2. INTRODUCTION:
ā¢ Polydipsia and polyuria(>5 mL/kg/hr) with dilute urine(osmolality <300 mOsm/L),
hypernatremia(>145mmol/l) and dehydration are the hallmarks of diabetes insipidus
ā¢ Patients are unable to conserve water and can become severely dehydrated when deprived of
water.
ā¢ Defective ability to concentrate urine in the kidneys, resulting in the production of large
quantities of dilute urine.
TYPES:
1. CENTRAL: vasopressin deficiency
2. NEPHROGENIC: vasopressin insensitivity at the level of the kidney
3. EPIDEMIOLOGY:
ā¢ Incidence: 3 in 100,000
ā¢ Can present at any age
ā¢ Prevalence: males=females.
ā¢ 10% hereditary
ā¢ X-linked nephrogenic DI: 90%
ā¢ Autosomal NDI:10%
Diabetes Insipidus
Pablo Saborio, MD,* Gary A. Tipton, MD,ā and James C.M. Chan, MD
7. CLINICAL FEATURES:
ā¢ Hereditary NDI, symptoms usually appear shortly after birth and most children are diagnosed
within the first year of life.
ā¢ Congenital NDI:
ā¢ Massive polyuria, volume depletion, hypernatremia, and hyperthermia.
ā¢ Irritability and crying
ā¢ Constipation
ā¢ Developmental delay and mental retardation.
ā¢ Enuresis, caused by large urine volumes, is common.
ā¢ Diminished appetite and poor food intake leading to poor weight gain.
ā¢ Growth abnormalities.
ā¢ Behavioral problems, including hyperactivity and short-term memory problems.
ā¢ Secondary form
ā¢ Generally present later in life with hypernatremia and polyuria.
ā¢ Developmental delay and behavioral abnormalities are less common
8. CENTRAL NEPHROGENIC
Age at presentation Infancy/between 5-6 yrs/rarely
adulthood
Antenatal hydramnios/neonatal
age/ early infancy
Incidence Rare Common
Etiology Often acquired cause Mostly acquired cause
Mode of inheritance AD/AR X linked /AD/AR
Gene AVP NPII, WFS-1 AVPR2, AQP2
Clinical presentation Marked thirst, growth failure Severe thirst, failure to thrive,
growth failure, mental
retardation
Mental retardation Rare ++
CENTRAL NEPHROGENIC
Basal urine osmolality Low Low
Basal plasma osmolality Normal/ Low Low
Post WDT urine Low Low
Post WDT plasma
osmolality
High High
post WDT SAVP levels Low or inappropriately normal High
Response to dDAVP Very good Poor
MRI Posterior pituitary
bright signal
Absent May be present
Long term prognosis Congenital: good
Acquired: depends on etiology
Short stature, mental retardation
commonly seen
10. DIAGNOSIS
ā¢ 24-hour urine volume
ā¢ Urine sugar
ā¢ Urea, electrolytes, calcium and creatinine
ā¢ Urine for early morning specific gravity or osmolality
ā¢ Blood gases
ā¢ Renal ultrasonography
ā¢ Diabetes Insipidus: High plasma osmolality(>300mosm/kg or sodium >146meq/l) with low urine
osmolality(<300 mosm/kg and urine specific gravity<1.005)
VASOPRESSIN RESPONSE TEST:
ā¢ To differentiate central DI from nephrogenic DI
ā¢ Urine osmolality is measured in 1 and 4 hour after vasopressin injection(0.1unit/kg)
ā¢ Increase in urine osmolality by >50% is suggestive of central DI
ā¢ Smaller increase than nephrogenic DI
11. ā¢ Normal plasma osmolality and low urine osmolality(<300mosm/kg) should undergo water
deprivation test
WATER DEPRIVATION TEST(HARE-HICKEY TEST):
Aim:
ā¢ To increase plasma osmolality above 300mosm/kg(or serum sodium above 146 meq/l) to allow
opportunity for maximal renal concentration
Renal failure and renal tubular acidosis should be excluded.
