This document discusses a case of a 68-year-old female smoker presenting with malaise and poor appetite. Lab results showed hyponatremia. A CT scan revealed a right lung nodule. The patient was diagnosed with SIADH secondary to the lung mass. The document then provides details on hyponatremia, the approach to evaluating and treating a patient with hyponatremia including the role of arginine vasopressin, SIADH, and treatment strategies such as fluid restriction, demeclocycline, urea, lithium, and the non-peptide vasopressin receptor antagonist tolvaptan. It summarizes results from the SALT trials demonstrating tolv

1. UZMA MEHDI, M.D, MS
NEPHROLOGY

2. Case
 Patient presentation in ER;
68-year-old female smoker
Malaise
Poor appetite
Mild neurologic symptoms
 Physical Exam;
130/75 mmHg, 88, no orthostatic changes.
 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.
 Diagnostic imaging
CT scan showed right lung nodule
 Diagnosis
Hyponatremia
SIADH secondary to lung mass

3. Hyponatremia
 Hyoponatremia
 Approach to the pt.
 AVP
 Siadh
 Treatment strategies of SIADH
 Non-peptide AVP receptor antagonist
 Salt Trial
 Samsca

4. Hyponatremia
 Hyponatremia defines as serum sodium
concentration <135meq/L.
 Most frequent electrolyte abnormality in the
hospitalized pt.
 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.
 (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).

5. Hyponatremia
 Changes in serum sodium concentration results
from derangements in water balance.
 Low serum sodium concentration denotes a
relative deficit of sodium and /or a relative
excess of water.
 As seen in the formula, hyponatremia may result
from either a decrease in the numerator or an
increase in the denominator.
Serum sodium = total body sodium
total body water

6. Approach to the patient with
Hyponatremia
 Check serum osmolality.
increased or decreased.
 Increased osmolality-----
---mannitol, glyceine or hyperglycemia
---movement of water from ICF to ECF
compartment. It causes translocational
hyponatremia.
 Decreased osmolality can be due to other
causes.

7. Approach to the pt with
hyponatremia
 Decreased serum osmolality --check
volume status. It could be:
Hypovolumeic,
Hypervolumeic or
Euvolumeic.

8. Approach to the patient with
Hyponatremia
 Hypovolumeic Hyponatremia
(Dehydartion)
Decrease Sodium
Decrease water
 Causes
Diarrhea
Diuretic use
Mineralcorticoid defeciency
Osmotic diuresis like mannitol

9. Approach to the patient with
Hyponatremia
 Hypervolumeic Hyponatremia
Sodium content unchanged
Increase water
 Causes
Heart Failure
Cirrhosis
Nephrotic syndrome

10. Approach to the patient with
Hyponatremia
 Euvolumeic Hyponatremia
Sodium content unchanged
Relative increase in water
 Cause
Syndrome of inappropriate diuretic hormone
(SIADH)

11. Approach to the patient with Hyponatremia
Hyponatremia with decreases serum osmolality
ECF volume ECF volume ECF volume
decreased normal (euvolumic) increased (edema)
Renal Extrarenal SIADH CHF
Diuretics GI losses Cirrhosis
Nephrotic syndrome
Urine Na Urine Na Urine Na Urine Na
TB Na
TB water
TB Na
TB water
TB Na
TB water

12. Arginine vasopressin( AVP)
aka
Antidiuretic hormone (ADH)
 Major hormone that controls the water
balance
 Release from pituitary glands
 Three receptors
V1a
V1b
V2

13. AVP
Increase
plasma
osmolality
Decrease
Intravascular
volume
V1a
receptors
V2
receptors
Regulate
vascular tone
Regulate water
reabsorption in
kidney

14. Vasopressin receptors
 V1A receptors
 smooth muscle cells of blood vessels
 vasoconstrictive action
 V1B receptors
 anterior pituitary
 Regulate pituitary ACTH secretion
 V2 Receptors
 collecting duct cells
 antidiuretic effects of vasopressin

15. Vasopressin Action
 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.

16. Collecting duct Cell
Luminal surface Basolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors fpr ADH
Recycling
vesicles for
AQP-2 ADH
Without
ADH
collecting
duct is
impermeable
to water.

17. Collecting duct cell
Luminal surface
Basolateral surface
Aquaporin 3
Aquaporin 4
V2 repceptors for ADH
AQP-2
ADH
In Presence
of ADH
collecting
duct is
permeable
to water.

