What is the diagnosis and treatment approach for Diabetes Insipidus (DI)?

Diagnosis of Diabetes Insipidus

Suspect diabetes insipidus in any patient presenting with polyuria, polydipsia, and inappropriately dilute urine (osmolality <200 mOsm/kg H₂O) combined with high-normal or elevated serum sodium—this triad is pathognomonic for the condition. 1

Initial Clinical Presentation

Key Symptoms to Identify

• Adults: Unexplained polydipsia and polyuria (>2.5 L per 24 hours despite attempts to reduce fluid intake) 2, 1
• Children: Polyuria, polydipsia, failure to thrive, and hypernatremic dehydration 3, 2
• Obtain comprehensive family history and construct a pedigree to identify potential familial cases, as genetic forms exist 1

Diagnostic Algorithm

Step 1: Initial Biochemical Work-Up (Mandatory)

Measure the following three parameters simultaneously 3, 2, 1:

• Serum sodium
• Serum osmolality
• Urine osmolality

The combination of urine osmolality <200 mOsm/kg H₂O with high-normal or elevated serum sodium confirms diabetes insipidus 1

Step 2: Distinguish Between Central vs. Nephrogenic DI

Use plasma copeptin levels as the primary differentiating test 2, 1:

• Copeptin >21.4 pmol/L → Suggests nephrogenic diabetes insipidus 2, 1
• Copeptin <21.4 pmol/L → Suggests central diabetes insipidus, proceed with further testing 2, 1

Step 3: Confirmatory Testing

For suspected nephrogenic DI:

• Perform morning urine osmolality test after overnight fluid avoidance 1
• Concentrations above 600 mOsm/L rule out diabetes insipidus 1
• Strongly pursue early genetic testing in all suspected cases, particularly in children and symptomatic females 3, 2, 1

Genetic testing panel should include at minimum 1:

• AVPR2 gene
• AQP2 gene
• AVP gene

For male offspring of known heterozygote female carriers of AVPR2 mutation:

• Perform genetic testing using umbilical cord blood 3

Step 4: Additional Diagnostic Considerations

Water deprivation test remains the classical gold standard but can be avoided if genetic testing provides definitive diagnosis 1, 4, 5. This is particularly important because genetic testing helps avoid unpleasant, challenging, and potentially harmful diagnostic procedures 1.

Imaging studies of the hypothalamic-pituitary region should be obtained to identify structural causes in suspected central DI 6, 5

Critical Diagnostic Pitfalls

• Early diagnosis prevents prolonged, unrecognized periods of severe hypertonic dehydration, which can cause significant morbidity and mortality 1, 7
• Genetic testing can provide early and definitive diagnosis with important implications for management, particularly in pediatric cases 1
• Always measure blood glucose to exclude diabetes mellitus, which can present with similar polyuria symptoms 3
• In patients with idiopathic central DI, close follow-up is mandatory since central DI can be the first sign of an underlying pathology (such as tumors or infiltrative disease) 5

Treatment Approach Based on Diagnosis

Central Diabetes Insipidus

Desmopressin is the treatment of choice and can be administered via multiple routes 8, 9:

• Starting dosage: 2-4 mcg daily as one or two divided doses by subcutaneous or intravenous injection 9
• Adjust morning and evening doses separately for adequate diurnal rhythm of water turnover 9
• Critical safety measure: Ensure serum sodium is normal before starting or resuming desmopressin 9
• Monitor serum sodium within 7 days and approximately 1 month after initiating therapy, then periodically 9
• Desmopressin is ineffective and not indicated for nephrogenic diabetes insipidus 9

Nephrogenic Diabetes Insipidus

For symptomatic infants and children, start combination therapy with thiazide diuretics and prostaglandin synthesis inhibitors (NSAIDs) 3, 2, 8:

• Thiazide diuretics combined with low-salt diet (≤6 g/day) can reduce diuresis by up to 50% in the short term 2, 8
• Add amiloride if hypokalemia develops 2
• Prostaglandin synthesis inhibitors are contraindicated during pregnancy 2

Dietary modifications are essential 3, 2:

• Low salt diet (≤6 g/day) and protein restriction (<1 g/kg/day) to reduce renal osmotic load 2
• Normal-for-age milk intake (instead of water) for infants to ensure adequate caloric intake 3, 2
• Consider tube feeding (nasogastric or gastrostomy) for repeated vomiting, dehydration episodes, or failure to thrive 3, 2, 8

Universal Management Principles (All Types)

Free access to fluid is absolutely essential in all patients with DI to prevent dehydration, hypernatremia, growth failure, and constipation 2, 8:

• Patients capable of self-regulating should determine fluid intake based on thirst sensation rather than prescribed amounts 2, 8
• Those who cannot self-regulate should be offered water frequently 2

When fasting is required (>4 hours):

• Administer intravenous 5% dextrose in water at maintenance rate with close monitoring 2

Each patient should have an emergency plan including a letter explaining their diagnosis with advice regarding intravenous fluid management 2

Monitoring Requirements

• Regular assessment of height and weight, especially in children 2
• Monitor serum sodium, potassium, chloride, bicarbonate, creatinine, and osmolality 2
• Assess urine osmolality and output 2
• Kidney ultrasound at least every 2 years to monitor for urinary tract dilatation and bladder dysfunction in nephrogenic DI 2
• More frequent sodium monitoring in patients ≥65 years and those at increased risk of hyponatremia 9