Nephrogenic diabetes insipidus

Nephrogenic Diabetes
Insipidus
By: Dr. Rajendra Shilpakar
Moderator: Dr. Asim shrestha

INTRODUCTION:
• 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
• Patients are unable to conserve water and can become severely dehydrated when deprived of
water.
• 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

EPIDEMIOLOGY:
• Incidence: 3 in 100,000
• Can present at any age
• Prevalence: males=females.
• 10% hereditary
• X-linked nephrogenic DI: 90%
• Autosomal NDI:10%
Diabetes Insipidus
Pablo Saborio, MD,* Gary A. Tipton, MD,† and James C.M. Chan, MD

CAUSES:
1. CENTRAL DI
• Genetic (autosomal dominant, AVP neurophysin gene mutation)
• Trauma (surgical or accidental)
• Congenital malformations (holoprosencephaly, septooptic dysplasia, encephalocele)
• Neoplasms (craniopharyngioma, germinoma, metastasis, lymphoma, leukemia)
• Infiltrative (Langerhans cell histiocytosis)
• Autoimmune (lymphocytic infundibuloneurohypophysitis)
• Infectious diseases(meningitis, tuberculosis, sarcoidosis)
• Drugs or toxin (ethanol, diphenylhydantoin, snake venom)
• Vascular(cerebral hemorrhage or infraction, brain death)
• Idiopathic(10%)

2. NEPHROGENIC DI
•Genetic (X-linked recessive, AVP V2 receptor gene mutation, , autosomal recessive or
dominant(10%), aquaporin 2 water channel gene mutation)
•Hypercalcemia
•Hypokalemia
•Drugs (lithium, demeclocycline, cisplatin, methoxyflurane)
•Infiltrating lesion(sarcoidosis, amyloidosis)
•Vascular: sickle cell anemia
•Mechanical: polycystic kidney disease, bilateral ureteral obstruction
•Solute diuresis: glucose, mannitol, sodium, radiocontrast dyes
•Idiopathic

PATHOPHYSIOLOGY OF WATER BALANCE:

CLINICAL FEATURES:
• Hereditary NDI, symptoms usually appear shortly after birth and most children are diagnosed
within the first year of life.
• Congenital NDI:
• Massive polyuria, volume depletion, hypernatremia, and hyperthermia.
• Irritability and crying
• Constipation
• Developmental delay and mental retardation.
• Enuresis, caused by large urine volumes, is common.
• Diminished appetite and poor food intake leading to poor weight gain.
• Growth abnormalities.
• Behavioral problems, including hyperactivity and short-term memory problems.
• Secondary form
• Generally present later in life with hypernatremia and polyuria.
• Developmental delay and behavioral abnormalities are less common

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

DIFFERENTIAL DIAGNOSIS
• Diabetes mellitus.
• Psychogenic polydipsia
• Cerebral salt wasting syndrome
• Hypercalcemia
• Chronic renal failure

DIAGNOSIS
• 24-hour urine volume
• Urine sugar
• Urea, electrolytes, calcium and creatinine
• Urine for early morning specific gravity or osmolality
• Blood gases
• Renal ultrasonography
• 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:
• To differentiate central DI from nephrogenic DI
• Urine osmolality is measured in 1 and 4 hour after vasopressin injection(0.1unit/kg)
• Increase in urine osmolality by >50% is suggestive of central DI
• Smaller increase than nephrogenic DI

• Normal plasma osmolality and low urine osmolality(<300mosm/kg) should undergo water
deprivation test
WATER DEPRIVATION TEST(HARE-HICKEY TEST):
Aim:
• 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

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:
• Collect baseline urine and blood (osmolality and electrolytes).
• Deprive of water after breakfast until significant dehydration occurs.
• Weigh every 2 hour; limit dehydration to 3% to 5% loss of body weight.
• Body weight, urine output and urine and blood osmolality monitored hourly.
• Test should be stopped when urine osmolality >750mosm/kg or specific gravity >1.010 or
Na>146meq/l or weight loss>5%
• Limit water deprivation to 7 hour (4 hour for infants).
• Collect urine and blood for osmolality and electrolytes.

TREATMENT
• Goal: Reduce polyuria and decrease the thirst so that the child is able to grow adequately and
maintain a normal life style
• Maintenance of adequate fluid intake and access to free water
• Minimizing urine output by limiting solute load with a low-osmolar, low-sodium diet and
administering medications directed at decreasing urine output.
• Human milk(6% of caloric intake) or a low- solute formula, such as Similac PM 60/40 is preferred
in infancy.
• Protein intake should constitute 8% of caloric intake, and sodium intake should be less than 0.7
mEq/kg per day.
• Most infants with congenital NDI require gastrostomy or nasogastric feedings to ensure adequate
fluid administration throughout the day and night.

• Thiazide diuretics (hydrochlorothiazide 2 to 3 mg/kg per day in three divided doses or
chlorothiazide 30 mg/kg per day).
• act at the distal convoluted tubule and inhibit cotransport of sodium and chloride.
• 50% reduction in polyuria.
• Side effects: hypokalemia and (rarely) neutropenia.
• 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.
• 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.
• Side effect: gastrointestinal bleeding, hyperkalemia, hypernatremia, and elevated creatinine
• Long-term side effects of indomethacin: deterioration of renal function.

• Amiloride
• Lithium-induced NDI.
• Reduces transcellular lithium transport, intracellular lithium concentration.
• Exogenous ADH
• Nonhereditary nephrogenic DI
• Increase the urine osmolality by 40 to 45 percent
• In hereditary diabetes insipidus: Genetic counseling and follow-up are important.
• Body temperature, appetite, and linear growth should be monitored at all follow-up clinic visits.

PROGNOSIS:
• Prevention of recurrent dehydration and hypernatremia in patients with congenital NDI has
significantly improved the neurodevelopmental outcome of these patients.
• However, behavioral issues may be present.
• Chronic use of nonsteroidal anti-inflammatory drugs can predispose patients to renal
insufficiency.
• Secondary NDI prognosis depends on the nature of the underlying disease.

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 saline–stimulated plasma copeptin had greater diagnostic
accuracy than the water-deprivation test in patients with hypotonic polyuria

REFERENCE:
• Nelson textbook of pediatrics, 21st edition
• American academy of pediatrics
• Uptodate
• Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus
By Detlef Bockenhauer and Daniel G. Bichet

Nephrogenic diabetes insipidus

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