ADH deficiency (central) or renal resistance (nephrogenic) causing dilute polyuria and hypernatremia if water access limited.
Also known as: diabetes insipidus, DI, central DI, nephrogenic DI, AVP deficiency, AVP resistance
Overview
Disorder of water balance defined by hypotonic polyuria due to either deficient secretion of arginine vasopressin (central DI, also called AVP deficiency) or renal resistance to AVP (nephrogenic DI, AVP resistance). Recent guidelines favor these descriptive names over 'diabetes insipidus' to prevent confusion with diabetes mellitus.
Epidemiology
Uncommon overall. Central DI more common than nephrogenic. Post-neurosurgical or traumatic CDI is the most common form encountered in hospitals. Lithium-induced nephrogenic DI is the most common drug cause. Congenital nephrogenic DI is rare and usually X-linked (AVPR2 mutation).
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Gestational DI: placental vasopressinase degradation of AVP (responds to desmopressin)
Primary polydipsia (compulsive water intake or low set-point) — not true DI but mimics it
Pathophysiology
AVP is synthesized in the supraoptic and paraventricular nuclei, transported down the pituitary stalk, and stored in the posterior pituitary. Plasma osmolality is sensed by hypothalamic osmoreceptors; AVP release increases water reabsorption in collecting ducts via V2 receptors and aquaporin-2. Loss of AVP secretion or V2 receptor/AQP2 function produces dilute polyuria. As long as thirst is intact and water access is unrestricted, serum sodium remains near normal; if not, severe hypernatremia develops.
Clinical presentation
Symptoms
Polyuria (often >3 L/day, can be much more), nocturia, polydipsia
Preference for ice water (classic in CDI)
Fatigue, weakness, irritability
Severe cases: confusion, lethargy, seizure (hypernatremia)
Signs / physical exam
Dehydration if access to water restricted
Hypotension, tachycardia (volume depletion)
Altered mental status with severe hypernatremia
Children: failure to thrive, fever, irritability
Classic findings
Adult with sudden onset of severe polyuria (>5 L/day) and polydipsia after pituitary surgery — CDI until proven otherwise. Lithium user with polyuria — nephrogenic DI.
Differential diagnosis
Primary polydipsia (psychogenic, dipsogenic) — Polydipsia drives polyuria; suppressed AVP appropriately; water deprivation test shows ability to concentrate urine (>600 mOsm/kg)
Resolving acute kidney injury (polyuric phase) — Self-limited; supportive care
Diagnostic workup
Diagnostic criteria
Polyuria + dilute urine (osm < serum osm) + appropriate response (or lack thereof) to water deprivation and DDAVP.
Labs
Simultaneous serum and urine osmolality
Serum Na (often high-normal or elevated in true DI; normal/low in primary polydipsia)
Plasma copeptin (a stable surrogate for AVP) — emerging tool to differentiate DI subtypes
BMP, calcium, glucose (rule out mimics)
Lithium level if applicable
24-hour urine volume to confirm polyuria (>3 L/day or >50 mL/kg/day)
Imaging
Pituitary MRI for suspected central DI — look for absence of posterior pituitary 'bright spot,' pituitary stalk thickening, mass, or infiltration
Renal ultrasound if obstructive uropathy or other renal pathology suspected
Diagnostic algorithm
Test
Central DI
Nephrogenic DI
Primary polydipsia
Baseline serum Na
High-normal / high
High-normal / high
Low-normal / low
Baseline urine osm
Low (<300)
Low (<300)
Low (<300)
After water deprivation, urine osm
Remains low
Remains low
Rises >600
After DDAVP, urine osm
Rises >50%
Minimal rise (<10-50%)
No further rise
Copeptin (basal or hypertonic-stim)
Low
High
Normal / appropriate
MRI posterior pituitary bright spot
Absent
Present
Present
Differentiating central DI, nephrogenic DI, and primary polydipsia.
Complications
Severe hypernatremia → altered mentation, seizure, intracranial bleed, death
Hypovolemic shock
Cerebral edema from too-rapid correction of hypernatremia
Hyponatremia from desmopressin over-treatment
Bladder atony from chronic polyuria
Failure to thrive in infants with congenital NDI
PANCE pearls
Pituitary surgery causes a classic 'triphasic response': polyuria (1st week) → SIADH (transient inappropriate retention, ~days 5-10) → permanent DI (or recovery). Watch for hyponatremia between phases.
Lithium is the most common acquired cause of nephrogenic DI; can persist after lithium discontinuation.
Primary polydipsia and DI BOTH cause polyuria — water deprivation test or copeptin testing distinguishes.
Hypernatremia correction must be SLOW (≤10-12 mEq/L per 24 h) to prevent cerebral edema.
Thiazides treat nephrogenic DI by paradoxically reducing urine volume (volume contraction enhances proximal sodium and water reabsorption).
After pituitary surgery, daily Na and ins/outs are essential for the first 7-10 days.
References
Working Group 2022 — Renaming of Diabetes Insipidus to AVP-Deficiency and AVP-Resistance (Working Group on Renaming Diabetes Insipidus, J Clin Endocrinol Metab 2022)
European Consensus 2022 — Diagnosis and Management of Central Diabetes Insipidus in Adults (Garrahy et al., J Clin Endocrinol Metab 2022)
Endocrine Society — Posterior pituitary disorders guidelines — multiple statements on hyponatremia and hypernatremia management
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