Diabetes Insipidus and SIADH Clinical Endocrinology: 2007

Joseph G. Verbalis, MD

hyponatremia treatment
guidelines:
2012 and beyond
Joseph G. Verbalis, MD
Professor of Medicine and Physiology
Chief, Endocrinology and Metabolism
Director, Georgetown-Howard Universities
Center for Clinical and Translational Science
Georgetown University
Washington, DC USA

Joseph G. Verbalis: disclosures

consultant: Astellas, Ferring,

Cardiokine, Otsuka
advisory board: Astellas, Otsuka
data safety board: Ferring
grant support: NHLBI, NIA, NCATS,
Otsuka

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

body fluid
compartments
water is the largest
component of our
body; since the
major determinant
of body water is
AVP-regulated
water excretion by
the kidneys, it
follows logically
that AVP must be
the most important
hormone in the
body

AVP stimulation and effects

hyperosmolality, baroreceptors,
hypovolemia, + – natriuretic
angiotensin II peptides

AVP
V1a Receptors V2 Receptors

vasoconstriction renal H2O

reabsorption

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

receptor-mediated effects of AVP

receptor
subtype site of action activation effects
vascular smooth vasoconstriction
muscle cells
platelets platelet aggregation
V1a lymphocytes and cytokine release
monocytes
liver glycogenolysis
ACTH and β -endorphin
V1b anterior pituitary
release
renal collecting duct
V2 principal cells free water absorption

AVP regulation of water reabsorption

from renal tubular cells

AQP3 Collecting Duct Cell

Collecting duct
Vasa recta

H2O

ATP
GTP Exocytic
AQP2
AVP (Gs) cAMP Insertion
AVP V2
Receptor
PKA H2O
AQP2

Recycling Endocytic
vesicle Retrieval
AQP4

Basolateral Luminal
membrane membrane

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

prevalence of dysnatremias at initial

presentation to a health care provider
(data from 303,577 samples on 120,137 patients available for analysis)

30 28.2 Acute hospital care

Ambulatory hospital care
25 Community care
21
Prevalence (%)

20

15

10
7.2

5
1.43
0.49 0.17 0.03 0.53 0.72 0.06 0.01 0.01
0
Na < 116 Na < 135 Na > 145 Na > 165

Hawkins. Clin Chim Acta 337:169-172, 2003

relationship between hospital admission

serum [Na+] and in-hospital mortality
0.20
Predicted Probability of
In-Hospital Mortality

0.15

0.10

0.05

110 115 120 125 130 135 140 145

Admission Serum [Na+] Concentration (mEq/L)

Wald et al. Arch Intern Med 170:294-302, 2010

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

chronic hyponatremia is also associated

with increased adverse outcomes

increased mortality over a 12-year period significantly increased

of outpatient follow-up risk of fracture

Hoorn et al. J Bone Mineral Res 26:1822-8, 2011

hyponatremic disorders

hypovolemia/dehydration
polydipsia
SIADH
extracellular fluid volume expansion
congestive heart failure
hepatic cirrhosis
bilateral ureteral obstruction

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

hyponatremia
can be
caused by
dilution from
retained
water, or by
depletion
from
electrolyte
losses in
excess of
water

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

U-Na+ excretion for

identification of EABV
with diuretics without diuretics

Fenske W. et al, JCEM 92:2991- 2997, 2008

SIADH: essential criteria

• true plasma hypoosmolality
• urine concentration inappropriate for
plasma osmolality (Uosm > 100 mOsm/kg
H2O)
• clinical euvolemia, no diuretic therapy
• absent renal sodium conservation (UNa > 30
mmol/L)
• normal thyroid, adrenal and renal function
modified from Bartter & Schwartz, Am J Med 42:790-806, 1967

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

plasma AVP levels are inappropriately

elevated in >95% of patients with SIADH

11
Plasma Vasopressin, pg/mL

10
9
8
7 Normal
6 Range
5
4
3
2
1
0

230 240 250 260 270 280 290 300 310

Plasma Osmolality, mOsm/kg H2O

Robertson et al. Am J Med 72:339, 1982

stimuli to AVP secretion

related to fluid independent of
homeostasis: fluid homeostasis:
hyperosmolality nausea
hypotension hypoxia
hypovolemia hypercarbia
angiotensin II hypoglycemia
stress: cytokines
physical activity

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

plasma plasma
osmolality AVP
(mOsm/kg H2O) (pg/ml)

