How can I distinguish central diabetes insipidus from nephrogenic diabetes insipidus in a patient with polyuria‑polydipsia, low urine osmolality and high serum osmolality?

Distinguishing Central from Nephrogenic Diabetes Insipidus

Plasma copeptin measurement is the primary test to differentiate central from nephrogenic diabetes insipidus: a copeptin level >21.4 pmol/L confirms nephrogenic DI, while levels <21.4 pmol/L indicate central DI or primary polydipsia. 1

Initial Diagnostic Confirmation

Before differentiating subtypes, confirm the diagnosis of diabetes insipidus by measuring serum sodium, serum osmolality, and urine osmolality simultaneously 1, 2:

• Pathognomonic triad: Urine osmolality <200 mOsm/kg H₂O + high-normal or elevated serum sodium + serum osmolality typically >300 mOsm/kg H₂O 1, 2
• This combination confirms diabetes insipidus but does not yet distinguish the subtype 1

Primary Differentiation Method: Plasma Copeptin

The Endocrine Society and European Society of Endocrinology recommend copeptin as the first-line differentiating test 1, 2:

• Copeptin >21.4 pmol/L = Nephrogenic DI (indicates significantly elevated ADH levels despite renal insensitivity) 1, 2
• Copeptin <21.4 pmol/L = Central DI or primary polydipsia (indicates deficient ADH production) 1

Why Copeptin Works

Copeptin is secreted in equimolar ratio to AVP (antidiuretic hormone) and mirrors AVP concentrations, but is far more stable and easier to measure than direct AVP assays 3. The fundamental pathophysiologic difference is:

• Central DI: Low or absent plasma ADH due to deficient production 4
• Nephrogenic DI: Normal or elevated plasma ADH, but kidneys are insensitive to it 4

Alternative Method: Desmopressin Trial

If copeptin measurement is unavailable, a desmopressin (DDAVP) trial differentiates the subtypes based on treatment response 1, 4:

Administration and Interpretation

• Give desmopressin (synthetic ADH) and measure urine osmolality response 1
• Central DI: Urine osmolality increases >50% (typically >61%), confirming ADH deficiency 1, 4
• Nephrogenic DI: Minimal or no response (<50% increase), confirming renal resistance to ADH 1, 4

Critical Safety Note

Desmopressin is ineffective and contraindicated for nephrogenic DI treatment 5. This trial is purely diagnostic—never continue desmopressin if nephrogenic DI is confirmed 4.

Water Deprivation Test: Use with Extreme Caution

The traditional water deprivation test followed by desmopressin administration has been the historical "gold standard" but has significant limitations 6, 3:

• Diagnostic accuracy is limited, especially for partial forms of DI 6, 3
• Duration is 17 hours, making it cumbersome for patients 3
• Risk of severe hypernatremic dehydration, particularly dangerous in infants and children, potentially causing seizures, developmental delay, and brain injury 1
• Should be avoided when NDI is strongly suspected based on clinical presentation and initial labs 1

When NDI is suspected (especially in infants with polyuria, failure to thrive, and hypernatremic dehydration), proceed directly to genetic testing rather than water deprivation 1, 2.

Genetic Testing for Nephrogenic DI

Early multigene panel testing provides definitive diagnosis and replaces provocative testing 1, 2:

• Test AVPR2 (X-linked, ~90% of congenital NDI), AQP2 (autosomal, <10%), and AVP genes 1, 2
• Include copy-number-variant analysis in an accredited diagnostic laboratory 1
• Prevents prolonged severe hypertonic dehydration and its neurological sequelae 1
• Enables family counseling, prenatal testing, and identification of female carriers 1

Required Workup After Subtype Diagnosis

If Central DI is Confirmed

Obtain MRI of the sella turcica with dedicated pituitary sequences 1, 2:

• Approximately 50% of central DI cases have identifiable structural causes (tumors, infiltrative diseases, inflammatory processes) 1
• T1 fine-cut sequences identify loss of the normal posterior pituitary "bright spot" (hyperintensity of neurosecretory granules) 2

If Nephrogenic DI is Confirmed

• Proceed with genetic testing as above 1, 2
• Assess for acquired causes: chronic kidney disease, medications (lithium, demeclocycline), electrolyte disorders (hypercalcemia, hypokalemia) 1

Treatment Implications Confirm the Diagnosis

The response to treatment further validates your diagnosis 4:

• Central DI: Responds to desmopressin (intranasal, oral, or subcutaneous routes) 1, 5
• Nephrogenic DI: Requires thiazide diuretics + NSAIDs + low-salt diet (<6 g/day) + protein restriction (<1 g/kg/day) 1, 4

Emergency Management Differs Critically

For hypernatremic dehydration:

• Nephrogenic DI: Use 5% dextrose in water (hypotonic fluid) at maintenance rates; avoid normal saline 1, 4
• Central DI: Can use desmopressin to reduce urine output 1

Common Pitfalls to Avoid

• Never restrict water access in any DI patient during diagnostic workup—this causes life-threatening hypernatremic dehydration 1
• Do not confuse diagnostic thresholds: Urine osmolality <200 mOsm/kg confirms DI diagnosis, but water deprivation test uses ≥300 mOsm/kg as the response threshold 1
• Do not give desmopressin to nephrogenic DI patients—it is ineffective and delays appropriate treatment 4, 5
• Check serum sodium within 7 days of starting desmopressin, as hyponatremia is the main complication 1