What is the diagnosis and treatment approach for a patient with diabetes insipidus?

Diagnosis and Treatment of Diabetes Insipidus

Initial Diagnostic Approach

Suspect diabetes insipidus in any patient presenting with polyuria (>3 liters/24 hours in adults), 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

Essential Initial Laboratory Work-Up

• Measure serum sodium, serum osmolality, and urine osmolality simultaneously as the first biochemical tests to confirm the diagnosis 1, 2
• The combination of urine osmolality <200 mOsm/kg with high-normal or elevated serum sodium definitively confirms diabetes insipidus 1
• Obtain a 24-hour urine volume measurement to quantify polyuria 1
• First rule out diabetes mellitus by checking blood glucose levels, as elevated glucose indicates diabetes mellitus rather than diabetes insipidus 1

Distinguishing Central from Nephrogenic Diabetes Insipidus

Plasma copeptin measurement is now the primary test to differentiate between central and nephrogenic diabetes insipidus, replacing the traditional water deprivation test in many centers 1, 2:

• Copeptin >21.4 pmol/L is diagnostic for nephrogenic diabetes insipidus 1, 2
• Copeptin <21.4 pmol/L indicates central diabetes insipidus or primary polydipsia and requires additional testing 1
• If copeptin testing is unavailable, a desmopressin trial can differentiate: response indicates central DI, no response indicates nephrogenic DI 1

Required Additional Work-Up

• For suspected central diabetes insipidus: 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
• For confirmed nephrogenic diabetes insipidus: perform genetic testing with a multigene panel including AVPR2, AQP2, and AVP genes, even in adults, to confirm diagnosis and guide family counseling 1, 2

Treatment of Central Diabetes Insipidus

Desmopressin is the treatment of choice for central diabetes insipidus and can be administered via multiple routes (intranasal, oral, subcutaneous, or intravenous). 1, 3, 4

Desmopressin Dosing

• For treatment-naïve patients: start with 2-4 mcg daily administered as one or two divided doses by subcutaneous or intravenous injection 4
• Adjust morning and evening doses separately for adequate diurnal rhythm of water turnover 4
• For patients switching from intranasal desmopressin: start with 1/10th the daily maintenance intranasal dose administered by subcutaneous or intravenous injection 4

Critical Monitoring for Desmopressin Therapy

The main complication of desmopressin therapy is hyponatremia, which can be life-threatening, leading to seizures, coma, respiratory arrest, or death. 4

• Ensure serum sodium is normal before starting or resuming desmopressin 4
• Check serum sodium within 7 days and at 1 month after initiating therapy, then periodically during treatment 1, 4
• Monitor more frequently in patients ≥65 years and those at increased risk of hyponatremia 4
• If hyponatremia occurs, desmopressin may need to be temporarily or permanently discontinued 4

Important Contraindications

Desmopressin is contraindicated in patients at increased risk of severe hyponatremia, including those with excessive fluid intake, illnesses causing fluid/electrolyte imbalances, and those using loop diuretics or systemic/inhaled glucocorticoids 4

Treatment of Nephrogenic Diabetes Insipidus

Desmopressin is ineffective and not indicated for nephrogenic diabetes insipidus. 4 Treatment instead focuses on reducing urine output through dietary modifications and pharmacological interventions.

Pharmacological Treatment

For symptomatic infants and children with nephrogenic diabetes insipidus, start combination therapy with thiazide diuretics and prostaglandin synthesis inhibitors (NSAIDs). 1, 2, 3

• Thiazide diuretics combined with a low-salt diet can reduce diuresis by up to 50% in the short term through mild volume depletion and increased proximal sodium/water reabsorption 2, 3
• Add NSAIDs (prostaglandin synthesis inhibitors) to enhance collecting duct water permeability 2, 3
• Add amiloride to thiazide therapy if hypokalemia develops 2
• NSAIDs are contraindicated during pregnancy and should be considered for discontinuation once patients reach adulthood or achieve complete continence 2

Essential Dietary Modifications

Implement a low-salt diet (≤6 g/day) and protein restriction (<1 g/kg/day) with dietetic counseling to reduce renal osmotic load and minimize urine volume. 1, 2, 3

• For infants with nephrogenic diabetes insipidus, provide normal-for-age milk intake (not water) to ensure adequate caloric intake 1, 2
• Consider tube feeding (nasogastric or gastrostomy) in infants and children with repeated vomiting, dehydration episodes, and/or failure to thrive 2, 3

Universal Management Principles for All Diabetes Insipidus Types

Fluid Management: The Most Critical Aspect

Patients with diabetes insipidus must have free access to fluid 24/7 to prevent dehydration, hypernatremia, growth failure, and constipation—restricting water access is a life-threatening error. 1, 2, 3

• For patients capable of self-regulation, fluid intake should be determined by their own thirst sensation rather than prescribed amounts, as their osmosensors are typically more sensitive and accurate than any medical calculation 1, 2, 3
• Infants and toddlers with diabetes insipidus cannot clearly express thirst, requiring caregivers to offer water frequently on top of regular fluid intake 1
• Individuals with cognitive impairment similarly cannot self-regulate and require close monitoring of weight, fluid balance, and biochemistry with proactive water offering 1

Intravenous Fluid Management

For intravenous rehydration in diabetes insipidus, use 5% dextrose in water (hypotonic fluid) at usual maintenance rates—NOT normal saline or electrolyte solutions. 1, 2

• When fasting is required (>4 hours), administer intravenous 5% dextrose in water at maintenance rate with close monitoring 2
• Avoid electrolyte-containing solutions like Pedialyte, which contains approximately 1,035 mg of sodium per liter and represents a substantial electrolyte load 1

Monitoring and Follow-Up

Clinical Follow-Up Schedule

• Infants (0-12 months): clinical follow-up including weight and height measurements every 2-3 months 1
• Adults: annual clinical follow-up including weight measurements 1

Laboratory Monitoring

• Infants (0-12 months): blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2-3 months 1
• Adults: annual blood tests including sodium, potassium, chloride, bicarbonate, creatinine, and uric acid 1
• Urinalysis including osmolality: annually for all age groups 1
• 24-hour urine volume and protein-creatinine or albumin-creatinine ratio: annually for adults 1

Imaging Follow-Up

• Perform renal ultrasound at least every 2 years to monitor for urinary tract dilation and/or bladder dysfunction from polyuria 1, 2
• The interval can be extended to 5 years for stable patients 1
• Ultrasound should be performed before and after bladder emptying, as dilation improves with double voiding in about one-third of patients 1

Chronic Kidney Disease Risk

Patients with diabetes insipidus have an increased risk of chronic kidney disease, with approximately 50% of adult patients having CKD stage ≥2, requiring more frequent follow-up according to KDIGO guidelines. 1

Emergency Management

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

• For emergency intravenous rehydration, use water and dextrose or glucose (e.g., 5% dextrose) 2
• Maintain close observation of clinical status, including neurological condition, fluid balance, body weight, and serum electrolytes 2
• Urgent evaluation is required for hypernatremic dehydration (serum sodium >145 mmol/L) with inability to access water, as this is a life-threatening condition 1

Multidisciplinary Care

Patients with diabetes insipidus should be managed by a multidisciplinary team including a (pediatric) nephrologist, dietitian, psychologist, social worker, and urologist. 1