What is nephrogenic diabetes insipidus?

Nephrogenic Diabetes Insipidus: Definition and Overview

Nephrogenic diabetes insipidus (NDI) is a disorder in which the kidneys cannot concentrate urine because the distal nephron is insensitive to arginine vasopressin (AVP), resulting in massive urinary water losses despite normal or elevated AVP levels. 1

Pathophysiology

• The fundamental defect in NDI is the kidney's inability to respond to AVP (also called antidiuretic hormone), which normally signals the collecting ducts to reabsorb water and concentrate urine. 1, 2

• At the molecular level, most hereditary cases involve mutations in either the AVPR2 gene (encoding the vasopressin type 2 receptor, ~90% of cases) or the AQP2 gene (encoding aquaporin-2 water channels, ~10% of cases). 3

• These genetic defects typically cause misfolded proteins that become trapped in the endoplasmic reticulum and cannot reach the apical membrane of collecting duct cells where they normally function. 4

• Acquired NDI—which is more common than hereditary forms—most frequently results from lithium therapy, chronic kidney disease, or electrolyte disturbances (particularly hypercalcemia and hypokalemia). 5, 6, 7

Clinical Presentation

Hallmark Symptoms

• Polyuria and polydipsia are the defining clinical features, developing as compensatory mechanisms to prevent life-threatening dehydration and hypernatremia. 1

• Patients with free access to water and intact thirst mechanisms typically maintain normal serum sodium levels through compensatory drinking that matches their urinary losses. 1

Age-Specific Presentations

Infants and Young Children:

• Hereditary NDI typically presents around 4 months of age with polyuria, failure to thrive, and hypernatremic dehydration. 4

• Affected infants show serum osmolality typically >300 mOsm/kg H₂O with inappropriately dilute urine (<200 mOsm/kg H₂O). 4

• Large fluid volumes required for compensation can cause gastroesophageal reflux and vomiting, sometimes described as "greedy" drinking followed by vomiting. 4

Adults and Older Children:

• Polydipsia becomes the predominant symptom, with patients often drinking several liters daily based on intense thirst. 4

• When properly compensated with adequate water access, serum sodium remains normal despite massive urine output. 1

Diagnostic Criteria

• The diagnostic triad consists of: (1) polyuria (>3 L/24 hours in adults), (2) inappropriately dilute urine (osmolality <200 mOsm/kg H₂O), and (3) high-normal or elevated serum osmolality/sodium. 1, 4

• Initial biochemical workup requires simultaneous measurement of serum sodium, serum osmolality, and urine osmolality. 1

• Plasma copeptin measurement (a stable AVP surrogate) is now the primary test to distinguish central from nephrogenic DI: levels >21.4 pmol/L indicate nephrogenic DI, while levels <21.4 pmol/L suggest central DI or primary polydipsia. 4, 5

• The traditional water deprivation test followed by desmopressin administration remains the gold standard when copeptin testing is unavailable—NDI patients show no significant increase in urine osmolality after desmopressin. 4, 6

Management Principles

Non-Pharmacological Cornerstone

• Free access to water 24/7 is absolutely essential and represents the cornerstone of NDI management—restricting water access is a life-threatening error. 1, 2, 4

• Patients capable of self-regulation should drink according to thirst sensation rather than prescribed amounts, as their osmosensors are more sensitive and accurate than any medical calculation. 4

• Dietary modifications include sodium restriction (≤6 g/day) and protein restriction (<1 g/kg/day) to reduce renal solute load and obligatory water excretion. 2, 4

Pharmacological Treatment

• First-line pharmacological therapy combines thiazide diuretics with prostaglandin synthesis inhibitors (NSAIDs), which can reduce urine output by up to 50%. 1, 2, 5

• Amiloride is particularly useful in lithium-induced NDI and can be combined with thiazides for additive effect. 1, 5

• When initiating pharmacological treatment, careful monitoring is critical because paradoxical hyponatremia may develop if patients maintain their previously high fluid intake. 1

Emergency Management

• For hypernatremic dehydration in NDI, use 5% dextrose in water (hypotonic solution) at usual maintenance rates—never use normal saline or isotonic fluids, as these increase renal osmotic load and worsen the condition. 1, 4

• Isotonic fluids should be reserved only for rare cases of hypovolemic shock. 4

• The hypotonic solution must not be given as a rapid bolus to prevent dangerous rapid falls in serum sodium. 4

Monitoring and Long-Term Complications

• Regular electrolyte monitoring is essential: every 2-3 months in infants, every 3-12 months in children, and annually in adults. 1, 2

• Renal ultrasound should be performed at least every 2 years to monitor for urinary tract dilation and bladder dysfunction from chronic polyuria. 4

• Approximately 50% of adult NDI patients develop chronic kidney disease stage ≥2, requiring more intensive follow-up according to KDIGO guidelines. 1, 2, 4

• Mental health disorders occur more frequently in NDI patients compared to the general population, warranting multidisciplinary care including psychological support. 4

Critical Pitfalls to Avoid

• Never restrict water access in NDI patients—this leads to severe hypernatremic dehydration and is potentially fatal. 4

• Avoid isotonic fluids (0.9% NaCl) in NDI patients with hypernatremia, as they worsen the condition. 1

• Do not confuse NDI with diabetes mellitus (which causes polyuria through osmotic diuresis from glucosuria) or SIADH (which presents with hyponatremia and concentrated urine). 4

• Infants and cognitively impaired patients cannot express thirst or self-regulate, requiring caregivers to proactively offer water frequently. 4