296
9
294 8
urine
7 osmolality
thirst 292
(mOsm/kg H2O)
maximal
osmotic 6
threshold 290 urine
5 1000 excretion
288
4 800 rate (ml/h)
286 3
600
250
284 2
500
400 1000
282 1 300

AVP 200

osmotic 280 0 100

threshold 0
0 250 500 750 1000
278
Urine volume (ml/h)

276

nephrogenic
SIAD
caused by an
activating
mutation of the
AVP V2R at the
same site that
also can cause
DI via an
inactivating
mutation

Feldman et al.
New Engl J Med
352:1884-90, 2005

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

acute hyponatremia is associated

with high morbidity and mortality

acute chronic
patients 14 52
duration < 12 hrs 3 days
serum [Na+] 112 ± 2 118 ± 1
stupor or coma 100% 6%
seizures 29% 4%
mortality 50% 6%
low [Na+] deaths 36% 0%

Arieff et al. Medicine 56:121, 1976 (hospital

consults in one year; [Na+]<128 mmol/L)

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

acute hyponatremia can cause death from

cerebral edema and brain herniation

normal brain hyponatremic brain

London marathon, April 22, 2007

“A 22-year-old man died after completing

his first London Marathon because he
drank too much water. David Rogers
collapsed at the end of the race and died
yesterday in Charing Cross Hospital.”

“Today it emerged the fitness instructor

from Milton Keynes died from
hyponatraemia, or water intoxication.
This is when there is so much water in
the body that it dilutes vital minerals such
as sodium down to dangerous levels. It
can lead to confusion, headaches and a
fatal swelling of the brain.”
p[Na+] = 122 mmol/L
drank Lucozade http://www.dailymail.co.uk/news/article-
450341/Marathon-victim-died-drinking-MUCH-water.html

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

chronic hyponatremia is associated

with much less severe symptomatology

acute chronic
patients 14 52
duration < 12 hrs 3 days
serum [Na+] 112 ± 2 118 ± 1
stupor or coma 100% 6%
seizures 29% 4%
mortality 50% 6%
low [Na+] deaths 36% 0%

Arieff et al. Medicine 56:121, 1976 (hospital

consults in one year; [Na+]<128 mmol/L)

brain volume
regulation
1. true loss of
brain solute
2. can reduce or
eliminate brain
edema despite
severe
hypoosmolality
3. time dependent
process

Gullans & Verbalis THIS IS NOT A NORMAL BRAIN!

Ann Rev Med
44:289-301, 1993

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

symptomatic hyponatremia:
neurological manifestations
• headache
• irritability
• nausea / vomiting
symptomatic but
• mental slowing less impaired;
• unstable gait / falls usually chronic
• confusion / delerium
• disorientation the degree of symptomatology
is a surrogate for the duration
of hyponatraemia
• stupor / coma
life-threatening;
• convulsions
usually acute
• respiratory arrest

pontine and extrapontine myelinolysis:

clinical manifestations

• tremor
• incontinence
• hyperreflexia, pathological
reflexes
• quadriparesis, quadriplegia
• dysarthria, dysphagia
• cranial nerve palsies
• mutism, locked-in syndrome

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

central
pontine
myelinolysis:
white areas in the
middle of the
pons indicate
massive
demyelination of
descending
axons
(corticobulbar
and corticospinal
tracts)

Wright, Laureno & Victor

Brain 102:361-385, 1979

safe correction of
hyponatremia
entails balancing
the risks of the
hyponatremia
versus the risks
of the correction;
these, in turn,
depend on the
degree of brain
volume
regulation that
has occurred

Verbalis
Trends Endocrinol Metab
3:1-7, 1992

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

managing the rate of correction

of hyponatremia

1. maximum correction for chronic hyponatremia:

≤12 mmol/L in the first 24 h
≤18 mmol/L in the first 48 h

2. even lower (≤8 mmol/L in any 24h period) if

any of the following are present:
• serum Na ≤105 mEq/L
• hypokalemia
• alcoholism and/or malnutrition
• liver disease
3. maximum correction for acute hyponatremia:
not ascertained, but much lower risk

treatments for hyponatremia

isotonic saline infusion

hypertonic saline infusion short-term
vaptan (conivaptan, tolvaptan)

fluid restriction
demeclocycline
furosemide + NaCl
mineralocorticoids long-term
urea
vaptan (tolvaptan)

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

hypertonic saline correction

• choose desired correction rate of plasma

[Na+] (e.g., 1.0 mEq/L/h)
• obtain or estimate patient’s weight (e.g.,
70 kg)
• multiply weight X desired correction rate
and infuse as ml/h of 3% NaCl (e.g., 70 kg
X 1.0 mEq/L/h = 70 ml/h infusion)

