The Impact of J. Herbert Patterson, Hyponatremia: … Renal collecting duct principal cells Renal free water absorption ... Schrier RW, ed. Atlas of Diseases of the Kidney . ... LiamisG

The Impact of Hyponatremia: Role of the Pharmacist in Improving Care

© 2012 Paradigm Medical Communications, LLC, except where noted. 1

The Impact of

Hyponatremia: Role of the Pharmacist

in Improving Care

J. Herbert Patterson, PharmD, FCCP (Chair)

Denise H. Rhoney, PharmD, FCCM, FCCP

© 2012 Paradigm Medical Communications, LLC except where noted.

OVERVIEW OF HYPONATREMIA

SCOPE OF THE PROBLEM



Learning Objective

• Examine the prevalence and clinical and economic

consequences of hyponatremia

Hyponatremia

• The most common electrolyte disorder seen in

clinical practice1-3

• Commonly defined as serum sodium concentration

([Na+]) ≤135 mEq/L, but cut-off values vary

Serum [Na+], mEq/L

<120 120-130 131-135

Severe

hyponatremia

Moderate

hyponatremia

Mild

hyponatremia

1. Ellison DH et al. N Engl J Med. 2007;356: 2064-2072. 2. Verbalis JG et al. Am J Med. 2007;120:S1-S21.

3. Upadhyay A et al. Am J Med. 2006;119(7A):S30-S35.



Hyponatremia: Incidence & Consequences

• Occurs in up to 3.2 to 6.1 million persons annually1

• Estimated 1 million hospitalizations annually with 1° or 2° discharge diagnosis of hyponatremia1

• Up to 15% of hospitalized patients, 24.5% of ICU patients2,3

• Hospital-acquired hyponatremia is common, tends to be more severe

• Associated with significant morbidity in patients with a variety of underlying disease states4

• May lead to death if not treated appropriately4,5

• Incidence increases with age6

ICU, intensive care unit.

1. Boscoe A et al. Cost Eff Resour Alloc. 2006;4:10. 2. Baylis PH. Int J Biochem Cell Biol. 2003;35:1495-1499. 3. Cawley M. Ann Pharmacother. 2007;41(5):840-850. 4. Adrogué HJ. Am J Nephrol. 2005;25:240-249. 5. Huda MSB et al. Postgrad Med J. 2006;82:216-219. 6. Upadhyay A et al. Am J Med. 2006;119(7A):S30-S35.

Hyponatremia is Underreported

• Clinical laboratory values vs ICD-9 codes 1999-2000

• 2632 cases of hyponatremia identified using laboratory

data alone

• 66% did not have appropriate ICD-9 code

– 94% of moderately hyponatremic patients

– 87% of severely hyponatremic patients

• Reported cases of hyponatremia from databases

represent only 1/3 of cases

Movig K et al. J Clin Epidemiol. 2003;56:530-535.



Hyponatremia is Often Mismanaged

• Review of 104 patients with serum [Na+] <125 mEq/L from

6-mo lab/chart data in a large teaching hospital

‒ 49% of diagnoses inconsistent with clinical details

‒ 33% had “significant” management errors

Huda MS et al. Postgrad Med J. 2006;82:216-219.

41

20

01020304050

Management Errors Appropriate

Management

Mortality, %

THE PATHOPHYSIOLOGIC MECHANISMS

UNDERLYING HYPONATREMIA



Learning Objective

• Describe the pathophysiology of hyponatremia as well as

its signs and symptoms

Role of Arginine Vasopressin (AVP)

in Regulating Water Balance

AVP V2 receptors

cAMP

Aquaporin-2

�� Plasma osmolality

�� Circulatory blood volume

Water reabsorption

Hyper-

osmolality Hypo-

volemia

AVP secretion

Adapted from Kim DK, Joo KW. Electrolyte Blood Press. 2009;7(2):51-59.

Baroreceptors

(left atrium,

aortic arch, etc)

AVP

synthesis

AVP storagePosterior

pituitary

Renal

collecting

duct

�� Circulatory

blood volume

Osmoreceptors

(hypothalamus)



Receptor-Mediated Effects of AVP

Verbalis JG. J Mol Endocrinol. 2002;29(1):1-9.

Zingg HH. Baillieres Clin Endocrinol Metab. 1996;10(1):75-96.

Montero S. et al J Applied Physiol. 2006;100(6):1902-1909.

Kjaer A. Acta Endocrinol. 1993;129:489-496.

Receptor

subtypeSite(s) of action Activation effects

V1a

• Vascular smooth muscle cells

• Platelets

• Lymphocytes and monocytes

• Liver

• Vasoconstriction, myocardial stimulation

• Platelet aggregation

• Cytokine release

• Glycogenolysis

V1b Anterior pituitary ACTH and β-endorphin release

V2 Renal collecting duct principal cells Renal free water absorption

Dysregulation of Normal AVP Response

Complicates Many Disease States

SIADH, syndrome of inappropriate antidiuretic hormone secretion; TBI, traumatic brain injury;

SAH, subarachnoid hemorrhage.

1. Gheorghiade M. J Am Coll Cardiol. 2005;46(10):1785-1791. 2. Porcel A et al. Arch Intern Med. 2002;162:323-328. 3. Torres JM

et al. Chest. 1998;113:387-390. 4. Edmonds ZV. J Hosp Med. 2012;7(suppl 4):S11-S13. 5. Tang WW et al. Am J Med. 1993;94(2):

169-174. 6. Agha A et al. J Clin Endocrinol Metab. 2004;89:5987-5992. 7. Speedy DB et al. Med Sci Sports Exerc. 1999;31:809-815.

During extreme exercise (marathons + triathlons), up to 29% of athletes develop hyponatremia.7

Disease StatePrevalence of Hyponatremia

in Hospitalized PtsMechanism

Heart failure (HF)1 20% – 30% Neurohormonal activation

Cirrhosis2 30% – 40% Neurohormonal activation

Community-acquired

pneumonia3,4 10% – 30% SIADH ± reset osmostat

AIDS5 38% SIADH

Neurologic injury (TBI, SAH,

infection, intracerebral

hemorrhage, massive

cerebral infarction, others)6

2.3% – 36.6% SIADH, idiopathic



<100 mOsm/L

(maximally dilute)

Polydipsia

≥100 mOsm/L

(inappropriately concentrated)

Impaired water excretion

Classification Algorithm

Hyperglycemia

Mannitol

>295 mOsm/kg

Hyperosmolar

HypervolemiaIncreased ECF volume

Cole CD et al. Neurosurg Focus. 2004;16:E9. Diringer MN, Zazulia AR. Neurologist. 2006;12(3):117-126.

