What are the causes, symptoms, and treatment of diabetes insipidus?

Diabetes Insipidus: Causes, Symptoms, and Treatment

Causes

Diabetes insipidus results from either deficiency of antidiuretic hormone (central DI) or kidney resistance to it (nephrogenic DI). 1

Central Diabetes Insipidus (Vasopressin Deficiency)

• Tumors are the most frequent secondary cause, particularly craniopharyngioma and germ cell tumors in the central nervous system 2
• Idiopathic cases may be caused by infundibulo-neurohypophysitis (autoimmune inflammation) 2
• Metastatic diseases commonly cause central DI, making MRI with dedicated pituitary sequences essential in all new cases 1
• Familial forms are inherited in an autosomal dominant pattern, with over 80 mutations identified in the AVP gene 2
• Infiltrative and inflammatory processes account for approximately 50% of identifiable structural causes 1

Nephrogenic Diabetes Insipidus (Vasopressin Resistance)

• X-linked mutations in the AVPR2 gene account for ~90% of congenital cases, causing misfolded V2 receptors trapped in the endoplasmic reticulum 1
• Autosomal mutations in the AQP2 gene cause <10% of congenital cases, with both recessive and dominant inheritance patterns 1
• Lithium therapy is the most common acquired cause, with approximately 50% of affected patients progressing to chronic kidney disease stage ≥2 1
• Chronic kidney disease and other inherited kidney disorders impair concentrating ability 1
• Female carriers of AVPR2 mutations are typically asymptomatic, but ~10% develop full NDI due to skewed X-inactivation 1

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Symptoms

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

Infants and Young Children

• Polyuria, failure to thrive, and hypernatremic dehydration are the classic presentation, with average diagnosis at 4 months of age 1, 3
• Feeding difficulties and vomiting occur frequently, often from gastroesophageal reflux exacerbated by large fluid volumes 1, 3
• Serum osmolality typically exceeds 300 mOsm/kg with inappropriately dilute urine <200 mOsm/kg 1
• "Greedy" drinking followed by vomiting is commonly reported in infants 1

Adults and Older Children

• Polydipsia is the predominant presenting symptom at diagnosis 1, 3
• Excessive thirst drives patients to drink several liters daily because intact osmosensors trigger thirst more sensitively than any medical calculation 1
• Nocturnal enuresis and "bed flooding" affect approximately 46% of patients from chronic polyuria 1
• Normal serum sodium at steady state is common when patients have free water access, because their thirst mechanism drives adequate replacement 1

Emergency Presentations

• Hypernatremic dehydration (serum sodium >145 mEq/L) occurs when water access is restricted and represents a life-threatening emergency 1, 4
• Seizures, developmental delay, and cognitive impairment can result from prolonged severe hypertonic dehydration 1

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Diagnosis

Measure serum sodium, serum osmolality, and urine osmolality simultaneously; urine osmolality <200 mOsm/kg with high-normal or elevated serum sodium confirms diabetes insipidus. 1, 3

Initial Diagnostic Steps

• Rule out diabetes mellitus first by checking fasting glucose and HbA1c, as diabetes mellitus causes polyuria through osmotic diuresis from glucosuria, not ADH deficiency 1, 3
• Obtain 24-hour urine volume to confirm polyuria (>3 L/day in adults); maintain usual fluid intake based on thirst during collection 1
• Perform MRI with dedicated pituitary/sella sequences in all cases of suspected central DI, as ~50% have identifiable structural causes 1, 3

Distinguishing Central from Nephrogenic DI

• Plasma copeptin >21.4 pmol/L is diagnostic for nephrogenic DI in adults, while <21.4 pmol/L indicates central DI or primary polydipsia 1, 5
• Desmopressin trial differentiates the two: response (urine osmolality increase >50%) confirms central DI, while no response confirms nephrogenic DI 1, 4, 6
• Water deprivation test is the gold standard but should be avoided when NDI is strongly suspected, as it risks severe hypernatremic dehydration, seizures, and brain injury 1, 6

