How do I use copeptin (C-terminal portion of provasopressin) to differentiate between diabetes insipidus (DI) and primary polydipsia in patients?

Using Copeptin to Differentiate Between Diabetes Insipidus and Primary Polydipsia

Baseline copeptin >21.4 pmol/L without any stimulation immediately diagnoses nephrogenic diabetes insipidus, while stimulated copeptin levels after hypertonic saline infusion or arginine/glucagon administration differentiate central diabetes insipidus from primary polydipsia using a cutoff of 4.9 pmol/L. 1, 2

Baseline Copeptin Measurement (No Stimulation Required)

For nephrogenic diabetes insipidus, measure baseline copeptin without any prior fluid deprivation or stimulation test:

• Copeptin >21.4 pmol/L = Nephrogenic DI (kidneys not responding to elevated vasopressin) 1, 3
• This threshold has been validated across multiple studies and unequivocally identifies nephrogenic DI 2, 4, 5
• No stimulation test needed when baseline copeptin exceeds this threshold 1, 6

Critical pitfall: A baseline copeptin <21.4 pmol/L does NOT rule out diabetes insipidus—it simply means you need stimulation testing to differentiate central DI from primary polydipsia 1, 3

Stimulated Copeptin Testing (For Central DI vs Primary Polydipsia)

When baseline copeptin is <21.4 pmol/L, you must perform osmotic or pharmacologic stimulation to differentiate central DI from primary polydipsia:

Hypertonic Saline Infusion Test (Gold Standard)

This is the most validated approach with superior diagnostic accuracy compared to water deprivation testing:

• Administer hypertonic saline infusion to raise serum sodium 2, 4, 5
• Copeptin <4.9 pmol/L after stimulation = Central DI 1, 2, 4, 5
• Copeptin ≥4.9 pmol/L after stimulation = Primary Polydipsia 2, 4, 5
• This cutoff has sensitivity and specificity >94% 6

Mandatory safety requirement: Monitor serum sodium every 30 minutes during the test to prevent dangerous hypernatremia 4, 5

Common side effects: Hypertonic saline frequently causes discomfort and side effects, which is why alternative stimulation methods are being studied 4

Alternative Stimulation Tests (Emerging Options)

Arginine infusion:

• Stimulates copeptin through non-osmotic mechanisms 4
• Better tolerated than hypertonic saline with fewer side effects 4
• Uses same 4.9 pmol/L cutoff for interpretation 4

Glucagon injection (1 mg subcutaneous):

• Stimulates the neurohypophysis and copeptin release 7
• Copeptin <4.6 pmol/L = Diabetes Insipidus (sensitivity 100%, specificity 90%) 7
• Copeptin ≥4.6 pmol/L = Primary Polydipsia 7
• Safer and simpler than hypertonic saline, though head-to-head comparisons are still needed 7, 4

Diagnostic Algorithm Summary

Step 1: Measure baseline copeptin without any stimulation or fluid deprivation 1, 2

Step 2: Interpret baseline result:

• If >21.4 pmol/L → Nephrogenic DI confirmed (stop here) 1, 6
• If <21.4 pmol/L → Proceed to Step 3 1, 3

Step 3: Perform stimulation test (hypertonic saline, arginine, or glucagon) 2, 7, 4

Step 4: Interpret stimulated copeptin:

• If <4.9 pmol/L (or <4.6 pmol/L for glucagon) → Central DI 2, 7, 4, 5
• If ≥4.9 pmol/L (or ≥4.6 pmol/L for glucagon) → Primary Polydipsia 2, 7, 4, 5

Key Advantages Over Water Deprivation Testing

Copeptin-based testing is superior to the traditional water deprivation test:

• Higher diagnostic accuracy (>94% sensitivity and specificity vs. limited accuracy with water deprivation) 2, 4, 5, 6
• Shorter test duration (hours vs. 17 hours for water deprivation) 2, 4
• Less cumbersome for patients 2, 4
• Direct measurement of the vasopressin system rather than indirect assessment 2, 5

Important caveat: The water deprivation test followed by desmopressin administration remains an alternative when copeptin testing is unavailable, though it has inferior diagnostic performance 1, 2

Confirming the Diagnosis Before Testing

Before measuring copeptin, confirm the patient actually has polyuria-polydipsia syndrome:

• Polyuria must be >3 liters/24 hours in adults 1, 8
• Urine osmolality must be <200 mOsm/kg with inappropriately dilute urine 1, 8
• Serum sodium should be high-normal or elevated (>145 mEq/L if water access restricted) 1, 8
• Rule out diabetes mellitus first with fasting glucose measurement 1, 8