Schrier RW, ed. Atlas of Diseases of the Kidney. Philadelphia, PA: Current Medicine. 1999:1.1-1.22.

[Na+] <135 mEq/L

<275 mOsm/kgHypo-osmolar

Assess serum osmolality

Assess urine osmolality

Excessive water intake

Assess volume status

EuvolemiaNormal ECF volume

HypovolemiaReduced ECF volume

275-295 mOsm/kgNormo-osmolar

Pseudohyponatremia

Na-free irrigant solutions

Etiologies of Hypo-osmolar Hyponatremia

Cole CD et al. Neurosurg Focus. 2004;16(4):E9.

Verbalis JG et al. Am J Med. 2007;120:S1-S21.

Hypervolemia

Heart failure

Cirrhosis

Nephrotic

syndrome

Anaphylaxis

Renal failure

Sepsis

Pregnancy

Euvolemia

SIADH

Tumors

CNS disorders

Drug-induced

Pulmonary diseases

Other

Glucocorticoid deficiency

Hypothyroidism

Primary polydipsia

Hypovolemia

Thiazide diuretics

Cerebral salt wasting

Mineralocorticoid deficiency

Salt-wasting nephropathy

Bicarbonaturia, glucosuria,

ketonuria

Gastrointestinal losses

Third space losses

Sweat losses



TCAs, tricyclic antidepressants; SSRIs, selective serotonin reuptake inhibitors;

MAOIs, monoamine oxidase inhibitors; CNS, central nervous system.

1. Adrogué HJ. Am J Nephrol. 2005;25:240-249. 2. Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153.

3. Ellison DH et al. N Engl J Med. 2007;356: 2064-2072. 4. Vaidya C et al. Cleve Clin J Med. 2010;77(10):

715-726. 5. Fourlanos S et al. Aust Prescr. 2003;26:114-117.

Hyponatremia: Risk Factors

Drugs

• Antidepressants

(TCAs, SSRIs, MAOIs)1,2

• Antiepileptics1

• Antihypertensives5

• Antipsychotics1

• Anticancer agents1

• Diuretics1

• NSAIDS3

• Opiate derivatives1

• Proton-pump inhibitors5

Miscellaneous conditions

• Adrenal insufficiency1

• Cirrhosis1

• CNS impairment1

• Heart failure1

• Low body weight2

• SIADH3

• Surgery or injury1

• Very old age3

• Very young age4

Mechanisms of Drug-Induced Hyponatremia

Antidepressants

Antipsychotics

Antiepileptics

Antineoplastic agents

Opiates

Antidiabetic drugs

Antiepileptics

IV cyclophospha-mide

NSAIDs

Thiazide diuretics/indapamide

Amiloride

Loop diuretics

↑↑↑↑ Effect of AVP at

renal tubule level

Altered Na / H2O

homeostasis

↑↑↑↑ Hypothalamic

production of AVP

Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153.



SSRI-Induced Hyponatremia

• Incidence: 0.5% ‒ 32%1

• Most cases during first few weeks of therapy1

– Normal serum [Na+] usually achieved within

2 weeks following discontinuation of drug

• Risk factors

– Older age2

– Concomitant diuretic therapy2

– Low body weight1

– Baseline serum [Na+] <138 mEq/L2

1. Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153.

2. Jacob S, Spinler SA. Ann Pharmacother. 2006;40(9):1618-1622.

CONSEQUENCES OF HYPONATREMIA

AND THEIR IMPACT ON PATIENTS



Learning Objectives



Osteoporosis

and

fractures

Hyponatremia

Consequences of Hyponatremia

Gait

disturbances

and falls

Neurologic

dysfunction and

decreased mental

function

Cerebral

edemaSeizures,

coma

Increased

mortality risk

Increased

hospital

LOS

Increased

rate of ICU

admission



Hyponatremia & Neurologic Dysfunction

The SF-12 is a subset of the SF-36 Health Survey and has been shown to reproduce at least 90% of the

variance in PCS-36 and MCS-36 in both general and patient populations.

Treatment of hyponatremia: Medical utility of vasopressin V2 receptor antagonism, Briefing document.

Advisory committee of the cardiovascular and renal drugs division of the US Food and Drug Administration.

June 25, 2008. www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed June 10, 2012.

SF-12 Mental Component Summary (MCS)

Depression

Hyponatremia, Gait, & Falls

• Case-control study of 122 patients with asymptomatic chronic hyponatremia (serum [Na+] 126 ± 5 mEq/L), 244 matched controls

• Hyponatremic patients more often admitted for falls than controls (21.3% vs 5.3%; P <.001)

• Frequency of falls the same—regardless of the level of hyponatremia

• Gait instability significantly increased in patients with chronic hyponatremia

• Attention errors increased 1.2-fold (P=.001) in hyponatremic patients compared with normal controls

– Comparable to increase observed after moderate alcohol

intake in healthy volunteers

Renneboog B et al. Am J Med. 2006;119:71.e1-8.



Reprinted from Renneboog B et al. Mild chronic hyponatremia is associated with falls, unsteadiness,

and attention deficits. Am J Med. 2006;119:71.e1-8. © 2006, with permission from Elsevier.

Gait stability assessed in 12 hyponatremic patients ([Na+] 124-130 mEq/L)

• Patients asked to walk on pressure mat.

• Skew from midline of path measured as length of walk.

