UZMA MEHDI, M.D, MSNEPHROLOGY

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

Hyponatremia

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.

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).

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

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.

Approach to the pt with hyponatremia Decreased serum osmolality --

check volume status. It could be:

Hypovolumeic, Hypervolumeic or Euvolumeic.

Approach to the patient with Hyponatremia Hypovolumeic Hyponatremia

(Dehydartion) Decrease Sodium Decrease water

Causes Diarrhea Diuretic use Mineralcorticoid defeciency Osmotic diuresis like

mannitol

Approach to the patient with Hyponatremia

Hypervolumeic Hyponatremia

Sodium content unchanged Increase water

Causes Heart Failure Cirrhosis Nephrotic syndrome

Approach to the patient with Hyponatremia

Euvolumeic Hyponatremia

Sodium content unchanged Relative increase in water

Cause Syndrome of inappropriate diuretic

hormone (SIADH)

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 CHFDiuretics 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

Arginine vasopressin( AVP) aka Antidiuretic hormone (ADH) Major hormone that controls the

water balance Release from pituitary glands Three receptors V1a V1b V2

AVP

Increase plasma osmolality

Decrease Intravascular volume

V1a receptors

V2 receptors

Regulate vascular tone

Regulate water reabsorption in kidney

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

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.

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.

Collecting duct cell

Luminal surfaceBasolateral surface

Aquaporin 3

Aquaporin 4

V2 repceptors for ADH

AQP-2

ADH

In Presence of ADH

collecting duct is

permeable to

water.

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

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.

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

Drugs induced Siadh

Common drugs

SSRI’s Ectasy Carbamazepine ddavp

Clinical manifestation of siadhAcute: (<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

Correcting hyponatremia

traditional approach;

add to the numerator

Serum sodium = Total body sodium

Total body water

Correcting hyponatremia

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.

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

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

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

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.

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)

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

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

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

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.

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

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

+

-

+

-

+

-

+

-

+

-

+

-

Results of SALT

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.

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.

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.

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.

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.

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

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).

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