Transcript UZMA MEHDI, M.D, MS NEPHROLOGY

UZMA MEHDI, M.D, MS
NEPHROLOGY
Case
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Patient presentation in ER;
68-year-old female smoker
Malaise
Poor appetite
Mild neurologic symptoms
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Physical Exam;
130/75 mmHg, 88, no orthostatic changes.
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Lab results
serum Na: 124, K: 3.2, Cl: 94, Hco3: 26; Bun: 16, Creatinine 0.6
Posm:249, Uosm:415; UNa: 48, uric acid : 1.8,
Normal thyroid function test and am cortisol level.
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Diagnostic imaging
CT scan showed right lung nodule
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Diagnosis
Hyponatremia
SIADH secondary to lung mass
Hyponatremia
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Hyoponatremia
Approach to the pt.
AVP
Siadh
Treatment strategies of SIADH
Non-peptide AVP receptor antagonist
Salt Trial
Samsca
Hyponatremia

Hyponatremia defines as serum sodium
concentration <135meq/L.
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Most frequent electrolyte abnormality in the
hospitalized pt.
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Essentially common in critical care units. In addition
to being a potentially life-threatening condition,
hyponatremia is an independent predictor of death
among intensive care unit and geriatric patients and
those with heart failure, and cirrhosis.
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(Arief at al 1976; Terian et al 1994; Borroni et al 2000; Lee et al 2000, Bennani et al 2003;
Goldberg et al 2004: Ruf et la 2005).
Hyponatremia

Changes in serum sodium concentration results
from derangements in water balance.
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Low serum sodium concentration denotes a
relative deficit of sodium and /or a relative
excess of water.
Serum sodium = total body sodium
total body water
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As seen in the formula, hyponatremia may result
from either a decrease in the numerator or an
increase in the denominator.
Approach to the patient with
Hyponatremia
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Check serum osmolality.
increased or decreased.
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Increased osmolality-------mannitol, glyceine or hyperglycemia
---movement of water from ICF to ECF
compartment. It causes translocational
hyponatremia.
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Decreased osmolality can be due to other
causes.
Approach to the pt with
hyponatremia
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Decreased serum osmolality --check
volume status. It could be:
Hypovolumeic,
Hypervolumeic or
Euvolumeic.
Approach to the patient with
Hyponatremia
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Hypovolumeic Hyponatremia
(Dehydartion)
Decrease Sodium
Decrease water
Causes
Diarrhea
Diuretic use
Mineralcorticoid defeciency
Osmotic diuresis like mannitol
Approach to the patient with
Hyponatremia
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Hypervolumeic Hyponatremia
Sodium content unchanged
Increase water
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Causes
Heart Failure
Cirrhosis
Nephrotic syndrome
Approach to the patient with
Hyponatremia
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Euvolumeic Hyponatremia
Sodium content unchanged
Relative increase in water
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Cause
Syndrome of inappropriate diuretic hormone
(SIADH)
Approach to the patient with Hyponatremia
Hyponatremia with decreases serum osmolality
ECF volume
ECF volume
decreased
normal (euvolumic)
TB Na
TB water
Renal
Diuretics
Urine Na
TB Na
TB water
Extrarenal
GI losses
Urine Na
SIADH
Urine Na
ECF volume
increased (edema)
TB Na
TB water
CHF
Cirrhosis
Nephrotic syndrome
Urine Na
Arginine vasopressin( AVP)
aka
Antidiuretic hormone (ADH)
Major hormone that controls the water
balance
 Release from pituitary glands
 Three receptors
V1a
V1b
V2
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AVP
Increase
plasma
osmolality
V1a
receptors
Regulate
vascular tone
Decrease
Intravascular
volume
V2
receptors
Regulate water
reabsorption in
kidney
Vasopressin receptors
V1A receptors
 smooth muscle cells of blood vessels
 vasoconstrictive action
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V1B receptors
 anterior pituitary
 Regulate pituitary ACTH secretion
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V2 Receptors
 collecting duct cells
 antidiuretic effects of vasopressin
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Vasopressin Action
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After binding of AVP to V2
receptors --- c-Amp is formed--increased expression of AQP2 and
AQP3 – insertion into cell
membrane.
Increase driving force for water
reabsorption.
 Increased water flow in collecting duct.
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Collecting duct Cell
Luminal surface
Basolateral surface
Recycling
vesicles for
AQP-2
Without
ADH
collecting
duct is
impermeable
to water.
Aquaporin 3
ADH
V2 repceptors fpr ADH
Aquaporin 4
Collecting duct cell
Luminal surface
Basolateral surface
AQP-2
Aquaporin 3
V2 repceptors for ADH
In Presence
of ADH
collecting
duct is
permeable
to water.
ADH
Aquaporin 4
SIADH
Inappropriate release of ADH causes
siadh.
 It is diagnosed by checking :
Serum sodium <135
Serum osmolality <280
Urine osmolality >100
Urine sodium >30
also low serum uric acid <4.0
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Causes of SIADH
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Central nervous system;
meningitis,
stroke,
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Pulmonary
pneumonia,
tuberculosis
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lung abcess,
Endocrine
Addison's disease,
hypopituitarism
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brain abcess,
acute psycosis
hypothyroidisim ,
Neoplastic
pancreatic or lung cancers.
Drugs induced SIADH
Increased ADH
ADH potentiation
Anti-depressant
carbamazepine
anti-psycotics
carbamazepine
platinum alkaloids
chlopropamide
cyclophosphamide
Nsaids
alkylating agents
interferon
levimasole
ADH like activity
vasopressin
ddavp
oxytocin
Drugs induced Siadh
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Common drugs
SSRI’s
Ectasy
Carbamazepine
ddavp
Clinical manifestation of siadh
Acute: (<48 hours)
 Stupor/coma
 Convulsions
 Respiratory arrest
Chronic; (>48 hours)
 Headache
 Irritability
 Nausea & vomiting
 Confusion & Disorientation
 Gait disturbance
Treatment with
3% NaCl
Treat with medicines
like Vaptans
Correcting hyponatremia