18. 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

19. Causes of SIADH
 Central nervous system;
meningitis, brain abcess,
stroke, acute psycosis
 Pulmonary
pneumonia, lung abcess,
tuberculosis
 Endocrine
Addison's disease, hypothyroidisim ,
hypopituitarism
 Neoplastic
pancreatic or lung cancers.

20. Drugs induced SIADH
Increased ADH ADH potentiation
Anti-depressant carbamazepine
anti-psycotics chlopropamide
carbamazepine cyclophosphamide
platinum alkaloids Nsaids
alkylating agents ADH like activity
interferon vasopressin
levimasole ddavp
oxytocin

21. Drugs induced Siadh
 Common drugs
SSRI’s
Ectasy
Carbamazepine
ddavp

22. Clinical manifestation of siadh
Acute: (<48 hours)
 Stupor/coma
 Convulsions Treatment with
 Respiratory arrest 3% NaCl
Chronic; (>48 hours)
 Headache
 Irritability Treat with medicines
 Nausea & vomiting like Vaptans
 Confusion & Disorientation
 Gait disturbance

23. Correcting hyponatremia
 traditional approach;
add to the
numerator
Serum sodium = Total body sodium
Total body water

24. Correcting hyponatremia
 Current approach;
Serum sodium = Total body sodium
Total body water
Subtract from the
the denominator

25. 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.

26. Treatment strategies for
chronic hyponatremia
Treatment Mechanism Advantages Limitations
Fluid restriction
(0.5- 1 liter/day)
Water intake Effective,
inexpensive
Poor compliance
Demeclocycline
(600-
1200mg/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

27. Rate of correction
 Acute symptomatic :
4 to 6 mEq/L in first 4 hours
Target <12 mEq/L in first 24 hours.
 Chronic:
Target correction at <8 mEq/L in first 24 hours
 Goal not to exceed;
12 mEq/L in first 24 hr
18 mEq/L in first 48 hr

28. 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, dysphagia,
seizures, coma and death
spastic quadriparesis.
 Risk factors for ODS:
severe malnutrition,
alcoholism,
advanced liver disease

29. The ideal therapy
 Water excretion without electrolyte excretion
(Na+ and K+) Aquresis.
 Prompt but safe correction in 24-48 hours;
<12mEq/L in first 24 hr
< 18mEq/L in first 48 hr
 Eliminates fluid restriction.
 Predictable and reliable action
 Sustained effect and titratable
 No unexpected side effects/toxicities.

30. Non-peptide AVP receptor
antagonist (Vaptans)
 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
 Vaptans lead to aquaresis, an electrolyte-
sparing 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)

31. Non-peptide AVP receptor
antagonist
tolvaptan lixivaptan satavaptan conivaptan
Receptor V2 V2 V2 V1a/V2
Route of
administration oral oral oral IV
Urine volume
Urine osmolality
Na excretion/
24 hours
Low dose
High Dose

32. Non-peptide AVP receptor
antagonist
tolvaptan lixivaptan satavaptan conivaptan
Receptor V2 V2 V2 V1a/V2
Route of
administration oral oral oral IV
Urine volume
Urine osmolality
Na excretion/
24 hours
Low dose
High Dose
Not available in United
states

33. SALT Trial
 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]
 225 pts with hyponatremia due to SIADH,
cirrhosis or CHF vs 223 controls.
 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

34. 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.
Primary end points;
 Change in serum sodium from baseline to day 4
and day 30.
 Serum sodium a week after discontinuation of
drug.

35. SALT Trial
 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
 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

36. 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
+
-
+
-
+
-
+
-
+
-
+
-

37. Results of SALT

38. Results of SALT
 In the SALT trials on Day 4, SAMSCA
increased serum sodium concentration by
4.8 mEq/L vs 0.2 mEq/L for placebo.
 On Day 30, SAMSCA increased serum
sodium concentration by 7.4 mEq/L vs
1.5 mEq/L for placebo.

39. Results of SALT

40. 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.

41. Results of SALT
 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.

42. Results of SALT
 Significant effect on fluid balance
With SAMSCA, urine output is greater than fluid
intake, which results in a net negative fluid balance.

43. 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.

44. 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

45. Samsca
 SAMSCA should be initiated and re-
initiated in patients only in a hospital
where serum sodium can be monitored
closely.
 Too rapid correction of serum sodium (e.g.,
>12 mEq/L/24 hours) can cause serious
neurologic sequel, including osmotic
demyelination syndrome (ODS).

46. Promise of Vasopressin
Antagonist
 Management of hyponatremia
Prompt,
Reliable and
Controlled
Permits out pt management