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When Is It Appropriate to Use Receptor Antagonists?

Ruediger W. Lehrich and Arthur Greenberg

Department of , Division of Nephrology, Duke University Medical Center, Durham, North Carolina

ABSTRACT is a common and challenging disorder. The mainstays of treatment serum during correction is al- until recently were water restriction and hypertonic saline. The first nonpeptide ways required. VRA offer a new ap- vasopressin (VRA) is now approved by the US Food and Drug proach to correct hyponatremia by re- Administration for use in patients with euvolemic and hypervolemic hyponatremia. versing the inability to excrete free water, VRA induce urinary dilution with an aquaresis that leads to an increase in serum thus remedying the fundamental patho- sodium concentration. In patients with , VRA modestly improve con- physiologic lesion. gestive symptoms but have no effect on short- or long-term mortality. Long-term effects have not been extensively studied, but serious adverse effects of VRA are rare, and the rate of rise in serum sodium that they produce seems unlikely to lead DEVELOPMENT OF VRA to osmotic demyelination. Beneficial effects beyond changing serum tonicity and alternative uses, such as in polycystic disease, need further exploration. This Although peptide antagonists of vaso- commentary discusses the current and potential indications for use of VRA. pressin receptors showed promise in an- imal models in the 1970s, they had par- J Am Soc Nephrol 19: 1054–1058, 2008. doi: 10.1681/ASN.2008010089 tial effect in humans and further development was abandoned. Subse- quently, nonpeptide receptor antago- Although patients with congestive heart duct cells. Because AQP3 and AQP4 are nists were identified and used success- failure (CHF), , or syndrome of constitutively expressed on the basolat- fully for the first time in humans in the inappropriate hormone se- eral membrane, insertion of AQP2 into early 1990s.6 In December 2005, the first cretion have disparate clinical features, the apical membrane is a critical limiting such compound, , a com- they share common pathophysiologic step in urinary concentration. bined vasopressin 1a receptor (V1aR) mechanisms for developing hyponatre- Hypovolemic hyponatremia rapidly and V2R antagonist, was approved by the mia: Failed urinary dilution associated responds to correction of volume deple- Food and Drug Administration for use in with water retention. Lack of suppres- tion. For treating euvolemic or hypervo- euvolemic hyponatremia. An indication sion of arginine vasopressin (AVP) re- lemic hyponatremia, however, conven- for hypervolemic hyponatremia was lease despite hypo-osmolality plays the tional approaches have been - granted more recently. Although effec- pivotal role; therefore, patients with any free water restriction, hypertonic saline tive in an oral formulation, conivaptan is of these disorders may respond to vaso- infusion, or , targeting an a potent CYP3A4 inhibitor. To protect pressin receptor antagonists (VRA).1–3 appropriately fast or slow correction, de- against the possibility of important drug The molecular target for AVP, the vaso- pending on the clinical situation. In interactions, its approval was limited to pressin 2 receptor (V2R), is one of three practice, of course, these therapies leave short-term, parenteral use. Three other vasopressin receptors. The intracellular much to be desired. Water restriction agents, , , and sat- effect of ligand binding depends on the can be difficult to implement. It is always localization of the receptor (Table 1). poorly tolerated and often of limited ef- Published online ahead of print. Publication date V2R located on the basolateral mem- ficacy. Hypertonic saline may lead to vol- available at www.jasn.org. brane of collecting duct cells are G-cou- ume overload or overly rapid correction Correspondence: Dr. Arthur Greenberg, Duke Uni- pled and activate the protein kinase A of chronic hyponatremia with osmotic versity Medical Center, Box 3014, Room 00554 signal cascade, leading to fusion of pre- demyelination. Formulas used to guide Duke Hospital South, Durham, NC 27710. Phone: 919-660-6860; Fax: 919-684-4476; E-mail: formed subapical vesicles containing dosage are complex and have been [email protected] membrane-bound aquaporin 2 (AQP2) shown to predict the rate of sodium rise Copyright ᮊ 2008 by the American Society of 4,5 into the apical membrane of collecting only variably. Frequent monitoring of Nephrology