Correction of Hyponatremia Stabilizes Gait

Gait instability significantly

increased in hyponatremia

Gait stability

normalized

Correctionof hyponatremia

Hyponatremia & Fractures in Ambulatory Falls

• Case-control study of bone fractures after incidental fall1

– Patients presenting with falls and fractures had significantly higher incidence of

hyponatremia (13.6%) than age-matched controls (3.9%)

– Hyponatremia drug-induced in 53% (36% diuretics, 17% SSRI),

due to SIADH in 37%

• Hyponatremia significantly associated with fracture occurrence (P<.01) 2

– Independent of age and gender2

• Even mild chronic hyponatremia increases fracture risk3

1. Gankam Kengne FG et al. Q J Med. 2008;101:583-588.

2. Sandhu HS et al. Int Urol Nephrol. 2009;41:733-737.

3. Koch L. Nat Rev Endocrinol. 2011;7:315.

Bone quality should be assessed

in all patients with chronic hyponatremia



Symptoms Correlate With Severity

& Rate of Decline in Serum [Na+]1

• Asymptomatic presentation

is common2

• May present with mild,

nonspecific symptoms1

• Degree of symptomatology

is surrogate for duration of

hyponatremia1

• Symptoms from

underlying disease process

is also common1

Symptom

Respiratory arrest

Coma

Seizures

Delirium

Restlessness

Lethargy

Headache

Fatigue

Confusion

Nausea + vomiting

Asymptomatic

Increasing

severity of

hyponatremia

and rate of

[Na+] decline

1. Bagshaw SM et al. J Can Anesth.2009;56:151-167.2. Ghali K. Cardiology. 2008;111:147-157.

Acute Versus Chronic Hyponatremia

• Symptomatic but less impaired: usually CHRONIC

• Life-threatening: usually ACUTE

Acute (≤48 h) Chronic (>48 h)

Symptoms include:

• Cerebral edema

• Seizures

• Increased mortality risk

Symptoms include:

• Nausea/vomiting

• Confusion or personality changes

• Neurological dysfunction

• Gait disturbances

• Seizures (with very low serum [Na+] levels)

Rapid correction reverses

cerebral edema without

sequelae

Rapid correction may cause brain dehydration

and osmotic demyelination syndrome (ODS)



Acute Versus Chronic Hyponatremia

H2O moves into brain along osmotic gradients,

causing symptomatic cerebral edema

Extracellular Na+

decreases byNa+ loss or H2O gain

Hypotonic state

Compensatory mechanism begins

Water gain

Cerebral swelling

When brain swelling >8%, it exceeds skull capacity

Acute hyponatremia(≤48 hours)

Chronic hyponatremia(>48 hours)

Gullans SR et al. Annu Rev Med. 1993;44:289-301.

Loss of electrolytes and osmolytes decreases brain solute content

Brain edema is virtually absent

Herniation and death

Pathophysiology Adaptation

TREATING HYPONATREMIA:

CONVENTIONAL AND EMERGING

THERAPEUTIC OPTIONS



Learning Objective

• Compare and contrast the pharmacology, efficacy,

and safety of conventional therapies as well as

those of newer agents

Treatment Overview

• Most important treatment factors– Severity of neurologic symptoms1,2

– Volume status1,2

– Acute vs chronic2,3

– Identify likely cause of hyponatremia1,4

• Principles to guide treatment– Weigh risks and benefits5

• Neurologic consequences can follow both failure to promptly treat

and excessively rapid rate of correction3

• Even modest improvement in serum [Na+] have survival benefits1,6

– Monitor serum [Na+] frequently2,6

– Address underlying disease and stop offending medications1

1. Ellison DH et al. N Engl J Med. 2007;356:2064-2072. 2. Lien YH et al. Am J Med. 2007;120:653-658.

3. Ghali K. Cardiology. 2008;111:147-157. 4. Verbalis JG et al. Am J Med. 2007;120:S1-S21. 5. Adrogue

HJ et al. N Engl J Med. 2000;342:1581-1589. 6. Vaidya C et al. Cleve Clin J Med. 2010;77(10):715-26.



Correct Serum [Na+]

to Safe Level at Safe Rate

Insufficient correction1

Cerebral

edema

Osmotic demyelination

syndrome (ODS)

Too aggressive correction1

• Raise [Na+] by <8-12 mEq/L in 1st 24 h1-3

• Raise [Na+] by <18 mEq/L in 1st 48 h1

• Symptomatic: 1 mEq/L/h until neurologic

symptoms resolve or [Na+] ≥120 mEq/L or a total

magnitude correction of 18 mEq/L is achieved1,2

1. Verbalis JG et al. Am J Med. 2007;120:S1-S21. 2. Kumar S et al. In: Atlas of Diseases

of the Kidney. 1999:1.1-1.21. 3. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.

Risks of Hyponatremia & Correction:

A Balancing Act

Acute hyponatremia

Marked brain edema

Minimal brain volume

regulation

Chronic symptomatic hyponatremia

Some brain edema

Partial brain volume

regulation

Chronic asymptomatic hyponatremia

Minimal brain edema

Complete brain volume

regulation

Verbalis JG. Trends Endocrinol Metab. 1992;3(1):1-7.

Risks of

hyponatremia

Risks of

correction



Serum [Na+] =Na+

E + K+E

Body water

2. Subtract from

the denominator

1. Add to the

numerator

Na+E, exchangeable sodium; K+

E, exchangeable potassium.

Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.

Correcting Hyponatremia

Treatments for Hyponatremia

1. Goldsmith SR. Am J Cardiol. 2005;95(suppl):14B-23B. 2. Verbalis JG. Endocrinol Nutr. 2010;57(suppl 2):30-40.

3. Kumar S et al. In: Schrier RW et al (eds). Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine,

Inc; 1999:1.1-1.22. 4. Rosner MH. Kidney Int. 2012;82(11):1154-1156. 5. Decaux G et al. Lancet. 2008;371:1624-1632.

Treatment1,2 Characteristics

Saline infusion

• Rapid response in symptomatic patients1

• Complex calculations1

• Not be used in edema-forming disorders2

Fluid restriction

• Inexpensive3

• Slow and limited response1,4

• Adherence concerns1,3

Demeclocycline

• No need to limit water intake3

• Targets excessive AVP1

• Slow response1,4

• Nephrotoxic in CHF and cirrhosis1,3,4

Loop diuretics• Allows relaxation of fluid restriction4

• May cause volume, K+ and Mg+ depletion1

AVP receptor antagonists

• Target excessive AVP4

• Aquaresis (solute free urine output) 1,3

• Not to be used in hypovolemic states5



The Role of Hypertonic Saline (HTS)

• When to consider hypertonic saline (3% NaCl)

– Symptomatic hyponatremia (seizure, coma)1

– Acute severe hyponatremia (<24 h, <120 mEq/L)2

– Hyponatremia worsening on normal saline (0.9% NaCl) 3

– Induced hypernatremic states for prevention/treatment of cerebral edema2

• Discontinue HTS when serum [Na+] reaches 120-130 mEq/L3

– Exception: states of cerebral edema with Na+ augmentation

• Safety concerns: Requires ICU monitoring2

• Adrogué-Madias formula, used to predict rise in [Na+] after HTS, may underestimate correction rate, increasing risk for inadvertent overcorrection1

• No randomized trials performed1

• HTS may or may not be combined with loop diuretic1

1. Zietse R et al. NDT Plus. 2009;2(Suppl 3): iii12–iii19. 2. Verbalis JG. Endocrinol Nutr. 2010;57(Supl. 2):30-40. 3. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.

