BASICS
DESCRIPTION
- A condition in which there is reduced ability to concentrate the urine due to impaired reabsorption of water in the renal collecting tubules
- It is characterized by poIyuria and, in sensate patients, pronounced thirst.
- Two main forms of diabetes insipidus (DI) are known. Central diabetes insipidus (CDI) represents vasopressin (antidiuretic hormone or ADH) deficiency. Nephrogenic diabetes insipidus (NDI) represents target end organ (renal tubule) unresponsiveness to vasopressin/ADH. Rarely, DI can be induced by pregnancy, known as gestational diabetes insipidus (GDI).
- System(s) affected: endocrine/metabolic/renal
EPIDEMIOLOGY
Incidence
- DI occurs in 3/100,000 persons in the general population.
- Vasopressin deficiency (CDI) may occur at any age and has no gender preference.
- NDI in children is most often congenital and usually manifests during infancy.
- The most common causes of acquired NDI are long-term lithium therapy and chronic hypercalcemia.
- Pediatric NDI is encountered in males more commonly, reflecting its X-linked recessive mode of inheritance.
Prevalence
- CDI: 1 in 25,000 persons;
- NDI: unknown
- GDI: 2 to 6 in 100,000 pregnancies (1)
ETIOLOGY AND PATHOPHYSIOLOGY
- CDI
- Inadequate secretion of vasopressin may be due to loss or malfunction of the neurosecretory cells of the neurohypophysis (posterior pituitary) and the pituitary stalk.
- Posterior pituitary lesions rarely cause CDI because ADH is produced in the hypothalamus and therefore, still may be secreted above the level of injury.
- Collecting tubule fails to reabsorb water effectively from filtrate due to ADH deficiency or absence.
- Can be complete or partial
- Etiology:
- Trauma/head injury: A study of 89 patients with traumatic brain injury found that primary hormonal dysfunction (including DI) occurred in 21% of patients and tended to occur in patients with the lowest Glasgow Outcome Scale scores (2).
- Neurosurgery: A study of 102 consecutive craniopharyngioma surgeries found that postoperative DI is more common in children than adults (80% vs. 63%), with higher incidence of permanent DI in children (55.6%) (3).
- Tumors (e.g., craniopharyngioma, lymphoma, metastasis)
- Infections (e.g., meningitis, encephalitis)
- Infiltrative diseases (e.g., sarcoidosis, histiocytosis)
- Hypoxic encephalopathy
- Vascular disorders
- Congenital: brain dysmorphisms may be identified in up to a quarter of children with CDI (4), but recognizable heritable defects only in 1-2%.
- NDI
- Target organ (renal) unresponsiveness to vasopressin
- Reabsorption of water from filtrate in collecting tubules is impaired despite presence of ADH.
- Can be complete or partial
- Etiology:
- Drug-induced (amphotericin B, colchicine, demeclocycline, foscarnet and other antivirals, aminoglycosides, lithium carbonate, loop diuretics, methoxyflurane). Inappropriate or excessive use of vasopressin antagonists such as tolvaptan mimics NDI.
- Heritable defects, including X-linked V2 receptor gene mutation and autosomal recessive aquaporin-2 gene mutation
- Electrolyte disorders, especially hypercalcemia and hypokalemia
- Renal tubular disorders
- Partial ureteral obstruction and postobstructive state
- GDI
- Placentally produced vasopressinase shortens half-life of vasopressin in circulation (1).
- It is usually a transient condition, but is commonly undiagnosed (1).
RISK FACTORS
- Intracranial neoplasm
- Infection
- Intracranial surgery (especially pituitary)
- Medications (amphotericin B, colchicine, demeclocycline, antiviral agents, aminoglycosides, lithium, loop diuretics, methoxyflurane)
- Head trauma
- Genetic predisposition
COMMONLY ASSOCIATED CONDITIONS
- NDI
- Potassium depletion
- Chronic hypercalcemia
- Renal amyloidosis
- Tubulointerstitial nephritides
- Sj ¶gren syndrome
- Sickle cell anemia
- Multiple myeloma
- Developmental delay (in congenital NDI)
- CDI
- Tumors (primary and metastatic)
- Infections (encephalitis, TB, syphilis)
- Xanthomatosis
- Sarcoidosis
- Histocytoses
- Wolfram syndrome (DIDMOAD: DI, diabetes mellitus, optic atrophy, deafness)
DIAGNOSIS
- Can be challenging, given the variety of causes and variable symptomatology
- DI not resulting from a recognizable, acute event (e.g., head trauma) tends to be indolent and, if water needs are adequately met, may be hard to detect.
- The degree of polyuria and patient's tolerance to it and associated thirst are highly variable.
- The defect in CDI and NDI may be of only partial and therefore less symptomatic.
- Rarely, patients may present with both types of DI simultaneously.
HISTORY
- Thirst (polydipsia); in CDI, patients often demonstrate a distinct preference for cold or iced drinks.
