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Summary Table

Category	Details
Risk Factors	Pituitary surgery, head trauma, craniopharyngioma, germinoma, sarcoidosis, Langerhans cell histiocytosis, autoimmune hypophysitis (central); chronic lithium therapy, hypercalcemia, hypokalemia, hereditary AVPR2 or AQP2 mutations, post-obstructive diuresis (nephrogenic); third trimester pregnancy (gestational)
Etiology	Deficient AVP secretion (central, complete or partial), renal resistance to AVP (nephrogenic), or accelerated AVP degradation (gestational) leading to inability to concentrate urine
Patient Presentation	Polyuria (>3 L/day), polydipsia, nocturia, craving for ice-cold water, fatigue; severe cases present with hypernatremic dehydration and altered mental status
Classic Physical Exam	Dry mucous membranes, poor skin turgor, hypotension if water access is restricted; otherwise often unremarkable in compensated patients
Key Diagnostic Results	Urine osmolality <300 mOsm/kg, urine specific gravity <1.005, serum osmolality >295 mOsm/kg, serum sodium often >145 mEq/L; failure to concentrate urine on water deprivation
Management	Desmopressin for central DI (dose individualized); thiazide diuretic with low-salt and low-protein diet, plus amiloride or NSAID, for nephrogenic DI; correct underlying cause; careful free water replacement for hypernatremia
Keywords	"Excessive thirst and urination," "craves ice water," "post-pituitary surgery," "lithium-treated patient," "dilute urine despite dehydration," "high-normal sodium," "loss of posterior pituitary bright spot"

1. Pathophysiology

Diabetes insipidus is a disorder of water homeostasis, not glucose. The central regulator is arginine vasopressin (AVP), also called antidiuretic hormone, synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. Rising plasma osmolality stimulates AVP release. AVP binds V2 receptors on the basolateral membrane of renal collecting duct principal cells, activating adenylyl cyclase and triggering insertion of aquaporin-2 (AQP2) channels into the apical membrane. Water then flows down its osmotic gradient into the hypertonic renal medulla, producing concentrated urine.

In central DI, the hypothalamus or posterior pituitary fails to secrete adequate AVP. Importantly, the posterior pituitary has substantial functional reserve, and roughly 80 to 90 percent of AVP-producing magnocellular neurons must be lost before overt symptoms appear. This explains why partial lesions produce a milder phenotype while complete stalk transection produces fulminant polyuria. Common causes include neurosurgery (especially transsphenoidal resection of pituitary adenoma), head trauma, tumors (craniopharyngioma, germinoma, metastases), infiltrative disease (sarcoidosis, Langerhans cell histiocytosis), autoimmune hypophysitis, and idiopathic disease.

In complete central DI, AVP secretion is essentially abolished and the collecting duct receives no signal at all. AQP2 channels remain entirely sequestered, urine osmolality stays close to that of plasma water (typically 50 to 200 mOsm/kg), and daily urine output may reach 8 to 20 L. These patients develop hypernatremia rapidly when water access is interrupted.

In partial central DI, residual AVP-secreting neurons still respond to osmotic stimuli, but the response is blunted. The patient can achieve modest urinary concentration under stress, but cannot reach the normal maximum of 800 to 1200 mOsm/kg. Daily urine volume is typically 3 to 6 L, and symptoms may be limited to nocturia or mild polyuria. The diagnostic difficulty is that the water deprivation response overlaps with primary polydipsia, in which chronic AVP suppression also produces medullary washout.

In nephrogenic DI, AVP is present but the kidney does not respond. Lithium is the most frequent acquired cause: it accumulates in principal cells via ENaC channels and downregulates AQP2 expression. Hypercalcemia and hypokalemia impair the medullary concentrating gradient. Hereditary forms involve X-linked V2 receptor mutations (most common) or autosomal AQP2 mutations.

In gestational DI, placental vasopressinase (cysteine aminopeptidase) degrades circulating endogenous AVP, typically presenting in the third trimester. Primary polydipsia is a mimicker rather than true DI: excessive water intake suppresses AVP physiologically, washes out the medullary gradient, and produces polyuria with dilute urine.

The cardinal physiologic consequence of any form of DI is free water loss. When patients have access to water, thirst drives compensatory drinking and serum sodium remains near the upper limit of normal. The danger emerges when access to water is restricted (intubated patients, infants, the elderly, the cognitively impaired), where rapid hypernatremic dehydration develops and may cause seizures, coma, or intracranial hemorrhage.

