1. Charles Cline MD, PhD Medical Director Otsuka Pharma Scandinavia
Hyponatremia
Charles Cline MD, PhD
Medical Director
Otsuka Pharma Scandinavia

2. Hyponatremia Physiology of salt & water regulation Classification
Pathophysiology
Symptoms and diagnosis
SIADH
Tolvaptan (SamscaTM)

3. [Na+] <135: 13-28% incidence1,2 [Na+] <130: 2-4% incidence1,3,4
Hyponatremia is the most common electrolyte disorder of hospitalized patients, with incidences from 2-28% depending on the serum [Na+] level used to define hyponatremia:
[Na+] <135: 13-28% incidence1,2
[Na+] <130: 2-4% incidence1,3,4
It’s clear from multiple studies over the last four decades that hyponatremia is the most common electrolyte disorder of hospitalized patients throughout the world. The incidence varies with the serum sodium level used to define hyponatremia. Most cases are in the range of mEq/L, where incidences as high as 28% have been reported. However, for more severe hyponatremia, which is usually defined as [Na+] <130 mEq/L, reported incidences generally range from 2 to 4%.
1. Flear et al. Lancet 2:26-31, 1981
2. Hawkins. Clin Chim Acta 337: , 2003
3. Natkunam et al. J Med 22:83-96, 1991
4. Berghmans et al. Support Care Cancer 8: , 2000

4. Vasopressin Secretion
Osmoreceptors
Baroreceptors
Posterior
lobe
Pituitary
VP is synthesised in the hypothalamus, stored in and released from the posterior pituitary
Vasopressin is synthesised in the hypothalamus and then stored in and released from the posterior pituitary. Release is regulated by way of osmolality and blood pressure via osmoreceptors and baroreceptos respectively.

5. Control of Sodium Balance
P-Na+ = mmol/l
Na+,Cl-, HCO3- = 86% extracellular fluid osmolality
P-Osmol = mosm/kg
P-Osmol = 2× [Na]mmol/l + [urea]mmol.l + [glucose]mmol/l
Main determinant of P-Na+ is plasma water content
Water content = intake + “insensible” losses + urinary dilution
Urinary dilution most important, determined by vasopressin
Under normal conditions, plasma sodium concentrations are finely maintained within the narrow range of mmol/l despite great variations in water and salt intake. Sodium and its accompanying anions, principally chloride and bicarbonate, account for 86% of the extracellular fluid osmolality, which is normally mosm/kg and calculated as (2× [Na]mmol/l + [urea]mmol.l + [glucose]mmol/l. The main determinant of the plasma sodium concentration is the plasma water content, itself determined by water intake (thirst or habit), “insensible” losses (such as metabolic water, sweat), and urinary dilution. The last of these is under most circumstances the most important and is predominantly determined by arginine vasopressin, which is synthesised in the hypothalamus and then stored in and released from the posterior pituitary. In response to arginine vasopressin, concentrated urine is produced by water reabsorption across the renal collecting ducts. This is mediated by specialised cellular membrane transport proteins called aquaporins.5-8

6. The Kidney

7. Vasopressin V2 receptor activation
Vasopressin V2 receptor activation. The binding of arginine vasopressin (AVP) to the V2 vasopressin receptor (V2R) stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A (PKA). This pathway increases the exocytosis of aquaporin water channel–containing vesicles (AQMCV) and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin 2 (AQ2) channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct (CD).
Free water resorbtion

8. Signaling mechanisms involved in aquaporin-2 (AQP-2) regulation
Proposed model for signaling mechanisms involved in aquaporin-2 (AQP-2) regulation in inner medullary collecting duct principal cells. See text for details. A1R, adenosine A1 receptor; AC, adenylyl cyclase; COX-1, cyclooxygenase 1; CREB, cAMP responsive element-binding protein; DAG, diacylglycerol; EP3, PGE2 receptor subtype 3; ET-1, endothelin-1; ETB, endothelin B receptor; Gi, inhibitory G protein; Gq, phospholipase C stimulatory G protein; Gs, stimulatory G protein; IP, inositol triphosphate; β , G protein β subunit; P, phosphorylation; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; V2R, vasopressin V2 receptor.
Importantly, the AVP-mediated effects on water reabsorption are modulated by local factors. The functional importance of local factors may, in part, relate to the relatively long AVP half-life of 10–35 min (15). As illustrated in the figure local AVP-counterregulatory factors in the CD principal cell include endothelin-1 (ET-1) (44) and PGE2 (10). ET-1 is formed and released from CD cells in response to changes in osmolality (45). However, the exact mechanisms are still under investigation. ET-1 activates ETB receptors in an autocrine/paracrine fashion to reduce PKA activation (see Fig. 1). Supporting this concept, inner medullary CD (IMCD) suspensions of CD-specific ET-1 knockout mice have enhanced AVP- and forskolin-stimulated cAMP formation and reduced plasma AVP levels (26). ETB receptor activation also stimulates cyclooxygenase-1 (COX-1) and PGE2 formation and release (46). The most abundant PGE2 receptor in the CD is the EP3 receptor subtype (38), which is a Gi protein-coupled receptor that inhibits AVP-induced cAMP formation in the CD (9, 10). In addition, EP3 receptor activation inhibits PKA via PLC-mediated activation of PKC (30). Of note, ETB receptors were found to be mainly localized to the basolateral membrane (46), whereas V2R (51) and EP3 receptors (65) were localized to both the luminal and basolateral membrane of CD cells, which is expected to further enhance the regulatory versatility.
Am J Physiol Regul Integr Comp Physiol 296: R419-R427, 2009