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

Nielsen et al., JASN 10:647-663, 1999

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

diuresis:
increased excretion of urine by the
kidney; includes water and typically
increased solute excretion as well

aquaresis:
increased excretion of water by the
kidney without increased solute, i.e.,
electrolyte-sparing excretion of free
water by the kidney

what aquaresis
really looks
like!

courtesy nephology fellows,

Lenox Hill Hospital, New York, NY

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

tolvaptan: SALT studies and

SALT-WATER open label extension study

Berl et al. J Am Soc Nephrol 4:705-712, 2010

SALT: mean increases in serum [Na+]

after 30 d in patients with
cirrhosis, HF, and SIADH

Control Tolvaptan
8 *
Delta increase in serum

7 *
Sodium (mmol/L)

*P<.05
6
5
*
4
3
2
1
0
cirrhosis HF SIADH

Schrier et al. NEJM 355:2099-2112, 2006

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

tolvaptan: SALT trials, SIADH patients

changes in SF-12 general health survey scores after
30 days of oral administration
7.5 placebo (n=39) p=0.051
tolvaptan (n=41)
5.47
p=0.019
5
3.64

2.5

-0.16 -0.45
0
Physical Component Score Mental Component Score
(physical function, body pain, (vitality, social function, calmness,
general health, physically limited sadness, emotionally limited
accomplishment) accomplishment)
Verbalis et al. Eur J Endocrinol 164:725–732, 2011

treatment of hyponatremia results in an

improvement of the MCS to the mean of
average U.S. adults
Depression
Cutpoint

hyponat hyponat
before after
rx rx Adult
Median

Adult
Mean
treatment

30 35 40 45 50 55

SF-12 Mental Component Summary (MCS)

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

fluid restriction
general guidelines:
• restrict all intake that is consumed by
drinking, not just water
• aim for a fluid restriction that is 500 ml/d
below the 24-hour urine output
• do not restrict sodium unless indicated

predictors of failure of fluid restriction:

• high urine osmolality (>500 mOsm/kg H2O)
• urine Na+ + K+ greater than the serum [Na+]
• 24-hour urine output <1,500 ml/d
• increase in serum [Na+] <2 mmol/L in 24h

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

approach to raising plasma osmolality

by fluid restriction

urine/plasma
recommended
electrolyte
fluid consumption
ratio
>1.0 0 mL
0.5–1.0 Up to 500 mL

<0.50 Up to 1 L

Furst H et al. Am J Med Sci 319:240-244, 2000

hyponatremia treatment algorithm

euvolemic hyponatremia (SIADH)
LEVEL 3 – SEVERE SYMPTOMS: hypertonic NaCl , followed by
vomiting, seizures, obtundation, fluid restriction ± vaptan
respiratory distress, coma

LEVEL 2 – MODERATE vaptan, followed by fluid

SYMPTOMS: nausea, confusion, restriction
disorientation, altered mental status

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

osmotic
demyelination
syndrome
(ODS)
no cases of CPM
have been reported
following correction
of hyponatremia with
vaptans in >5,000
patients to date

Wright, Laureno & Victor

Brain
102:361-385, 1979

hyponatremia treatment algorithm

euvolemic hyponatremia (SIADH)
LEVEL 3 – SEVERE SYMPTOMS: hypertonic NaCl , followed by
vomiting, seizures, obtundation, fluid restriction ± vaptan
respiratory distress, coma

LEVEL 2 – MODERATE vaptan, followed by fluid

SYMPTOMS: nausea, confusion,
disorientation, altered mental status
LEVEL 1 – NO OR MINIMAL
SYMPTOMS: headache, irritability,
inability to concentrate, altered mood,
depression
restriction
fluid restriction, but vaptan under
select circumstances:
• inability to tolerate fluid restriction or
failure of fluid restriction
• unstable gait and/or high fracture risk
• very low sodium level (<125 mEq/L) with
increased risk of developing symptomatic
hyponatremia
• need to correct serum [Na+] to safer
levels for surgery or procedures, or for
ICU/hospital discharge
• prevention of worsened hyponatremia with
increased fluid administration
• therapeutic trial for symptom relief

