Diabetes Insipidus
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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Risk factors
- Central (AVP deficiency): pituitary/hypothalamic surgery (especially craniopharyngioma, macroadenoma), TBI, Sheehan syndrome, autoimmune (lymphocytic infundibuloneurohypophysitis), granulomatous (sarcoidosis, Langerhans cell histiocytosis, TB), metastatic disease, infection, pituitary stalk lesions, idiopathic
- Nephrogenic (AVP resistance): chronic lithium (most common acquired), hypercalcemia, hypokalemia, post-obstructive uropathy, sickle cell, amyloidosis, demeclocycline, foscarnet, cidofovir, ifosfamide, X-linked AVPR2 mutation, autosomal AQP2 mutation
- 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)
- Osmotic diuresis (diabetes mellitus, mannitol, post-obstructive) — Hyperglycemia, glucosuria; urine NOT dilute
- Loop diuretic / drug-induced polyuria — Drug history
- Hypercalcemia / hypokalemia — Can cause nephrogenic DI; check electrolytes
- Chronic kidney disease — Concentrating defect; eGFR low
- 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 |
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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