1054 ISSN : 1046-6673/1906-1054 J Am Soc Nephrol 19: 1054–1058, 2008 www.jasn.org CLINICAL COMMENTARY

Table 1. Vasopressin receptors, localization, and effectsa Receptor Localization Effect V1a Vascular smooth muscle , myocardial hypertrophy Platelets Platelet aggregation Hepatocytes Glycogenolysis Myometrium Uterine contraction V1b (V3) Anterior pituitary ACTH release V2 Basolateral membrane, collecting tubule Insertion of AQP2 water channels into apical membrane Induction of AQP2 synthesis Vascular endothelium vWF and factor 8 release Vascular smooth muscle Vasodilation aAQP2, aquaporin 2; vWF, von Willebrand factor.

avaptan, each a selective V2R antagonist intravenously to patients with hypervo- mmol/L on day 4 and 135.7 Ϯ 5.0 (V2RA), are in various stages of develop- lemic or euvolemic hyponatremia, so- mmol/L on day 30 in patients who re- ment for commercial use. Tolvaptan is dium rose approximately 8 mEq/L dur- ceived active drug but only from 128.7 Ϯ the furthest along, and the highest qual- ing the first 24 h in the group that 4.1 to 129.7 Ϯ 4.9 and 131.0 Ϯ 6.2 ity data are available for this congener. received active drug versus 0.5 mEq/L in mmol/L, respectively, in the placebo Characteristics of these agents are sum- the group that was treated with fluid re- group. The rise in sodium exceeded 12 marized in Table 2. striction alone. Electrolyte-free water ex- mmol/L per 24 h in only four of the 225 cretion was higher and minimum uri- patients who received tolvaptan. Dry nary osmolality lower in the active drug mouth and increased thirst and urina- USE OF VRA IN HYPONATREMIA group.8 tion were more frequent in the treatment Schrier et al.9 conducted two identical group, and the remainder of adverse ef- Decaux7 demonstrated in 2001 that oral trials to test the efficacy of oral tolvaptan fects was similar in both groups. Serious administration of conivaptan in two pa- in patients with euvolemic and hypervo- adverse effects potentially a result of tients with well-established, longstand- lemic hyponatremia. Suitably named tolvaptan treatment occurred in eight ing syndrome of inappropriate antidi- SALT-1 and SALT-2 for Study of As- patients: Hypotension, dizziness, syn- uretic hormone secretion led to a rise in cending Levels of Tolvaptan in Hypona- cope, acute renal failure, and hypernatre- sodium with a concomitant decrease in tremia, an American and international mia. This study clearly demonstrated body weight. This effect was sustained, cohort of 448 patients was randomly as- that orally administered tolvaptan effec- reversing only after discontinuation of signed to tolvaptan or placebo. In tively and safely treats euvolemic and hy- conivaptan (Figure 1). In a placebo-con- SALT-1, sodium rose from 128.5 Ϯ 4.5 pervolemic hyponatremia. trolled trial of conivaptan administered mmol/L at baseline to 133.9 Ϯ 4.8 In smaller studies, the selective V2RA

Table 2. Characteristics and clinical indications for the combined V1a/V2 receptor blocker conivaptan and the selective V2 receptor blockers tolvaptan, lixivaptan, and satavaptana Parameter Conivaptan Tolvaptanb Characteristics receptor antagonism V1a and V2 V2 route of administration Intravenousc Oral osmolarity Decreased Decreased free water clearance Increased Increased ϩ Na /24 h Unchanged Unchanged Recommendations for use euvolemic hyponatremia (SIADH)d Yese Yes, once available hypervolemic hyponatremia (CHF)d Yese Yes, once available hypervolemic hyponatremia (cirrhosis)d No, safety data lacking Yes, once available hypervolemic hyponatremiad Never Never acute symptomatic hyponatremia Not yet, insufficient data Not yet, insufficient data ADPKD No data Phase III trial ongoing CHF No, no data Selected patients with severe congestive symptoms aADPKD, autosomal dominant polycystic kidney disease; CHF, congestive heart failure; SIADH, syndrome of inappropriate antidiuretic hormone secretion. bLike tolvaptan, lixivaptan and are selective V2RA with similar characteristics and anticipated indications. cConivaptan is effective when administered orally, but only the parenteral formulation is approved by the Food and Drug Administration. dRefers to chronic and non–life-threatening hyponatremia. eFood and Drug Administration–approved indication.

