of nephrology. mini-monograph - hdcn for the jasn, american journal of kidney disease, clinical...

M I N I - M O N O G R A P H

Endorsed by the American Societyof Nephrology.

Sole support provided byan educational grant fromAstellas Pharma US, Inc.

This monograph will provide an overview of a scientific symposium entitled CurrentConcepts in Neurohormones: Vasopressin and the Kidney, held on November 10,2005, during the American Society of Nephrology 38th Annual Meeting and ScientificSession in Philadelphia, Pennsylvania.

AGENDA

12:15 PM – 12:20 PM OPENING REMARKSRobert W. Schrier, MD, Chair

12:20 PM – 12:40 PM EFFECT OF VASOPRESSIN ON RENAL AND SYSTEMIC PHYSIOLOGYRobert W. Schrier, MD

12:40 PM – 1:00 PM EMERGING OPTIONS IN THE MANAGEMENT OF FLUIDDYSREGULATION AND ELECTROLYTE IMBALANCERichard H. Sterns, MD

1:00 PM – 1:10 PM PANEL DISCUSSIONRobert W. Schrier, MD, and Richard H. Sterns, MD

1:10 PM – 1:15 PM CLOSING REMARKSRobert W. Schrier, MD

Chair

ROBERT W. SCHRIER, MDProfessor of MedicineUniversity of Colorado School of MedicineDenver, ColoradoHonoraria: None

RICHARD H. STERNS, MDProfessor of MedicineUniversity of Rochester School of Medicine and DentistryChief, Department of MedicineRochester General HospitalRochester, New YorkHonoraria: None

FACULTY

1

This activity is supported by an educational grant from Astellas Pharma US, Inc.

B I O G R A P H Y

2 C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : V A S O P R E S S I N A N D T H E K I D N E Y

Robert W. Schrier, MD, Professor of Medicine, was for-

merly Chairman of the Department of Medicine at the

University of Colorado School of Medicine for 26 years

and Head of the Division of Renal Diseases and Hypertension

for 20 years. In 1989 he was elected a member of the Institute

of Medicine of the National Academy of Sciences. He has

been President of the Association of American Physicians, the

American Society of Nephrology, the National Kidney Foun-

dation, and the International Society of Nephrology. Dr Schrier

is a Master of the American College of Physicians and an

Honorary Fellow of the Royal College of Physicians. He has

authored over 850 scientific papers and edited 45 books in

renal medicine, geriatrics, drug usage, and kidney disease. His

research contributions center on the pathogenesis of acute

renal failure, genetic renal disorders, mechanisms of renal cell

injury, diabetic nephropathy, and renal and hormonal control

of body fluid volume in cirrhosis, cardiac failure, nephrotic syn-

drome, and pregnancy. He brings to his research interests a

unique combination of expertise in body fluid control mecha-

nisms, renal function, and cardiovascular function. He has

advanced a unifying hypothesis of sodium and water regula-

tion in health and disease, stimulating worldwide interest in the

biomedical science community. Dr Schrier’s research has been

funded by the National Institutes of Health for the last 35 years.

During Dr Schrier’s 26 years as Chairman of the Depart-

ment of Medicine at the University of Colorado, the full-time

faculty increased from approximately 75 to 500. The annual

research grants gathered by the department’s full-time faculty

rose from approximately $3 to $100 million, including the con-

tributions to the General Clinical Research and Cancer

Centers. The house staff and fellow training programs also

became nationally prominent. Thirty endowed research chairs

between $1.5 and $2 million each were established. For these

contributions, Colorado Governor Bill Owens announced an

Honorary Proclamation designating May 4, 2002, as Robert W.

Schrier Day in Colorado and Mayor Wellington Webb pro-

claimed May 4, 2002, to be Robert W. Schrier Day in the City

and County of Denver. In 2002, Dr Schrier also received the

prestigious Belle Bonfils-Stanton Award for Contributions in

Science and Medicine.

Dr Schrier has received honorary degrees from DePauw

University, the University of Colorado, the University of Silesia,

and the Medical College of Ohio. He has received the highest

awards of the American College of Physicians (John Phillips

Award), the National Kidney Foundation (David Hume Award),

the American Society of Nephrology (John Peters Award), the

International Society of Nephrology (Jean Hamburger Award),

the German Society of Nephrology (Franz Vollhard Award), the

Western Society of Clinical Investigation (Mayo Soley Award),

the Association of Professors of Medicine (Robert H. Williams

Award), the American Kidney Fund (National Torchbearer

Award), the Association of American Physicians (Francis Blake

Award), the Acute Renal Failure Commission (Bywaters Award),

the New York Academy of Medicine (The Edward N. Gibbs

Memorial Award), the University of Strasburg (Louis Pasteur

Medal), the Grand Hamdan International Award for Medical

Sciences, and the Alexander von Humboldt Research Award

for his contributions in biomedical research, education, and

clinical medicine.

