What is the appropriate evaluation and management for a patient with suspected diabetes insipidus, including differentiation between central and nephrogenic forms and first‑line therapies?

Diabetes Insipidus: Evaluation and Management

Initial Clinical Recognition

Suspect diabetes insipidus in any patient presenting with the pathognomonic triad: polyuria (>2.5–3 L/24 hours), polydipsia, and inappropriately dilute urine (osmolality <200 mOsm/kg H₂O) combined with high-normal or elevated serum sodium. 1, 2

• In children, look specifically for polyuria, polydipsia, failure to thrive, and hypernatremic dehydration 1, 3
• Adults typically present with unexplained polydipsia and polyuria despite attempts to reduce fluid intake 1
• Critical pitfall: First rule out diabetes mellitus by checking fasting glucose and HbA1c, as diabetes mellitus causes polyuria through osmotic diuresis from glucosuria, not ADH deficiency 1

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Diagnostic Algorithm

Step 1: Initial Biochemical Work-Up

Measure serum sodium, serum osmolality, and urine osmolality simultaneously as the first-line diagnostic tests. 1, 2, 4

• The combination of urine osmolality <200 mOsm/kg with high-normal or elevated serum sodium (typically >145 mEq/L with restricted water access) confirms diabetes insipidus 1, 2
• Serum osmolality is typically >300 mOsm/kg H₂O in DI 1
• Also obtain 24-hour urine volume, serum creatinine, and electrolytes 1

Step 2: Differentiate Central vs. Nephrogenic DI

Use plasma copeptin measurement as the primary differentiating test—this is the most accurate and avoids the risks of water deprivation testing. 1, 4, 5, 6

• Copeptin >21.4 pmol/L = nephrogenic DI 1
• Copeptin <21.4 pmol/L = central DI or primary polydipsia 1

Alternative approach if copeptin unavailable: Perform a desmopressin trial 1

• Response to desmopressin (urine osmolality increase >50%, typically >61%) = central DI 1
• No response to desmopressin = nephrogenic DI 1

Avoid water deprivation testing when DI is strongly suspected, as it is uncomfortable, technically challenging, and may precipitate severe hypernatremic dehydration, seizures, and brain injury. 1, 5

Step 3: Identify Underlying Etiology

For central DI: 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 nephrogenic DI: Order genetic testing with a multigene panel including AVPR2, AQP2, and AVP genes with copy-number-variant analysis 1

• X-linked NDI (AVPR2 mutations) accounts for ~90% of congenital cases 1
• Autosomal NDI (AQP2 mutations) accounts for <10% of congenital cases 1
• Genetic testing provides definitive diagnosis and avoids hazardous provocative tests 1
• Review medication list for lithium and other drugs that can cause acquired nephrogenic DI 1

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Treatment Approach

Central Diabetes Insipidus

Desmopressin is the treatment of choice for central DI. 1, 2, 3, 7

Dosing regimen: 3, 7

• Starting dose: 2–4 mcg daily as one or two divided doses by subcutaneous or intravenous injection
• For patients switching from intranasal desmopressin: use 1/10th the daily maintenance intranasal dose
• Adjust morning and evening doses separately for adequate diurnal rhythm of water turnover
• Titrate based on adequate sleep duration and appropriate (not excessive) water turnover

Critical monitoring for hyponatremia: 7

• Ensure serum sodium is normal before starting or resuming desmopressin
• Measure serum sodium within 7 days and at 1 month after initiating therapy
• Monitor periodically during treatment, more frequently in patients ≥65 years
• If hyponatremia occurs, desmopressin may need temporary or permanent discontinuation

Nephrogenic Diabetes Insipidus

Use combination therapy with thiazide diuretics plus NSAIDs, along with dietary modifications. 1, 2, 3

Pharmacotherapy: 1, 2

• Thiazide diuretics combined with prostaglandin synthesis inhibitors (NSAIDs)
• This combination can reduce urine output and required water intake by up to 50% 1

Dietary modifications: 1, 2, 3

• Low-salt diet (≤6 g/day for adults, age-appropriate for children)
• Protein restriction (<1 g/kg/day for adults, age-appropriate for children)
• These reduce renal osmotic load and minimize urine volume 1

Note: Desmopressin is ineffective and not indicated for nephrogenic DI 7

Universal Management Principles for All DI Patients

Patients with DI must have free access to fluid 24/7 to prevent dehydration, hypernatremia, growth failure, and constipation. 1, 2, 3

• Patients capable of self-regulation should determine fluid intake based on thirst sensation rather than prescribed amounts, as their osmosensors are typically more sensitive than any medical calculation 1
• Never restrict water access in DI patients—this is a life-threatening error that leads to severe hypernatremic dehydration 1, 2

For emergency IV rehydration: Use 5% dextrose in water (hypotonic fluid) at usual maintenance rates, NOT normal saline or electrolyte solutions 1, 3

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Ongoing Monitoring and Follow-Up

Clinical Follow-Up Schedule

Infants (0–12 months): 1

• Clinical follow-up with weight and height measurements every 2–3 months
• Blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2–3 months
• Urinalysis including osmolality annually

Adults: 1

• Annual clinical follow-up including weight measurements
• Annual blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid)
• Annual urinalysis including osmolality, protein-creatinine or albumin-creatinine ratio, and 24-hour urine volume

Imaging Surveillance

Perform renal ultrasound at least every 2 years to monitor for urinary tract dilatation and/or bladder dysfunction from chronic polyuria. 1, 3

• Approximately 46% of patients develop urological complications including nocturnal enuresis and incomplete bladder voiding 1
• Interval can be extended to 5 years for stable patients 1
• Ultrasound should be performed before and after bladder emptying 1

Chronic Kidney Disease Risk

Patients with DI have increased risk of chronic kidney disease, with approximately 50% of adult patients developing CKD stage ≥2. 1, 3

• Follow KDIGO guidelines for CKD monitoring based on stage 1

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Emergency Planning

Each DI patient should have an emergency plan including: 2, 3

• A letter explaining their diagnosis with IV fluid management advice (5% dextrose in water, NOT normal saline)
• Contact information for their specialist
• Medical alert bracelet or card 2

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Multidisciplinary Care

Manage DI patients with a multidisciplinary team including a (pediatric) nephrologist, dietitian, psychologist, social worker, and urologist. 1