Disorders of Water Balance:

DiabetesInsipidus and SIADH

Louis J . Muglia, MD PhD
Division of Pediatric Endocrinology and
Metabolism
Washington University School of Medicine
Physiology of Volume and
Osmolarity Balance
Renin-angiotensin-
aldosterone system
Modulates sodium
retention by kidney
Serves to restore
intravascular volume
status
Once euvolemic will
be suppressed and
sodium will be lost in
urine
Vasopressin/thirst
Modulates water
ingestion/excretion
Serves to restore
normal osmolarity,
activated to restore
volume with severe
hypovolemia
Normal Regulation of Body
Water
Hypothalamic Nuclei in Water
Regulation
Arginine Vasopressin Structure
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH
2
1
9
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Pro-Gly-NH
2
1
9
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-DArg-Gly-NH
2
1
9
NH
2
-
NH
2
-
dDAVP
Oxytocin
AVP
Vasopressin Gene Structure
AVP Signal
Neurophysin II Copeptin
Gly-Lys-Arg Arg
Exon A Exon B Exon C
Vasopressin Receptors
V1a - localized to smooth muscle, hepatocytes,
and platelets. Induces calcium flux and
phosphatidyl inositol hydrolysis.
V1b - localized to pituitary corticotrophs,
augments ACTH release. Similar ligand binding
and signaling to V1a.
V2 - renal collecting ducts, periglomerular
tubules, vascular endothelial cells. Activates
adenylyl cyclase and stimulates vWF, VIIIa, and
plasminogen activator.
QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.
V2 Receptor Structure and
Mutations
From Brenner and Rector's, The Kidney,Volume 2, A. Bonnardeaux and D.G. Bichet 2004
QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.
Aquaporin-2 Structure and
Mutations
From Brenner and Rector's, The Kidney,Volume 2, A. Bonnardeaux and D.G. Bichet 2004
Stimuli for Vasopressin Release
Serum Osmolarity
Depleted Intravascular Volume
Nausea
Nicotine
Hypoglycemia
Relationship of Vasopressin
Release and Thirst
Changes in Water Regulation
during Pregnancy
Effect of Volume Changes on
Vasopressin Release
0 1 2 3 4 5 6 7 8 9 10
0
25
50
75
100
Age (years)
B
o
d
y

