What is nephrogenic diabetes insipidus?

What is Nephrogenic Diabetes Insipidus

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

Core Pathophysiology

The fundamental defect in NDI lies in the kidney's inability to respond to vasopressin, even when the hormone is present at normal or elevated concentrations. 1, 2 This insensitivity prevents water reabsorption in the collecting ducts, forcing the kidneys to excrete large volumes of dilute urine regardless of the body's hydration status. 3

Molecular Basis

• The underlying molecular defects involve mutations in two key proteins: the vasopressin V2 receptor (AVPR2 gene) or the aquaporin-2 water channel (AQP2 gene). 2, 4
• These mutations typically cause misfolded proteins that become trapped in the endoplasmic reticulum, preventing their proper trafficking to the cell membrane where they would normally function. 5
• Without functional V2 receptors or aquaporin-2 channels, the collecting duct cells cannot respond to vasopressin's signal to reabsorb water. 6

Genetic Forms

X-Linked NDI (90% of Congenital Cases)

• Approximately 90% of hereditary NDI cases result from loss-of-function mutations in the AVPR2 gene located on chromosome Xq28. 2, 6
• This X-linked recessive inheritance pattern means affected males express the full disease phenotype. 7
• Female carriers are typically asymptomatic, but about 10% develop full NDI symptoms due to skewed X-inactivation. 5
• Some AVPR2 variants cause partial vasopressin insensitivity rather than complete resistance. 5

Autosomal NDI (Less Than 10% of Congenital Cases)

• Mutations in the AQP2 gene (chromosome 12q13) account for the remaining hereditary cases. 2, 6
• Both autosomal recessive and autosomal dominant inheritance patterns occur. 5, 2
• The dominant form is often under-diagnosed because patients may partially compensate for their concentrating defect. 5
• Most AQP2 mutations produce aquaporin-2 proteins that remain trapped in the endoplasmic reticulum. 5

De Novo Mutations

• Approximately 20% of apparently isolated cases arise from de novo mutations occurring during oogenesis, making family history negative. 5

Acquired NDI

• The most common acquired cause is chronic lithium therapy. 4, 3
• Other causes include chronic kidney disease, electrolyte disturbances (hypokalemia, hypercalcemia), and various medications. 4, 3
• Acquired NDI involves disturbance of the aquaporin-2 shuttle mechanism. 3

Clinical Presentation

Infants and Young Children

• The average age at diagnosis is approximately 4 months. 5
• Cardinal symptoms include polyuria, polydipsia, failure to thrive, and hypernatremic dehydration. 7, 5
• Infants present with inappropriately dilute urine (osmolality <200 mOsm/kg H₂O) despite elevated serum osmolality (typically >300 mOsm/kg H₂O). 5
• "Greedy" drinking followed by vomiting is commonly reported, reflecting gastro-esophageal reflux exacerbated by large fluid volumes. 7, 5
• Without adequate fluid replacement, infants develop severe hypernatremic dehydration that can cause seizures, developmental delay, and cognitive impairment. 5

Adults and Older Children

• Polydipsia is the predominant presenting symptom in this age group. 5
• Adults with unexplained polydipsia and polyuria (>2.5 L per 24 hours despite attempts to reduce intake) should be evaluated for NDI. 5
• Serum osmolality remains typically >300 mOsm/kg H₂O with urine osmolality <200 mOsm/kg H₂O. 5

Diagnostic Pathognomonic Triad

The combination of three findings is pathognomonic for diabetes insipidus:

• Polyuria (>3 liters/24 hours in adults) 5
• Inappropriately dilute urine (osmolality <200 mOsm/kg H₂O) 7, 5
• High-normal or elevated serum sodium (>145 mEq/L when water access is restricted) 5

Critical Diagnostic Threshold

• The diagnostic threshold for NDI is urine osmolality <200 mOsm/kg H₂O in the presence of serum hyperosmolality. 5
• This must not be confused with the water-deprivation test response threshold of ≥300 mOsm/kg H₂O. 5
• Even patients with partial NDI maintain urine osmolality well below 300 mOsm/kg and certainly below 400 mOsm/kg. 5

Distinguishing NDI from Central Diabetes Insipidus

• Response to desmopressin is the key differentiating test: NDI patients show minimal or no response, while central DI patients show a positive response. 1
• Plasma copeptin measurement provides an alternative diagnostic approach: levels >21.4 pmol/L indicate NDI, while levels <21.4 pmol/L suggest central DI or primary polydipsia. 5
• In NDI, plasma vasopressin (or copeptin) levels are normal or elevated, whereas central DI shows low levels. 2, 4

