50%

Low, not increasing

Urine osmolality

No indication for the testb

Increase by 100% in complete central DI and 15% to 50% in partial central DI

No elevation

a Primary polydipsia is usually psychogenic but may also be related to medications causing dry mucous membrane, structural hypothalamic thirst center lesions, or perceived health benefit of drinking large volumes of fluids.

b As the results of the fluid deprivation test are normal.

ADH, antidiuretic hormone; DI, diabetes insipidus; IV, intravenous; SC, subcutaneous.

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