9. Classification of hyponatremia
Hypovolemic
Hypervolemic
Euvolemic (normovolemic)

10. Hypovolemic Extrarenal loss, urine sodium <30 mmol/l
Dermal losses, such as burns, sweating
Gastrointestinal losses, such as vomiting, diarrhoea
Pancreatitis
Renal loss, urine sodium >30 mmol/l
Diuretics
Salt wasting nephropathy
Cerebral salt wasting
Mineralocorticoid deficiency (Addison's disease)

11. Hypervolemic* Urine sodium <30 mmol/l Congestive cardiac failure
Cirrhosis with ascites
Nephrotic syndrome
Urine sodium >30 mmol/l
Chronic renal failure
*Paradoxical retention of sodium and water despite a total body excess of each; baroreceptors in the
arterial circulation perceive hypoperfusion, triggering an increase in vasopressin release and
net water retention

12. Euvolemic Urine sodium >30 mmol/l
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)†
Hypothyroidism
Hypopituitarism (glucocorticoid deficiency)
Water intoxication: Primary polydipsia
Excessive administration of parenteral hypotonic fluids
Post-transurethral prostatectomy
†SIADH is a diagnosis of exclusion

13. hyponatremia can be caused by depletion from electrolyte losses in excess of water, or by dilution from retained water
There are only two ways in which patients can become hyponatremic. One can view the body as a beaker two‑thirds full of water, which is divided between the intracellular compartment where potassium is the major solute, the extracellular compartment where sodium is the solute. Under normal conditions, there is a balance between fluid coming in and fluid excreted by the kidneys.
In this model, one can become hyponatremic because of a depletion of solute – either through the skin as sweat, the GI tract as diarrhea, or the kidney as renal salt wasting. In that case, hyponatremia develops with a decreased ECF volume; this is called a depletional hyponatremia.
Alternatively, if there is a tightening of the outlet “spigot’, then not enough ingested fluid can be excreted. This leads to retention of the excess water, shown by the yellow bar, which dilutes the concentration of sodium in the extracellular compartment and the potassium in the intracellular compartment. This is called a dilutional hyponatremia.

14. Levels of hyponatremia
mmol/l = Mild hyponatremia: Usually asymptomatic
< mmol/l = Moderate hyponatremia: Nausea, malaise
< mmol/l = Severe hyponatremia: Headache, lethargy, restlessness, disorientation follow, as the sodium concentration falls below
Severe and rapidly evolving hyponatremia: seizure, coma, permanent brain damage, respiratory arrest, brain stem herniation, death

15. Hyponatremia - neurological manifestations
headache
irritability
nausea/vomiting
mental slowing
confusion/delerium
disorientation
stupor/coma
convulsions
respiratory arrest
symptomatic but less impaired; usually chronic
In summary, the symptoms attributable to hyponatremia can be divided into two major categories: 1) those that are severe and potentially life-threatening, which usually occur in patients with acute (i.e., <48h duration) hyponatremia, and 2) those that are more moderate and non-life-threatening, which usually occur in patients with more chronic types of hyponatremia.
life-threatening, usually acute

16. Neurological symptoms and P-Na concentrations
In studies, going back several decades now, it has been well documented that the majority of the symptomatology of hyponatremia is neurological, ranging from confusion to stupor/coma, seizures, and potentially respiratory arrest. It is also well known that there is an inverse correlation between this symptomatology and how low the serum sodium level is.
However, it is also recognized that there is a large individual variability in the manifestation of those symptoms relative to the serum sodium level. Some patients are alert and without apparent symptoms despite sodium levels less than 120 mEq/L, while others at risk for imminent death with the same serum sodium levels. This is now known to be largely related to whether the hyponatremia is acute or chronic.
Arieff et al., Medicine 55: , 1976

17. Symptoms Related to severity and rapidity of fall in P-Na
Creates osmotic gradient between extracellular and intracellular fluid in brain cells, causing movement of water into cells, increasing intracellular volume, and resulting in tissue edema, raised intracranial pressure, and neurological symptoms A B

