What are the causes and treatments for water wasting symptoms, such as excessive thirst and urination, including central and nephrogenic Diabetes Insipidus (DI)?

Water Wasting: Causes and Management

Primary Causes of Water Wasting

Water wasting with excessive thirst and urination is most commonly caused by diabetes insipidus (DI), which exists in two main forms: central DI (deficiency of antidiuretic hormone/AVP) and nephrogenic DI (kidney resistance to AVP). 1, 2

Central Diabetes Insipidus

• Results from deficiency of arginine vasopressin (AVP) due to destruction of vasopressin neurons in the hypothalamus or posterior pituitary 3, 4
• Requires 80-90% destruction of hypothalamic vasopressin neurons to produce clinical DI, explaining why even large sellar lesions may not cause symptoms until surgically resected 5
• Common causes include: anatomic lesions (tumors, infiltrative diseases), surgical trauma (especially transsphenoidal hypophysectomy), head trauma, and autoimmune destruction 6, 5
• Approximately 50% of cases have identifiable structural causes on MRI, making pituitary imaging with dedicated sella sequences essential 2

Nephrogenic Diabetes Insipidus

• Results from kidney resistance to AVP action at the collecting duct level 1, 4
• Most commonly acquired from lithium therapy in adults 1
• Congenital forms present in infancy (mean age ~4 months) with polyuria, polydipsia, failure to thrive, and hypernatremic dehydration 1, 7
• Secondary inherited forms include Bartter syndrome (types 1,2, or 5), distal renal tubular acidosis, nephronophthisis, and apparent mineralocorticoid excess 1

Other Causes of Water Wasting

• Primary polydipsia: excessive water intake despite normal AVP secretion and action, most common in psychiatric patients 3, 4
• Poorly controlled diabetes mellitus: causes osmotic diuresis from glucosuria with high urine osmolality (>300 mOsm/kg), distinguishing it from DI 1, 2
• Hyperglycemia, elevated angiotensin levels, and certain drugs (clonidine) can stimulate excessive drinking 1

Diagnostic Approach

The diagnostic triad for DI is: polyuria (>3 L/24h in adults), inappropriately dilute urine (osmolality <200 mOsm/kg), and high-normal or elevated serum sodium. 2

Initial Evaluation

• Measure simultaneously: serum sodium, serum osmolality, urine osmolality, and 24-hour urine volume 1, 2
• Urine osmolality <200 mOsm/kg with serum sodium >145 mEq/L is pathognomonic for DI 2
• Rule out diabetes mellitus first by checking blood glucose (fasting ≥126 mg/dL or random ≥200 mg/dL indicates diabetes mellitus, not DI) 2

Differentiating Central from Nephrogenic DI

• Plasma copeptin measurement is the primary differentiating test: levels >21.4 pmol/L indicate nephrogenic DI, while levels <21.4 pmol/L suggest central DI or primary polydipsia 1, 2
• For copeptin <21.4 pmol/L: perform hypertonic saline or arginine stimulation testing 1
• Desmopressin trial: response (urine osmolality increase >50%) confirms central DI; no response indicates nephrogenic DI 2, 6
• Water deprivation test remains the gold standard when copeptin testing is unavailable 3, 8

Additional Workup

• MRI of sella with dedicated pituitary sequences if central DI suspected to identify structural causes 2
• Genetic testing with multigene panel (AVPR2, AQP2, AVP genes) if nephrogenic DI confirmed, even in adults 2
• Renal ultrasound to assess for urological complications (urinary tract dilation, bladder dysfunction) from chronic polyuria 1, 2

Treatment Strategies

Central Diabetes Insipidus

Desmopressin (DDAVP) is the treatment of choice for central DI, administered intranasally, orally, or by injection 2, 6