Fluid Restriction

• Fluid restriction very patient-specific1

• Standard procedure: restrict fluid to <1 L/d1

• Slow rate of improvement2

• Poor patient adherence2

• Predictors of failure3

‒ High urine osmolality (>500 mOsm/kg H2O)

‒ Urine [Na+] and [K+] > serum [Na+]

‒ 24-h urine output <1,500 mL/d

‒ Increase in serum [Na+] <2 mEq/L in 24 h

1. Goldsmith SR. Am J Cardiol. 2005;95(suppl):14B-23B. 2. Rosner MH. Kidney Int. 2012;82:1154–1156.3. Courtesy of Joseph G. Verbalis, MD.



Demeclocycline

• Causes a nephrogenic form of diabetes insipidus, decreasing

urine concentration even in the presence of high plasma AVP

levels

• Dose: 600 to 1,200 mg/d in divided doses

– Takes several days to achieve maximal diuretic effects

– Wait 3 to 4 days before deciding to increase the dose

• Can cause

– Reversible azotemia

– Nephrotoxicity, especially in patients with cirrhosis

• Monitor renal function on a regular basis and

discontinue if increasing azotemia

Verbalis JG et al. Am J Med. 2007;120(11A):S1-S21.

The Vaptans: Overview

1. Decaux G et al. Lancet. 2008;371:1624-1632. 2. Hline SS et al. Ther Clin Risk Manag.

2008;4(2):315-326. 3. Verbalis JG. Cleve Clin J Med. 2006;73(Suppl 3):S24-S33.

4. Zietse R et al. NDT Plus. 2009; 2(Suppl 3):iii12-19. 5. Ross E, Sigal SH. J Hosp Med.

2010;5(6):S8-S17. 6. Zmily HD et al. Int J Nephrol Renovas Dis. 2011;4:57-71.

Agent

Receptor

Selectivity/

Affinity

RteT-1/2,

h

Urine

Volume

Urine

Osmolality

FDA

Approval

Status

Therapy

Duration

Conivaptan

Mixed (V1A+V2);1

10-fold higher

affinity V2 vs V1A2

IV1 3-81,2 ↑↑↑↑3,4 ↓↓↓↓3,4Approved

200554 d1

Tolvaptan

Selective for V2;3,4

V2 affinity 1.8××××native AVP;

V2 affinity 29××××that of V1A

Oral1 6-121,6 ↑↑↑↑3,4 ↓↓↓↓3,4Approved

20095

Long-

term5

Lixivaptan V23,4 Oral1 7-101 ↑↑↑↑3,4 ↓↓↓↓3,4 Phase III4 NA



The Vaptans: Mechanism of Action

Vasa recta

(reabsorption)

2V2 receptor

AQP2

Vaptan

AVPAVP

Collecting duct

(excretion)

AQP2, aquaporin 2.

H2O

H2O

Conivaptan Double-Blind Clinical Trial

• Double-blind, placebo-controlled, randomized, multicenter study

• 84 patients euvolemic/hypervolemic hyponatremia

(serum [Na+] 115 to <130 mEq/L)

• Common etiology of hyponatremia – SIADH

– Lung disease, abdominal infection, or malignancy

– CHF

• All patients received ≤2 L/d fluid restriction

• Conivaptan administered 20 mg loading dose (over 30 min) with

4-d continuous infusion of either 40 mg/d or 80 mg/d infusion

• Serum or plasma [Na+] assessed at pre-dose (hour 0) and at

4, 6, 10, and 24 h post-dose on all treatment days

Zeltser D et al. Am J Nephrol. 2007;27:447-457.



Conivaptan Double-Blind Clinical Trial (continued)

• Mean increase in serum [Na+] from baseline significantly higher with conivaptan at 24, 48, 72 h after treatment

– Conivaptan 80 mg:

8.1–8.8 mEq/L

– Conivaptan 40 mg:

6.4–6.9 mEq/L

– Placebo:

0.4–1.9 mEq/L

From Zeltser D et al. Am J Nephrol. 2007;27:447-457.

© 2007 S. Karger AG, Basel. Used with permission.

From Zeltser D et al. Am J Nephrol. 2007;27:447-457.

© 2007 S. Karger AG, Basel. Used with permission.

Conivaptan Double-Blind Clinical Trial (continued)

• Mean free water clearance significantly higher from baseline to treatment Days 1 and 2 with conivaptan 40 + 80 mg/d (P<.001, P=.03, P=.01 vs placebo)

‒ Greatest increase on treatment Day 1

• Most common adverse effects included hypotension, postural hypotension, infusion site inflammation, pyrexia, and hyperkalemia

‒ No occurrence of ODS

**

ǂ



Conivaptan Open-Label Trial:

Serum [Na+] at Day 11 & Day 34

VAPRISOL® (conivaptan hydrochloride injection) [prescribing information]. Deerfield, Ill:

Astellas Pharma US, Inc.; February 2007.

120

125

130

135

140

Baseline Day 11 Day 34

Vaprisol 20 mg/d (n=37)

Vaprisol 40 mg/d (n=214)

Me

an

se

rum

[N

a+

], m

Eq

/L

Tolvaptan for Hyponatremia:

SALT-1 & SALT-2

• Double-blind, randomized, multicenter studies of 448 patients with

euvolemic or hypervolemic hyponatremia (serum [Na+] <135 mEq/L)

treated with placebo or tolvaptan, 15 mg/d

– For first 4 d, dose could be increased from 15 to 30 mg or from 30 to 60 mg

according to regimen designed for slow correction of serum [Na+] to

≥135 mEq/L

– If serum [Na+] rose above 145 mEq/L or increased too fast (>12 mEq/L in 24 h

or >8 mEq/L in 8 h on Day 1), the next dose was withheld or decreased, or

fluid intake was increased

• Within 8 h after first tolvaptan dose, serum [Na+] levels significantly higher in tolvaptan group than in placebo group

– 20% had normalized serum [Na+] vs 4% receiving placebo

Schrier RW et al. N Engl J Med. 2006;355:2099-2112.