- Polyuria (50 to 60 mL/kg/day for age <10 years; 40 to 50 mL/kg/day for ≥10 years of age)
- Nocturia, bed wetting
- Dehydration
- Headache
- Visual disturbances
- Onset of polydipsia is typically more rapid in CDI than in NDI.
- Family history of polyuria
- In children-enuresis, anorexia, linear growth defects, and frequent fatigue may be found.
- In infants-crying, irritability, poor growth, hyperthermia, and weight loss are often found.
PHYSICAL EXAM
Signs of dehydration and an enlarged bladder may be present, but otherwise the exam is usually unremarkable.
DIFFERENTIAL DIAGNOSIS
- DM: DI cannot be diagnosed in presence of hyperglycemia or glycosuria.
- Increased solute load for excretion, as occurs with high salt intake; osmotic diuresis
- Postobstructive diuresis
- Psychogenic polydipsia (usually associated with low plasma sodium <137 mEq/L)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Blood chemistries (hypernatremia, hyperglycemia) (4)[C]
- Kidney function tests (5)[C]
- Plasma osmolality (4)[C]
- Urine osmolality (5)[C]
- Urine specific gravity (4)[C]
- Radioimmunoassay of plasma or urinary vasopressin, following adequate osmotic hypovolemic stimulus (see above) is confirmatory and may aid in distinguishing mixed and partial defects.
- Low urine specific gravity and osmolality alone are not diagnostic of DI. However, a urine osmolality >600 mOsm/L rules out DI.
- Urine-to-plasma osmolality ratio may be difficult to interpret; low ratios may be found in patients with primary polydipsia. However, plasma osmolality >300 mOsm/L, urine osmolality <300 mOsm/L, or urine-to-plasma osmolality ratio <1 in a patient with polyuria are suggestive and indicative of need for definitive testing (5)[C].
- Water deprivation test (Miller-Moses test) evaluates the ability to concentrate urine in response to conditions expected to maximally stimulate ADH secretion (reduction in volume of ≥3% and/or serum sodium level ≥145). Response to exogenous ADH aids in differentiating between CDI and NDI; tests include:
- Water is withheld, and urine and plasma osmolality are measured at hourly intervals (<7 hours total is generally sufficient).
- A rise in urine osmolality indicates an intact ADH response.
- A rise in plasma osmolality or failure of urine osmolality to rise indicates poor ADH response.
- Performing the test during the day, not overnight, minimizes risk of serious volume depletion/hyponatremia; patients with DI will continue to urinate even when dehydrated.
- If the results support the diagnosis of DI, desmopressin should be administered to determine ability of collecting tubule to respond to hormone (CDI vs. NDI) (5)[C].
- If the diagnosis of DI is made, further workup should be aimed at identifying etiology. In case of CDI, this might include cerebral MRI (5)[C].
Follow-Up Tests & Special Considerations
If initial MRI shows thickened pituitary stalk (suspicious for CDI), repeat MRI every 3 to 6 months (5)[C].
Test Interpretation
Degeneration of neurosecretory neurons in the neurohypophysis
TREATMENT
GENERAL MEASURES
- Control fluid balance; prevent dehydration.
- Check weight daily.
- Careful follow-up and management of electrolytes
- NDI: Correct hypercalcemia and hypokalemia, and discontinue causative medications (6)[C].
MEDICATION
- Therapy depends on type of DI.
- CDI (5,6)[C]
- In early infancy, fluids alone may suffice.
- Desmopressin (DDAVP), a derivative of vasopressin, may be given orally, parenterally (IV, IM, SC), or intranasally:
- Nasal: Starting dose is 10 μg at bedtime to prevent nocturia, with additional doses during the day as needed; max dose = 40 μg/day
- Oral: Start 0.05 mg BID, increase total dose to 0.2 to 0.8 mg/day divided BID-TID; max dose = 1.2 mg/day
- IV/SC: 1 to 2 μg BID
- Precautions: Desmopressin should be used cautiously following surgery on patients with intracranial lesions because of the risk of inducing or exacerbating cerebral edema.
- Vasopressin is preferred at this time due to its short-acting nature (4)[A].
- An overdose of desmopressin may produce water intoxication and hyponatremia in patients with excessive water intake. Patients with CDI often have exaggerated response to first few doses of desmopressin due to chronic upregulation of V2 receptors.
- Vasopressin has vasopressor and antidiuretic activity, increasing water resorption at collecting ducts:
- 5 to 10 U IM/SC BID q6h; max dose = 60 U/day; pediatric: 2.5 to 10 U IM/SC BID q6h
- Side effects include abdominal cramping, hypertension, and angina
- Contraindicated in patients with hypertension, angina, coronary artery disease
- Pregnancy Category B
- Other agents: In mild or partial cases of CDI, drugs such as chlorpropamide, clofibrate, or carbamazepine are sometimes used as an alternative to vasopressin analogues, as they can stimulate native ADH secretion.
- In both the initiation and maintenance phases of therapy with vasopressin analogues, care must be taken to avoid overcorrection (hyponatremia) and rapid fluctuations in serum osmolality.
- NDI (6)[C]
- Does not respond to desmopressin (DDAVP)
- Remove offending agent(s).