J Am Soc Nephrol 19: 1054–1058, 2008 Using Vaptans 1055 CLINICAL COMMENTARY www.jasn.org

142 64 63 138 62

132 61 60 126 59 Body weight (kg) Body Serum Na (mEq/L) 120 58

0 28 56 84 91 98 105 119 Days Conivaptan (20 mg BID) Water restriction (30 g/day)

Figure 1. Patient who had chronic hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion and underwent treatment with oral conivaptan, water restriction, and urea. Changes in body weight (F) and changes in serum sodium (᭜) are depicted. BID, twice a day. Reprinted from Decaux,7 with permission. lixivaptan and satavaptan also were more posite of patient-assessed global clinical tially more deleterious vasoconstrictor effective than placebo in treating euvo- status and body weight at 7 d or at dis- V1aR effect unopposed or even augmented lemic or hypervolemic hyponatremia. In charge; however, the observed effect was as AVP levels rose with treatment. all of the reported trials, orthostatic hypo- modest and entirely driven by the differ- tension, dizziness, or other symptoms of ence in weight loss from aquaresis, which USE OF VRA IN POLYCYSTIC volume depletion were noted, and adjust- was a mean of 1.82 kg in the tolvaptan KIDNEY DISEASE ment of dosing was often required to mit- group and 0.85 kg in the placebo group. In patients with autosomal dominant igate this effect of aquaresis. The effect of Serum sodium during the administration polycystic kidney disease (ADPKD), un- the drugs to increase thirst has the potential of tolvaptan rose by 2 mmol/L at discharge. opposed cAMP promotes cystogenesis to blunt their efficacy.10–12 There were some improvements in sec- by stimulating fluid secretion and cellu- ondary end points, namely dyspnea and lar proliferation in evolving cysts.16 V2R in the tolvaptan treatment group. act through cAMP to mediate their intra- USE OF VRA IN HEART FAILURE Dry mouth, thirst, and polyuria were sig- cellular effect. It was hypothesized and nificantly more common in the tolvaptan confirmed in animal models that V2RA Levels of , angiotensin, and group, although the incidence of serious lower cAMP levels and retard cyst devel- aldosterone all are increased in CHF, and adverse effects was similar. In long-term opment.17,18 A phase IIb trial in humans blockade of their effects has been repeat- follow-up conducted for up to 2 yr (me- with ADPKD and normal renal function edly shown to improve survival.13 The hy- dian 9.9 mo), neither a mortality benefit to determine the effect of increasing pothesis that outcome could be improved nor a reduction in heart failure hospitaliza- dosages of tolvaptan was recently com- by interference with the maladaptive in- tions was observed with tolvaptan. Taken pleted.19 A phase III trial studying the crease in AVP observed in patients with together, these trials indicate that tolvaptan disease progression of ADPKD in pa- heart failure was tested in the Efficacy of can improve some CHF symptoms in the tients who are receiving tolvaptan is on- Vasopressin Antagonism in Heart Failure short term, but it does not improve mor- going.20 Outcome Study with Tolvaptan (EVER- tality in the long term. Importantly, the EST) trials.14,15 In two identical, short- drug was well tolerated and safe. One pos- WHEN AND HOW SHOULD term, multicenter, international trials, pa- sible conclusion to be drawn from EVER- VASOPRESSIN ANTAGONISTS BE tients who were hospitalized with EST is that elevated AVP levels are not ac- USED? decompensated CHF were given either tually harmful in CHF; however, it is also Euvolemic and Hypervolemic tolvaptan or placebo within 48 h of admis- possible that no benefit was observed be- Hyponatremia sion. A total of 2072 patients received cause the fixed dosage of tolvaptan that was The controversy about how rapidly hy- tolvaptan, which was superior to placebo used was too low or because tolvaptan’s se- ponatremia should be corrected has been in achieving the primary end point, a com- lective blockade of the V2R left the poten- largely resolved.4 The key point is that