Tolvaptan for Hyponatremia:

SALT-1 & SALT-2 (continued)

• Increase in serum [Na+] in

tolvaptan group sustained 30 d

• Most common adverse effects included thirst, dry mouth, fatigue,

polyuria, constipation, hyperglycemia

‒ No occurrence of ODS

Schrier RW et al. N Engl J Med. 2006;355:2099-2112. Figure from: Advisory committee of the cardiovascular

and renal drugs division of the US FDA. June 25, 2008. www.fda.gov/ohrms/dockets/ac/08/briefing/2008-

4373b1-05.pdf. Accessed January 12, 2012.

Serum [Na+], mEq/L

SALT-1 SALT-2

Baseline 128.5 ± 4.5 129.0 ± 3.5

Day 4 133.9 ± 4.8 135.3 ± 3.6

Day 30 135.7 ± 5.0 135.9 ± 5.9

SALTWATER Open-Label Extension: Increases

in Serum [Na+] Maintained >2 Years


June 25, 2008. www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed February 6, 2012.



SALT Trials:

Effect of Tolvaptan on SF-12

• Mental Component Summary Score (MCS)‒ Statistically greater mean

improvement observed with tolvaptan than with placebo

‒ Represents clinically meaningful improvement in mental function

• Physical Component Summary Score (PCS)‒ Changes between groups

not significantly different

‒ Improvement of hyponatremia in chronic illnesses does not dramatically change overall physical burden of the disease



EVEREST: Tolvaptan in CHF

• Randomized, double-blind, multicenter trial of 4133 patients hospitalized

for ADHF and treated with tolvaptan (30 mg/d) or placebo for ≥60 d in

addition to standard therapy. Only 8% of patients had hyponatremia

(<134 mEq/L). HF hospitalization ≤48 h.

– LVEF ≤40%

– Fluid overload; ≥2 of the following

• Jugular venous distention ≥10 cm

• Pedal edema

• Dyspnea

– Exclusions

• Creatinine >3.5 mg/dL; K+ >5.5 mEq/L; Hgb <9 g/dL

• Recent or planned revascularization or device implant

• Acute MI during hospitalization

• Systolic blood pressure <90 mm Hg

Konstam MA et al. JAMA. 2007;297:1319-1331.



EVEREST: Tolvaptan in CHF (continued)

• Short-term results favored tolvaptan vs placebo

‒ Improved dyspnea by Day 1

‒ Significant reductions in body weight due to fluid loss at Day 1

and Day 7/ discharge

• Long-term results on morbidity and mortality showed no

significant difference between tolvaptan and placebo

LVEF, left ventricular ejection fraction; Hgb, hemoglobin; STEMI, ST segment elevation

myocardial infarction.

Konstam MA et al. JAMA. 2007;297:1319-1331.

Pro

po

rtio

n W

ith

ou

t E

ven

t

Post-hoc Exploratory Analysis EVEREST:

CV Mortality & Morbidity





Meta-analysis: Vaptans for Hyponatremia

• 15 RCTs of vaptans with or w/o fluid restriction

• Primary result: Normal or significant increase in

serum [Na+] at 3-7 d

• Vaptan treatment significantly increased

– Early response rate (11 trials): RR, 3.15; 95% CI, 2.27-4.37

– Late response rate (4 trials): RR, 2.27; 94% CI 1.79-2.89

• Rates of hypernatremia (6 trials):

RR, 2.21; 95% CI, 0.61-7.96

• No cases of ODS

Rozen-Zvi B et al. Am J Kidney Dis. 2010;56(2):325-337.

The Vaptans: Pharmacokinetics

Tolvaptan1

• ≥40% of dose is absorbed

• Peak concentrations between 2 and 4 h

• Food does not impact bioavailability

• Metabolized by CYP3A

• Mean terminal half-life 12 h

Conivaptan2

• Mean terminal half-life 5-8.6 h

• Mean clearance 9.5-18.7 L/h3

• Metabolized by CYP3A

1. Samsca™ (tolvaptan) [prescribing information]. Rockville, MD: Otsuka America Pharmaceutical, Inc.;

November 2009. 2. Vaprisol® (conivaptan hydrochloride injection) [prescribing information]. Deerfield,

Ill: Astellas Pharma US, Inc.; February 2011. 3. Mao ZL et al. Clin Ther. 2009;31(7):1542-1550.



The Vaptans: Dosing

Tolvaptan1

• Should be initiated and

reinitiated only in a hospital

• Initial oral dose of 15 mg

administered once daily without

regard to meals

• Increase to 30 mg once daily

after at least 24 h

• Maximum dose 60 mg once daily

• Avoid fluid restriction during

first 24 h of therapy

Conivaptan2

• Loading dose: 20 mg IV

over 30 min

• Maintenance infusion

20-40 mg over 24 h (if desired)

• May be administered for

additional 1 to 4 d

• To minimize risk of vascular

irritation

– Administer through large veins

– Change infusion site every 24 h


November 2009.

2. Vaprisol® (conivaptan hydrochloride injection) [prescribing information]. Deerfield, Ill:


Tolvaptan Administration via NG Tube

• Bioavailability of tolvaptan 15 mg crushed and administered

via NG tube vs oral tablet swallowed intact – Randomized crossover study in 28 healthy fasted adults

– Each dose administered with 240 mL H2O

– CI90% for AUC not within 80%-125%, so bioequivalence could not be

concluded

– May be viable alternative dosing route with clinical monitoring

*Represents geometric mean.

AUC, area under the curve; Cmax,, maximum concentration.

McNeely EB et al. Pharmacotherapy. 2012;32:e114. Abstract 25.

Parameter NG* Oral* Ratio, % CI90%

AUCt (ng*h/mL) 381 512 74.3 68.1 ‒ 81.0

AUC∞ (ng*h/mL) 391 527 74.2 68.1 – 80.9

Cmax (ng/mL) 77.6 87.3 88.9 80.1 – 98.6



The Vaptans: Precautions

Conivaptan/Tolvaptan

• Do not use with potent CYP3A and PGP inhibitors

• Do not use in hypovolemic patients

• Use with caution in patients with hepatic or renal impairment

• Recommend frequent monitoring of serum [Na+] and volume

• Do not administer to anuric patients, as no benefit is expected

Tolvaptan1

• Do not use in patients who are unable to sense or appropriately respond to thirst

Conivaptan2

• May cause significant infusion site reactions1. Samsca™ (tolvaptan) [prescribing information]. Rockville, MD: Otsuka America Pharmaceutical, Inc.;

November 2009.



