Diabetes insipidus (DI)

Also titled as ADH-related causes of polyuria & polydipsia

ADH is also called AVP (arginine vasopressin)

Polyuria (eg, >3 L urine/24 hours) is suggested by frequent urination and nocturia.
Mild Euvolemic hypernatremia is present; this common finding in DI reflects ongoing water losses and maintains a stimulus for compensatory polydipsia (in patients with intact thirst reflex).
Low urine osmolality (<300 mOsm/kg HO) and low urine specific gravity (<1.006) in the setting of high serum osmolality (>250 mOsm/kg HO) reflect inappropriately dilute urine.

<aside> 💡 In young children, hereditary nephrogenic diabetes insipidus (eg, family history of polydypsia/polyuria) is the most common cause.

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<aside> 💡 (formerly called central and nephrogenic diabetes insipidus [DI]

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Normally, elevated serum osmolality triggers ADH release, leading to increased collecting duct permeability to free water, water reabsorption, and production of highly concentrated urine (eg, urine osmolality >800 mOsm/kg).

However, patients with ADH deficiency (AVP-D) or resistance (AVP-R) have decreased water reabsorption and persistently low urine osmolality (<300 mOsm/kg) despite high serum osmolality (>300 mOsm/kg).

	Primary polydipsia	AVP deficiency(central DI)	AVP resistance(nephrogenic DI)
Defect	• ↑ Water intake	• ↓ ADH release from pituitary	• Renal ADH resistance (normal or ↑ ADH)
Etiology	• Antipsychotics
• Anxiety, psychiatric conditions	• Idiopathic
• Trauma
• Pituitary surgery
• Ischemic encephalopathy	• Chronic lithium use
• Hypercalcemia
• Hereditary (AVPR2 mutations)
• CKD
Clinical features	• Low serum Na	• High-normal or elevated serum Na*	• Normal or mildly elevated serum Na*

In AVP-D, serum sodium is usually slightly elevated or high-normal, which serves to stimulate thirst and continued water intake needed to compensate for urinary water losses. Uric acid may be slightly elevated if mild dehydration is present; more severe hypernatremia can result if the thirst mechanism is impaired (eg, hypothalamic lesion). Patients with AVP-R typically have an intact thirst mechanism that is sufficient to maintain normal or high-normal sodium levels.

Diabetes insipidus can remain undiagnosed because the body often compensates for water losses with a demand for increased fluid intake (eg, increased thirst).

Polyuria and dilute urine in the setting of normal serum sodium and fluid intake

Normally, antidiuretic hormone (ADH) stimulates renal water reabsorption when serum osmolality is high (eg, following water deprivation). ADH resistance or deficiency causes DI, which presents with dilute urine (low urine osmolality) and polyuria (often worse at night).

Nephrogenic DI is caused by renal ADH resistance. One of the most common causes in adults is lithium, which accumulates in renal collecting ducts and blocks responsiveness to ADH. After water deprivation (eg, overnight fasting), serum osmolality rises (eg, >295 mOsmol/kg, often with hypernatremia) and ADH increases appropriately; however, urine osmolality remains low.
Central DI can occur following hypothalamic or posterior pituitary damage (eg, trauma, infection) and leads to deficient ADH secretion. After water deprivation, serum osmolality rises but ADH remains low; therefore, urine osmolality remains low. Lithium use is only rarely associated with central DI (Choice C).

A desmopressin challenge can differentiate central from nephrogenic DI (as desmopressin causes increased urine osmolality only in central DI).

During pregnancy, placental produced enzymes (eg, vasopressinase) increase ADH breakdown and can worsen symptoms, thereby unmasking undiagnosed DI. Some women develop transient DI of pregnancy due to an exaggerated response to vasopressinase. This phenomenon may resolve with delivery but recur in subsequent pregnancies.

Complete workup (eg, challenge with desmopressin, an ADH analogue) is required to confirm the precise etiology of DI (ie, central DI due to insufficient ADH levels vs nephrogenic DI due to renal resistance to ADH).

Hydrochlorothiazide (HCTZ) is not as effective as desmopressin as monotherapy for central DI. HCTZ can be combined with desmopressin for an additive effect. However, HCTZ is preferred for nephrogenic DI. HCTZ causes mild volume depletion that increases proximal water and sodium reabsorption.

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