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SIADH
Most frequent cause of hyponatremia
First described by Schwartz et al in 1957 in 2 pts withbronchogenic carcinoma
Arginine vasopressin was then identified
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ADH
Synthesized in hypothalamus
Transported down to posterior pituitary Released in response to hyperosmolality (major stimuli,
mediated through osmoreceptors in hypothalamus) or
hypovolemia (via baroreceptors in left atrium, aortic arch, etc)
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ADH
Binds to V2 receptors in collecting tubules
stimulates cyclic adenosine monophosphate leads to insertion of aquaporin-2 channels into apical
membranes
The goal is to facilitate the transport of solute-free water
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Figure Freeze-fracture appearance ofvasopressin-induced intramembrane particle(IMP) aggregates in toad urinary bladder (A),
toad epidermis (B), and rat kidney collectingduct (C). The morphology of the aggregates isdifferent in all three vasopressin target cells. Inthe bladder, the aggregates are tightly packedlinear arrays, in the skin they form orthogonally
packed square arrays, and in the collectingduct principal cell they form loose clusters thatare often located in shallow depressions on thecell surface. Bar = 0.25 m.
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Figure Aquaporin-2 (AQP2) is internalized by clathrin-coated pits. Aand B,Immunogoldlabeling of AQP2 in clathrin-coated pits (arrows)at the apical plasma membrane ofcollecting duct principal cells. An antibody against an external epitope of AQP2 wasused. Cand D,Label-fracture images of LLC-PK1 cells expressing AQP2. Immunogold
label for AQP2 is located in intramembrane particle (IMP) clusters on the membrane (C,arrows; and is associated with membrane invaginations that resemble clathrin-coatedpits (D,arrows). For more details, see Sun TX, et al. Bars = 0.25 m.
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SIADH => SIAD
A slight misnomer
The name implies inappropriate secretion
1/3rdof pts do secrete AVP independent of plasma osmolality
Others exhibit reset osmostatAVP is fully supressed, butserum Na level is lower than nl
AVP levels may be undetectable in some pts
Some aquaporin mutations lead to concentrated urine in the
absence of AVP Therefore, the new term, Syndrome of Inappropriate
Antidiuresis (SIAD) has been proposed
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Patterns of plasma levels of arginine vasopressin (AVP; also known as the antidiuretic hormone), ascompared with plasma sodium levels in patients with SIAD, are shown. Type A is characterized by
unregulated secretion of AVP, type B by elevated basal secretion of AVP despite normal regulation by
osmolality, type C by a "reset osmostat," and type D by undetectable AVP. The shaded area
represents normal values of plasma AVP. Adapted from Robertson
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Disorders associated with SIAD
Malignancies
Carcinomas, lymphomas, sarcoma
Pulmonary disorders
Infectious, asthma, CF
CNS disorders
Infectious, bleeding, masses, MS
Drugs
Chlorpropramide, SSRIs, cyclophosphomide, ecstasy
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Diagnosis of SIAD
Essential features
hyponatremia
plasma osm100
clinical euvolemia
urinary Na>40
nl thyroid/adrenal fxn, no recent diuretic use
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Dx of SIAD
Supplemental features
uric acid
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Volume status assesment
Sometimes, clinical assesment of volume status is
imprecise. Dr. Berl suggests the following:
Rule out volume contraction by infusing 2L of NS over 24-48
hours.
Urine osm has to be less than 500 (to avoid severe worsening of
hypoNa)
If hypoNa corrects, this suggests volume depletion
NEJM 356:2064-2072
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Why 500 osms?
Where did Berl come up with that magic number?
Goldfarb and Rose both tell me that osmolality of
administered IVF must exceed osmolality of urine Who is right?
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Goldfarb-Rose Hypothesis
Prior acceptance that isotonic saline (308 osms) infusion in
SIAD is useless Electrolytes are excreted in urine
Urine osmolality in SIAD is typically >300
water is retained => worsening hypoNa
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Berls Axiom
Previous study showed an increase in plasma Na of pts with
SIADH from 124 to 127 mEq/l after IV NS (Musch et al Am J
Med 1995;99: 348-55) Mean initial urinary osmolality was 429 mosm/kg
So why not give SIAD pts isotonic saline?
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Treating SIADH with isotonic saline
Musch et al conducted a prospective study of 17 pts with
SIADH (Q J Med 1998; 91:749-753)
Goal to predict the response to isotonic saline based on either
Uosm and UNa+K
2L infusion over 24 hours
Initial plasma Na 115-130
All pts met the criteria for SIADH
Water restriction (
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Results
11 men, 6 women
mean age 64+13
Underlying conditions of 17 pts
Lung cancer (6) Other pulm diseases (4)
Cerebral traumatism (2)
Ovarian CA/sarcoma/cortical atrophia (1 each)
Idiopathic SIADH (2)
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Results cont.
t0 t24
Sodium 126+5 127+6
Potassium4+0.4 3.9+0.5
UNa+K 128+61 163+41
Uosm 502+128 497+113
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Weak correlation
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Strong correlation
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Discussion
11 / 17 pts increased their plasma Na after 2L infusion
Uosms exceeded the osmolality of isotonic saline
6 / 17 pts aggravated their hypoNa
mean Uosm > 538 mosm/kg
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Prvs assumption that rise in plasma Na by 5 mEq/L after 2L
NS infusion/24h suggests hypovolemia may be incorrect
This response can be observed in SIAD pts as well
Differentiate by high urinary salt excretion
salt-depleted hypovolemic pts conserve salt
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