The Vaptans: Drug-Drug Interactions

Tolvaptan1

● Substrate of CYP3A

● Concomitant use of tolvaptan

and potent CYP3A inhibitors

(ketoconazole, itraconazole,

clarithromycin, ritonavir, or

indinavir) is contraindicated

● Does not significantly change

pharmacokinetics of other CYP3A

substrates

● Coadministration with digoxin

results in a 1.3-fold increase in

digoxin

Conivaptan2

• Substrate/inhibitor of CYP3A

• Concomitant use of conivaptan

and potent CYP3A inhibitors

(ketoconazole, itraconazole,

clarithromycin, ritonavir, or

indinavir) is contraindicated


November 2009.





Monitoring Patients on Conivaptan

• Only for use in hospitalized patients

• Administer through large veins, change infusion site every 24 h to minimize risk of vascular irritation

• Monitor serum [Na+] and neurologic status appropriately, as serious neurologic sequelae can result from overly rapid correction (>12 mEq/L in 24 h)

• Discontinue conivaptan if patient develops undesirably rapid rate of rise of serum [Na+], and carefully monitor serum [Na+] and neurologic status – If serum [Na+] continues to rise, do not resume treatment

– If hyponatremia persists or recurs, and patient has had no evidence of neurologic sequelae of rapid rise in serum [Na+], conivaptan may be resumed at reduced dose

Vaprisol® (conivaptan hydrochloride injection) [prescribing information]. Deerfield, Ill:


Velez JC et al. Nephrol Dial Transplant. 2010;25(5):1524-1531.

Monitoring Patients on Tolvaptan

• The medication MUST be started in the hospital

• Obtain serum [Na+] every 4-6 h for 48 h

– While no cases of ODS have been reported, there are many instances where

the correction rate can be too fast

• After 48 h, the vast majority reach a steady state and can be safely

discharged with outpatient monitoring

• Check serum [Na+] once a week for the first month, then monthly

once stable

• As many as 20%-30% of patients (especially those with the highest

urine osmolalities) may need concomitant water restriction

to see a rise in serum [Na+]

Samsca™ (tolvaptan). [prescribing information]. Rockville, MD. Otsuka America Pharmaceutical, Inc.

November 2009.

Schrier RW et al. N Engl J Med. 2006;355:2099-2112.



The Vaptans: Postdischarge Therapy

Verbalis JG. Endocrinol Nutr. 2010;57(Suppl 2):30-40.

SIADH Etiology RR of Chronic SIADH

Tumors producing AVP ectopically

Drug-induced, agent continued

Brain tumors

Subarachnoid hemorrhage

Idiopathic

Stroke

Chronic obstructive pulmonary disease

Inflammatory brain lesions

Traumatic brain injury

Nausea, pain, prolonged exercise

Drug-induced, agent discontinued

Pneumonia

Postoperative hyponatremia

High

Low

Need for postdischarge vaptan therapy should be based on

the etiology of SIADH and the risk of chronic SIADH

Treatment Algorithm

Fluid restriction; vaptan under select circumstances:

•Inability to tolerate fluid restriction or failure of fluid restriction

•Prevention of worsened hyponatremia with increased fluid

administration

•Unstable gait and/or high fracture risk

•Serum [Na+] <125 mEq/L

•Need to correct serum [Na+] to safer levels for surgery / procedures or ICU / hospital discharge

• Therapeutic trial for symptom relief

Euvolemichyponatremia

Verbalis JG et al. Am J Med. 2007;120:S1-S21.

Hypovolemichyponatremia

Level 1:

No or

minimal

symptoms

Hypervolemichyponatremia

Saline or hypertonic

NaCL± fludrocortisone

Level 2:

Moderate

symptoms

Level 3:

Severe

symptoms

Vaptan ±±±± fluid

restriction


restriction

Hypertonic NaCl

followed by fluid

restriction ±±±± vaptan

Hypertonic NaCl

followed by fluid

restriction ±±±± vaptan��


restriction��



IMPACT OF HYPONATREMIA

ON HEALTH SYSTEMS

Learning Objective





Impact of Hyponatremia on Selected

Hospital Outcomes

Community-Acquired

Hyponatremia (37.9%)

• In-hospital mortality

OR 1.52 (CI, 1.36-1.69)

• Higher likelihood of

discharge to short-

or long-term care

(37.5% vs 33.7%)

• 14% prolongation

in LOS

Admission [Na+]

<138 mEq/L

Wald R et al. Arch Intern Med. 2010;170:294-302.

Hospital Aggravated

Hyponatremia (5.7%)


OR 2.30 (CI, 1.75-3.02)


discharge to short- or

long-term care

• Prolonged LOS

Hospital-Acquired

Hyponatremia (38.2%)


OR 1.66 (CI, 1.39-1.98)


discharge to short- or

long-term care (45.7%

vs 31.9%)

• Increase in LOS

(median, 5 vs 4 d)

Decline in admission

[Na+] at least 2 mEq/L

Serum [Na+] nadir

<138 mEq/L

Hyponatremia is an Independent Risk

Factor for In-Hospital Mortality• 1-year study of 4123 patients (≥65 y) admitted to community hospital;

3.5% had admission serum [Na+] <130 mEq/L1

‒ Linear trend in mortality evident as serum [Na+] decreased

‒ Admission hyponatremia significant predictor of in-hospital mortality (RR, 1.95; P<.006)

• Even mild hyponatremia is associated with increased in-hospital mortality2

1. Terzian C et al. J Gen Intern Med. 1994;9:89-91. 2. Waikar SS et al. Am J Med. 2009;122:857-865.

8

15

19

0

5

10

15

20

>129 mEq/L 120-129 mEq/L <120 mEq/L

Mortality, %1



Whyte M et al. Int J Clin Pract. 2009;63:1451-1455.

