Editorial

What Is the Role of Vaptans in Routine ClinicalNephrology?

Daniel G. Bichet

Clin J Am Soc Nephrol 7: 700–703, 2012. doi: 10.2215/CJN.02990312

Hyponatremia is the most common electrolyte dis-order encountered in hospitalized patients, and bothcommunity- and hospital-associated hyponatremia areassociated with in-hospital mortality and heightened re-source consumption (1). As described byWald et al. (1) intheir evaluation of close to 100,000 hospitalizations duringtheir 7-year study, it is not knownwhether hyponatremiais a marker of the severity of the underlying condition(s)or a direct contributor to the adverse outcomes observed.With the advent of vasopressin V2 receptor antagonists(termed vaptans) to treat hyponatremic patients, this im-portant clinical question could be tested. The Study of As-cending Levels of Tolvaptan in Hyponatremia (SALT)studies have demonstrated that tolvaptan, an oral vaso-pressin V2 receptor antagonist, was effective in increasingserum sodium concentration at day 4 and day 30 (2). Asa follow-up, 111 patients with hyponatremia receivedtolvaptan for a mean of 701 days, with maintenance ofthe increased serum sodium (3). These important studiesincludedmildly symptomatic patients, but patientswith aserum sodium ,120 mmol/L in association with neuro-logic impairment were excluded. Vaptans are expensivedrugs and their use in symptomatic patients has not beenassessed. Vaptans seem to be as safe as urea according toSoupart et al. (7) in the present issue ofCJASN, and urea isnot expensive at all. The authors are suggesting that bothvaptans and urea should be tested to decrease adverseoutcomes in symptomatic and nonseverely symptom-atic hyponatremic patients. Soupart et al. and Decauxet al. from twodifferent hospitals in Belgiumhave beenpromoting the use of oral urea to treat patients withhyponatremia (4–7).

Urea Is a Nonspecific Treatment forHyponatremia: It Will “Drag” Excess Water inUrine because of Simple Math (Box 1)

If you assume a maximally diluted urine of ;60mOsm/kg and a solute excretion of an adult maleof 900 mOsm/d, then V 5 900/60 5 15 L/d. A urine

osmolality of 60 corresponds to a maximal ability todilute urine. In this condition, the antidiuretic hor-mone, vasopressin, is suppressed and the vasopressinV2 receptor on the basolateral side of the principal cellsof the collecting duct is not activated; therefore, there isno aquaporin 2 expressed on the luminal side to trans-fer water transcellularly and to be retrieved to the renalvasa recta. By contrast, if vasopressin is not suppressedby hypotonicity as occurs in the syndrome of inap-propriate antidiuretic hormone secretion (syndromeof inappropriate antidiuretic hormone secretion[SIADH]), heart failure, and cirrhosis, urinary osmo-lality is higher than plasma osmolality and you havenow to think quantitatively about the physiology ofurine concentration and the effect of oral urea: (Boxes2 and 3).You can also use different numbers: if urinary osmo-

lality is fixed at 800 mOsm/kg and if daily intake is 700mmol 1 500 mmol of urea, the urinary daily volumeswill be 1200/800 5 1.5 L.

Urea Is Not Expensive and Has a Bitter Taste“Medicinal urea” 30 g 3 1 month will be less than

$50 here in Montreal, and this low cost is mainly relatednot to urea per se (,$0.50/30 g) but to the 15 g/30 gdoses that have to be weighed and placed into smallpackages. This could be simplified by prescribing tea-spoonfuls of a larger bottle like nephrologists do forKayexalate and the chronic treatment of hyperkalemia.Urea has “an unpleasant taste” (7). I decided to test itmyself. I mixed 15 g in 120 ml of cold orange juice: itdoes not smell of anything but the bitterness is strong. Iused the full 300 ml orange juice bottle to dilute it com-pletely to decrease the bitterness; if I would have beenon water restriction, these 300 ml would have decreasedmy allowed daily water intake. Urea is included inthe list of bitter compounds reviewed by Meyerhofet al. (8).Taste receptor cells are assembled into taste buds

that are distributed across different papillae of thetongue and palate epithelium (9). Chandrashekar et al.(9) provided localization of these bitter taste recep-tors: circumvallate papillae at the very back of thetongue and foliate papillae at the posterior lateraledge of the tongue contain thousands for the formerand hundreds for the latter taste buds. While ingest-ing urea, I had the distinct perception of bitterness in

Department ofMedicine andPhysiology, Hopital duSacre-Coeur deMontreal, Universitede Montreal,Montreal, QuebecCanada

Correspondence: Dr.Daniel G. Bichet,Hopital du Sacre-Coeur, Centre deRecherches, 5400Gouin Ouest,Montreal, Quebec H4J1C5, Canada. E-mail:daniel.bichet@umontreal.ca

www.cjasn.org Vol 7 May, 2012700 Copyright © 2012 by the American Society of Nephrology

the back lateral part of my tongue; I read the article byChandrashekar et al. afterward.

