What are the causes, diagnostic workup, and management of nephrogenic diabetes insipidus?

Nephrogenic Diabetes Insipidus: Causes, Diagnosis, and Management

Pathophysiology and Causes

Nephrogenic diabetes insipidus (NDI) results from the kidney's insensitivity to arginine vasopressin (AVP), preventing urine concentration despite normal or elevated plasma AVP levels. 1

Congenital Causes

• X-linked recessive mutations in the AVPR2 gene (encoding the vasopressin V2 receptor) account for approximately 90% of hereditary NDI cases 2
• Autosomal recessive or dominant mutations in the AQP2 gene (encoding aquaporin-2 water channels) cause the remaining 10% of hereditary cases 2
• The molecular defect involves misfolded proteins retained in the endoplasmic reticulum, preventing proper trafficking to the cell membrane 1

Acquired Causes

• Lithium therapy is the most common acquired cause, affecting approximately 10% of patients on long-term treatment (≥15 years) 3
• Hypercalcemia and hypokalemia disrupt the aquaporin-2 shuttle mechanism 4
• Other medications including foscarnet, clozapine, antimicrobials, and cytostatics in critically ill patients 3
• Chronic kidney disease and other inherited kidney diseases affecting concentrating ability 1

Clinical Presentation

Infants and Children

• Mean age at diagnosis is approximately 4 months with polyuria, failure to thrive, and signs of dehydration as typical presenting symptoms 1
• Hypernatremic dehydration with serum osmolality usually >300 mOsm/kg H₂O 1
• Inappropriately dilute urine with osmolality typically <200 mOsm/kg H₂O despite elevated serum osmolality 1
• Gastroesophageal reflux and vomiting from large fluid volume intake 1
• Infants are at particular risk as they cannot express thirst clearly and lack free access to fluids 5

Adults

• Polydipsia is the predominant symptom at diagnosis in older children and adults 1
• Polyuria defined as >3 liters per 24 hours 5
• Patients may present with weight loss, fatigue, and confusion rather than classic polydipsia, especially in elderly 5

Diagnostic Workup

Initial Laboratory Assessment

Measure serum sodium, serum osmolality, and urine osmolality simultaneously as the initial biochemical workup. 5, 6

• Diagnostic triad: Polyuria (>3 L/24h in adults) + inappropriately dilute urine (osmolality <200 mOsm/kg) + high-normal or elevated serum sodium (>145 mEq/L with restricted water access) 5, 6
• Serum osmolality typically >300 mOsm/kg H₂O due to hypernatremia 1
• Urine osmolality <200 mOsm/kg H₂O (though can be higher in milder cases) 1

Distinguishing Central from Nephrogenic DI

Plasma copeptin measurement is the primary test to differentiate central from nephrogenic DI. 7, 6

• Copeptin >21.4 pmol/L is diagnostic for nephrogenic DI in adults, indicating elevated ADH levels 7, 6
• Copeptin <21.4 pmol/L suggests central DI or primary polydipsia, requiring additional testing 6
• Alternative approach: Desmopressin trial - response indicates central DI, minimal/no response confirms nephrogenic DI 7, 6

Confirmatory Testing

• Water deprivation test: Patients with NDI maintain urine osmolality <300 mOsm/kg H₂O despite water deprivation 4, 2
• Desmopressin administration: Little or no increase in urine osmolality confirms NDI 4
• 24-hour urine collection for volume and osmolality measurement 6

Genetic Testing

Obtain genetic testing with a multigene panel including AVPR2, AQP2, and AVP genes if NDI is confirmed, even in adults. 6

Additional Workup

• Serum electrolytes, creatinine, and uric acid 6
• MRI of the sella with dedicated pituitary sequences if central DI cannot be excluded 6
• Renal ultrasound to assess for urinary tract dilation from chronic polyuria 6

Management

Universal Principles

All NDI patients must have free access to fluid 24/7 - this is non-negotiable and life-saving. 5, 6

