Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
1
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
consultant: Astellas, Ferring,
Cardiokine, Otsuka
advisory board: Astellas, Otsuka
data safety board: Ferring
grant support: NHLBI, NIA, NCATS,
Otsuka
Joseph G. Verbalis: disclosures
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
2
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,
hypovolemia,
angiotensin II
vasoconstriction renal H2O
reabsorption
baroreceptors,
natriuretic
peptides
AVP
–+
V1a Receptors V2 Receptors
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
3
receptor-mediated effects of AVP
receptor
subtype site of action activation effects
V1a
vascular smooth
muscle cells
platelets
lymphocytes and
monocytes
liver
vasoconstriction
platelet aggregation
cytokine release
glycogenolysis
V1banterior pituitary
ACTH and ββββ-endorphin
release
V2
renal collecting duct
principal cellsfree water absorption
AVP regulation of water reabsorption
from renal tubular cells
AVPAVP V2
Receptor
AQP3
AQP4
Basolateral
membrane
Luminal
membrane
H2O
H2OAQP2
Exocytic
InsertioncAMP
ATP
PKA
Recyclingvesicle
AQP2
Endocytic
Retrieval
GTP(Gs)
Co
llectin
g d
uct
Vasa r
ecta
Collecting Duct Cell
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
4
prevalence of dysnatremias at initial
presentation to a health care provider
0.49
28.2
1.430.060.17
21
0.53 0.010.03
7.2
0.720.01
0
5
10
15
20
25
30
Na < 116 Na < 135 Na > 145 Na > 165
Pre
va
len
ce
(%
)
Acute hospital care
Ambulatory hospital care
Community care
Hawkins. Clin Chim Acta 337:169-172, 2003
(data from 303,577 samples on 120,137 patients available for analysis)
relationship between hospital admission
serum [Na+] and in-hospital mortality
Wald et al. Arch Intern Med 170:294-302, 2010
0.20
0.15
0.10
0.05
110 115 120 125 130 135 140 145
Admission Serum [Na+] Concentration (mEq/L)
Pre
dic
ted
Pro
bab
ilit
y o
f
In-H
osp
ital M
ort
ality
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
5
chronic hyponatremia is also associated
with increased adverse outcomes
significantly increased
risk of fracture
increased mortality over a 12-year period
of outpatient follow-up
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
6
hyponatremia
can be
caused by
dilution from
retained
water, or by
depletion
from
electrolyte
losses in
excess of
water
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
7
U-Na+ excretion for
identification of EABV
Fenske W. et al, JCEM 92:2991- 2997, 2008
with diuretics without diuretics
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
8
Robertson et al. Am J Med 72:339, 1982
plasma AVP levels are inappropriately elevated in >95% of patients with SIADH
0
7
10
11
9
8
6
5
43
21
230 240 250 260 270 280 290 300 310
Plasma Osmolality, mOsm/kg H2O
Pla
sm
a V
as
op
res
sin
, p
g/m
L
Normal
Range
stimuli to AVP secretion
related to fluid
homeostasis:
hyperosmolality
hypotension
hypovolemia
angiotensin II
independent of
fluid homeostasis:
nausea
hypoxia
hypercarbia
hypoglycemia
stress: cytokines
physical activity
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
9
1
296
294
292
290
288
286
284
282
280
278
276
plasma
osmolality
(mOsm/kg H2O)
plasma
AVP
(pg/ml)
urine
osmolality
(mOsm/kg H2O)thirst
osmotic
threshold
AVP
osmotic
threshold
100
300
2
3
4
5
6
7
8
9
0
0 250 500 750 10000
200
400
600
800
1000
Urine volume (ml/h)
maximal
urine
excretion
rate (ml/h)
1000500
250
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
10
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%
acute chronic
Arieff et al. Medicine 56:121, 1976 (hospital
consults in one year; [Na+]<128 mmol/L)
acute hyponatremia is associated
with high morbidity and mortality
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
11
normal brain hyponatremic brain
acute hyponatremia can cause death from
cerebral edema and brain herniation
“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 Lucozadehttp://www.dailymail.co.uk/news/article-
450341/Marathon-victim-died-drinking-MUCH-water.html
London marathon, April 22, 2007
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
12
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%
acute chronic
Arieff et al. Medicine 56:121, 1976 (hospital
consults in one year; [Na+]<128 mmol/L)
chronic hyponatremia is associated
with much less severe symptomatology
1. true loss of
brain solute
2. can reduce or
eliminate brain
edema despite
severe
hypoosmolality
3. time dependent
process
brain volume
regulation
THIS IS NOT A NORMAL BRAIN!Gullans & Verbalis
Ann Rev Med
44:289-301, 1993
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
13
symptomatic hyponatremia:
neurological manifestations
• headache
• irritability
• nausea / vomiting
• mental slowing
• unstable gait / falls
• confusion / delerium
• disorientation
• stupor / coma
• convulsions
• respiratory arrest
life-threatening;
usually acute
symptomatic but
less impaired;
usually chronic
the degree of symptomatology
is a surrogate for the duration
of hyponatraemia
pontine and extrapontine myelinolysis:
clinical manifestations
• tremor
• incontinence
• hyperreflexia, pathological
reflexes
• quadriparesis, quadriplegia
• dysarthria, dysphagia
• cranial nerve palsies
• mutism, locked-in syndrome
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
14
central pontine myelinolysis:
white areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbarand corticospinaltracts)
Wright, Laureno & Victor
Brain 102:361-385, 1979
safe correction of hyponatremia entails balancingthe 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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
15