traditional approach;
add to the
numerator
Serum sodium = Total body sodium
Total body water
Correcting hyponatremia
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Current approach;
Serum sodium = Total body sodium
Total body water
Subtract from the
the denominator
Treatment strategies for Acute
hyponatremic emergencies
3% NaCl: 100ml bolus for severe
symptoms.
 3% NaCl@1 to 2ml/kg/hr for 2 to 4 hours
plus furosemide.
 Goal: correction by 4 to 6 mEq/L in first
few hours.
 Monitor closely to avoid excessive
correction.
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Treatment strategies for
chronic hyponatremia
Treatment
Mechanism
Advantages
Limitations
Fluid restriction Water intake
(0.5- 1 liter/day)
Effective,
inexpensive
Poor compliance
Demeclocycline
(6001200mg/d)
Inhibits action
of adh
Easily available
3-4 days for
onset,
nephrotoxicity
Urea
(30mg/d)
Osmotic
diuresis
Decreased risk
Poor
palatability,
Avoid in ckd
Lithium
(up to
900mg/d)
Inhibits action
of adh
Easily available
Slow onset,
toxicity
Rate of correction
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Acute symptomatic :
4 to 6 mEq/L in first 4 hours
Target <12 mEq/L in first 24 hours.
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Chronic:
Target correction at <8 mEq/L in first 24 hours
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Goal not to exceed;
12 mEq/L in first 24 hr
18 mEq/L in first 48 hr
Importance of appropriate serum
sodium correction

Too-rapid correction of hyponatremia (e.g., >12
mEq/L/24 hours) can cause osmotic
demyelination syndrome (ODS) resulting in:
dysarthria,
seizures,
spastic quadriparesis.
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Risk factors for ODS:
severe malnutrition,
alcoholism,
advanced liver disease
dysphagia,
coma and death
The ideal therapy
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Water excretion without electrolyte excretion
(Na+ and K+) Aquresis.
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Prompt but safe correction in 24-48 hours;
<12mEq/L in first 24 hr
< 18mEq/L in first 48 hr
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Eliminates fluid restriction.
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Predictable and reliable action
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Sustained effect and titratable
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No unexpected side effects/toxicities.
Non-peptide AVP receptor
antagonist (Vaptans)
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Aquaretic nonpeptide arginine vasopressin
receptor (AVPR) antagonists are safe and
effective hyponatremia therapies.
Varbalis,JG at al, Hyponatremia treatment guidelines 2007, Am J of
Med, 2007 Nov;120(11 Suppl 1):S1-21
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Vaptans lead to aquaresis, an electrolytesparing excretion of free water, that results in
the correction of serum sodium concentration.
Vasopressin antagonists in treatment of hyponatremia; Olszewski,W; Pol Arch MED
Wewn, 2007 Aug:117(8)
Non-peptide AVP receptor
antagonist
tolvaptan lixivaptan
Receptor
Route of
administration
V2
oral
satavaptan
conivaptan
V2
V2
V1a/V2
oral
oral
Urine volume
Urine osmolality
Na excretion/
24 hours
Low dose
High Dose
IV
Non-peptide AVP receptor
antagonist
tolvaptan lixivaptan
Receptor
Route of
administration
Urine volume
Urine osmolality
Na excretion/
24 hours
V2
oral
satavaptan
conivaptan
V2
V2
V1a/V2
oral
oral
Not available in United
states
Low dose
High Dose
IV
SALT Trial
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Multicenter randomized, placebo-controlled,
double-blind phase 3 studies (Study of
Ascending Levels of Tolvaptan in Hyponatremia
1 and 2) [SALT-1 and SALT-2]
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225 pts with hyponatremia due to SIADH,
cirrhosis or CHF vs 223 controls.
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Serum Na <135 without neurological symptoms.
R.W.Schrier et al; Tolvaptan,a selective oral vasopressin v2 receptor
antagonist, for hyponatremia. New Eng JM, vol 355, no 20.Nov 16,2006
SALT Trial
Pt were randomly assigned to placebo vs 15mg
of tolvaptan
 Dose of tolvaptan was increased to 30mg and
then to 60mg if necessary.
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Primary end points;
 Change in serum sodium from baseline to day 4
and day 30.
 Serum sodium a week after discontinuation of
drug.
SALT Trial
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Significant increase in as early as 8 hours :
7% of tolvaptan-treated patients had an increase in
serum sodium greater than 8 mEq/L
vs 1% of placebo-treated patients
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Results consistent among patients with
heart failure, cirrhosis, and SIADH
The average rates of serum sodium correction
during the treatment initiation (first 24 hours) were
3.83 mEq/L for SAMSCA (15 mg) and
0.30 mEq/L for placebo
SALT Trial
Serum Sodium
tolavaptan
placebo
Baseline
128.5 + 4.5
128.7 + 4.1
Day 4
133.9 + 4.8
129.7 + 4.9
Day 30
135.7 + 5.0
131.0 + 6.2
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Results of SALT
Results of SALT
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In the SALT trials on Day 4, SAMSCA
increased serum sodium concentration by
4.8 mEq/L vs 0.2 mEq/L for placebo.
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On Day 30, SAMSCA increased serum
sodium concentration by 7.4 mEq/L vs
1.5 mEq/L for placebo.
Results of SALT
SALT Trial
None of the patients in these studies had
evidence of osmotic demyelination
syndrome (ODS) or related neurologic
sequel.
 In patients receiving SAMSCA who
develop too-rapid rise in serum sodium,
discontinue or interruption of treatment
with SAMSCA and administration of
hypotonic fluid was considered.
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Results of SALT
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Reduced need for fluid restriction
Fluid restriction during the first 24 hours of
therapy with SAMSCA may increase the
likelihood of overly rapid correction of
serum sodium and should be avoided.
Results of SALT
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Significant effect on fluid balance
With SAMSCA, urine output is greater than fluid
intake, which results in a net negative fluid balance.
Samsca
SAMSCA is indicated for the treatment of
clinically significant hypervolemic and
euvolemic hyponatremia (serum sodium
<125 mEq/L ) in heart failure, cirrhosis,
and SIADH.
 It is available in 15mg, 30mg and 60mg
tablets.
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Samsca
SAMSCA is contraindicated in the
following conditions:
 Urgent need to raise serum sodium acutely
 Inability of the patient to sense or
appropriately respond to thirst
 Hypovolemic hyponatremia
 Concomitant use of strong CYP 3A
inhibitors
 Anuric patients
Samsca
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SAMSCA should be initiated and reinitiated in patients only in a hospital
where serum sodium can be monitored
closely.
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Too rapid correction of serum sodium (e.g.,
>12 mEq/L/24 hours) can cause serious
neurologic sequel, including osmotic
demyelination syndrome (ODS).
Promise of Vasopressin
Antagonist
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Management of hyponatremia
Prompt,
Reliable and
Controlled
Permits out pt management