Long-Term Complications

Renal Complications

• Approximately 50% of adult NDI patients develop chronic kidney disease stage ≥2. 5, 8
• Chronic polyuria can cause urological complications including urinary tract dilatation and bladder dysfunction in about 46% of patients. 5
• Renal ultrasound monitoring is recommended at least every 2 years to detect these complications. 5, 8

Neuropsychological Impact

• Mental health disorders are reported more frequently in individuals with NDI compared to the general population. 5
• Prolonged severe hypernatremic dehydration in infancy can lead to seizures, developmental delay, and permanent cognitive impairment. 5

Management Principles

Fluid Management (Cornerstone of Treatment)

• Free access to water 24/7 is absolutely essential to prevent life-threatening hypernatremic dehydration. 5, 8
• 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. 5
• Never restrict water access in NDI patients—this is a life-threatening error. 5

Pharmacological Treatment

• For symptomatic infants and children, combination therapy with thiazide diuretics plus prostaglandin synthesis inhibitors (NSAIDs) is recommended. 7, 5
• Thiazides induce mild volume depletion, increasing proximal sodium and water reabsorption, which can reduce urine output by up to 50% in the short term. 7
• In patients with thiazide-induced hypokalemia, amiloride should be added. 7
• Drug treatment effectiveness often diminishes with age—usage decreases from 85% in childhood to 56% in adulthood. 7

Dietary Modifications

• Low-salt diet (≤6 g/day) reduces renal osmotic load and enhances thiazide effectiveness. 7, 5
• Protein restriction (<1 g/kg/day) decreases obligatory water excretion. 5, 8
• Support from a dietitian experienced with NDI is recommended to ensure nutritional adequacy. 7

Nutritional Support in Infants

• Many infants show preference for water over nutritional fluids, and transition to solid foods may be delayed. 7
• Tube feeding (nasogastric or gastrostomy) should be considered for infants with repeated vomiting/dehydration episodes and/or growth failure. 7
• In retrospective studies, 20-30% of children with NDI received tube feeding at some point, with approximately 25% having gastrostomy placement. 7
• Tube feeding is rarely continued beyond 4 years of age. 7

Emergency Management of Hypernatremic Dehydration

• The recommended rehydration fluid is 5% dextrose in water (hypotonic solution) at usual maintenance rates—normal saline should be avoided. 5
• 5% dextrose matches the dilute urinary losses characteristic of NDI. 5
• Never administer as a rapid bolus to prevent sudden falls in serum sodium. 5
• Isotonic fluids are reserved only for rare cases of hypovolemic shock. 5
• When feasible, allow patients to drink according to thirst. 5

Genetic Testing and Counseling

• Early genetic testing using a multigene panel (AVPR2, AQP2, AVP genes with copy-number-variant analysis) is strongly recommended in all patients with suspected NDI. 7, 5
• Testing should be performed in laboratories accredited for diagnostic genetic testing. 7
• Genetic testing in all symptomatic females is recommended, as female carriers can manifest disease. 7
• Umbilical cord blood testing is strongly recommended for male newborns of known AVPR2 mutation carriers to facilitate early monitoring and intervention. 7, 5
• Genetic diagnosis enables recurrence risk counseling, prenatal testing, pre-implantation genetic testing, and identification of at-risk relatives. 5

Monitoring Requirements

Infants (0-12 Months)

• Clinical follow-up including weight and height measurements every 2-3 months. 5
• Blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2-3 months. 5, 8
• Urinalysis including osmolality annually. 5

Children and Adults

• Clinical follow-up annually for adults. 5
• Blood tests (electrolytes, creatinine, uric acid) every 3-12 months in children, annually in adults. 5, 8
• Urinalysis including osmolality, protein-creatinine ratio, and 24-hour urine volume annually. 5
• Renal ultrasound at least every 2 years (can extend to 5 years for stable patients). 5

Multidisciplinary Team

• Management should involve a nephrologist, dietitian, psychologist, social worker, and urologist. 5, 8

Critical Pitfall to Avoid

When NDI is strongly suspected based on clinical presentation and initial biochemistry, water-deprivation testing should be omitted because it is uncomfortable, technically challenging, and may precipitate severe hypernatremic dehydration, seizures, and brain injury. 5 Proceed directly to genetic testing for definitive diagnosis. 5