2. Classification and Clinical Manifestation

Type	Underlying Defect	AVP Status	Daily Urine Volume	Distinguishing Clinical Clue
Complete Central DI	Severe loss (>90%) of AVP-secreting neurons	Absent (<10% of normal)	8 to 20 L	Abrupt onset after pituitary surgery or stalk transection; dramatic response to desmopressin
Partial Central DI	Reduced AVP secretion from limited neuronal loss	Reduced (10 to 50% of normal)	3 to 6 L	Insidious onset; nocturia or mild polyuria; intermediate response on water deprivation; modest desmopressin response
Acquired Nephrogenic DI	Renal resistance to AVP	Normal or elevated	3 to 8 L	Lithium use, hypercalcemia, hypokalemia, post-obstructive diuresis, sickle cell disease
Hereditary Nephrogenic DI	AVPR2 mutation (X-linked, ~90%) or AQP2 mutation (autosomal)	Normal or elevated	Severe in infancy	Male infants with failure to thrive, vomiting, fever, hypernatremic dehydration
Gestational DI	Placental vasopressinase degrades AVP	Endogenous AVP degraded	Variable	Third trimester onset; resolves 4 to 6 weeks postpartum; responds to desmopressin (resistant to vasopressinase)
Primary Polydipsia	Excess water intake suppresses AVP	Appropriately suppressed	Variable, often >5 L	Low-normal or low serum sodium; psychiatric history; improves with fluid restriction

Clinically, all forms present with polyuria (>3 L/day or >50 mL/kg/day), polydipsia, and nocturia. A preference for ice-cold water is a classic vignette clue. Pediatric patients may present with enuresis, irritability, failure to thrive, and unexplained fevers.

Patients post-pituitary surgery may follow a triphasic pattern: initial DI (days 1 to 5) from axonal shock, transient SIADH (days 6 to 11) from release of stored AVP from degenerating neurons, then permanent DI if magnocellular damage is extensive. This pattern is testable and management-altering.

3. Diagnostic Workup

Test	Purpose	Expected Finding in DI
Serum sodium and osmolality	Initial screening	Sodium high-normal or elevated (>145 mEq/L); serum osm >295 mOsm/kg
Urine osmolality and specific gravity	Initial screening	Urine osm <300 mOsm/kg; specific gravity <1.005
24-hour urine volume	Confirm true polyuria	>3 L/day in adults; >50 mL/kg/day
Fingerstick glucose	Exclude osmotic diuresis from diabetes mellitus	Normal in DI
Water deprivation test (Miller-Moses)	Differentiate DI from primary polydipsia and grade severity	Urine fails to concentrate adequately despite rising serum osmolality
Desmopressin challenge	Differentiate central from nephrogenic, and complete from partial	Urine osm rise: complete central >100%, partial central 15 to 50%, nephrogenic <10%
Plasma copeptin (stimulated)	Modern surrogate for AVP	Low in central; high in nephrogenic
MRI brain (sella and hypothalamus)	Identify structural cause of central DI	Loss of posterior pituitary T1 bright spot; mass lesion or stalk thickening
Serum calcium, potassium, lithium level	Reversible causes of nephrogenic DI	Hypercalcemia, hypokalemia, or therapeutic to toxic lithium level

The workup begins by confirming that polyuria is true and hypotonic. Order paired serum and urine osmolality. The diagnostic signature of DI is inappropriately dilute urine in the face of elevated serum osmolality, which a healthy kidney would never permit. A urine osmolality below 300 mOsm/kg with serum osmolality above 295 mOsm/kg essentially establishes the diagnosis of a concentrating defect. Always check fingerstick glucose first to exclude osmotic diuresis from diabetes mellitus.

If the patient is compensating by drinking and serum osmolality is not yet elevated, proceed to a water deprivation test, the traditional best initial functional test. Fluids are withheld under monitoring, with hourly measurement of body weight, urine volume, urine osmolality, and serum sodium. A normal patient or one with primary polydipsia will concentrate urine to >600 to 800 mOsm/kg. A patient with DI will continue to produce dilute urine and develop rising serum osmolality. The test is stopped when serum osm exceeds 295 to 300 mOsm/kg, weight loss exceeds 3 to 5 percent, or urine osmolality plateaus.

At that endpoint, administer desmopressin 2 to 4 mcg subcutaneously or 10 mcg intranasally and recheck urine osmolality at 1 and 2 hours. The interpretation is structured around the magnitude of the rise:

Diagnosis	Urine Osm at End of Water Deprivation	Rise After Desmopressin
Normal or Primary Polydipsia	>600 to 800 mOsm/kg	<10% (kidney already maximally concentrated)
Complete Central DI	<300 mOsm/kg (no concentration)	>100% (often doubles or triples)
Partial Central DI	300 to 700 mOsm/kg (some concentration)	15 to 50% above water-deprivation peak
Complete Nephrogenic DI	<300 mOsm/kg	<10% (no response to AVP)
Partial Nephrogenic DI	300 to 500 mOsm/kg	<45% rise but with persistently subnormal final value

Partial central DI and primary polydipsia are the most diagnostically challenging pair, since both can produce intermediate urine osmolality on deprivation and modest rises with desmopressin. The discriminator is baseline serum sodium: high-normal in partial central DI, low-normal in primary polydipsia.