• Intranasal desmopressin: 10 mcg per dose using nasal spray; pediatric patients requiring <10 mcg should use rhinal tube delivery system 6
• Critical monitoring: check serum sodium within 7 days and at 1 month after starting treatment, then periodically, as hyponatremia is the main complication 2
• Fluid intake adjustment: patients should reduce fluid intake based on physician guidance once treatment initiated 6
• Alternative routes needed when intranasal delivery compromised (nasal congestion, atrophy, post-surgical nasal packing) 6

Nephrogenic Diabetes Insipidus

Combination therapy with thiazide diuretics plus NSAIDs (prostaglandin synthesis inhibitors), along with dietary modifications, is recommended for symptomatic patients. 1, 2, 9

• Thiazide diuretics + NSAIDs can reduce urine output and required water intake by up to 50% in the short term 2, 9
• Dietary modifications are essential:
  • Low-salt diet (≤6 g/day) 1, 2, 9
  • Protein restriction (<1 g/kg/day) 1, 2, 9
  • These reduce renal osmotic load and minimize urine volume 2
• Loop diuretics should be used with caution due to ototoxicity risk (greater with furosemide and torsemide, less with bumetanide) 1

Universal Management Principles

All patients with DI must have free access to fluid 24/7 to prevent dehydration, hypernatremia, growth failure, and constipation. 1, 2, 9, 7

• Patients capable of self-regulation should determine fluid intake based on thirst sensation rather than prescribed amounts, as their osmosensors are more sensitive and accurate than medical calculations 1, 2
• Infants and cognitively impaired patients cannot self-regulate and require caregivers to offer water frequently on top of regular fluid intake, with close monitoring of weight, fluid balance, and biochemistry 1, 2
• Infants with nephrogenic DI should receive normal-for-age milk intake (not just water) to guarantee adequate caloric intake 1, 2
• 20-30% of children with nephrogenic DI require tube feeding at some point to ensure adequate nutrition and hydration 9

Intravenous Fluid Management

For patients requiring IV hydration (e.g., prolonged fasting >4 hours before anesthesia), use 5% dextrose in water at usual maintenance rates—NOT normal saline or electrolyte solutions. 1, 2, 9

• Monitor blood glucose regularly as glucose infusion can cause hyperglycemia with subsequent osmotic diuresis 1
• Urine volume typically decreases considerably with IV dextrose as it provides no renal osmotic load 1

Critical Pitfalls to Avoid

Never restrict water access in DI patients—this is a life-threatening error leading to severe hypernatremic dehydration. 2, 9

• Water restriction without sodium restriction is futile and harmful in most cases, as excessive sodium ingestion stimulates thirst through increased ECF osmolality 1
• Do not use electrolyte solutions (Pedialyte, normal saline) for routine hydration in DI patients; use plain water or hypotonic fluids 2, 9
• Infants are at highest risk for rapid progression to severe dehydration as they lack free access to fluid and cannot communicate thirst effectively 7
• Desmopressin use in pediatric patients requires careful fluid restriction to prevent hyponatremia and water intoxication 6
• Nasal spray cannot deliver <10 mcg doses accurately; use rhinal tube for smaller pediatric doses 6

Monitoring and Follow-up

Routine Monitoring

• Infants (0-12 months): clinical follow-up with weight/height every 2-3 months; blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2-3 months; urinalysis with osmolality annually 2
• Adults: annual clinical follow-up with weight measurements; annual blood tests and urinalysis (including osmolality, protein-creatinine ratio, 24-hour urine volume) 2
• Renal ultrasound at least every 2 years to monitor for urinary tract dilation and bladder dysfunction; interval can extend to 5 years for stable patients 2
• Approximately 46% of patients develop urological complications from chronic polyuria, including nocturnal enuresis and incomplete bladder voiding 2

Emergency Planning

• Every patient should have a medical alert bracelet or card identifying their DI diagnosis 9
• Emergency plan should include specific IV fluid instructions (5% dextrose in water, NOT normal saline) 2, 9
• Approximately 50% of adult patients with DI have CKD stage ≥2, requiring more frequent follow-up per KDIGO guidelines 2