W
a
t
e
r

(
%

o
f

b
o
d
y

w
e
i
g
h
t
)
Total
Intracellular
Extracellular
Change in Body Water with Age
Body Fluids
Total body water: 80% of body weight in
infants, 60% in children and adults
Extracellular: 40% of BW in infants, 20% later
(15% interstitial and 5% intravascular)
Intracellular: 40% of BW
Sodium is the principal volume regulator,
exerting effects over TBW
Water Requirements
What is maintenance fluid volume?
Losses per day:
Respiratory and skin: 500 ml/m
2
/d
Gastrointestinal: 100 ml/m
2
/d
Urine (at 400-500 mOsm/kg): 1150 ml/m
2
/d
Sources:
Water of oxidation: 250 ml/m
2
/d
Net: 1,500 ml/m
2
/d
Calculation of Water Deficit
Water deficit = usual BW - current BW
Usual BW = current weight x 0.6 x current
Osm/normal Osm
Electrolyte Requirements
Sodium: 20 - 50 mEq/m
2
/d
Potassium: 20 - 50 mEq/m
2
/d
Calcium (elemental):
Newborns 50-75 mg/kg/d (term)
Infants 600 mg/d
Children 800 mg/d
Adolescents 1200 mg/d
Acute treatment of hypocalcemia: 10 mg/kg IV
followed by 50 mg/kg/d IV
Glucose Requirements
Providing 5% dextrose-containing solutions
normally adequate to stop ketone production in
normal individuals, but still catabolic
Important to prevent catabolism in patients with
inborn errors of metabolism, so provide at least
hepatic glucose production rate = 0.0014x
3
-
0.214x
2
+ 10.411x - 9.084 (x is body weight in kg;
glucose prodution rate in mg/min)
For children, this is approximately 6-8 mg/kg/min
Determination of Ongoing Losses
Measure volume of output site - emesis,
stool, ostomy drainage, etc.
Know general electrolyte composition of
drainage from that site (e.g., sodium in
gastric contents = 50 mEq/l; bile 130 mEq/l;
stool 50 mEq/l) to determine best
replacement fluid
What determines urine volume?
Solute excretion - usually 500 mOsm/m
2
/d
Urine concentration
If maximally concentrated = 1200 mOsm/kg
If minimally concentrated = 100 mOsm/kg
So, for SIADH you need to provide
500/1200 + 0.5 + 0.1 - 0.25 = 0.8 l/m
2
/d
For DI, same calculations lead to 5 l/m
2
/d -
dont try and replace urine output!
Acute Fluid Resuscitation
Weigh the patient
For signs of cardiovascular compromise,
volume expand with isotonic saline (0.9%
NaCl or Ringers lactate) in 10-20 cc/kg
boluses
Consider including 5% dextrose (if only
acutely hypoglycemic, 2-4 cc/kg D25)
Isotonic Dehydration
Most common form of dehydration (80%)
Proportional loss of water and solute, thus no
redistribution from ECF to ICF
Typically replace half the deficit over 8 h and
remainder over next 16 h
Alternatively, can provide 3 l/m
2
/d in replacement
phase
D5 1/4-1/2 NS appropriate depending upon
ongoing sodium losses
Hyponatremia with Dehydration
(Na
+
< 130mEq/L)
With appropriate increase in vasopressin
Severe dehydration
Decreased effective circulating volume
CHF, cirrhosis, nephrotic syndrome, positive
pressure ventilation
Therapy: rehydration with salt-containing
fluid for dehydration.
Correction of Hyponatremic
Dehydration
Similar management as isotonic dehydration
except for calculation of additional sodium
replacement
Extra Na+ = (135-measured Na) x total body
water
Example: 10% dehydration in 30 kg child with Na
128 mEq/l = (135-128) x 0.6 x 30 = 126 mEq;
water deficit 0.6*30*0.1= 1.8 L
Therefore, to replace half deficit over 12 h give 63
mEq in 0.9 L or D5 .45 NS at 75 cc/h above
maintenance
Symptomatic Hyponatremia
Mental status changes, seizures
Rapid correction of sodium up to level that
stops seizure activity
Use 3% NaCl to deliver approximately 5
mEq/kg/hr. If due to SIADH, give lasix to
prevent sodium dumping with volume
expansion.
Adaptation to Hyponatremia
Limitations in Correction of
Hyponatremia
Acute changes can probably be safely
corrected in a rapid fashion
Chronic (more than 24 h) hyponatremia
should be corrected slowly (<0.5
mEq/L/hr) to avoid central pontine
myelinolysis
Hyponatremia without Dehydration
(Na
+
< 130 mEq/L)
With inappropriate increase in vasopressin
(SIADH)
Uncommon, but many etiologies.
Therapy: Fluid restriction - restrict to
volume required for excretion of solute with
maximally concentrated urine (0.4 l/m
2
/d)
plus insensible loss (0.4 l/m
2
/d). If mental
status changes, 3% normal saline and lasix.
Hyponatremia
(Na
+
< 130 mEq/L)
Due to sodium chloride loss
Renal disease
Mineralocorticoid deficiency
Diuretic use
Gastrointestinal disease
Cystic fibrosis
Increased secretion of ANP (cerebral salt-wasting)
Therapy: salt supplementation
The Natriuretic Peptides
Cys
Cys
NH
2
NH
2
NH
2
HOOC
HOOC
HOOC
ANP
BNP
CNP
NPR-A, C
NPR-B, C
LIGAND RECEPTOR
Cys
Cys
Cys
Cys
Findings in Cerebral Salt-
Wasting
SIADH CSW CDI
Plasma volume