The Vaptans to Treat Euvolemic orHypervolemic HyponatremiaVaptans are nonpeptide vasopressin V2 receptor antag-

onists, and they look like vasopressin; therefore, they areable to bind reversibly to the vasopressin V2 receptor andto induce a conformation change of the vasopressin V2receptor that will not allow its interaction with theG-binding protein. This “blocked” conformation will notallow GDP release from Gs-a: the receptor–G protein com-plex will not be activated. As a consequence, there will beno activation of adenylyl cyclase, no generation of cyclic-AMP, and no insertion of AQP2 water channels in the lu-minal membrane of the principal cells of the collectingducts (Figure 1). We suppose that it is working like this,but a seven transmembrane receptor image in embracewith a G protein and the interface of the two Gs-a subdo-mains forming the nucleotide binding pocket has only beenobtained recently for the b-adrenergic receptor (10) and notfor the vasopressin V2 receptor. This mechanism of actionindicates that the vaptans are specific treatment for hypo-natremic states with high vasopressin plasma levels includ-ing patients with the syndrome of inappropriateantidiuretic hormone secretion (SIADH: euvolemic hypo-natremia), liver cirrhosis with ascites and edema, and se-vere heart failure (hypervolemic hyponatremia). Conivaptanfor intravenous use and tolvaptan for oral administrationare now on the market for the treatment of euvolemic(Europe) or euvolemic and hypervolemic (United States);in Canada, only tovaptan is on the market for both euvole-mic and hypervolemic hyponatremic states. It is an expen-sive medication, US $244/d, extensively commented on byGross et al., long time warriors in the hyponatremia field

(11). In a recent study based on SALT-1 and-2 trials, tolvaptanuse was found to be associated with a shorter hospital staycompared with placebo among patients with SIADH: whenthe drug cost for 4 days of inpatient tolvaptan therapy wasincluded, tolvaptan was associated with a mean hospitalcost reduction of $694 per admission in the United States(12). The meta-analysis of 15 randomized controlled trialscomparing vaptans with placebo, no treatment, and/orfluid restriction clearly showed an improvement or nor-malization of serum sodium without major side effects(13). There were six trials for tolvaptan, four trials forsatavaptan, three trials for conivaptan, and two trials forlixivaptan. In the tolvaptan trial, plasma sodium increasedby 4.8–3.5 mEq/L at day 4 and from 7.4 to 4.2 mEq/L atday 30 for all patients with a plasma sodium ,135 mEq/L(213 patients on tolvaptan and 203 patients on placebo)(2). These patients had little or no neurologic symptomsattributed to hyponatremia, and the important group ofpatients with a serum sodium ,120 mEq/Lwith neuro-logic impairment was excluded from these studies be-cause it was felt that they would not benefit from thetrial if they were to enter the placebo group. In all thepatients tested there was no report of osmotic demyelinationsyndrome (14). A strategy for the controlled correction ofprofound hyponatremia has been proposed by Sternset al. (15) to help seasoned nephrologists treating “doubledigit hyponatremia” and afraid of iatrogenic injury fromovercorrection. Sterns et al. underlined the high risk of un-intentional overcorrection if the cause of water retention isreversible and provided teaching points to treat profoundhyponatremia and correction goals for severe chronic hypo-natremia; I am using his teaching points and correction goalsand I am trying to enforce them not only to medical studentsbut also to nurses when I am writing chart orders related tothe treatment of real patients, especially late in the eveningin the emergency room or in the intensive care unit.

Clin J Am Soc Nephrol 7: 700–703, May, 2012 Editorial: Vaptans in Clinical Nephrology, Bichet 701

Vaptan Therapy Is Ineffective but Urea Is Effective inthe Vasopressin-Independent Form of InappropriateAntidiuresis caused by Constitutive Activation ofVasopressin V2 ReceptorsLoss-of function mutations in the type 2 vasopressin

receptor (AVPR2) lead to nephrogenic diabetes insipidus,with affected patients producing large amounts of diluteurine (16). Conversely, gain-of-function mutations inAVPR2 lead to nephrogenic syndrome of inappropriateantidiuresis (NSIAD), the mirror image of nephrogenic di-abetes insipidus, and affected patients produce persis-tently concentrated urine despite low or absent levels ofvasopressin. In all previously described NSIAD cases,substitution of arginine-137 by either a cysteine or a

leucine (R137C/L) induces the spontaneous activation ofthe vasopressin V2 receptor that could not be reversed byvaptans (17). The inability of vaptans to decrease urineosmolality in NSIAD might be related to the constitutivedesensitization and endocytosis of the receptor bearingthe mutations R137L/C. Huang et al. (18) have reportedthat, after administration of 30%–50% oral urea solutions,serum sodium could be normalized in these children.