18. Adaptive response to hyponatremia
Rapid adaptation hours to days transport out of NaCl and K
Slow adaptation loss of organic solutes including glutamate, taurine, myo-inositol, and glutamine from intracellular to extracellular compartments. Induces water loss and ameliorates brain swelling

19. Central Pontine Myelinolysis
Blood-brain barrier becomes permeable, rapid correction of hyponatremia and allows complement mediated oligodendrocyte toxicity (can occur widely in the brain)
Alcoholics with malnutrition, premenopausal or elderly women on thiazide diuretics, and patients with hypokalaemia or burns are at increased risk
Neurological injury is typically delayed 2 to 6 days after elevation of Na concentration
Neurological symptoms generally irreversible (dysarthria, dysphagia, spastic paraparesis, lethargy, seizures, coma, death)

20. Central Pontine Myelinolysis
White areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbar and corticospinal
tracts), usually associated with overly rapid correction
of hyponatremia using hypertonic saline
Wright, Laureno, Victor .
Brain 102: , 1979

21. Examination in patient with hyponatremia
Evaluation of volume status
Skin turgor
Pulse rate
Postural blood pressure
Jugular venous pressure
Consider central venous pressure monitoring
Examination of fluid balance charts
General examination for underlying illness
Congestive cardiac failure
Cirrhosis
Nephrotic syndrome
Addison's disease
Hypopituitarism
Hypothyroidism

22. Investigations in patient with hyponatremia
Urinary sodium
Plasma glucose and lipids*
Renal function
Thyroid function
Peak cortisol during short synacthen test†
Plasma and urine osmolality‡
If indicated: chest x ray, and computed tomography and magnetic resonance imaging of head and thorax
*Pseudohyponatraemia due to artefactual reduction in plasma sodium in the presence of marked elevation of plasma lipids or proteins should no longer be seen with the measurement of sodium by ion specific electrodes; hyperglycaemia causes true hyponatraemia, irrespective of laboratory method.
†May be unhelpful in pituitary apoplexy, in which patients may still “pass” the test.
‡For SIADH: plasma osmolality < 270 mosm/kg with inappropriate urinary concentration (> 100 mosm/kg), in a euvolaemic patient after exclusion of hypothyroidism and glucocorticoid deficiency).

23. P-AVP levels are inappropriately elevated in most patients with SIADH11 10 9 8
Normal Range 7
Plasma Vasopressin (pg/mL) 6 5
The cause of the inability to excrete ingested fluid in dilutional hyponatremias is known to be the pituitary hormone arginine vasopressin (AVP). This is shown best in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is the quintessential example of a dilutional hyponatremia. Individual patients with SIADH, shown here, have inappropriately elevated serum AVP levels in relation to their serum osmolality. When serum osmolality falls below 280 to 285 mOsm/kg, AVP secretion should be suppressed into this yellow area. When it is not, that constitutes an osmotically inappropriate AVP secretion, which in turn causes water retention and a dilutional hyponatremia. 4 3 2 1
230
240
250
260
270
280
290
300
310
Plasma Osmolality (mOsm/kg)
Robertson et al. Am J Med 72: , 1982 23

24. Causes of SIADH Cancers Pulmonary diseases CNS disorders Drugs Other
Carcinomas
(eg. lung, oropharynx, gastro-intestinal tract, genitourinary tract)
Lymphomas
Sarcomas
Infections
(eg. pneumonia, abscess, tuberculosis)
Asthma
Cystic fibrosis
COPD
Acute respiratory failure
Positive-pressure ventilation
Infection
(eg. encephalitis, meningitis)
Bleeding and masses
(eg. SAH, brain tumours, head trauma)
(eg. multiple sclerosis, Guillain-Barre syndrome)
Stimulation of vasopressin release or enhancement of its action
(eg. chlorpropamide, SSRIs, carbamazepine, anti-psychotic drugs
Vasopressin analogues
(eg. desmopressin, oxytocin, vasopressin)
Hereditary
Idiopathic
Transient
(eg. endurance exercise, general anaesthesia)
AIDS
SIADH is commonly caused by medications, cancers, central nervous system disorders and pulmonary diseases1,2
Small-cell lung cancer is a common cause of SIADH.3
SIADH occurs in about 10% of patients with SCLC. Although SIADH is associated with a wide range of tumours, SCLC accounts for about 75% of cancerous cases associated with SIADH.3
SIADH is also frequently encountered in neurosurgical patients, 4,5 often confounded by prescribed medication (Neurosurgical patients are often taking drugs such as carbamazepine, serotonin-specific reuptake inhibitors and synthetic vasopressin).5
Notes references:
Ellison DH, et al. N Engl J Med. 2007;356:
Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.
Vanhees SL, et al. Anns Oncol. 2000;11:
Sherlock M, et al. Clin Endo. 2006;64:
Sherlock M, et al. Postgrad Med J. 2009;85:
AIDS = Acquired immune deficiency syndrome; CNS = Central nervous system; COPD = Chronic obstructive pulmonary disease; SAH = Subarachnoid haemorrhage; SSRIs = selective serotonin reuptake inhibitors
Ellison DH, et al. N Engl J Med. 2007;356: Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. 24

