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in part. Increased hematocrit value, associated with increased blood viscosity, may increase the impedance of the systemic circulation and the ventricular afterload. All these changes might contribute to accelerated left ventricular dys-function or hypertrophy and might offset the ben-efits of improved myocardial and peripheral oxy-genation.

Taken together, these two studies suggest cau-tion in the full correction of anemia in patients with chronic kidney disease. Currently, there are several additional multicenter trials of complete as compared with partial correction of anemia in patients with chronic kidney disease; Dr. Remuzzi is participating in one of them. Although we need more information about the ideal target level and should consider the present guidelines in-complete, it seems wisest to refrain from complete correction of anemia in persons with chronic kidney disease.

Dr. Remuzzi reports receiving lecture fees from Abbott, Sanofi-Aventis, and AstraZeneca. No other potential conflict of interest relevant to this article was reported.

From the Mario Negri Institute for Pharmacological Research, Bergamo, Italy (G.R.).

KDOQI, National Kidney Foundation. KDOQI clinical prac-tice guidelines and clinical practice recommendations for ane-mia in chronic kidney disease. Am J Kidney Dis 2006;47:Suppl 3:S11-S145. [Erratum, Am J Kidney Dis 2006;48:518.]

Locatelli F, Aljama P, Barany P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephol Dial Transplant 2004;19:Suppl 2:ii1-ii47.

Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemo-globin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-84.

Singh AK, Szczech L, Tang KL, et al. Correction of anemia

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with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085-98.

Besarab A, Bolton WK, Browne JK, et al. The effects of nor-mal as compared with low hematocrit values in patients with car-diac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584-90.

Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-blind comparison of full and partial anemia cor-rection in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005;16:2180-9.

Levin A, Djurdjev O, Thompson C, et al. Canadian random-ized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis 2005;46:799-811.

Rossert J, Levin A, Roger SD, et al. Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis 2006;47: 738-50.

Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358: 1305-15.

Livio M, Gotti E, Marchesi D, Mecca G, Remuzzi G, de Gaetano G. Uraemic bleeding: role of anaemia and beneficial effect of red cell transfusions. Lancet 1982;2:1013-5.

Lafferty HM, Anderson S, Brenner BM. Anemia: a potent modulator of renal hemodynamics in models of progressive re-nal disease. Am J Kidney Dis 1991;17:Suppl 1:2-7.

Scott Brimble K, McFarlane A, Winegard N, Crowther M, Churchill DN. Effect of chronic kidney disease on red blood cell rheology. Clin Hemorheol Microcirc 2006;34:411-20.

Alfrey AC. Role of iron and oxygen radicals in the progres-sion of chronic renal failure. Am J Kidney Dis 1994;23:183-7.

Facchini FS, Saylor KL. A low-iron-available, polyphenol- enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes 2003;52:1204-9.

Key TJ, Fraser GE, Thorogood M, et al. Mortality in vege-tarians and nonvegetarians: detailed findings from a collabora-tive analysis of 5 prospective studies. Am J Clin Nutr 1999;70:Suppl:516S-524S.

Michiels JJ, Berneman Z, Van Bockstaele D, van der Planken M, De Raeve H, Schroyens W. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding com-plications, and the molecular etiology of essential thrombocy-themia and polycythemia vera: therapeutic implications. Semin Thromb Hemost 2006;32:174-207.Copyright © 2006 Massachusetts Medical Society.

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Vasopressin Antagonists — Progress and PromiseRichard M. Hays, M.D.

Hyponatremia is the most common in-hospital electrolyte disorder that a physician encounters. Its management has been the subject of numer-ous studies and reviews. In patients with chronic heart failure or cirrhosis, water retention, medi-ated by the vasopressin V

2 receptor in the renal

collecting tubule, is an initially positive defense against a decrease in cardiac output or the dilated splanchnic circulation in cirrhosis.1 The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is, of course, another matter. Water re-tention in SIADH serves no physiologic purpose,

and hyponatremia may be serious enough to re-quire emergency measures.