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

hyponatremia 4.50
increased the risk 4.00
of fracture in CKD 3.50

95% Confidence Interval

independently of 3.00
osteoporosis 2.50

1,408 female patients 2.00

from Cork, Ireland
1.50
adjusted for age, T-score,
amenorrhea, steroid use, 1.00
liver disease, smoking
0.50
and EtOH use, liver
disease, and 0.00
osteoporosis treatments <135 136–137 138–140 141–142 143–145 >145
Serum Sodium (mmol/L)

Kinsella et al. Clin J Am Soc Nephrol 5:275-280, 2010

correction of hyponatremia normalizes gait

stability in “asymptomatic” hyponatremia
serum [Na+] = 130 mEq/L serum [Na+] = 139 mEq/L
80 80
60 60
40 40
20 20
0 0
-500 -400 -300 -200 -100 -20 -100 -200 -500 -400 -300 -200 -100 -20 100 200 200
-40 -40
-60 -60
-80 -80
-100 -100
-120 -120

serum [Na+] = 124 mEq/L serum [Na+] = 135 mEq/L

140
120 100
100 80
80 60
60 40
40
20 20
0 0
-500 -400 -300 -200 -100 -20 0 -100 -200 -400 -300 -200 -100 -20 100 200 200
-40 -40
-60 -60
-80
-100 -80
-120 -100
-120

Renneboog et al. Am J Med 119:71, 2006

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

increased risk of falls with

“asymptomatic” hyponatremia

Adjusted
Group n % Falls Odds ratio
odds ratio*

9.45 67.43
“asymptomatic”
chronic 122 21.3% (2.64–34.09) (7.48–607.42)
hyponatremia
p<0.001 p<0.001

normonatremic
244 5.35% 1.00 1.00
controls

*adjusted for age, sex and covariates

Renneboog et al. Am J Med 119:71, 2006

hyponatremia induces marked

bone loss in rats

normonatremic hyponatremic
[Na+] = 140 [Na+] = 115

Verbalis, Barsony, et al. JBMR 25:554-663, 2010

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

hyponatremia induces a 5-fold increase in

osteoclasts compared to normonatremic
controls by TRAP staining
*
20
normonatremic
TRAP + MNC/area

15

10

5 hyponatremic

0
Solid + dDAVP
Liquid + dDAVP

Verbalis, Barsony, et al. JBMR 25:554-663, 2010

odds ratio for hyponatremia as a predictor

of osteoporosis in NHANES III database
100.0
odds ratio (95% CI)

10.0 7.66
5.81
2.85 2.87
1.03 1.41
1.0

total hip femoral neck

0.1 (p=0.043) p<0.003)

bone mineral density by of hip measured by DEXA;

results adjusted for age, sex, BMI, physical activity, serum
vitamin D (ng/mL) and diuretic use

mean serum [Na+] = 133.0 ± 0.2 mmol/L

Verbalis, Barsony, et al. JBMR 25:554-663, 2010

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

why does hyponatremia

cause osteoporosis???

one-third of total body sodium is stored in

bone, and mobilization of this sodium from
bone during prolonged deprivation
requires the resorption of bone matrix,
similar to the release of stored calcium to
compensate for calcium deprivation

Bergstrom & Wallace. Bone as a sodium and potassium reservoir.

J Clin Invest 33:867-873, 1954.

Edelman, James, Baden & Moore. Electrolyte composition of bone

and the penetration of radiosodium and deuterium oxide into dog
and human bone. J Clin Invest 33:122-131, 1954.

hyponatremia-induced activation of ROS

pathways in serum and in osteoclasts
differentiated from RAW264.7 cells

Barsony et al.
JBC
286(12):10864-75, 2011

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

1. osteoporosis
2. hypogonadism
3. cardiac fibrosis
4. sarcopenia
5. decreased
body fat

Barsony et al. AGE, Jan 5 2012 [Epub ahead of print]

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

Barsony et al. AGE, Jan 5 2012 [Epub ahead of print]

evidence-based medicine
the Japanese eat a low fat diet and have lower rates of
cardiovascular disease than the English and Americans

the French eat a high fat diet and have lower rates of
cardiovascular disease than the English and Americans

the Chinese drink little alcohol and have lower rates of

cardiovascular disease than the English and Americans

the Italians drink much alcohol and have lower rates of

cardiovascular disease than the English and Americans
evidence-based conclusions?
eat and drink whatever you want
it’s speaking English that kills you
courtesy of Dr. Peter Liu, University of Toronto

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Diabetes Insipidus and SIADH Clinical Endocrinology: 2007
Joseph G. Verbalis, MD

tolvaptan:
need to
continue
therapy after
discharge
depends on
the etiology
of the SIADH

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