What are the tests for diagnosing diabetes insipidus?

Diagnostic Testing for Diabetes Insipidus

Initial biochemical work-up should include serum sodium, serum osmolality, and urine osmolality in all patients with suspected diabetes insipidus, followed by early genetic testing for nephrogenic diabetes insipidus or plasma copeptin measurement to differentiate between central and nephrogenic forms. 1, 2

Initial Clinical Suspicion and Basic Laboratory Tests

Suspect diabetes insipidus in patients presenting with:

• Polyuria and polydipsia with inappropriately dilute urine (urine osmolality <200 mOsm/kg H₂O) in the setting of high-normal or elevated serum sodium 1, 2
• In children specifically: failure to thrive and hypernatremic dehydration 1, 3
• In adults: unexplained polydipsia and polyuria 1, 2

The first-line diagnostic tests are:

• Serum sodium 1, 2
• Serum osmolality 1, 2
• Urine osmolality 1, 2

Genetic Testing (First-Line for Nephrogenic Diabetes Insipidus)

For suspected nephrogenic diabetes insipidus, genetic testing should be performed early and is strongly recommended before proceeding to other diagnostic tests. 1, 2

Specific genetic testing recommendations:

• Use a massively parallel sequencing-based multigene panel including at minimum AVPR2, AQP2, and AVP genes (the latter for differential diagnosis of central diabetes insipidus) 1
• Test all symptomatic females for AVPR2 and AQP2, as 10% of females with AVPR2 mutations develop complete nephrogenic diabetes insipidus phenotype 1, 3
• In male offspring of known heterozygote AVPR2 mutation carriers, perform genetic testing on umbilical cord blood immediately after birth to prevent primary manifestations through early treatment 1, 3
• Perform testing only in laboratories accredited for diagnostic genetic testing 1

Plasma Copeptin Measurement (When Genetic Testing Unavailable or Inconclusive)

If genetic testing is not available or inconclusive (5-10% of cases), plasma copeptin measurement is the preferred next step. 1

Copeptin diagnostic thresholds:

• Baseline plasma copeptin >21.4 pmol/L is diagnostic for nephrogenic diabetes insipidus in adults 1, 2
• Plasma copeptin <21.4 pmol/L should prompt testing for central diabetes insipidus or primary polydipsia 1, 2
• For central diabetes insipidus, copeptin <4.9 pmol/L after hypertonic saline stimulation differentiates central diabetes insipidus from primary polydipsia with high diagnostic accuracy 4

Important caveats: Copeptin measurement is more established in adults; pediatric diagnostic values are less well-defined 1. Direct AVP measurement is technically challenging and not recommended due to hormone instability 1, 4.

Stimulation Tests for Copeptin

When baseline copeptin is indeterminate (<21.4 pmol/L), perform stimulation testing:

Hypertonic saline infusion test:

• More accurate than water deprivation test for differentiating central diabetes insipidus from primary polydipsia 4
• Requires sodium monitoring every 30 minutes during infusion 4
• Side effects are common 4

Arginine infusion test:

• Simpler and better tolerated alternative to hypertonic saline 4
• Significantly stimulates copeptin release 4

Water Deprivation Test (Traditional Approach)

The water deprivation test remains an option when copeptin testing is unavailable, though it has limited diagnostic accuracy and is cumbersome for patients. 5, 4, 6

Water deprivation test interpretation:

• Urine osmolality >680 mOsm/kg after water deprivation has 100% sensitivity for diagnosing primary polydipsia 6
• Urine osmolality >800 mOsm/kg has 96% sensitivity and 100% specificity for primary polydipsia 6
• Post-deprivation desmopressin administration helps differentiate central from nephrogenic diabetes insipidus: response indicates central diabetes insipidus, no response indicates nephrogenic diabetes insipidus 5, 7

Critical limitation: Plasma AVP levels during water deprivation do not reliably differentiate between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia 6. The test duration is approximately 17 hours and overlapping results occur frequently, particularly in partial forms 4, 8.

Differential Diagnosis Considerations

Key distinguishing features to evaluate:

• Acquired nephrogenic diabetes insipidus: adult onset, lithium intake history 1
• Central diabetes insipidus: response to desmopressin (DDAVP) 1
• Primary polydipsia: response to water deprivation 1
• Diabetes mellitus: high urine osmolality, hyperglycemia, glucosuria 1

Diagnostic Algorithm Summary

1. Measure serum sodium, serum osmolality, and urine osmolality in all patients with polyuria/polydipsia 1, 2
2. If nephrogenic diabetes insipidus suspected: perform genetic testing first 1, 2
3. If genetic testing unavailable/inconclusive: measure plasma copeptin 1, 2
   • Copeptin >21.4 pmol/L = nephrogenic diabetes insipidus 1, 2
   • Copeptin <21.4 pmol/L = proceed to stimulation test (hypertonic saline or arginine) 1, 4
4. If copeptin unavailable: perform water deprivation test with desmopressin challenge 5, 6, 7