Not required in the presence of hypernatremia
12. After fluid deprivation After DDAVP Diagnosis
<300mosm/kg >750mosm/kg Central DI
<300mosm/kg <300mosm/kg Nephrogenic DI
>750mosm/kg - Primary polydipsia
300-750mosm/kg <750mosm/kg Partial DI
Method:
ā¢ Collect baseline urine and blood (osmolality and electrolytes).
ā¢ Deprive of water after breakfast until significant dehydration occurs.
ā¢ Weigh every 2 hour; limit dehydration to 3% to 5% loss of body weight.
ā¢ Body weight, urine output and urine and blood osmolality monitored hourly.
ā¢ Test should be stopped when urine osmolality >750mosm/kg or specific gravity >1.010 or
Na>146meq/l or weight loss>5%
ā¢ Limit water deprivation to 7 hour (4 hour for infants).
ā¢ Collect urine and blood for osmolality and electrolytes.
13.
14. TREATMENT
ā¢ Goal: Reduce polyuria and decrease the thirst so that the child is able to grow adequately and
maintain a normal life style
ā¢ Maintenance of adequate fluid intake and access to free water
ā¢ Minimizing urine output by limiting solute load with a low-osmolar, low-sodium diet and
administering medications directed at decreasing urine output.
ā¢ Human milk(6% of caloric intake) or a low- solute formula, such as Similac PM 60/40 is preferred
in infancy.
ā¢ Protein intake should constitute 8% of caloric intake, and sodium intake should be less than 0.7
mEq/kg per day.
ā¢ Most infants with congenital NDI require gastrostomy or nasogastric feedings to ensure adequate
fluid administration throughout the day and night.
15. ā¢ Thiazide diuretics (hydrochlorothiazide 2 to 3 mg/kg per day in three divided doses or
chlorothiazide 30 mg/kg per day).
ā¢ act at the distal convoluted tubule and inhibit cotransport of sodium and chloride.
ā¢ 50% reduction in polyuria.
ā¢ Side effects: hypokalemia and (rarely) neutropenia.
ā¢ The tendency toward hypokalemia can be countered with potassium supplementation or the use
of potassium-sparing diuretics. as amiloride 0.1 to 0.2 mg/kg per day to a maximum of 10 mg/
per day.
ā¢ In addition, indomethacin 0.25 to 3 mg/kg per day in two divided doses or aspirin 10 to 30 mg/kg
per day in two divided doses has an additive effect on hydrochlorothiazide in reducing water
excretion in some patients.
ā¢ Side effect: gastrointestinal bleeding, hyperkalemia, hypernatremia, and elevated creatinine
ā¢ Long-term side effects of indomethacin: deterioration of renal function.
16. ā¢ Amiloride
ā¢ Lithium-induced NDI.
ā¢ Reduces transcellular lithium transport, intracellular lithium concentration.
ā¢ Exogenous ADH
ā¢ Nonhereditary nephrogenic DI
ā¢ Increase the urine osmolality by 40 to 45 percent
ā¢ In hereditary diabetes insipidus: Genetic counseling and follow-up are important.
ā¢ Body temperature, appetite, and linear growth should be monitored at all follow-up clinic visits.
17. PROGNOSIS:
ā¢ Prevention of recurrent dehydration and hypernatremia in patients with congenital NDI has
significantly improved the neurodevelopmental outcome of these patients.
ā¢ However, behavioral issues may be present.
ā¢ Chronic use of nonsteroidal anti-inflammatory drugs can predispose patients to renal
insufficiency.
ā¢ Secondary NDI prognosis depends on the nature of the underlying disease.
18. RECENT ADVANCE:
A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus
Fenske W et al. New England Journal of Medicine. 2018 Aug 2; 379:428.
AIM: Compare indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate
of arginine vasopressin.
METHODS: From 2013 to 2017, 156 patients recruited with hypotonic polyuria at 11 medical centers to undergo
both water-deprivation and hypertonic saline infusion tests. Plasma copeptin was measured when the plasma sodium
level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the
overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the
basis of medical history, test results, and treatment response, with copeptin levels masked.