ROBERT W. SCHRIER, MD

A B S T R A C T

3C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : V A S O P R E S S I N A N D T H E K I D N E Y

R O B E R T W . S C H R I E R , M D

Body fluid volume regulation is involved in virtually all facets of medicine and the kid-

ney responds to the increased neurohumoral activity that occurs with arterial under-

filling. While there are receptors on the low-pressure side of the circulation, the

dominant baroreceptors are in the high-pressure arterial side of the circulation. Removal of

the tonic inhibition from these receptors occurs during arterial underfilling secondary to

either a decrease in cardiac output (eg, volume depletion, low-output cardiac failure) or pri-

mary arterial vasodilation (eg, high-output cardiac failure, cirrhosis, and pregnancy) and

leads to multifactorial neurohumoral and renal responses. The lecture will discuss these con-

ditions and neurohumoral responses to the arterial underfilling that accompanies them.

Chen Y-C, CadnapaphornchaiMA, Schrier RW. Clinicalupdate on renal aquaporins.Biol of the Cell. 2005;97:357-371.

Schrier RW, Chen Y-C,Cadnapaphornchai MA. From finch to fish to man: roleof aquaporins in body fluidand brain water regulation.Neuroscience. 2004; 129:897-904.

Schrier RW, Abraham WT.Hormones and hemodynamicsin heart failure. N Engl J Med.1999;341:577-585.

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5C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : V A S O P R E S S I N A N D T H E K I D N E Y


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C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : VA S O P R E S S I N A N D T H E K I D N E Y

Richard H. Sterns, MD, is Professor of Medicine at the

University of Rochester School of Medicine and

Dentistry and Chief, Department of Medicine, at

Rochester General Hospital, both in New York. Dr Sterns

received his medical degree from the University of Penn-

sylvania School of Medicine in Philadelphia, and completed

the first 2 years of his internal medicine residency at San

Francisco General Hospital and the University of California,

San Francisco Medical Center, respectively. He completed the

third year of his residency and served a year as Chief Resident

in internal medicine at Albert Einstein College of Medicine of

Yeshiva University in New York, and went on to finish a

nephrology fellowship at the University of Pennsylvania

School of Medicine.

Dr Sterns is a member of several national and interna-

tional professional organizations including the American

Society of Nephrology, the International Society of Nephro-

logy, and the American Heart Association. He is a manuscript

reviewer for the JASN, American Journal of Kidney Disease,

Clinical Nephrology, and Kidney International, among others,

and has authored several articles and book chapters related

to hyponatremia. His research interests are focused on the

effect of osmotic disturbances on the brain and the pathogen-

esis of osmotic demyelination syndrome. Dr Sterns has lec-

tured at both national and international meetings and has

participated in major professional meetings around the

United States.

RICHARD H. STERNS, MD

B I O G R A P H Y

7

A B S T R A C T

8 C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : VA S O P R E S S I N A N D T H E K I D N E Y

R I C H A R D H . S T E R N S , M D

The first successful treatment of acute symptomatic

hyponatremia was first described in 1935.1 A 50-year-

old woman with postoperative hyponatremia and

impending herniation responded to 130 mL of 5% saline.

