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American Journal of Kidney Diseases

Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan

Published:February 22, 2018DOI:https://doi.org/10.1053/j.ajkd.2017.12.002

      Background

      Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pretherapy parameters can predict the rapidity of response to tolvaptan in SIADH.

      Study Design

      Multicenter historical cohort study.

      Setting & Participants

      Adults with SIADH or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration ≤ 130 mEq/L at 5 US hospitals.

      Predictors

      Demographic and laboratory parameters.

      Outcomes

      Rate of change in serum sodium concentration.

      Measurements

      Spearman correlations, analysis of variance, and multivariable linear mixed-effects models.

      Results

      28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P < 0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r = −0.78; P < 0.001), serum urea nitrogen concentration (SUN; r = −0.76; P < 0.001), and estimated glomerular filtration rate (r = 0.58; P = 0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (≤121 mEq/L) and low baseline SUN concentrations (≤10 mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24-hour increase of 15.4 mEq/L) than the other 3 categories (P < 0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time.

      Limitations

      Lack of uniformity in serial serum sodium concentration determinations and documentation of water intake.

      Conclusions

      Baseline serum sodium and SUN values are predictive of the rapidity of hyponatremia correction following tolvaptan use in SIADH. We advise caution when dosing tolvaptan in patients with both low serum sodium and SUN concentrations.

      Index Words

      Editorial, p. 763
      Overly rapid correction of chronic hyponatremia is an undesired event that can potentially lead to irreversible neurologic damage resulting from brain dehydration due to an adaptive loss of intracellular osmoles in the brain of chronically hyponatremic individuals.
      • Norenberg M.D.
      Central pontine myelinolysis: historical and mechanistic considerations.
      • Sterns R.H.
      • Riggs J.E.
      • Schocet S.S.
      Osmotic demyelination syndrome following correction of hyponatremia.
      Cases of osmotic demyelination syndrome (ODS) have been reported in association with administration of hypertonic
      • Brunner J.E.
      • Redmond J.M.
      • Haggar A.M.
      • Kruger D.F.
      • Elias S.B.
      Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: a prospective magnetic resonance imaging study.
      • Kleinschmidt-Demasters B.
      • Norenberg M.
      Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.
      • Norenberg M.D.
      • Papendick R.E.
      Chronicity of hyponatremia as a factor in experimental myelinolysis.
      • Verbalis J.G.
      • Martinez A.J.
      Neurological and neuropathological sequelae of correction of chronic hyponatremia.
      or isotonic saline solution.
      • Corona G.
      • Simonetti L.
      • Giuliani C.
      • Sforza A.
      • Peri A.
      A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum.
      • Ellis S.J.
      Extrapontine myelinolysis after correction of chronic hyponatraemia with isotonic saline.
      Vasopressin receptor antagonists are now available to treat hyponatremia. Conivaptan, a nonselective V1a/V2 receptor antagonist, is available by intravenous route, and tolvaptan, a selective V2 receptor antagonist, is available as an oral formulation.
      • Jovanovich A.J.
      • Berl T.
      Where vaptans do and do not fit in the treatment of hyponatremia.
      Although no cases of ODS have been directly and solely attributed to a vasopressin receptor antagonist, a case of ODS with concomitant use of tolvaptan and diuretics was recently reported,
      • Malhotra I.
      • Gopinath S.
      • Janga K.C.
      • Greenberg S.
      • Sharma S.K.
      • Tarkovsky R.
      Unpredictable nature of tolvaptan in treatment of hypervolemic hyponatremia: case review on role of vaptans.
      and cases in patients concomitantly treated with tolvaptan and hypertonic saline solution have been submitted to the US Food and Drug Administration.

      US Food & Drug Administration, US Department of Health and Human Services. Samsca (tolvaptan) tablets. September 28, 2011. www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022275s003ltr.pdf. Accessed March 14, 2017.

      Therefore, it is critical to recognize patients at increased risk for rapid correction of hyponatremia when they are treated with tolvaptan.
      Cases of euvolemic hyponatremia caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) exhibit a more rapid and larger increase in serum sodium concentration in response to tolvaptan than those with hypervolemic hyponatremia.
      • Schrier R.W.
      • Gross P.
      • Gheorghiade M.
      • et al.
      Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
      Overcorrection of hyponatremia has been reported in patients with SIADH treated with tolvaptan.
      • Torres A.C.
      • Wickham E.P.
      • Biskobing D.M.
      Tolvaptan for the management of syndrome of inappropriate antidiuretic hormone secretion: lessons learned in titration of dose.
      • Vaghasiya R.P.
      • DeVita M.V.
      • Michelis M.F.
      Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      Further illustrating this phenomenon, reports of requirement of administration of intravenous 5% dextrose in water (D5W) solution following treatment with a vasopressin receptor antagonist to revert overcorrection of SIADH-induced hyponatremia have emerged.
      • Vaghasiya R.P.
      • DeVita M.V.
      • Michelis M.F.
      Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      We sought to examine whether baseline demographic, clinical, or laboratory characteristics of treated patients could influence the magnitude of the response to tolvaptan in SIADH. We also analyzed a cohort of patients with congestive heart failure (CHF) treated with tolvaptan for comparison. Because our previous report in conivaptan-treated patients with SIADH revealed a significant correlation between the increase in serum sodium concentration and glomerular filtration rate (GFR) and serum urea nitrogen (SUN) values,
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      we hypothesized that kidney function parameters may predict the magnitude of the increase in serum sodium concentration following tolvaptan administration in patients with SIADH.

