How is nephrogenic diabetes insipidus diagnosed and what are its causes?

Diagnosis of Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus is diagnosed by demonstrating inappropriately dilute urine (osmolality <200 mOsm/kg H₂O) in the presence of high-normal or elevated serum sodium, followed by genetic testing to confirm the diagnosis and avoid potentially harmful water deprivation or desmopressin tests. 1

Initial Clinical Suspicion

Suspect NDI in the following presentations:

• Infants and children: Polyuria, polydipsia, failure to thrive, and hypernatremic dehydration 1
• Adults: Unexplained polyuria and polydipsia despite attempts to reduce fluid intake 2
• Average age at diagnosis: Approximately 4 months in hereditary cases 3

Diagnostic Algorithm

Step 1: Initial Biochemical Work-Up

Measure simultaneously 1, 2:

• Serum sodium
• Serum osmolality
• Urine osmolality

Pathognomonic findings for diabetes insipidus 1:

• Urine osmolality <200 mOsm/kg H₂O (inappropriately dilute)
• High-normal or elevated serum sodium
• Serum osmolality typically >300 mOsm/kg H₂O 3

Step 2: Distinguish NDI from Central DI

Plasma copeptin measurement is the primary differentiating test 2:

• Copeptin >21.4 pmol/L: Diagnostic for nephrogenic DI (indicates elevated ADH levels despite inability to concentrate urine) 2, 4
• Copeptin <21.4 pmol/L: Suggests central DI or primary polydipsia; requires additional testing 2

Alternative approach if copeptin unavailable: Desmopressin trial 2:

• No response (urine osmolality remains <200 mOsm/kg): Confirms NDI 2, 4
• Response (urine osmolality increases >50%): Indicates central DI 2

Step 3: Genetic Testing (Definitive Diagnosis)

Genetic testing should be performed early and can replace water deprivation or desmopressin tests, which are potentially harmful 1:

• Use a multigene panel including AVPR2, AQP2, and AVP genes 1, 2
• Include copy number variant analysis 1
• Perform in an accredited diagnostic laboratory 1

Critical advantage: Genetic testing prevents prolonged periods of severe hypertonic dehydration that can cause seizures, developmental delay, and cognitive impairment 1

Additional Diagnostic Considerations

Family History and Pedigree Construction

• Essential to identify familial cases 1
• 20% of isolated cases have de novo mutations arising during oogenesis 1

24-Hour Urine Collection

• Confirms polyuria (>3 liters/24 hours in adults) 2
• Must collect all urine over exactly 24 hours 2
• Patient should maintain usual fluid intake based on thirst, not artificially restrict or increase 2

Imaging Studies

• MRI of sella with dedicated pituitary sequences if central DI suspected (to rule out structural causes) 2
• Renal ultrasound at baseline and every 2 years to monitor for urinary tract dilation from chronic polyuria 2

Common Pitfalls to Avoid

Do not perform water deprivation tests when NDI is strongly suspected 1:

• These tests are unpleasant, challenging, and potentially harmful
• Can cause severe hypernatremic dehydration, seizures, and brain damage
• Genetic testing provides definitive diagnosis without these risks

Do not confuse with diabetes mellitus 2:

• Check blood glucose first to rule out diabetes mellitus (fasting glucose ≥126 mg/dL)
• Diabetes mellitus causes polyuria through osmotic diuresis from glucosuria, not ADH deficiency

Recognize that urine osmolality 200-300 mOsm/kg does not confirm NDI 2:

• Many conditions cause this range (partial dehydration, CKD, early renal disorders)
• True NDI requires urine osmolality definitively <200 mOsm/kg with serum hyperosmolality

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Causes of Nephrogenic Diabetes Insipidus

Congenital (Hereditary) Causes

X-Linked NDI (90% of congenital cases)

AVPR2 gene mutations (chromosome Xq28) 1, 5:

• Encodes the vasopressin V2 receptor
• Inherited in X-linked recessive manner
• Predominantly affects males
• Most mutations cause misfolded receptors trapped in endoplasmic reticulum, unable to reach plasma membrane 6
• Some variants cause partial insensitivity to AVP 1

Female carriers 1:

• Usually asymptomatic but 10% develop complete NDI phenotype
• Due to X-inactivation of the chromosome without the mutation
• Genetic testing recommended even in females with overt NDI

Autosomal NDI (<10% of congenital cases)

AQP2 gene mutations (chromosome 12q13.12) 1, 5:

• Encodes aquaporin-2 water channel
• Can be autosomal recessive (OMIM #222000) or autosomal dominant (OMIM #125800)
• Affects males and females equally
• Autosomal dominant form may be underdiagnosed as patients can partially compensate 1
• Most mutations lead to proteins trapped in endoplasmic reticulum 6

Acquired Causes

Drug-Induced NDI

Lithium (most common acquired cause) 7, 8, 9:

• Long-term lithium administration is the main cause of acquired NDI
• Disturbs aquaporin-2 shuttle mechanism

Other medications 7, 9:

• Various drugs can cause acquired NDI (specific agents not detailed in guidelines)

Metabolic Disturbances

Electrolyte disorders 7, 9:

• Hypokalemia: Impairs renal concentrating ability
• Hypercalcemia: Disturbs aquaporin-2 function

Chronic Kidney Disease

Renal parenchymal disease 3:

• Chronic kidney disease impairs concentrating ability
• Approximately 50% of adult NDI patients have CKD stage ≥2 3, 2
• Other inherited kidney disorders can contribute

Molecular Mechanism of Acquired NDI

Disturbance of aquaporin-2 shuttle 9:

• Underlying molecular basis of most acquired forms
• Prevents proper water channel trafficking to apical membrane

Genetic Counseling Implications

Importance of genetic diagnosis 1:

• Informs recurrence risks for family planning
• Enables prenatal and preimplantation genetic testing options
• Allows presymptomatic testing for at-risk family members
• In X-linked NDI, identifies female carriers for reproductive counseling

Umbilical cord blood testing 1:

• Strongly recommended in male offspring of AVPR2 mutation carriers
• Prevents primary manifestations through early treatment and monitoring