Clinical evidence of volume depletion

+ +
Serum sodium/osmolality

Urine sodium/osmolality

Urine flow rate
Plasma renin activity
Plasma aldosterone concentration
or
Plasma AVP concentration
or
BUN/Creatinine
/ / /
Hematocrit
Albumin concentration
Serum uric acid concentration
or
Plasma ANP or BNP concentration
Treatment
Fluid restriction
Salt and fluid
replacement
Salt poor fluid
replacement
Hyponatremia without Dehydration
(Na
+
< 130 mEq/L)
With normal regulation of vasopressin
Primary polydipsia
Decreased free water clearance
Adrenal (glucocorticoid) deficiency
Hypothyroidism
Drugs
Cyclophosphamide, tegretol, cis-platinum
Therapy at underlying cause
Hyponatremia
(Na
+
< 130 mEq/L)
With normal osmolarity
Hyperglycemia
Decrease in serum sodium 1.6 mEq/L for each 100
mg/dl increase in glucose above 100 mg/dl
Hyperlipidemia - factitious
Evaluation of Hyponatremia
Hypertonic Dehydration
Volume loss with serum sodium above 150 mEq/L
Goal is to lower sodium not more rapidly than 0.5
mEq/L/h and correct fluid deficit over 48 - 72 h
To calculate water deficit:
Deficit = ((Na
measured
- 140)/140)0.6 Weight
now
Can also begin therapy with fluids at 2 l/m
2
/d and
monitor rate of correction
D5 0.2NS or D5W (diabetes insidipus) appropriate
rehydration fluids
How do you evaluate polyuria
and polydipsia?
History
Objective assessment
Random labs
Additional outpatient laboratories
Water deprivation test
Imaging studies
Laboratory Confirmation of DI
Polyuria and polydipsia with serum Osm
above 300 mOsm/kg and urine Osm less
than 300 mOsm/kg
Not usually achieved with random
screening labs
Proceed to water deprivation
Water Deprivation Testing
Water Deprivation Phase
Obtain initial weight, vitals and document duration of pretest water restriction (if
any)
Place intravenous line to assist with repeated blood drawing, and place foley
catheter in children too young to provided hourly voided urine specimens
Obtain baseline serum Na, vasopressin, urine osmolality and urine specific
gravity.
Begin (or continue) water deprivation
Measure and record hourly a flow sheet:
o Weight, HR, BP, urine output and urine specific gravity.
o Stat laboratory testing: serum sodium and urine osmolality.
If Na <145, urine osmolality<600, and there is no clinical evidence of significant,
symptomatic hypovolemia, continue water deprivation.
If urine osmolality is above 1000, or above 600 and stable over 2 measures, stop
test. Patient does not have diabetes insipidus.
If serum osmolality is above 300 and urine osmolality is below 600, the patient
has diabetes insipidus. Proceed to Vasopressin response phase
Vasopressin Response Phase
Collect blood for vasopressin level.
Administer Pitressin, 1 unit/m
2
, SQ
Allow the patient to eat, and drink, limiting fluid intake to the volume of urine
produced during the entire testing period (water deprivation and vasopressin
response)
30 and 60 minutes after Pitressin, measure vital signs, urine output, and urine
specific gravity, and send urine to lab for osmolality.
A two fold increase in urine osmolality indicates central diabetes insipidus.
An increase of less then 2 fold in urine osmolality is consistent with nephrogenic
diabetes insipidus.
Causes of Diabetes Insipidus
Central DI
Genetic: Familial Autosomal Dominant, Wolfram
(DIDMOAD), Septo-optic Dysplasia
Trauma
Iatrogenic
Anatomical defects in hypothalamus
Neoplasms
Infiltrative,autoimmune, infectious diseases
Increased vasopressin metabolism
Causes of Diabetes Insipidus
Nephrogenic DI
Genetic: X-linked vasopressin V2 receptor
mutations; Autosomal recessive aquaporin 2
mutations
Acquired
Drugs: demeclocycline, lithium
Electrolyte disturbance: hypercalcemia,
hypokalemia
Renal damage
Triphasic Response after
Pituitary Stalk Damage
Postoperative Days
U
r
i
n
e

V
o
l
u
m
e
3-7 days
Perioperative Fluid Management for
Hypothalamic/Pituitary Surgery
Provide basal fluids to replace insensible losses
and obligate urine output assuming maximally
concentrated urine = 1 L/m
2
/d with D5 1/4NS
Replace urine output to a maximum of 4 L/m
2
/d
with D5W
If patient has DI, expect serum sodium to run
about 150 mEq/L
Alternatively, can restrict fluids to 1 L/m
2
/d and
give Pitressin intravenously at 1.5 mU/kg/h
Chronic Management of Central
Diabetes Insipidus
With intact thirst mechanism, fluids based
upon thirst and dDAVP dosed to allow 1-2
hours of polyuria per day to minimize risk
for hyponatremia
Relative potency: Oral 1, Nasal 20-100,
subQ 200-1000
With disrupted thirst, both fluids and
dDAVP need to be prescribed.
Treatment of Nephrogenic DI
Identify underlying disorder and treat
Minimize solute load for excretion (foods
with the highest caloric/osmotic load ratio)
Thiazides to decrease GFR and distal tubule
water delivery
With amiloride or indomethacin