25. Diagnosing SIADH
Essential and supplemental diagnostic criteria for SIADH
Essential1,2
Hyponatraemia < 135 mmol/l
Plasma hypo-osmolality < 275 mOsm/Kg
Urine osmolality > 100 mOsm/Kg
Clinical euvolaemia
No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes)
No clinical signs of hypervolaemia (oedema, ascites)
Increased urinary sodium excretion with normal salt and water intake ≥ 30 mmol/l
Absence of other potential causes of euvolaemic hypo-osmolality
Exclude hypothyroidism, hypocortisolism, renal disease and recent diuretic use
Supplemental1,3
Failure to correct hyponatraemia after 0.9% saline infusion
Correction of hyponatraemia through fluid restriction
Abnormal water load test over 4 hours
Plasma vasopressin inappropriately elevated relative to plasma osmolality
SIADH is a diagnosis of exclusion.1
It is a disorder of sodium and water balance characterised by hypotonic hyponatraemia and impaired urinary dilution in the absence of renal disease or any identifiable physiological (osmotic or nonosmotic) stimulus known to release vasopressin.1,2
A common misinterpretation is that is that urine osmolality must be greater than plasma osmolality at all levels of plasma osmolality.3 Urine osmolality only needs to be inappropriately elevated for any plasma osmolality < 275 mOsm/kg.3
Some patients with SIADH can have low urinary sodium if they become hypovolaemic or solute depleted.3
A water load test is rarely used because of the risks involved.4
As >90% of hyponatraemic patients have an elevated vasopressin level, its role as a diagnostic criterion for SIADH is limited.5 In addition, many clinicians do not have access to vasopressin assay facilities.
Notes references:
Robertson GL. American J Med. 2006;119(7A):
Ellison DH, et al. N Engl J Med. 2007;356:
Janicic N, et al. Endocrinol Metab Clin N Am. 2003;32:
Verbalis J. Best Pract Res Clin Endocrinol Metab. 2003;17(4):
Bayliss PH. IJBCB 2003;35:
Ellison DH, et al. N Engl J Med. 2007;356: Janicic N, et al. Endocrinol Metab Clin N Am. 2003;32:
Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. 25

26. Types of SIADH Plasma AVP (pmol/l) Plasma osmolality (mOsm/kg) 20 1510 15 20
Plasma osmolality (mOsm/kg)
Plasma AVP (pmol/l) A B C

27. Assessing and managing hyponatremia

28. Disadvantages of conventional treatments
Mechanism 1-3
Disadvantage 1-3
Fluid restriction
Induces negative water balance
Increases plasma osmolality and plasma sodium
Poor patient compliance
Slow onset of action (2-3 days, may prevent discharge)
Hypertonic saline
Increases water excretion and replaces sodium
Difficult to administer (IV)
Complex calculations needed to estimate appropriate rate of sodium correction
Risk of overly rapid sodium correction leading to osmotic demyelination syndrome
Demeclocycline
Impairs vasopressin action at renal tubules
Induces nephrogenic diabetes insipidus
Unpredictable response (may cause hypernatraemia)
Renal and liver toxicities
Slow onset of action (3-4 days)
Urea
Decreases sodium excretion
Poor compliance due to bad taste
Lithium
Inconsistent results
Rarely used due to toxicity
Loop diuretics
Increase water excretion by inhibiting sodium and chloride re-absorption in the loop of Henle and distal tubule
Electrolyte imbalance (eg. hypokalaemia, exacerbation of hyponatraemia)
Current therapies for hyponatraemia are not satisfactory
Traditional treatments have several limitations:1-3
Patient adherence to fluid restriction is often difficult to maintain
IV saline solutions involve complex calculations of the expected plasma sodium concentration and the rate at which sodium is replaced
Conventional pharmacologic agents take several days to achieve maximal effect and often result in toxicities
Notes references:
Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S1-21.
Douglas I. Cleve Clin J Med. 2006; 73 Suppl 3: S4-12.
Ellison DH, et al. N Engl J Med. 2007;356:
1. Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S1-21.
2. Douglas I. Cleve Clin J Med. 2006; 73 Suppl 3: S4-12.
3. Ellison DH, et al. N Engl J Med. 2007;356: 28

29. SIADH Intracerebral aneurysm
135
125
120
115
plasma Na+ mmols/L
3% NaCl
N-saline
Fluid restrict