1056 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 1054–1058, 2008 www.jasn.org CLINICAL COMMENTARY acute hyponatremia and chronic hypo- quired no matter what regimen is se- because they did produce a modest ben- natremia are different and must be man- lected, and the hypertonic saline can be efit in the short-term EVEREST trial.14 aged with different goals in mind. In restarted if the rise in sodium falters. acute, severe hyponatremia, the brain In chronic hyponatremia, V2RA has had little time to compensate for the likely offer an ideal treatment option for FUTURE DIRECTIONS fall in serum sodium by shedding intra- patients with euvolemic or hypervolemic cellular osmoles. from hyponatremia, because they specifically As stressed here, more studies to delin- water uptake may be present or immi- reverse the pathophysiologic derange- eate the role of VRA in the treatment of nent, and severe alterations in sensorium ment present. Their optimal use remains acute hyponatremia are needed. Chronic with a high risk for seizures or other ad- to be determined, but the results of trials hyponatremia can lead to nausea, fa- verse events such as noncardiac pulmo- with all four agents are consistent and tigue, and cognitive impairment. Rever- nary edema are present. Here, the risk of promising. The rate of rise of serum so- sal of these symptoms has been the justi- persistent marked hyponatremia far ex- dium induced by these agents is on the fication for treatment of chronic ceeds any risk from correction of serum order of 6 to 9 mmol/L in the first 48 h, hyponatremia. A few studies have docu- sodium. Therapy with an agent that is providing reassurance against the risk for mented the degree of impairment with certain to raise sodium is essential. Con- overly rapid correction and osmotic de- hyponatremia or improvement with cor- versely, in chronic hyponatremia, the myelination.8–10 Furthermore, the drugs rection of hyponatremia.9,22 More would brain has had time to adjust. Intracellular are relatively short acting. Stopping them be welcome. The results of V2R blockade and organic osmolytes have when the rate of sodium rise is above tar- in experimental models of polycystic been shed, cerebral edema is unlikely, get provides a margin of safety. No cases kidney disease are very encouraging. Hu- and symptoms are bothersome but typi- of osmotic myelination have been re- man data are awaited with great inter- cally not life-threatening. Treatment reg- ported with V2RA. This is reassuring, est.20 Finally, the effects of V1aR block- imens must take into account the risk for but a caveat applies in that all of the stud- ade need more scrutiny. In particular, we permanent neurologic sequelae from os- ies were carried out in highly selected need to know whether V1aR blockade is motic demyelination caused by overly populations that were carefully followed safe for patients with cirrhosis or benefi- rapid correction. Therapy should be de- by investigators with a special interest in cial in patients with CHF. liberate, with the goal of correcting so- hyponatremia. The risk will be higher dium by no more than 12 mmol/L in the when the drugs are in general use. first 24 h and no more than a total of 18 Tolvaptan, lixivaptan, and satavaptan REFERENCES mmol/L in the first 48 h.21 are selective V2RA. Conivaptan is a com- Although V2RA should work in acute bined V1a/V2 blocker. A note of caution 1. Schrier RW: Pathogenesis of sodium and wa- severe hyponatremia, no published data applies when considering the use of ter retention in high-output and low-output address this assertion; all of the studies conivaptan in patients with hypervole- cardiac failure, , cirrho- sis, and pregnancy (2). N Engl J Med 319: testing V2RA in patients with hyponatre- mic hypernatremia as a result of cirrho- 1127–1134, 1988 mia were randomized, placebo-con- sis. V1aR blockade would be expected to 2. Schrier RW: Pathogenesis of sodium and wa- trolled trials that of necessity excluded cause splanchnic vasodilation. Whether ter retention in high-output and low-output this patient population that could not the resulting increase in portal venous cardiac failure, nephrotic syndrome, cirrho- ethically have been randomly assigned to pressure or, potentially, a fall in systemic sis, and pregnancy (1). N Engl J Med 319: 1065–1072, 1988 receive placebo. 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V2RA may be of benefit in selected pa- onist conivaptan, urea, or . Am J Close monitoring of serum sodium is re- tients with severe congestive symptoms, Med 110: 582–584, 2001

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