Until now, the management of hyponatremia has centered on a series of graded steps, starting with water deprivation in the mildest cases and extending to the careful administration of saline in symptomatic patients.2 Management is not al-ways easy, especially in the patient with chronic heart failure or marked hyponatremia, for whom pontine and extrapontine myelinolysis are poten-tial hazards if correction occurs too rapidly.

For many years, there has been interest in de-

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editorials

n engl j med 355;20 www.nejm.org november 16, 2006 2147

veloping vasopressin V2-receptor antagonists as

therapeutic agents that would allow the physician to deal more directly and safely with the problem of hyponatremia. There has also been a growing understanding that the V

2 receptor may not be the

only important player in hyponatremia. Others include the V

1A receptor, involved in the pressor actions of the hormone, and the V

1B receptor, in-volved in vasopressin-stimulated secretion of adre-nocorticotropin, and other less well character-ized receptors.3,4 Activation of the V

1A receptor is especially important in the treatment of patients with euvolemic and hypervolemic hyponatremia, who have high, sustained plasma levels of vaso-pressin. Indeed, vasopressin received its name from the early observation that it is a powerful pressor of the peripheral circulation and, as has been shown in studies in dogs, a constrictor of the coronary arterial bed.5 Evidence from studies in animals suggests that vasopressin has direct effects on the heart, increasing calcium levels in the cultured myocyte6 and producing myocyte hypertophy in the isolated perfused rat heart.7 Vasopressin may also potentiate the synthesis of endothelin and contribute to the effects of angio-tensin II, as discussed by Udelson et al.8 The role of the V

1A receptors in the treatment of patients with cardiovascular disease has recently been re-viewed by Goldsmith.9

These V1A-mediated actions increase in impor-

tance in view of the fact that in patients with heart failure, systemic vasopressin levels may rise early in the course of the disease, before hypo-natremia develops.10,11 All these considerations have encouraged the design and trial of vaso-pressin-receptor antagonists, which may permit the physician to intervene early to block the ad-verse effects of the hormone.

The design and evaluation of receptor antag-onists have a long and painful history. Peptide antagonists of the V

2 receptor were the first com-

pounds tried; although effective in animal mod-els, these compounds were ineffective or actually proved to be agonists in humans. More recently, with the help of high-throughput technology, nonpeptide-receptor antagonists have been gen-erated and shown to be effective in humans. Several are under investigation in clinical trials. Tolvaptan, a V

2-receptor antagonist, and conivap-

tan (Vaprisol, Astellas), a combined V1/V

2-receptor

antagonist, are, respectively, in phase 3 clinical trials and approved for parenteral use in the Unit-ed States. Both tolvaptan and conivaptan are ben-zazepine derivatives (Fig. 1).

In this issue of the Journal, Schrier et al. report the results of two multicenter, randomized, pla-cebo-controlled, double-blind trials of oral tolvap-tan involving subjects with hyponatremia.12 The subjects had chronic heart failure, cirrhosis, SIADH, or hyponatremia from other causes, with

TolvaptanConivaptan

CH3

H3C

H3C

N

N

HN

O

O

NH

N

OH

Cl

O

O

NH

Figure 1. Structure of the Oral Vasopressin-Receptor Antagonists Conivaptan and Tolvaptan.

Copyright © 2006 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by MANUEL MORENO MD on August 17, 2008 .

T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 355;20 www.nejm.org november 16, 20062148

a severity ranging from mild to marked. This re-port, combining the results of two trials in the Study of Ascending Levels of Tolvaptan in Hypo-natremia (SALT-1 and SALT-2), is one of a recent series of reports on the efficacy of V

2 antagonists

in the treatment of hyponatremia discussed by Schrier et al.12 The current report presents results for a 30-day period in which many of the subjects (number not given) were treated in an outpatient, rather than an in-hospital, setting and includes a self-administered assessment of the subjects’ physical and mental well-being. This report con-firms earlier studies in showing that tolvaptan significantly and rapidly increased serum sodium concentrations and urine output above those in control subjects receiving placebo. Furthermore, the increase was sustained over the 30 days of each of the two trials and fell during the week after discontinuation of the drug. Tolvaptan was started at a dose of 15 mg per day and the dose was increased during the next 4 days to 30 mg per day, then to 60 mg per day, in accordance with the study protocol that an increased dose be ad-ministered to subjects whose serum sodium con-centration remained less than 135 mmol per liter and had increased less than 5 mmol per liter during the prior 24 hours after receipt of the ini-tial dose. In 4 of the 223 subjects assigned to tolvaptan, the predefined potentially clinically im-portant serum sodium concentration of 146 mmol per liter was exceeded during the first 24 hours after the initial treatment; data are not provided on excessive serum sodium concentrations dur-ing the full study period. The dose was reduced or discontinued for a day or the fluid intake was increased if the serum sodium reached unaccept-ably high concentrations. Side effects included thirst and dry mouth; more serious adverse events occurring in eight subjects assigned to tolvaptan included hypotension, dizziness, and syncope. Adverse events occurred in the control group as well, often reflecting underlying disease; these in-cluded cardiac failure, hepatic encephalopathy, acute dyspnea, and edema. The number of deaths was similar in the combined tolvaptan and pla-cebo groups. In scores on the self-administered questionnaire, subjects with marked hyponatre-mia who received tolvaptan showed improvement in some cognitive domains of the mental compo-nent, including overall well-being and ability to concentrate, but scores on the physical compo-

nent showed no significant differences between the two groups.

The study is encouraging in terms of the ef-ficacy of tolvaptan as a V

2-receptor antagonist

and its use, at least during a limited period, in the outpatient setting. At the same time, it is clear that careful oversight of the use of this agent is required, not only by means of frequent clin-ic visits and measurement of serum sodium, but also through daily measurement of body weight by patients. An important question is the extent to which added benefits might be realized if the V

1A-mediated actions of vasopressin were brought under control with the use of combined V

1A/V2-

receptor antagonists.9 This question remains to be answered in future studies of this promising new generation of receptor antagonists.

No potential conflict of interest relevant to this article was re-ported.

From the Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.

Schrier RW. Water and sodium retention in edematous dis-orders: role of vasopressin and aldosterone. Am J Med 2006;119:Suppl 1:S47-S53.

Janicic N, Verbalis JG. Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 2003;32:459-81.

Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69:2124-30.

Streefkerk JO, van Zwieten PA. Vasopressin receptor antago-nists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol 2006;26:141-8.

Maturi MF, Martin SE, Markle D, et al. Coronary vasocon-striction induced by vasopressin: production of myocardial is-chemia in dogs by constriction of nondiseased small vessels. Circulation 1991;83:2111-21.

Xu YJ, Gopalakrishnan V. Vasopressin increases cytosolic free [Ca2+] in the neonatal rat cardiomyocyte: evidence for V1 subtype receptors. Circ Res 1991;69:239-45.

Fukuzawa J, Haneda T, Kikuchi K. Arginine vasopressin in-creases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor. Mol Cell Biochem 1999;195:93-8.

Udelson JE, Smith WB, Hendrix GH, et al. Acute hemody-namic effects of conivaptan, a dual V(1a) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Cir-culation 2001;104:2417-23.

Goldsmith SR. Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists? Am J Med 2006;119:Suppl 1:S93-S96.

Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dys-function with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:1724-9.

Nakamura T, Funayama H, Yoshimura A, et al. Possible vas-cular role of increased plasma arginine vasopressin in conges-tive heart failure. Int J Cardiol 2006;106:191-5.

Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selec-tive oral vasopressin V

2-receptor antagonist, for hyponatremia.

N Engl J Med 2006;355:2099-112.Copyright © 2006 Massachusetts Medical Society.

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