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
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
3. maximum correction for acute hyponatremia:
not ascertained, but much lower risk
treatments for hyponatremia
isotonic saline infusion
hypertonic saline infusion
vaptan (conivaptan, tolvaptan)
fluid restriction
demeclocycline
furosemide + NaCl
mineralocorticoids
urea
vaptan (tolvaptan)
long-term
short-term
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
16
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)
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
17
Nielsen et al., JASN 10:647-663, 1999
X
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
18
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
19
tolvaptan: SALT studies and
SALT-WATER open label extension study
Berl et al. J Am Soc Nephrol 4:705-712, 2010
0
1
2
3
4
5
6
7
8
*
*
*
Delt
a i
ncre
ase i
n s
eru
m
So
diu
m (
mm
ol/L
) *P<.05
Control Tolvaptan
cirrhosis HF SIADH
SALT: mean increases in serum [Na+]
after 30 d in patients with
cirrhosis, HF, and SIADH
Schrier et al. NEJM 355:2099-2112, 2006
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
20
tolvaptan: SALT trials, SIADH patients
changes in SF-12 general health survey scores after 30 days of oral administration
placebo (n=39)
tolvaptan (n=41)
(physical function, body pain,
general health, physically limited
accomplishment)
(vitality, social function, calmness,
sadness, emotionally limited
accomplishment)
p=0.019
p=0.051
-0.16
3.64
0
2.5
5
7.5
Physical Component Score Mental Component Score
-0.45
5.47
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
30 40 50
SF-12 Mental Component Summary (MCS)
Adult
Mean
Adult
Median
554535
Depression
Cutpoint
hyponat
after
rx
hyponat
before
rx
treatment
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
21
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
fluid restriction
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
22
Furst H et al. Am J Med Sci 319:240-244, 2000
urine/plasma
electrolyte
ratio
recommended
fluid consumption
>1.0 0 mL
0.5–1.0 Up to 500 mL
<0.50 Up to 1 L
approach to raising plasma osmolality
by fluid restriction
hyponatremia treatment algorithmeuvolemic hyponatremia (SIADH)
vaptan, followed by fluid
restriction
hypertonic NaCl , followed by
fluid restriction ± vaptan
LEVEL 3 – SEVERE SYMPTOMS:
vomiting, seizures, obtundation,
respiratory distress, coma
LEVEL 2 – MODERATE
SYMPTOMS: nausea, confusion,
disorientation, altered mental status
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
23
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 algorithmeuvolemic hyponatremia (SIADH)
vaptan, followed by fluid
restriction
hypertonic NaCl , followed by
fluid restriction ± vaptan
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
LEVEL 3 – SEVERE SYMPTOMS:
vomiting, seizures, obtundation,
respiratory distress, coma
LEVEL 2 – MODERATE
SYMPTOMS: nausea, confusion,
disorientation, altered mental status
LEVEL 1 – NO OR MINIMAL
SYMPTOMS: headache, irritability,
inability to concentrate, altered mood,
depression
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
24
hyponatremia
increased the risk
of fracture in CKD
independently of
osteoporosis
1,408 female patients
from Cork, Ireland
adjusted for age, T-score,
amenorrhea, steroid use,
liver disease, smoking
and EtOH use, liver
disease, and
osteoporosis treatments
Kinsella et al. Clin J Am Soc Nephrol 5:275-280, 2010
4.50
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
<135 136–137 138–140 141–142 143–145 >145
95%
Co
nfi
den
ce In
terv
al
Serum Sodium (mmol/L)
serum [Na+] = 124 mEq/L
-500 -400 -300 -200 -100 -100 -2000
-40
-60
-80
0
-100
-120
140
-20
120
100
80
60
40
20
serum [Na+] = 130 mEq/L
-500 -400 -300 -200 -100 -100 -200
80
60
40
20
-20
-40
-60
-80
0
-100
-120
correction of hyponatremia normalizes gait
stability in “asymptomatic” hyponatremia
serum [Na+] = 139 mEq/L
100 200 200-500 -400 -300 -200 -100
80
60
40
20
-20
-40
-60
-80
0
-100
-120
serum [Na+] = 135 mEq/L
100 200 200-400 -300 -200 -100
80
60
40
20
-20
-40
-60
-80
0
-100
-120
100
Renneboog et al. Am J Med 119:71, 2006
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
25
increased risk of falls with
“asymptomatic” hyponatremia
Group n % Falls Odds ratio Adjusted
odds ratio*
“asymptomatic”
chronic
hyponatremia
122 21.3%
9.45
(2.64–34.09)
p<0.001
67.43
(7.48–607.42)
p<0.001
normonatremic
controls244 5.35% 1.00 1.00
*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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
26
hyponatremia induces a 5-fold increase in
osteoclasts compared to normonatremic
controls by TRAP staining
normonatremic
hyponatremic
20
10
5
0
TR
AP
+ M
NC
/are
a
*
15
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
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
100.0
10.0
1.0
0.1
od
ds
ra
tio
(9
5%
CI)
total hip
(p=0.043)
femoral neck
p<0.003)
7.66
2.85
1.03
2.87
5.81
1.41
mean serum [Na+] = 133.0 ± 0.2 mmol/L
Verbalis, Barsony, et al. JBMR 25:554-663, 2010
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
27
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
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
28
1. osteoporosis
2. hypogonadism
3. cardiac fibrosis
4. sarcopenia
5. decreased
body fat
Barsony et al. AGE, Jan 5 2012 [Epub ahead of print]
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
29
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 youcourtesy of Dr. Peter Liu, University of Toronto
Diabetes Insipidus and SIADH
Joseph G. Verbalis, MD
Clinical Endocrinology: 2007
30
tolvaptan:
need to
continue
therapy after
discharge
depends on
the etiology
of the SIADH