RESULTS: Out of 144, 82 patients (57%) primary polydipsia, central diabetes insipidus in 59 (41%), and
nephrogenic diabetes insipidus in 3 (2%). Overall, 141 patients included in the analysis, the indirect water-deprivation
test determined the correct diagnosis in 108 patients and the hypertonic saline infusion test (with a copeptin cutoff
level of >4.9pmol per liter) determined the correct diagnosis in 136 patients The indirect water-deprivation test
correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients and the
hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients. Adverse event
(desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test.
CONCLUSIONS: Direct measurement of hypertonic salineāstimulated plasma copeptin had greater diagnostic
accuracy than the water-deprivation test in patients with hypotonic polyuria
19. REFERENCE:
ā¢ Nelson textbook of pediatrics, 21st edition
ā¢ American academy of pediatrics
ā¢ Uptodate
ā¢ Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus
By Detlef Bockenhauer and Daniel G. Bichet
Polyuria is characterized by a urine volume in excess of 2 l/m2/24 h or approximately 150 ml/kg/24 h at birth, 100ā110 ml/ kg/24 h until the age of 2 years and 40ā50 ml/kg/24 h in the older child and adult.
polydypsia, defined as water intake of more than 2 L/ m2/d (or more than 5 L/d)
Osmolality is calculated as follows: 2(Na + K) + (Glucose/ 18) + (BUN/2.8)
āOsmolalityā and āOsmolarityā. When the solutes are expressed as milliosmoles/ kilogram (mOsm/kg) of the solvent, it is referred to as āOsmolalityā and when expressed as milliosmoles/liter (mOsm/L) of the solvent, we refer it as āOsmolarityā.
. Central secretion of arginine vasopressin (AVP). AVP is secreted by the posterior pituitary in relation to paraventricular nuclear and supraoptic nuclei. AVP exerts its action at target sites in the kidney. B. Water channel recycling. At the basolateral membrane of the renal cortical collecting duct cell, AVP is bound to vasopressin V2 receptor (V2R). G protein links V2R to adenylate cyclase (AC), increasing the concentration of cyclic adenosine monophosphate (cAMP). The cAMP- dependent protein kinase A (PKA) acts on recycling vesicles that carry the tetrameric water channel proteins. The water channels are fused, by exocytic insertion, to the apical basement membrane to increase water permeability. When AVP becomes unavailable, the water channels are retrieved (endocytic retrieval).
This allows water movement along its osmotic gradient into the hypertonic inner medullary interstitium from the tubule lumen and excretion of concentrated urine
aquaporin-3 and aquaporin-4 are expressed on the basolateral mem- brane of the collecting duct cells and aquaporin-1 is expressed in the proximal tubule. These channels may also contribute to urinary con- centrating ability.
Regulation of vasopressin (VP) secretion and serum osmolality. Hyperosmolality, hypovolemia, and hypotension are sensed by osmosensors, volume sensors, and barosensors, respectively. These stimulate both VP secretion and thirst. VP, acting on the kidney, causes increased reabsorption of water (antidiuresis). Thirst causes increased water ingestion. The results of these dual negative feedback loops cause a reduction in hyperosmolality or in hypotension or hypovolemia. Additional stimuli for VP secretion include nausea, hypoglycemia, and pain.
After multiple episodes of hyperna- tremic dehydration, patients can have
Because of the need to consume large volumes of water during the day, patients often have
This is easily dif- ferentiated from diabetes insipidus by the hyperglycemia, ketonuria, glucosuria, and high anion gap aci- dosis associated with diabetic keto- acidosis.
also must be included in the differential diagnosis. Although the polyuria of chronic renal failure is less severe than that seen in diabetes insipidus, it is more difficult to reverse azotemia with hydration.
Then classify on the basis of response to avp
Risk of dehydration
The diuretics increase sodium loss by inhibiting its reabsorption in the cortical diluting tubule.
No long-term side effects have been reported with this combi- nation of medications.
have partial rather than complete resistance to antidiuretic hormone (ADH). It is therefore possible that attaining supraphysiologic hormone levels will increase the renal effect of ADH to a clinically important degree.
The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate.