Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is resistance of the renal collecting duct to antidiuretic hormone (ADH, vasopressin), causing excretion of large volumes of dilute urine.

• Hereditary NDI: X-linked recessive AVPR2 mutations (90%, males), autosomal AQP2 variants (10%).
• Acquired causes (commoner): lithium (most common; 20 to 40% of long-term users), hypercalcaemia, hypokalaemia, chronic kidney disease, post-obstructive uropathy, tubulointerstitial disease, sickle cell disease, amyloidosis, Sjögren, drugs (demeclocycline, amphotericin, cidofovir, foscarnet, ifosfamide, tenofovir).
• Pathophysiology: failure of V2 receptor signalling or aquaporin-2 insertion, with polyuria (over 3 L/day, urine osmolality under 300 mOsm/kg).
• Complications: dehydration, hypernatraemia (especially in infants), growth failure, mental retardation (in untreated congenital cases), hydronephrosis, bladder dilatation.

• Infants: irritability, poor feeding, vomiting, constipation, fever, failure to thrive, recurrent dehydration, hypernatraemia, seizures.
• Children and adults: polyuria, polydipsia, nocturia, enuresis, preference for cold water.
• Hypernatraemia if fluids are restricted or thirst impaired.
• Lithium: polyuria in 20–40%, may persist after stopping.
• Hydroureteronephrosis from high urine flow.

• Polyuria with dilute urine (osmolality under 300 mOsm/kg) and normal or high serum sodium and osmolality.
• Water deprivation test: failure to concentrate urine above 300 mOsm/kg after fluid restriction; no increase after desmopressin 2 micrograms SC/IV (or 20 micrograms intranasal): distinguishes NDI (urine osmolality increases under 50%) from central DI (increases over 50%).
• Plasma copeptin (unstimulated over 21.4 pmol/L) suggests NDI; hypertonic saline-stimulated copeptin test.
• Calcium, potassium, creatinine, glucose, lithium level; urine calcium.
• Genetic testing (AVPR2, AQP2) for congenital forms.
• Renal ultrasound for hydronephrosis; exclude primary polydipsia and osmotic diuresis (glucose).

• Correct underlying cause: stop lithium (if psychiatrically feasible), correct hypercalcaemia and hypokalaemia, relieve obstruction.
• Free access to water at all times; avoid dehydration; in infants frequent water supplementation between feeds.
• Low sodium diet (under 2 g/day) and low protein (about 1 g/kg/day) to reduce solute load and urine volume.
• Thiazide diuretics: hydrochlorothiazide 25 to 50 mg daily (2 to 4 mg/kg/day in children), reduces urine output by 30 to 50% through volume contraction and increased proximal reabsorption; monitor potassium and sodium.
• Amiloride 5 to 10 mg daily (children 0.3 mg/kg) for lithium-induced NDI (blocks lithium entry via ENaC), often with thiazide; potassium-sparing.
• Indomethacin 1.5 to 2.5 mg/kg/day (adults 25 to 50 mg three times daily) as adjunct; ibuprofen alternatives (monitor kidney function and gastrointestinal toxicity).
• High-dose desmopressin is occasionally effective in partial NDI.
• Experimental: chemical chaperones, sildenafil, statins.
• Treat hypernatraemia gradually: free water orally, or 5% dextrose IV at a rate lowering sodium by under 10 mmol/L/day.
• Monitor growth, sodium, kidney function, hydronephrosis; genetic counselling and prenatal diagnosis.