This lecture explains the basics of diabetes insipidus, its types, causes, diagnosis, laboratory investigations, prognosis, management, case based learning and related aspects.
Outline of Lecture
Diabetes insipidus
Definition
Diabetes insipidus (DI) is a disease characterized by polyuria and polydipsia due to decrease secretion or action of antidiuretic hormone (ADH)
Types of Diabetes Insipidus
Neurogenic- also called central or pituitary, it is caused by a deficiency of the antidiuretic hormone, vasopressin.
Nephrogenic- caused by a defect in the receptor to the hormone, vasopressin, located in the kidneys.
Gestagenic- caused by a deficiency of the antidiuretic hormone, vasopressin, during pregnancy.
Dipsogenic- form of primary polydipsia, abnormal thirst and excessive intake of liquids.
Normal Physiology
Vasopressin is synthesized by the supraoptic and paraventricular nuclei of the hypothalamus
It is then transported to the posterior pituitary and stored.
Vasopressin release from posterior pituitary is primarily regulated by changes in plasma osmolality
The primary site of vasopressin action in the kidney is at the collecting duct
Vasopressin receptors are classified as V1 and V2
causes of neurogenic DI
Primary inherited forms—rare
Autosomal Dominant form
Wolfram syndrome
septo-optic dysplasia
Causes of neurogenic DI
Secondary or acquired causes—more common
tumors of the suprasellular and chiasmatic regions (craniopharyngiomas, optic gliomas, germinomas)
Head injury
Operations (near pituitary or hypothalamus)
Systemic diseases (encephalitis, histiocytosis, turberculosis, leukemia)
Autoantibodies to vasopressin-producing cells
In the newborn, DI has been reported in association with asphyxia, IVH, intravascular coagulopathy, Listeria monocytogenes sepsis, and bacterial meningitis and encephalitis.
Approx 20% of cases of DI are idiopathic
Nephrogenic diabetes (NDI)
Causes of Nephrogenic DI
Primary inherited causes
Mutations that affect the V2 receptor as well as the AQP 2 water channel
The V2 receptor gene is localized in the X chromosome
V2 receptor mutations may also appear de novo
Inherited autosomal recessive forms of nephrogenic DI also reported (mutation localized to chromosome 12)
Secondary or acquired forms
More common than primary forms
Drugs (lithium, ampho B, demeclocycline)
Can be associated with prolonged intervals of hypercalcemia or hypokalemia
Can be present in conjunction with inherited disorders of renal development (Polycystic kidney disease, renal dysplasia)
Disease processes that injure the collecting duct & surrounding tubules (sickle cell anemia, chronic pyelonephritis, urinary tract obstruction)
Gene Locus
Genetic Mutation
After testing of the AVPR2 gene, located at Xq28, almost 100% of disease-causing mutations result in individuals having NDI.
All types of mutations, such as frame shifts and splicing can be observed in the gene.
There are no other known phenotypes associated with AVPR2 gene mutations.
Protein Activity
Normally, the hormone, vasopressin links to the receptor, vasopressin-2 receptor (V2R), located in the collecting duct of the kidney. X-linked NDI is caused by a mutation on the V2R gene. The mutation inhibits the linkage of the hormone and receptor and the reabsorption of water by the kidneys.
Symptoms of Nephrogenic DI
POLYURIA, chronic passage of large volumes of urine
POLYDIPSIA, chronic, excessive thirst
OTHER
fever
irritability
constipation
failure to thrive
lack of appetite
vomiting
high blood levels of sodium
Patient History
How much fluid intake per day
Voiding patterns
Dietary intake
Drug history
Clinical Manifestations
POLYURIA
POLYDIPSIA
Signs and symptoms of chronic dehydration
Infants: irritability, poor feeding, growth failure, intermittent high fevers
In children who have acquired bladder control, enuresis may be the first symptom
Clinical Manifestations
Neurogenic DI
Hypothalamic tumors: growth disturbances, progressive cachexia or obesity, hyperpyrexia, sleep disturbance, sexual precocity, or emotional disorders
Lesions initially causing DI may eventually destroy the anterior pituitary and its associated endocrine axis
Laboratory investigations
Urine is usually pale and colorless
Urine analysis and urine electrolytes
Urine specific gravity varies b/w 1.001 and 1.010
Urine osmolality 50-300 mosm/kg
Serum osmolality may vary widely, depending on hydration status
Other renal function studies usually normal
Serum vasopressin measurement
Imaging
Renal ultrasound
Magnetic resonance imaging.
Tumors—calcifications; enlargement of sella turcica; increased width of suture lines
“Bright spot”—differentiates between posterior pituitary and anterior pituitary; present in normal pts; absent or ectopic in pts with hypothalamic-neurohypophyseal tract lesions
Diagnosis
Administration of desmopressin
In neurogenic DI, desmopressin will raise Urine osmolality& suppress urine out put.
In nephrogenic DI, desmopressin produces no increase in Urine osmolality and no suppression of Urinary out put.
In normal individuals, desmopressin administration can cause a vasodilatory response (flushing, fall in diastolic BP, rise in HR), believed to be mediated by extra renal V2 receptors
Water deprivation test
In patients with severe neurogenic DI, overnight water deprivation results in elevation of Serum and urine osmolality after administration of vasopressin.
In nephrogenic DI there is no effect on serum & urine osmolality after administration of desmopressin.
Treatment
The cause of the underlying condition should be treated when possible
Neurogenic DI
Administration of desmopressin, usually intranasal.
Desmopressin binds almost exclusively to V2 receptors and is more resistant to degradation by body peptidases than endogenous vasopressin
Therefore, the antidiuretic effects of desmopressin last 8-10 hr, compared with 1-3 hr for endogenous vasopressin
Dose: 5-10 mcg intranasal, given in single or divided doses; < 2 y/o: 0.15-0.5 mcg/kg/24 hr
IV/SC therapy also available
Nephrogenic DI
Ensure a sufficient intake of water to replace the large urinary water losses
Stop causative medications, if applicable
Low sodium diet
Drugs that reduce polyuria
Thiazide diuretics (hydrochlorothiazide)
Prostaglandin synthesis inhibitors (indomethacin)
Potassium-sparing diuretics (amiloride)
Management
Check serum electrolytes frequently
After episodes of dehydration, these patients usually require replacement of large quantities of water, but not sodium
Involve endocrine and nephrology services (and genetics, if indicated, for genetic counseling)
Prognosis
Neurogenic DI
Prognosis often determined by the underlying etiologic process
neurogenic DI may be transient or long-standing
Uncomplicated neurogenic DI can be managed effectively; permits a high quality of life for affected patients
Nephrogenic DI
Good prognosis, if careful clinical and laboratory monitoring
There are isolated reports of chronic renal failure in patients with nephrogenic DI
Case study
A 5 yr old boy presented with polyuria and polydipsia for the last 1 month. His urine output was > 3 L per 24 hrs.
On investigations
Glucose (within range 3.3-11.1 mmol/L)
Urea (within range 1.8-6.4 mmol/L)
Creatinine were not deranged
urine osmolality 60 mosm/L
Case study
Water deprivation test performed.
Urine osmolality increased only to 160 mosm/L
Desmopressin 10µg intra-nasally given
Urine osmolality 610 mosm/L
Serum osmolality 295 mosm/L
Diagnosis: neurogenic DI