Acute hyponatremia (<24 h) causes life-threatening cerebral

edema, and our treatment of the condition has changed lit-

tle in the ensuing 70 years; the prompt administration of

hypertonic saline (the most definitive way to increase the

serum sodium concentration) relieves symptoms and may

be life saving.2,3

Given time, the brain adapts to hyponatremia as elec-

trolytes and organic osmolytes are shed by brain cells.4,5

These adaptations minimize cerebral edema, making death

from herniation vanishingly rare, and symptoms much more

subtle than acute hyponatremia.4-9 In addition, because it takes

several days for brain cells to recover organic osmolytes lost

during the adaptation to hyponatremia, patients with chronic

hyponatremia (>48 h) are susceptible to osmotic demyelina-

tion from rapid correction of their electrolyte disturbance.7-11

Thus, particularly in patients with chronic hyponatremia, man-

agement must not only be prompt and definitive; it must also

be limited, with therapy targeted at correction by no more

than 8 mEq/L per day in most patients.4

The serum sodium concentration reflects the ratio of the

body’s content of sodium and potassium and its content of

water. Traditional approaches to the management of hypona-

tremia have focused on the numerator of this equation.1,2,4,12

Recently, vasopressin-receptor antagonists have become

available for clinical trials, making it possible to focus attention

on the denominator.13-16 Blood vessel vasoconstriction and

myocardial function are modulated by V1a receptors located

on vascular smooth muscle cells and cardiomyocytes. In addi-

tion, V1a receptors are found on platelets (affecting platelet

aggregation), lymphocytes and monocytes (affecting coagu-

lation factor release), and in the adrenal cortex (affecting

glycogenolysis). Vasopressin’s effects on the kidney’s collect-

ing duct principal cells are mediated by V2 receptors, leading

to free-water absorption. Several antagonists to vasopressin

are currently being studied in clinical trials. These include

tolvaptan and lixivaptan, which are pure V2 antagonists, and

conivaptan, which is a dual V1a/V2 antagonist.

Antagonists of vasopressin’s V2 receptor promote

water loss without affecting sodium or potassium balance;

they are thus called “aquaretics.” In a study of 254 patients

with heart failure, tolvaptan demonstrated a significant

decrease in body weight and edema in modestly volume-

overloaded patients. Urinary output was increased and there

was normalization of hyponatremia associated with heart fail-

ure. In the Acute and Chronic Therapeutic Impact of a

Vasopressin Antagonist in Congestive Heart Failure (ACTIV in

CHF) randomized, placebo-controlled trial, 3 doses of tolvap-

tan were compared to standard therapy in 80 patients with

acute decompensated heart failure. Body weight decreased

significantly in the tolvaptan group compared with the place-

bo group and the hyponatremia noted in 22% of patients was

corrected. No change in renal function was noted. A post-hoc

analysis showed lower mortality in the combined tolvaptan

groups at 60 days, although the study was not powered or

designed to prospectively show mortality. Lixivaptan in vari-

ous doses was studied in 44 patients with hyponatremia of

various causes. There was a significant increase in free-water

clearance and serum sodium. Further studies are ongoing.

Conivaptan was studied in 142 patients with severe

heart failure (New York Heart Association [NYHA] Class III-IV,

left ventricular ejection fraction [LVEF] 21%-26%). In this multi-

center study, patients were randomized to placebo (n=38) or

1 of 3 dose groups of conivaptan: 10 mg (n=37), 20 mg (n=32),

or 40 mg (n=35). Concomitant background medications were

given within 2 hours of catheter insertion, which was fol-

lowed by a 6- to 16-hour stabilization period. Pulmonary

artery catheterization was used to assess hemodynamic

changes, which required the eligible patients to have a pul-

monary capillary wedge pressure (PCWP) of >16 mm Hg and

a cardiac index of <2.8 L/min/m2 at baseline. Both PCWP and

right atrial pressure (RAP) were significantly reduced after

drug administration in the 20-mg (P<.01) and 40-mg (P<.05)

conivaptan groups compared with placebo, without signifi-

cant change in cardiac index, pulmonary artery pressures,

systemic or pulmonary vascular resistance, systemic arterial

pressure, or heart rate. The peak effect on PCWP was sus-

tained for approximately 8 hours after administration. Urine

output in the conivaptan-treated group was significantly

greater than in the placebo group (P<.001), and demonstrat-

ed a dose-dependent response that peaked at 2 to 3 hours

after the dose was administered. Similarly, urine osmolality

was significantly reduced by all doses of conivaptan (P<.05),

without a significant change in serum osmolality, serum sodi-

um, or serum potassium levels (although there was a small,

dose-dependent trend toward higher serum sodium in the

conivaptan groups).17-19

A B S T R A C T , c o n t ’ d

9C U R R E N T C O N C E P T S I N N E U R O H O R M O N E S : VA S O P R E S S I N A N D T H E K I D N E Y


In a phase 3, randomized, double-blind, placebo-con-

trolled study presented at the American Heart Association,

patients with hyponatremia (Na+ 115 mEq/L to <130 mEq/L)

were randomized to receive a 20-mg bolus injection of coni-

vaptan followed by conivaptan infusion of 40 mg/day (n=29)

or 80 mg/day (n=26) for 4 days. A third group received place-

bo (n=29). The study group consisted of a mixed population

of euvolemic patients (72%, 62%, and 65% in the placebo,

40-mg, and 80-mg groups, respectively) and hypervolemic

patients (28%, 38%, and 35% in the placebo, 40-mg, and 80-mg

groups, respectively). Heart failure was the cause of hypona-

tremia in approximately 30% of patients. At both doses, coni-

vaptan was significantly better than placebo in increasing

serum sodium over the 4-day period (P=.001). The increase in

serum sodium seen with conivaptan 40 mg/day and 80 mg/day

was dose related and gradual over the 4-day period.