The most accurate test in modern practice is plasma copeptin, the C-terminal fragment of pre-pro-vasopressin that is co-secreted with AVP in equimolar amounts but is far more stable. Hypertonic saline-stimulated copeptin below 4.9 pmol/L identifies central DI, with greater accuracy than the water deprivation test, and can distinguish partial central DI from primary polydipsia where the older test struggles. Where available, copeptin-based testing is becoming the gold standard.

Once central DI is confirmed, an MRI of the pituitary and hypothalamus is mandatory to exclude tumor, infiltrative disease, or stalk lesion. The classic radiologic finding is absence of the posterior pituitary bright spot on T1-weighted images, reflecting depletion of AVP-containing neurosecretory granules. Stalk thickening raises suspicion for germinoma, sarcoidosis, or histiocytosis and warrants further evaluation.

4. Management and Treatment

Type	First-Line Therapy	Adjuncts and Notes
Complete Central DI	Desmopressin 0.1 to 0.4 mg PO BID-TID, 10 to 40 mcg intranasal daily, or 1 to 2 mcg SC/IV BID	Lifelong therapy; titrate to symptoms; allow brief daily breakthrough to avoid hyponatremia
Partial Central DI	Lower-dose desmopressin (often 0.05 to 0.1 mg PO BID or 5 to 10 mcg intranasal daily)	Some patients managed with adequate fluid intake alone if symptoms are mild
Nephrogenic DI	Treat reversible cause; low-salt, low-protein diet; hydrochlorothiazide 25 mg daily	Add amiloride 5 to 10 mg daily (especially for lithium-induced); consider indomethacin
Gestational DI	Desmopressin (resistant to placental vasopressinase)	Resolves 4 to 6 weeks postpartum
Primary Polydipsia	Fluid restriction; address underlying psychiatric illness	Do NOT give desmopressin (risk of severe hyponatremia)
Acute Hypernatremia	Free water replacement with 0.45% NaCl or D5W	Lower serum Na no faster than 10 to 12 mEq/L per 24 hours to avoid cerebral edema

The first management priority in any DI patient is to assess volume status and serum sodium. A hemodynamically stable, alert patient with access to water can usually be managed outpatient. A patient with hypernatremia, altered mentation, or restricted oral intake requires hospitalization and careful free water replacement.

For central DI, the cornerstone is desmopressin, a synthetic AVP analogue with selective V2 activity (no V1 vasoconstrictive effect) and a longer half-life. Dosing differs by severity. Complete central DI typically requires 0.1 to 0.4 mg orally two to three times daily, 10 to 40 mcg intranasally per day divided into one or two doses, or 1 to 2 mcg subcutaneously every 12 hours for inpatients. Partial central DI is managed with lower doses, often 0.05 to 0.1 mg orally twice daily or 5 to 10 mcg intranasally daily, sometimes only at bedtime to control nocturia. Some patients with mild partial DI tolerate the condition well with adequate fluid access alone and do not require chronic pharmacotherapy. The principal complication is iatrogenic hyponatremia, so patients are taught to allow a small daily window of breakthrough polyuria before the next dose to permit free water excretion.

For nephrogenic DI, exogenous AVP will not work because the defect is at the receptor or channel level. Management has three pillars. First, remove the offending agent: stop lithium if possible (in consultation with psychiatry, because abrupt discontinuation can destabilize bipolar disorder), correct hypercalcemia, replete potassium. Second, institute a low-sodium, low-protein diet to reduce solute load and obligate water loss. Third, use medications that paradoxically reduce urine output. Hydrochlorothiazide 25 mg daily induces mild volume contraction, increases proximal tubular sodium and water reabsorption, and decreases delivery to the diluting segments. Amiloride 5 to 10 mg daily is particularly useful for lithium-induced nephrogenic DI because it blocks the ENaC channel through which lithium enters principal cells. Indomethacin or other NSAIDs reduce renal prostaglandin synthesis (which normally antagonizes AVP) and can be added in resistant cases, with attention to renal and gastric toxicity.

For gestational DI, desmopressin is safe and effective because it is not degraded by placental vasopressinase. Symptoms resolve within 4 to 6 weeks after delivery.

