What are the diagnostic steps and treatment options for nephrogenic diabetes insipidus?

Diagnostic Approach and Management of Nephrogenic Diabetes Insipidus

Genetic testing is the preferred first-line diagnostic approach for suspected nephrogenic diabetes insipidus (NDI), as it provides an early and definitive diagnosis while avoiding potentially harmful diagnostic procedures. 1

Initial Diagnostic Evaluation

Clinical Suspicion

• Suspect NDI in:
  • Infants/children with polyuria, polydipsia, failure to thrive, and hypernatremic dehydration
  • Adults with unexplained polyuria and polydipsia 1, 2

Initial Laboratory Assessment

1. Measure serum sodium, serum osmolality, and urine osmolality
2. Pathognomonic findings:
   • Inappropriately diluted urine (urinary osmolality <200 mOsm/kg H₂O)
   • High-normal or elevated serum sodium 1, 2

Diagnostic Algorithm

First-Line Diagnostic Test

• Genetic testing for suspected NDI cases 1
  • Use massively parallel sequencing-based multigene panel including:
    • AVPR2 (X-linked NDI, ~90% of cases)
    • AQP2 (autosomal recessive or dominant NDI, ~10% of cases)
    • AVP (for differential diagnosis of central DI) 1, 3
  • Perform in laboratories accredited for diagnostic genetic testing
  • Include copy number variant analysis

Special Considerations for Genetic Testing

• Test umbilical cord blood in male offspring of known heterozygote female carriers of AVPR2 mutations
• Test all symptomatic females for both AVPR2 and AQP2 mutations 1

Alternative Diagnostic Tests (if genetic testing unavailable/inconclusive)

1. Plasma copeptin measurement (stable surrogate for AVP)

   • Baseline levels >21.4 pmol/l diagnostic for NDI in adults 1
   • If <21.4 pmol/l, further testing needed to differentiate from central DI or primary polydipsia

2. Water deprivation test

   • Only if genetic testing and copeptin measurement unavailable
   • Caution: potentially harmful, especially in children 1, 4

Differential Diagnosis

• Central diabetes insipidus (AVP deficiency)
• Primary polydipsia
• Poorly controlled diabetes mellitus
• Secondary forms of inherited NDI (Bartter syndrome)
• Distal renal tubular acidosis
• Nephronophthisis and ciliopathies
• Apparent mineralocorticoid excess
• Acquired NDI (lithium-induced) 1, 5

Treatment Approach

Non-Pharmacological Management

1. Fluid management

   • Ad libitum access to fluid to prevent dehydration
   • Allow self-regulation based on thirst in capable patients 1
   • For infants: normal-for-age milk intake instead of water to ensure adequate calories

2. Dietary modifications

   • Low-salt diet (<6 g/day or 2.4 g sodium)
   • Low-protein diet (<1 g/kg/day)
   • Adequate caloric intake 1, 2

Pharmacological Treatment

1. First-line combination therapy:

   • Thiazide diuretics (reduces urine output by up to 50%)
   • Prostaglandin synthesis inhibitors (NSAIDs)
   • Amiloride (particularly for lithium-induced NDI) 1, 6

2. Dosing for children:

   • Hydrochlorothiazide: 3 mg/kg/day
   • Amiloride: 0.3 mg/kg/day (divided three times daily) 6

Management of Acute Dehydration

1. Intravenous rehydration:

   • Use 5% dextrose in water (not isotonic saline)
   • Initial rate calculation to avoid decrease in serum sodium >8 mmol/l/day
   • Close monitoring of clinical status, fluid balance, weight, and electrolytes 1, 7

2. Fluid administration rates:

   • Adults: 25-30 mL/kg/24h
   • Children (first 10 kg): 100 mL/kg/24h
   • Children (10-20 kg): 50 mL/kg/24h
   • Children (remaining weight): 20 mL/kg/24h 2

Long-term Monitoring

• Regular blood tests every 3-12 months (more frequent in children)
  • Electrolytes
  • Renal function
  • Uric acid levels
• Ultrasound monitoring of urinary tract every 2-3 years
  • To detect hydronephrosis
  • Bladder wall hypertrophy
  • Post-micturition residue 2

Genetic Counseling

• Recommend counseling for affected individuals and carriers
• Discuss inheritance patterns, recurrence risks, and implications for family planning
• Consider prenatal testing for pregnancies at increased risk 1

Pitfalls to Avoid

• Don't use isotonic saline for routine rehydration (only for hypovolemic shock)
• Don't administer dextrose 5% as a bolus (risk of rapid decrease in serum sodium)
• Don't correct hypernatremia too quickly (limit sodium decrease to <8 mmol/L/day)
• Don't overlook the need for specialized care in hospitalized patients 1, 2, 7