Vaptans for 1 Year followed by Urea for 2 Years in12 Patients with SIADHSoupart et al. (7) demonstrated in this issue of CJASN

that hyponatremia increased from 125 to 135 mEq/L under

Figure 1. | Schematic representation of the effect of the vaptans to block vasopressin increased water permeability in the principal cells of thecollecting duct. (A) AVP is bound to the V2 receptor (a G-protein–coupled receptor [GPCR]) on the basolateral membrane. The basic process ofGPCR signaling consists of three steps: (1) a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu; (2)a heterotrimeric G-protein with a, b, and g subunits that is inactive when reversibly bound to GDP but active when bound to GTP (when AVPbinds to the GPCR, it causes a conformational change in the receptor that allows it to act as a guanine nucleotide exchange factor); and (3) theG-protein’s a subunit, together with the boundGTP, can dissociate from the b and g subunits to stimulate adenylyl cyclase and generate cAMP.The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic transmembrane domains separated by a largecytoplasmic loop and terminates in a large intracellular tail. The dimeric structure (C1 andC2) of the catalytic domains is represented. Conversion ofATP to cAMP takes place at the dimer interface. Two aspartate residues (in C1) coordinate two metal cofactors (Mg21 or Mn21 represented here astwo small black circles), which enable the catalytic function of the enzyme (21). Adenosine is shown as an open circle and the three phosphategroups (ATP) are shown as smaller open circles. Protein kinase A (PKA) is the target of the generated cAMP. The binding of cAMP to the regulatorysubunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) asshown here are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase anchoring protein. The local concentrationand distribution of the cAMP gradient is limited by phosphodiesterases (PDEs). Cytoplasmic vesicles carrying the water channels (represented ashomotetrameric complexes) are fused to the luminalmembrane in response toAVP, thereby increasing thewater permeabilityof thismembrane. Thedissociationof theA-kinase anchoringprotein from the endocytic vesicle is not represented.Microtubules andactin filaments are necessary for vesiclemovement toward themembrane.WhenAVP is not available, or the receptor blockedbyavaptan,AQP2water channels are retrievedbyanendocyticprocess, and water permeability returns to its original low rate. Aquaporin-3 (AQP3) and aquaporin-4 (AQP4) water channels are expressed con-stitutively at the basolateral membrane. (B) Schematic representation of the vasopressin V2 receptorwith seven transmembrane helices (H1–H7)withbinding sites forAVPand aV1antagonist,OPC1268,V2 antagonists havemore extensive, competitive, anddeeper transmembrane binding.Modifiedwith permission from Macion-Dazard et al. (22). Satavaptan and tolvaptan are inverse agonists: in pharmacological terms, an inverse agonist is anagent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. A prerequisite for an inverseagonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level activity in the absence of any ligand. An agonistincreases the activity of a receptor above its basal level while an inverse agonist decreases the activity below the basal level.

702 Clinical Journal of the American Society of Nephrology

tolvaptan or satavaptan. After discontinuation of vaptans,hyponatremia recurred in the 12 participants, but urea treat-ment improved plasma sodium to the same 135 mEq/Lvalue. One patient on vaptan stopped his medication be-cause of excessive thirst, and one episode of hypernatremia(155 mEq/L) was observed in an 89-year-old man withpneumonia. The authors have had considerable previousexperience with acute (4) and long-term urea treatment(19), but this is the first observation of long-term adminis-tration of vaptans followed by urea. Given the similar effi-cacy and tolerance, Soupart et al. propose that prospectivetrials evaluating morbidity, mortality, and quality of lifeshould be done.

Hyponatremia Could Be Better Recognized,Evaluated, and TreatedI hope that all the clinical evaluations, pathophysiolog-

ical evaluations, and treatment of hyponatremic cases thathave been found to be suboptimal in large hospital settings(20) could benefit from the clinical and therapeutic ap-proaches provided by the vaptan studies: we know thatlarge prospective randomized studies to evaluate vaptans/urea/dehydration in neurologically symptomatic andasymptomatic patients are difficult to do and to finance,but we can now propose specific or urea treatment foreuvolemic and hypervolemic hyponatremic patients know-ing their limitations and the absolute necessity to treat severeneurologic symptoms associated with hyponatremia (withhypertonic saline) and to fear overtreatment and osmoticdemyelination.

DisclosuresD.G.B. has received honoraria from Otsuka Pharmaceuticals and

PepsiCo Inc.; grant/research support fromOtsukaPharmaceuticals;and paid expenses from Otsuka Pharmaceuticals and PepsiCo Inc.D.G.B. has consulted for Otsuka Pharmaceuticals and PepsiCo Inc.and is amemberof theSpeakersBureau forOtsukaPharmaceuticals.

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3. Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG,Ouyang J, Czerwiec FS; SALTWATER Investigators: Oral tolvaptanis safe and effective in chronichyponatremia. J AmSocNephrol21:705–712, 2010

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Published online ahead of print. Publication date available at www.cjasn.org.

See related article, “Efficacy and Tolerance of Urea Compared withVaptans for Long-Term Treatment of Patients with SIADH,” onpages 742–747.

Clin J Am Soc Nephrol 7: 700–703, May, 2012 Editorial: Vaptans in Clinical Nephrology, Bichet 703