What are the diagnostic tests for diabetes insipidus?

Diagnostic Testing for Diabetes Insipidus

The diagnosis of diabetes insipidus requires demonstrating inappropriately dilute urine (osmolality <200 mOsm/kg) in the presence of high-normal or elevated serum sodium/osmolality, followed by plasma copeptin measurement or desmopressin challenge to distinguish central from nephrogenic forms. 1

Initial Laboratory Assessment

The cornerstone of diagnosis involves documenting the pathognomonic laboratory pattern:

• Measure simultaneous serum sodium, serum osmolality, and urine osmolality during periods when the patient is symptomatic with polyuria 2, 1
• A urine osmolality <200 mOsm/kg combined with serum osmolality ≥300 mOsm/kg or elevated serum sodium confirms diabetes insipidus 1, 3
• Do not assume normal basic labs rule out diabetes insipidus—you must specifically document this relationship during elevated serum osmolality 1
• If urine is appropriately concentrated relative to serum osmolality, diabetes insipidus is effectively ruled out 1

Distinguishing Central vs. Nephrogenic Diabetes Insipidus

Once diabetes insipidus is confirmed, determine the subtype:

Plasma Copeptin Measurement (Preferred Modern Approach)

• Baseline plasma copeptin >21.4 pmol/L is diagnostic for nephrogenic diabetes insipidus in adults 1, 3
• Copeptin <21.4 pmol/L requires further testing to distinguish central diabetes insipidus from primary polydipsia 1
• For distinguishing central DI from primary polydipsia, copeptin measurement after hypertonic saline stimulation with a cutoff of 4.9 pmol/L provides superior diagnostic accuracy compared to water deprivation testing 4
• Copeptin is a stable surrogate marker for arginine vasopressin (AVP) and overcomes technical limitations of direct AVP measurement 4, 5

Desmopressin (DDAVP) Challenge Test (Alternative/Traditional Approach)

• Administration of desmopressin results in increased urine osmolality and decreased urine volume in central diabetes insipidus, while nephrogenic diabetes insipidus shows no response 2, 1, 3
• This functional test distinguishes central from nephrogenic forms when copeptin measurement is unavailable 1, 6
• Prior to desmopressin administration, confirm serum sodium is normal to avoid hyponatremia risk 7

Water Deprivation Test (Historical Gold Standard, Now Less Preferred)

• The traditional water deprivation test has limited diagnostic accuracy, is cumbersome (17 hours duration), and has been largely superseded by copeptin-based testing 4, 5
• This test may still be used when copeptin measurement is unavailable, but requires close monitoring 6, 8

Genetic Testing

• If nephrogenic diabetes insipidus is confirmed (copeptin >21.4 pmol/L or lack of DDAVP response), perform genetic testing with a multigene panel including at least AQP2, AVPR2, and AVP genes 1, 3
• Genetic testing identifies the cause in 90-95% of congenital nephrogenic diabetes insipidus cases 1

Imaging Studies

Once central diabetes insipidus is confirmed biochemically, MRI with and without IV contrast using high-resolution pituitary or skull base protocols is mandatory 2, 1, 3

• Thin-section T1-weighted images identify the typical T1 signal hyperintensity ("bright spot") of normal neurosecretory granules in the posterior pituitary 2
• Absence of this bright spot suggests central diabetes insipidus or ectopic posterior pituitary 2, 3
• MRI detects mass lesions (craniopharyngioma, germ-cell tumors, histiocytosis), infiltrative processes (sarcoidosis, lymphocytic hypophysitis), and traumatic etiologies 2, 3
• CT with IV contrast is less sensitive than MRI and should only be considered in emergency settings, not as first-line investigation 2

Differential Diagnosis Exclusion

• Primary polydipsia typically shows lower (not elevated) serum sodium and osmolality due to excessive water intake 1, 3
• Patients with primary polydipsia respond to water deprivation with appropriate urine concentration 3
• High-normal serum osmolality (around 300 mOsm/kg) argues strongly against primary polydipsia 1, 3
• Poorly controlled diabetes mellitus shows high urine osmolality, hyperglycemia, and glucosuria—distinctly different from the dilute urine of diabetes insipidus 1

Critical Diagnostic Algorithm

1. Document the pathognomonic pattern: Measure simultaneous serum and urine osmolality during polyuria 1
2. If urine osmolality <200 mOsm/kg with serum osmolality ≥300 mOsm/kg → Diabetes insipidus confirmed 1, 3
3. Measure baseline plasma copeptin: >21.4 pmol/L = nephrogenic DI; <21.4 pmol/L = proceed to step 4 1, 3
4. If copeptin <21.4 pmol/L: Perform hypertonic saline stimulation with copeptin measurement (cutoff 4.9 pmol/L) OR desmopressin challenge 1, 4
5. If central DI confirmed: Obtain MRI with contrast using pituitary protocols 2, 3
6. If nephrogenic DI confirmed: Perform genetic testing (AQP2, AVPR2, AVP genes) 1, 3

Common Pitfalls

• Never initiate desmopressin treatment before confirming normal serum sodium and establishing the specific DI subtype, as this can cause life-threatening hyponatremia 3, 7
• Do not order MRI as the initial diagnostic test—biochemical confirmation must come first 1
• Borderline or unclear osmolality patterns require copeptin measurement or functional testing; do not make assumptions 1
• If genetic testing or copeptin measurement is unavailable or inconclusive (5-10% of cases), functional testing with desmopressin challenge becomes mandatory 1