Failure to Measure Plasma & Urinary OsmolalitiesAssociated With Increased Hyponatremia Mortality

• 113 patients with severe hyponatremia (serum [Na+] ≤120 mEq/L)

• Relationship between lack of investigation for hyponatremia and increased mortality

14.3 12.79.8

32 3430

0

10

20

30

40

Serum Osmolality

Measured

Urine Osmolality

Measured

Paired Osmolality

Measured

Mortality, %

Yes

No

Impact of Hyponatremia on Cost in

Hospitalized Patients With Heart Failure

With permission from Shorr AF et al. Congest Heart Fail. 2011;17(1):1-7.

© 2011 John Wiley & Sons. All rights reserved.

$1,132

$509

$99

-$400

$100

$600

$1,100

$1,600

Severe

hyponatremia

Hyponatremia Normonatremia

(Ref)

Hypernatremia

Attributable Cost (95% CI)

Reference



Effect of Serum [Na+] & Tolvaptan

on LOS in Hospitalized Patients With HF

• Objectives of this post-hoc analysis of EVEREST trial

– Compare LOS between normonatremic (n=1789) and hyponatremic (n=216)

patients who were randomized to placebo

– Evaluate the effect of tolvaptan (n=225) compared with placebo (n=216) on

LOS in hyponatremic patients

• LOS in hyponatremic vs normonatremic patients

– Serum [Na+] <135 mEq/L: LOS + 3.06 d (P<.001)

– More severe hyponatremia: LOS + 5.17 d (P<.001)

• LOS tolvaptan vs placebo

– 1.72 d shorter vs placebo (P=NS)

– 2.12 d shorter in patients with more severe hyponatremia

(P=NS)

Cyr PL et al. Am J Health Syst Pharm. 2011;68(4):328-333.

Economic Benefit of Tolvaptan

in Hyponatremic HF Patients

• Hospital cost and LOS for DRG hospitalizations of adult HF patients with

complications, comorbidities estimated from HCUP 2008 NIS database

• Reductions in LOS associated with tolvaptan estimated from EVEREST

trial data for hyponatremic patients

• Cost offset model used to evaluate impact of tolvaptan on LOS and

hospital cost

– LOS reduced 0.81 d among HF hospitalizations

– $265 total cost savings per admission (based on wholesale acquisition cost of

$250/d)

– Supports clinical and economic benefit of tolvaptan use

– Study limitation: Clinical trial patient profiles and relative LOS

reductions may not be applicable to real-world patient populations

DRG, diagnosis-related group; HCUP, Healthcare Cost and Utilization Project;

NIS, Nationwide Inpatient Sample.

Chiong JR et al. J Med Econ. 2012;15(2):1-9.



SIADH Cost Analysis• Cost estimate methods

– HCUP 2009 Nationwide Inpatient Sample database• 21,718 patients hospitalized for SIADH: mean LOS of 5.7 d, mean total hospital

costs of $8667

– Used tolvaptan treatment duration of 4 d at cost of $250/dose

– LOS reduction estimate based upon SALT-1 and SALT-2 trials• SIADH patients receiving tolvaptan had shorter hospital LOS (4.98 vs 6.19 d)

• Results

– Cost offset model estimated LOS reduction of 1.11 d and total cost offset of $694 per admission

• 95% CI for cost offset using Monte Carlo simulation was $73‒$1405

– Cost-neutral break-even mean duration of tolvaptan inpatient use: 6.78 d

– Applying data to the 21,718 patients identified in the HCUP population, use of tolvaptan to treat these patients would result in total cost offset >$15 million

Dasta JF et al. Hosp Practice. 2012;40(1):1-8.

Many Roles of the Pharmacist

Monitor for hyponatremia development +

resolution

Consider a more pathophysiologic

approach to diagnosis and treatment

Consider drug-related causes of

hyponatremia

Ensure appropriate monitoring for morbidities of hyponatremia

Ensure optimal management of hyponatremia

Participate in clinical decision making

Participate in formulary decision making

and address cost-containment concerns

beyond acquisition costs

Educate clinicians on hyponatremia

Development of preventative hospital

systems directed toward hyponatremia



Top 10 Take-Aways

1. When hyponatremia is present, consider drug-related causes

2. Be vigilant for cognitive dysfunction at any level of hyponatremia

3. Chronic consequences of hyponatremia

4. Impact of hyponatremia on costs and outcomes is real

5. Role of AVP in pathophysiology of SIADH and hypervolemia

6. Treatment algorithm

7. Rate of serum [Na+] correction

8. Monitor, monitor, monitor during [Na+] correction for safety

9. Vaptans are necessary "tool" in treatment algorithm

for hyponatremia

10. Vaptan AEs, drug interactions

SUPPLEMENTAL SLIDES



Costs of Hyponatremia

• Direct costs estimated at $1.6 to $3.6 billion annually1

– Hospitalization costs account for ≈70%

• Associated with worse clinical and economic outcomes2

• Patients with hyponatremia have

– 12% to 58% increased risk of requiring ICU stay2,3

– Adjusted mean LOS of 3.06 d longer4

– 12% to 64% increased risk of requiring discharge to short- or

long-term care facility5

– 41.2% higher cost at 6 mo; 45.7% higher at 1 y6

LOS, length of stay.

1. Boscoe A et al. Cost Eff Resour Alloc. 2006;4:1-11. 2. Zilberberg MD et al. BMC Pul Med. 2008;8:16.

3. Callahan MA et al. Postgrad Med. 2009;121(2):186-191. 4. Cyr PL et al. Am J Health Syst Pharm.

2011;15(68(4):328-333. 5. Wald R et al. Arch Intern Med. 2010;170:294-3024. 6. Shea AM et al.

J Am Soc Nephrol. 2008;19:764-770.

10 Most Common Diagnoses Among

Hospitalized Patients With Hyponatremia

aIncludes the 4-digit code for Hyponatremia (276.1).

Zilberberg MD et al. Curr Med Res Opin. 2008; 24(6):1601-1608, ©2008, Informa Healthcare. Adapted with permission of Informa Healthcare.

ICD-9-CM Discharge Code

Hyponatremia Present (n=10,899)

486 Pneumonia, Organism Unspecified 6.0%

038 Septicemia 5.5%

276 Disorders of Fluid, Electrolyte, and Acid-base Balancea 5.3%

428 Heart Failure 5.3%

250 Diabetes Mellitus 5.0%

584 Acute Renal Failure 3.9%

410 Acute Myocardial Infarction 3.2%

966 Complications Peculiar To Certain Specified Procedures 2.1%

518 Other Diseases Of Lung 2.0%

491 Chronic Bronchitis 1.8%



Change in Serum [Na+] & Mortality

Waikar SS et al. Am J Med. 2009;122:857-865.