• Patients capable of self-regulation should determine fluid intake based on thirst sensation rather than prescribed amounts, as osmosensors are more sensitive than medical calculations 5, 6
• Never restrict water access - this is a life-threatening error leading to severe hypernatremic dehydration 6

Pharmacological Treatment

Initiate combination therapy with thiazide diuretics plus NSAIDs for symptomatic patients. 7, 6, 8

• Thiazide diuretics (e.g., hydrochlorothiazide) reduce urine output by inducing mild volume depletion, enhancing proximal tubule sodium and water reabsorption 8, 4
• NSAIDs (e.g., indomethacin) inhibit prostaglandin synthesis, reducing glomerular filtration rate and enhancing water reabsorption 8, 4
• Amiloride can be used as an alternative or addition, particularly in lithium-induced NDI 8, 3
• Combination therapy can reduce urine output and required water intake by up to 50% 6

Dietary Modifications

Implement a low-salt diet (≤6 g/day) and protein restriction (<1 g/kg/day) to reduce renal osmotic load. 5, 6, 2

• Low-sodium diet decreases obligatory water excretion 6, 8
• Protein restriction minimizes urea-driven osmotic diuresis 6, 8

Emergency Management

For hypernatremic dehydration, use 5% dextrose in water (hypotonic fluid) at usual maintenance rates, NOT normal saline. 1, 7, 6

• Dextrose 5% solution matches the dilute urinary losses in NDI 1
• Do not administer as a bolus due to risk of rapid sodium decrease 1
• Isotonic fluids are only appropriate for hypovolemic shock, which is exceedingly rare in NDI 1
• Allow the patient to drink to thirst if possible 1

Monitoring and Follow-up

Check serum sodium within 7 days and at 1 month after starting treatment, then periodically, as hyponatremia is the main complication. 5, 6

Infants (0-12 months)

• Clinical follow-up with weight and height measurements every 2-3 months 6
• Blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2-3 months 6
• Urinalysis including osmolality annually 6

Adults

• Annual clinical follow-up with weight measurements 6
• Annual blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) 6
• Annual urinalysis with osmolality, protein-creatinine ratio, and 24-hour urine volume 6

Imaging

• Renal ultrasound at least every 2 years to monitor for urinary tract dilation and bladder dysfunction 6
• Interval can be extended to 5 years for stable patients 6
• Perform ultrasound before and after bladder emptying, as dilation improves with double voiding in one-third of patients 6

Special Populations

Infants require normal-for-age milk intake for adequate calories, not electrolyte solutions. 6

• Infants and cognitively impaired patients cannot self-regulate and require caregivers to offer water frequently 6
• Approximately 50% of adult NDI patients have CKD stage ≥2, requiring more frequent monitoring per KDIGO guidelines 5, 6

Critical Pitfalls to Avoid

• Do not confuse with diabetes mellitus - check blood glucose first to rule out osmotic diuresis from glucosuria 6
• Avoid paradoxical water intoxication when initiating thiazide-NSAID combination therapy - monitor water balance closely and implement strict protocols 9
• Do not use normal saline for rehydration in NDI - use 5% dextrose instead 1, 7
• Recognize that urine osmolality 200-300 mOsm/kg can occur in CKD without representing true DI - diagnosis requires osmolality definitively <200 mOsm/kg with serum hyperosmolality 5, 6
• For lithium-induced NDI, close monitoring with 12-hour trough lithium levels of 0.4-0.6 mmol/L and yearly urine volume measurements can help prevent progression 3

Complications and Long-term Outcomes

• Approximately 46% develop urological complications including nocturnal enuresis, incomplete bladder voiding, and urinary tract dilation 6
• Mental health conditions are more prevalent in NDI patients than the general population, though etiology remains unclear 1
• Without proper treatment, severe dehydration and hypernatremia lead to high morbidity and mortality 8