Diagnostic Algorithm for Diabetes Insipidus
Initial Baseline Assessment
Begin by measuring serum sodium, serum osmolality, urine osmolality, and urine volume to establish baseline values 1. The combination of polyuria with inappropriately diluted urine (osmolality <200 mOsm/kg H₂O) alongside high-normal or elevated serum sodium is pathognomonic for diabetes insipidus 1.
- If urine osmolality is <300 mOsm/kg in the setting of normal-to-high serum osmolality, this confirms failure of urinary concentration and indicates diabetes insipidus 2
- Construct a comprehensive family history and pedigree to identify potential familial cases, particularly important for suspected congenital nephrogenic DI 1
Primary Diagnostic Testing: Copeptin Measurement
Plasma copeptin measurement is now the preferred initial diagnostic approach, serving as a stable surrogate marker for arginine vasopressin 1.
Copeptin-Based Diagnostic Thresholds:
- Baseline plasma copeptin >21.4 pmol/L is diagnostic for nephrogenic DI in adults 1, 2
- For central DI, copeptin <2.5 pmol/L with plasma osmolality >290 mOsm/kg confirms the diagnosis 3
- Copeptin levels can be measured without prior fluid deprivation for nephrogenic DI diagnosis 4
Stimulated Copeptin Testing (when baseline is indeterminate):
- Hypertonic saline infusion with copeptin measurement: a copeptin level of 4.9 pmol/L differentiates central DI from primary polydipsia with high diagnostic accuracy 4
- Critical caveat: Sodium monitoring every 30 minutes is mandatory during hypertonic saline testing to prevent dangerous hypernatremia 4
- Alternative: Arginine infusion with subsequent copeptin measurement is simpler and better tolerated than hypertonic saline, though head-to-head comparison data are still lacking 4
Alternative/Traditional Testing: Water Deprivation Test
If copeptin testing is unavailable, the water deprivation test remains the gold standard, though it has significant limitations 5, 6.
Water Deprivation Test Interpretation:
- Urine osmolality >680 mOsm/kg after water deprivation rules out DI with 100% sensitivity 3
- Urine osmolality >800 mOsm/kg yields 96% sensitivity and 100% specificity for diagnosing primary polydipsia 3
- Important limitation: The test has a long duration (17 hours), is cumbersome for patients, and has limited overall diagnostic accuracy 4
- Direct AVP measurement during water deprivation does not reliably differentiate between central DI, nephrogenic DI, and primary polydipsia 3
Distinguishing Central from Nephrogenic DI
Once DI is confirmed, differentiation between central and nephrogenic forms is essential:
For Nephrogenic DI:
- Early genetic testing is strongly recommended when congenital nephrogenic DI is suspected, as it provides definitive diagnosis and enables precise genetic counseling 1
- Baseline copeptin >21.4 pmol/L confirms nephrogenic DI 1, 2
- Look for medication history (lithium, loop diuretics) or systemic conditions causing renal resistance 7
For Central DI:
- Copeptin <2.5 pmol/L with elevated plasma osmolality confirms central DI 3
- MRI imaging of the pituitary/hypothalamus is needed to determine etiology once central DI is biochemically confirmed 8
- Assess for history of head trauma, pituitary surgery, or infiltrative diseases 1
Special Populations
Infants and Children:
- Feeding difficulties, failure to thrive, vomiting, and hypernatremic dehydration are common presentations 1
- Genetic testing should be prioritized early in this population 1
Adults:
- Polydipsia is the predominant symptom at diagnosis 1
- More frequent sodium monitoring is required in patients ≥65 years old 7
Critical Pitfall to Avoid
Never restrict water access during the diagnostic workup unless actively performing a water deprivation test under close monitoring 1, 2. Patients with DI require ad libitum fluid access to prevent life-threatening dehydration, hypernatremia, and associated complications 2. Ensure serum sodium is normal before initiating any diagnostic testing 7.