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 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 TreatmentMechanismAdvantagesLimitations Fluid restriction (0.5- 1 liter/day) Water intakeEffective, inexpensive Poor compliance Demeclocycline (600- 1200mg/d) Inhibits action of adh Easily available3-4 days for onset, nephrotoxicity Urea (30mg/d) Osmotic diuresis Decreased riskPoor palatability, Avoid in ckd Lithium (up to 900mg/d) Inhibits action of adh Easily availableSlow 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 tolvaptanlixivaptansatavaptanconivaptan Receptor 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 tolvaptanlixivaptansatavaptanconivaptan Receptor 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.  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