Conivaptan was well tolerated in all patients.20

Management of hyponatremia is dependent on many

factors—most importantly, the acuteness of onset. Current

management options are limited and include the extremes of

hypertonic saline and water restriction, but in the future, aquaret-

ics may find their place in our therapeutic armamentarium.

1. Helwig FC, Schutz CB, CurryDE. Water intoxication: mori-bund patient cured byadministration of hypertonicsalt solution. JAMA. 1938;110:644-645.

2. Hew-Butler T, Almond CS,Ayus JC, et al. Consensusstatement of the FirstInternational Exercise-Associated HyponatremiaConsensus DevelopmentConference. Clin J SportMed. 2005;15:208.

3. Halberthal M, Halperin ML,Bohn D. Lesson of the week:acute hyponatraemia in chil-dren admitted to hospital:retrospective analysis of fac-tors contributing to its devel-opment and resolution.BMJ. 2001;322:780-782.

4. Adrogue HJ, Madias NE.Hyponatremia. N Engl JMed. 2000;342:1581-1589.

5. Arieff AI, Llach F, Massry SG.Neurological manifestationsand morbidity of hypona-tremia: correlation with brainwater and electrolytes.Medicine. 1976;55:121-129.

6. Chow KM, Kwan BC, SzetoCC. Clinical studies of thi-azide-induced hyponatremia.J Natl Med Assoc.2004;96:1305.

7. Ellis SJ. Severe hyponatrem-ia: complications and treat-ment. QJM. 1995;88:905-909.

8. Sterns RH. Severe sympto-matic hyponatremia; treat-ment and outcome. A studyof 64 cases. Ann Intern Med.1987;107:656-664.

9. Sterns RH, Cappuccio JD,Silver S. Neurologic seque-lae after treatment of severehyponatremia: a multicenterperspective. J Am SocNephrol. 1994;4:1522-1530.

10.Ashraf N, Locksley R, ArieffAI. Thiazide-induced hypona-tremia associated with deathor neurologic damage inoutpatients. Am J Med.1981;70:1163-1168.

11.Martin RJ. Central pontineand extrapontine myelinoly-sis: the osmotic demyelina-tion syndromes. J NeurolNeurosurg Psychiatry.2004;75(suppl 3):iii22.

12.Licata G, Di Pasquale P,Parrinello G, et al. Effects ofhigh-dose furosemide andsmall-volume hypertonic

saline solution infusion incomparison with a highdose of furosemide asbolus in refractory conges-tive heart failure: long-termeffects. Am Heart J.2003;145:459-466.

13.Goldsmith SR. Current treat-ments and novel pharmaco-logic treatments forhyponatremia in congestiveheart failure. Am J Cardiol.2005;95:14B-23B.

14.Gheorghiade M, Gattis WA,O’Connor CM, et al. Effectsof tolvaptan, a vasopressinantagonist, in patients hospi-talized with worsening heartfailure: a randomized con-trolled trial. JAMA.2004;291:1963-1971.

15.Lee CR, Watkins ML,Patterson JH, et al.Vasopressin: a new target forthe treatment of heart failure.Am Heart J. 2003;146:9-18.

16.Verbalis JG. Vasopressin V2receptor antagonists. J MolEndocrinol. 2002;29:1-9.

17.Udelson JE. Acute hemody-namic effects of conivaptan,a dual V1a and V2 vaso-pressin receptor antagonist,in patients with advancedheart failure. Circulation.2001;104:2417-2423.

18.Goldsmith SR, Bisaha JG,Smith N. Evaluating the effi-cacy and safety of the novelvasopressin V1a and V2receptor antagonist conivap-tan for the treatment ofacute decompensated chron-ic heart failure: study proto-col. J Card Fail.2004;10(suppl):S85.

19.Verbalis JG, Bisaha JG, SmithN. Novel vasopressin V1a andV2 antagonist (conivaptan)increases serum sodium con-centration and effective waterclearance in patients withhyponatremia. J Card Fail.2004;10(suppl):S27.

20.Verbalis J. Novel vaso-pressin V1a and V2 antago-nist (conivaptan) increasedserum sodium concentrationand effective water clearancein hyponatremia clinical tri-als. Abstract presented atAmerican Heart AssociationScientific Conference;November 10, 2004; NewOrleans, Louisiana.

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