Genetic Testing

• Early multigene panel testing (AVPR2, AQP2, AVP genes with copy-number-variant analysis) provides definitive diagnosis and replaces dangerous provocative tests 1, 3
• Genetic confirmation prevents prolonged severe dehydration and enables genetic counseling, prenatal testing, and identification of at-risk relatives 1
• Umbilical-cord-blood testing is strongly recommended for male newborns of known AVPR2-mutation carriers 1

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Treatment

Central Diabetes Insipidus

Desmopressin is the treatment of choice for central DI, administered intranasally, orally, or by injection. 1, 3, 2

• Starting dose is typically 2-4 mcg subcutaneously or intravenously in divided doses 1
• Oral disintegrating tablet formula increases quality of life and decreases hyponatremia incidence compared to nasal formulations 2
• Check serum sodium within 7 days and at 1 month after starting treatment, then periodically, as hyponatremia is the main complication 1
• Allow free access to water at all times to prevent dehydration, hypernatremia, growth failure, and constipation 1, 3

Nephrogenic Diabetes Insipidus

Combination therapy with thiazide diuretics plus NSAIDs, along with dietary modifications, can reduce urine output by up to 50%. 1, 7

Pharmacological Treatment

• Thiazide diuretics (e.g., hydrochlorothiazide) are first-line agents 7
• NSAIDs (prostaglandin synthesis inhibitors) are added for synergistic effect 1, 7
• Amiloride is used particularly in lithium-induced NDI 7
• Medications can be used isolated or in combination depending on response 7

Non-Pharmacological Management

• Low-salt diet (≤6 g/day) and protein restriction (<1 g/kg/day) reduce renal osmotic load and minimize urine volume 1, 7
• Free access to plain water or hypotonic fluids 24/7 is essential; never restrict water access, as this is life-threatening 1
• Infants should receive normal-for-age milk intake to guarantee adequate calories, but not electrolyte solutions 1
• Patients capable of self-regulation should drink based on thirst rather than prescribed amounts, as their osmosensors are more accurate 1

Emergency Management of Hypernatremic Dehydration

Use 5% dextrose in water (hypotonic fluid) at usual maintenance rates for IV rehydration; avoid normal saline or electrolyte solutions. 1

• 5% dextrose matches the dilute urinary losses characteristic of DI 1
• Never give as a rapid bolus to prevent sudden fall in serum sodium 1
• Isotonic fluids are reserved only for rare cases of hypovolemic shock in DI patients 1
• Allow patients to drink according to thirst when feasible 1

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Monitoring and Follow-up

Routine Clinical Monitoring

• Infants (0-12 months) require clinical follow-up every 2-3 months including weight and height measurements 1
• Adults require annual clinical follow-up including weight measurements 1
• Blood tests (sodium, potassium, chloride, bicarbonate, creatinine, uric acid) every 2-3 months for infants and annually for adults 1
• Urinalysis including osmolality annually for all age groups 1

Imaging Surveillance

• Renal ultrasound at least every 2 years to monitor for urinary tract dilation and bladder dysfunction from polyuria 1
• Interval can be extended to 5 years for stable patients 1
• Ultrasound before and after bladder emptying is recommended, as dilation improves with double voiding in one-third of patients 1

Multidisciplinary Care

• Management by a team including nephrologist, dietitian, psychologist, social worker, and urologist is recommended 1
• Mental health disorders are more frequent in individuals with NDI compared to the general population 1

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Critical Pitfalls to Avoid

• Never restrict water access in DI patients—this is a life-threatening error leading to severe hypernatremic dehydration 1
• Do not use normal saline or electrolyte solutions (like Pedialyte) for rehydration in DI; use 5% dextrose in water 1
• Avoid water deprivation testing when NDI is strongly suspected, as it can precipitate seizures and brain injury 1
• Do not confuse DI with diabetes mellitus—they are completely unrelated conditions involving different organ systems 3
• Infants and cognitively impaired patients cannot self-regulate—caregivers must offer water frequently and monitor weight, fluid balance, and biochemistry closely 1