- Correct electrolyte imbalances (i.e., hypokalemia, hypercalcemia).
- Thiazide diuretics decrease sodium and chloride absorption in the distal tubule and thus enable more sodium and water absorption in the proximal tubule. Thiazide diuretics should be avoided in patients taking lithium, as they may raise lithium levels to toxic range.
- Lithium-induced NDI (7)[A]
- Amiloride
- Adult 10 to 20 mg/day for acute presentation, then 10 mg/day for maintenance
- Monitor potassium levels for hyperkalemia in the elderly and those with DM and renal impairment.
- Contraindicated in diabetic nephropathy, AKI/CKD, and in those with elevated potassium at baseline
- Pregnancy Category B
- GDI
- Desmopressin is the treatment of choice in patients with CDI or GDI (pregnancy Category B).
ISSUES FOR REFERRAL
- Dilatation of urinary tract (may be secondary to large urine volumes)
- CDI: complications of primary disease (tumor, histiocytosis, etc.)
- NDI: Evaluate causes of inciting factors; evaluate intrinsic renal disease if present.
- Subnormal growth rate
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Severe dehydration and hypernatremia: Free water repletion should be done at a controlled rate to prevent overly rapid correction.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Regular follow-up at 2- to 3-week intervals initially and 3 to 4 months later
- Adjust treatment on the basis of urine and electrolyte concentrations.
- Following moderate to severe traumatic brain injury, testing should be done in 6 and 12 months after injury.
DIET
- Normal, with free access to fluids
- Young infants with NDI may benefit from low-solute formula.
- A low-sodium, low-protein diet may reduce urine output in NDI.
PATIENT EDUCATION
- Monitor urinary pattern using diaper count.
- Explain importance of maintaining water balance.
- Special precautions during travel, hot weather, exertion, and vomiting and/or diarrhea to avoid dehydration.
PROGNOSIS
- Most reversible cases of NDI are caused by medications, and patient symptoms improve with removal of the offending agent. NDI due to lithium may be irreversible (8,9)[A].
- Generally good prognosis depending on underlying disorder
COMPLICATIONS
- Dilatation of the urinary tract has been observed (probably secondary to large volume of urine).
- In both CDI and NDI, other complications due to any causative illness should be anticipated and addressed.
- Without treatment, dehydration can lead to confusion, stupor, and coma.
- Subnormal growth rate
REFERENCES
11 Aleksandrov N, Audibert F, Bedard MJ, et al. Gestational diabetes insipidus: a review of an underdiagnosed condition. J Obstet Gynaecol Can. 2010;32(3):225-231.22 Krahulik D, Zapletalova J, Frysak Z, et al. Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults. J Neurosurg. 2010;113(3):581-584.33 Pratheesh R, Swallow DM, Rajaratnam S, et al. Incidence, predictors and early post-operative course of diabetes insipidus in paediatric craniopharygioma: a comparison with adults. Childs Nerv Syst. 2013;29(6):941-949.44 Werny D, Elfers C, Perez FA, et al. Pediatric central diabetes insipidus: brain malformations are common and few patients have idiopathic disease. J Clin Endocrinol Metab. 2015;100(8):3074-3080.55 Devin JK. Hypopituitarism and central diabetes insipidus: perioperative diagnosis and management. Neurosurg Clin N Am. 2012;23(4):679-689.66 Di Iorgi N, Napoli F, Allegri AE, et al. Diabetes insipidus-diagnosis and management. Horm Res Paediatr. 2012;77(2):69-84.77 Makaryus AN, McFarlane SI. Diabetes insipidus: diagnosis and treatment of a complex disease. Cleve Clin J Med. 2006;73(1):65-71.88 Rej S, Herrmann N, Shulman K. The effects of lithium on renal function in older adults-a systematic review. J Geriatr Psychiatry Neurol. 2012;25(1):51-61.99 Garofeanu CG, Weir M, Rosas-Arellano MP, et al. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis. 2005;45(4):626-637.
CODES
ICD10
- E23.2 Diabetes insipidus
- N25.1 Nephrogenic diabetes insipidus
ICD9
- 253.5 Diabetes insipidus
- 588.1 Nephrogenic diabetes insipidus
SNOMED
- Diabetes insipidus (disorder)
- Nephrogenic diabetes insipidus (disorder)
- Neurohypophyseal diabetes insipidus (disorder)
- Hereditary nephrogenic diabetes insipidus
- Familial central diabetes insipidus (disorder)
- Acquired nephrogenic diabetes insipidus
CLINICAL PEARLS
- To distinguish primary polydipsia from DI in a patient with polyuria, a patient with primary polydipsia will have a normal response to a water restriction test and normal levels of plasma ADH.
- Vasopressin (IM) had been used previously but has been replaced by desmopressin, which provides the antidiuretic but not the vasoconstrictive activity of vasopressin for the treatment of CDI.
- The goal for adult patients with congenital NDI is to prevent dehydration by ensuring proper fluid intake.
- Genetic testing should be recommended for access to genetic counseling and to facilitate newborn screening.