Diagnostic Approach to Diabetes Insipidus
Suspect diabetes insipidus in any patient presenting with polyuria (>3 L/24h in adults), polydipsia, and inappropriately dilute urine (osmolality <200 mOsm/kg) combined with high-normal or elevated serum sodium—this triad is pathognomonic for the condition. 1
Initial Clinical Assessment
Key Presenting Features
- Adults: Unexplained polydipsia and polyuria (>2.5 L per 24 hours despite attempts to reduce fluid intake) warrant evaluation 1
- Children: Polyuria, polydipsia, failure to thrive, and hypernatremic dehydration are the classic presentation 1
- Critical distinction: First check blood glucose to exclude diabetes mellitus (fasting glucose ≥126 mg/dL or random ≥200 mg/dL with symptoms), as diabetes mellitus causes polyuria through osmotic diuresis from glucosuria, not ADH deficiency 1
Step 1: Initial Biochemical Work-Up
- Serum sodium
- Serum osmolality
- Urine osmolality
- 24-hour urine volume
Diagnostic confirmation: The combination of urine osmolality <200 mOsm/kg with high-normal or elevated serum sodium confirms diabetes insipidus 1. A urine osmolality of 170 mOsm/kg is inappropriately dilute in the presence of serum hyperosmolality 1.
Important Caveat
Many conditions can cause urine osmolality in the 200-300 mOsm/kg range without representing true diabetes insipidus, including partial dehydration, chronic kidney disease, or early stages of various renal disorders 1. True DI requires urine osmolality definitively <200 mOsm/kg in the setting of serum hyperosmolality 1.
Step 2: Differentiate Central vs. Nephrogenic DI
Primary Method: Plasma Copeptin Measurement
Copeptin is now the preferred diagnostic test to distinguish between central and nephrogenic diabetes insipidus 1, 2:
- Copeptin >21.4 pmol/L: Diagnostic for nephrogenic DI in adults 3, 1, 2
- Copeptin <21.4 pmol/L: Indicates central DI or primary polydipsia; requires additional testing with hypertonic saline or arginine stimulation 3, 1
Copeptin (CT-proAVP) is released in an equimolar 1:1 ratio with AVP and is far more stable and easier to measure than AVP itself 3. Because copeptin values >21.4 pmol/L are significantly higher than those observed in patients with other polyuric disorders, for most adult patients with NDI no additional diagnostic testing is needed 3.
Alternative Method: Desmopressin Trial
If copeptin measurement is unavailable, a desmopressin trial can differentiate between central and nephrogenic DI 1:
- Response to desmopressin (increased urine osmolality, decreased urine output): Central DI
- No response to desmopressin: Nephrogenic DI
Step 3: Genetic Testing for Nephrogenic DI
If nephrogenic DI is confirmed, strongly recommend genetic testing using a massively parallel sequencing-based multigene panel that includes at least AVPR2, AQP2, and AVP genes 3, 1. This should be performed in a laboratory accredited for diagnostic genetic testing 3.
Rationale for genetic testing: 3
- Identifies the specific genetic cause in 90-95% of cases
- Distinguishes partial from complete NDI (important for prognosis and treatment)
- Enables presymptomatic testing for at-risk family members
- Informs reproductive counseling and family planning
- Identifies de novo mutations (occur in 20% of isolated cases)
Special consideration: Genetic testing is recommended even for females with overt NDI, as 10% of females with AVPR2 pathogenic variants develop the complete NDI phenotype due to X-inactivation 3.
Step 4: Water Deprivation Test (When Other Methods Unavailable)
The water deprivation test followed by desmopressin administration remains the gold standard when copeptin measurement is not available 1, 4, 5, but has important limitations and contraindications.
Absolute Contraindications: 6
- Confirmed nephrogenic DI (especially in infants and young children)
- Pre-existing hypernatremia (Na >145 mmol/L)
- Clinical evidence of dehydration
- Advanced chronic kidney disease (stage ≥G4)
Critical Pitfall
The water deprivation test has limited diagnostic accuracy compared to copeptin measurement and carries significant risk of hypernatremic dehydration and neurological complications, particularly in children 6. Avoid this test when possible in favor of copeptin measurement and genetic testing 6.
Step 5: Determine Etiology of Central DI
If central DI is confirmed, obtain MRI of the sella with dedicated pituitary sequences, as approximately 50% of cases have identifiable structural causes, including tumors, infiltrative diseases, or inflammatory processes 1. All patients with newly developed hormonal deficiencies should undergo MRI with pituitary or sella slices 1.
Additional Monitoring
- Serum electrolytes (sodium, potassium, chloride, bicarbonate)
- Serum creatinine and uric acid
- Follow-up imaging as clinically indicated 1
Differential Diagnoses to Exclude
| Condition | Distinguishing Features |
|---|---|
| Acquired NDI | Adult onset, induced by lithium intake [3] |
| Primary polydipsia | Response to water deprivation; copeptin <21.4 pmol/L [3] |
| Diabetes mellitus | High urine osmolality, hyperglycemia, glucosuria [3,1] |
| SIADH | Hyponatremia, low serum osmolality, inappropriately high urine osmolality [1] |
Critical Safety Considerations
Before initiating or resuming any treatment, ensure serum sodium is normal 7. Measure serum sodium within 7 days and approximately 1 month after starting therapy, and periodically during treatment 7. More frequent monitoring is required in patients ≥65 years and those at increased risk of hyponatremia 7.