In acute hypernatremia from DI, calculate the free water deficit using:

$$\text{Water deficit (L)} = 0.6 \times \text{weight (kg)} \times \left(\frac{[\text{Na}^+]_{\text{measured}}}{140} - 1\right)$$Replace this deficit with 5 percent dextrose or half-normal saline orally or intravenously, while ensuring serum sodium falls no faster than 10 to 12 mEq/L per 24 hours to avoid cerebral edema. Begin desmopressin concurrently in central DI to halt ongoing losses.

The next best step when post-neurosurgical polyuria appears is to check paired serum and urine osmolality before giving any desmopressin. Empiric therapy without confirming the diagnosis can mask the diagnostic picture and precipitate hyponatremia, particularly because postoperative patients are at risk of the triphasic response in which an early DI phase is followed by transient SIADH on days 6 to 11. A short-acting parenteral desmopressin given as needed, rather than a fixed standing regimen, is preferred in the immediate postoperative period.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Diabetes mellitus (uncontrolled)	Polyuria, polydipsia, nocturia	Hyperglycemia and glucosuria; osmotic diuresis with elevated urine osmolality, not low
Primary (psychogenic) polydipsia	Polyuria, dilute urine, polydipsia	Low-normal or low serum sodium; suppressed AVP; concentrates urine on water deprivation
Partial central DI vs primary polydipsia	Both show intermediate urine osmolality and partial response to desmopressin	Baseline sodium high-normal in partial central DI, low-normal in primary polydipsia; stimulated copeptin discriminates clearly
SIADH	Disorder of AVP regulation	Hyponatremia with concentrated urine; opposite electrolyte and osmolality picture from DI
Diuretic use (covert)	Polyuria, polydipsia	Urine osmolality variable; hypokalemia common; diuretic detectable on urine screen
Chronic kidney disease with concentrating defect	Nocturia, dilute urine	Elevated creatinine, abnormal urinalysis, slower onset, smaller daily urine volumes
Hypercalcemia of malignancy	Polyuria, polydipsia, dehydration	Markedly elevated calcium drives the picture; treating hypercalcemia resolves polyuria
Cerebral salt wasting (post-neurosurgery)	Polyuria after brain injury, hypernatremia possible	Patient is volume-depleted; high urinary sodium; treated with salt and volume, not desmopressin
Post-obstructive diuresis	Polyuria	History of recent urinary tract obstruction relief; self-limited

6. Traps and High-Yield Pearls

The classic trap is confusing diabetes insipidus with diabetes mellitus because the keywords "polyuria" and "polydipsia" appear in both. The discriminator is the glucose: in DM the urine is full of solute and has high osmolality, while in DI the urine is essentially water with osmolality below 300 mOsm/kg. Always check a fingerstick glucose before launching into a DI workup.

The second trap is the partial central DI versus primary polydipsia dilemma. Both produce intermediate urine osmolality on water deprivation and both can show some rise in urine osmolality with desmopressin. Students who memorize only "DI fails to concentrate, polydipsia concentrates normally" miss the partial cases entirely. The discriminator is the baseline serum sodium (high-normal in partial central DI, low-normal in primary polydipsia), the clinical context (psychiatric history versus pituitary lesion or trauma), and stimulated copeptin if available.

The third trap is giving desmopressin without first distinguishing central from nephrogenic DI, or worse, giving it to a patient with primary polydipsia who will then develop dangerous hyponatremia. The water deprivation test followed by desmopressin challenge, or copeptin testing, must come before chronic therapy.

A fourth trap is the post-neurosurgical patient with the triphasic response. A trainee who treats early DI aggressively with standing desmopressin may then push the patient into severe hyponatremia when the SIADH phase begins on day 6 to 11. Treat as needed with short-acting desmopressin and reassess sodium and urine output frequently rather than locking in a fixed regimen.

Another testable subtlety is the lithium patient. The vignette will describe a patient on long-standing lithium for bipolar disorder presenting with polyuria. The right answer is nephrogenic DI, and the management pearl is amiloride, which blocks lithium uptake into principal cells and is more useful here than thiazide alone. Stopping lithium often does not fully reverse the defect if exposure has been prolonged.

In pediatric vignettes, watch for the male infant with failure to thrive, recurrent fevers, vomiting, and hypernatremic dehydration. The answer is X-linked nephrogenic DI from an AVPR2 mutation. These infants do not respond to desmopressin, and management is dietary plus thiazide and amiloride.

Recognize the classic vignette phrase "patient craves ice-cold water", which is near-pathognomonic shorthand for DI and is a tell that the question stem is steering you toward a water balance disorder rather than an endocrine or metabolic alternative.

The core competency being tested is the ability to recognize inappropriate urinary dilution in the setting of plasma hypertonicity, distinguish complete from partial central DI and central from nephrogenic DI through the desmopressin response, and manage acute hypernatremia at a safe correction rate without precipitating cerebral edema.

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