0

10

20

30

40

50

In-hospital 1-year 5-year

Crude Mortality, %

Normonatremia

Resolution of Hyponatremia

Persistent Hyponatremia

Acquired Hyponatremia

Adjusted HR for Mortality

In-hospital 1-year 5-year

Normonatremia (n=42176) 1 (ref) 1 (ref) 1 (ref)

Resolution of Hyponatremia (n=3794) 1.26 1.19 1.18

Persistent Hyponatremia (n=4524) 2.37 1.55 1.32

Acquired Hyponatremia (n=1974) 2.44 1.54 1.4

Role of AVP in Edematous Disorders

Janicic N et al. Endocrinol Metab Clin North Am. 2003;32:459-481.

CHF�� Cardiac output

Cirrhosis�� Peripheral resistance dueto splanchnic vasodilation

Arterial underfilling

Stimulation of arterial

baroreceptors

Nonosmotic release of AVP

Impaired H2O excretion

Hypervolemic hyponatremia



SIADH: Pathophysiology

• Caused by excessive levels of AVP as a result of disease, drug-induced

pituitary release of AVP, or ectopic production of AVP

• AVP secretion not

suppressed appropriately

when plasma osmolality falls

below the osmotic threshold1,2

• The inability to suppress

AVP secretion results in:

– Impaired renal water excretion

– Increased total body water

– Hyponatremia

• “Dilute serum, nondilute urine”

1. Verbalis JG. J Mol Endocrinol. 2002;29:1-9.

2. Robertson GL et al. Am J Med. 1982;72:339-353.

Reprinted from Robertson GL, Aycinena P, Zerbe RL.

Neurogenic disorders of osmoregulation. Am J Med.

1982;72(2):339-353. ©1982, with permission

from Elsevier.

Essential Criteria

for Diagnosis of SIADH

• ↓↓↓↓ Effective osmolality of the ECF (Posm <275 mOsm/kg H2O)

• Inappropriate urinary concentration (Uosm >100 mOsm/kg H2O)

with normal renal function at some level of hypo-osmolality)

• Clinical euvolemia (no signs of hypovolemia or hypervolemia)

• Elevated urinary Na excretion despite normal salt and

H2O intake

• No other potential causes of euvolemic hypo-osmolality

Posm, plasma osmolality; Uosm, urinary osmolality.

Janicic N, Verbalis JG. Endocrinol Metab Clin North Am. 2003;32(2):459-481.



Data from Nzerue CM et al. J Natl Med Assoc. 2003;95:335-343.

Morbidities in Hospitalized Patients

With Symptomatic Hyponatremia

51.7

22.5

4.8 3.6 2.2 2.20

10

20

30

40

50

60

Patients, %

Hyponatremia Associated With Increased

Mortality in Patients in the ICU

• Retrospective study in 77 medical, surgical, and mixed ICUs

in Austria

• 151,486 adults admitted consecutively over 10 years (1998-2007)

– Borderline (130 ≤ [Na+] <135 mEql/L) hyponatremia: 13.8%

– Mild hyponatremia (125 ≤ [Na+] <130 mEq/L): 2.7%

– Severe hyponatremia ([Na+] <125 mEq/L): 1.2%

• Independent mortality risk with increasing severity of hyponatremia

– Borderline: OR, 1.32 (95% CI, 1.25-1.39)

– Mild: OR, 1.89 (95% CI, 1.71-2.09)

– Severe: OR, 1.81 (95% CI, 1.56-2.10)

Funk GC et al. Intensive Care Med. 2010;36(2):304-311.



Impact of Hyponatremia on Mortality in

Hospitalized Patients With Heart Failure

Shorr AF et al. Congest Heart Fail. 2011;17(1):1-7.

Group n[Na+],

mEq/LOR 95% CIa

Severe hyponatremia 6117 ≤130 1.78 1.59-1.99

Hyponatremia 18,445 131-135 1.29 1.19-1.40

Normonatremia (ref) 87,682 136-145 1.0

Hypernatremia 3725 >145 1.55 1.34-1.80

aAll P <.0001

Impact of Hyponatremia

on Survival in Cirrhosis

Reprinted with permission from Kim W et al. N Engl J Med. 2008;359(10):1018-1026.

© 2008 Massachusettes Medical Society. All rights reserved.

Serum [Na+] and RR of death after adjustment for MELD score



Healthcare Costs Determinants

Healthcare costs

Direct (medical and nonmedical)

Opportunity(lost opportunity,

foregone revenue)

Indirect (morbidity, mortality)

Intangible (emotional

pain + suffering, inconvenience)

Costs of Admission Hyponatremia (adjusted for clinical & demographic variables)

Moderate-Severe

(≤129 mEq/L)

32% ICU admission

Total costs

$19,519

8 Day LOS

Callahan MA et al. Postgrad Med. 2009;121(2):186-191.

Mild-Moderate (130-134 mEq/L)

26% ICU admission

8 Day LOS

Total costs $18,054

Normal

(135-145 mEq/L)

22% ICU admission

6 Day LOS

Total costs

$17,085

Difference

= $2434

Difference

= $969



Costs Associated With Hyponatremia

in the United States

• Direct cost of treating hyponatremia estimated as $1.6 to $3.6 billion

annually1

– Based on inpatient hospital discharge data, published literature, an expert

consensus panel

• 1-year medical costs for patients with hyponatremia were $19,215

vs $9,257 for normonatremic patients2

– Data from managed care database of >162,000 patients

• In hospitalized patients, $2,289 increase in costs attributable to

hyponatremia3

– Based on data from 39 hospitals and 198,281 patients

1. Boscoe A et al. Cost Eff Resour Alloc. 2006;4:10.

2. Shea AM et al. J Am Soc Nephrol. 2008;19(4):764-770.

3. Zilberberg MD et al. Curr Med Res Opin. 2008;24(6):1601-1608.

Documents

The Impact of J. Herbert Patterson, Hyponatremia: … Renal collecting duct principal cells Renal free water absorption ... Schrier RW, ed. Atlas of Diseases of the Kidney . ... LiamisG