      Methods

      Study Design

      We conducted a multicenter retrospective review of medical records to identify patients treated with oral tolvaptan between 2010 and 2015. The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board at the Medical University of South Carolina Hospital, as well as each of the other participating sites: Wake Forest Baptist Medical Center, Beaufort Memorial Hospital, University of Florida Health Jacksonville, and Duquesne University Hospital. Data were collected by each hospital biomedical informatics center and condensed from the 5 sites for analysis centrally at Medical University of South Carolina. Patients were identified based on documentation of tolvaptan administration during a hospitalization from a centralized pharmacy data warehouse at each participating institution. All data were deidentified; thus, the need for informed consent was waived.

      Study Population

      The study population consisted of hospitalized adult patients 18 years or older treated with an initial daily dose of 15 mg of tolvaptan. Eligible patients had a diagnosis of moderate to severe hypo-osmolal hyponatremia, defined as serum sodium concentration ≤ 130 mEq/L and serum osmolality ≤ 280 mOsm/kg, caused by either SIADH (defined as euvolemic hyponatremia with inappropriate urinary concentration, ie, urine osmolality > 100 mOsm/kg and urine sodium excretion > 20 mEq/L
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      • Decaux G.
      • Musch W.
      Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone.
      • Rose B.D.
      • Post T.W.
      Clinical Physiology of Acid-Base and Electrolyte Disorders.
      • Segal M.S.
      • Wingo C.S.
      Disorders of water balance.
      • Verbalis J.G.
      • Adler S.
      • Schrier R.W.
      Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion.
      ), or by CHF (defined as hypervolemic hyponatremia with echocardiographic evidence of systolic or diastolic dysfunction and urine sodium excretion < 20 mEq/L for those not taking diuretics). Each patient needed documented failure to correct hyponatremia despite 24 or more hours of free water restriction (≤1 L/d). To reduce the risk for rapid correction, fluid restriction was discontinued at the time of initiation of tolvaptan therapy. Exclusion criteria included initial daily dose of tolvaptan different than 15 mg (ie, 3.75, 7.5, or 30 mg); concomitant treatment with desmopressin, diuretics, demeclocycline, hypertonic or normal saline solution, other sodium/water-based therapies such as D5W, sodium phosphate, sodium chloride, or sodium bicarbonate; or inability to conclusively diagnose SIADH or CHF based on insufficient or inconsistent data. For patients who were started on water- or sodium-based therapies after the initial tolvaptan administration, data were censored from the beginning of the administration of the water- or sodium-based therapy and onward. The purpose of censoring data from the initiation of an intervention to slow the rate of correction and onward was not to bias results toward overcorrection, but rather to specifically analyze the sole effect of tolvaptan on the rate of correction and not the effect of combined therapies, such as tolvaptan plus intravenous D5W solution. Patients with hypervolemic hyponatremia from CHF were allowed to be on diuretic therapy for inclusion.

      Assessments

      We collected demographic and clinical data at baseline and throughout the first 24 hours following tolvaptan administration. Laboratory parameters included serum creatinine, SUN, serum uric acid, serum potassium, serum sodium and osmolality, and urine sodium and osmolality. Baseline parameters were considered those obtained within 4 hours before the first administered dose of tolvaptan. Kidney function was estimated using the 4-variable isotope-dilution mass spectrometry–traceable Modification of Diet in Renal Disease (MDRD) Study equation
      • Levey A.S.
      • Coresh J.
      • Greene T.
      • et al.
      Using standardized serum creatinine values in the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate.
      or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      Medical records were manually reviewed to ascertain the presumed cause of hyponatremia and documentation of prior failure to correct hyponatremia with fluid restriction.

      Study End Points

      The primary end point was absolute change in serum sodium concentration during the first 24 hours following the first dose of tolvaptan. Rapid correction of hyponatremia was defined as an increase in serum sodium concentration > 12 mEq/L after 24 hours of therapy.
      • Rose B.D.
      • Post T.W.
      Clinical Physiology of Acid-Base and Electrolyte Disorders.
      A more conservative definition of rapid correction (>8 mEq/L in 24 hours) was also examined.

      Statistical Analysis

      Because as many as 10 serum sodium measurements were obtained for study participants during the 24-hour period (at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours), linear mixed-effects models (LMEMs) were used to conduct multivariable repeated-measures analyses.
      • Fitzmaurice G.M.
      • Laird N.M.
      • Ware J.H.
      Applied Longitudinal Analysis.
      • Nakagawa S.
      • Schielzeth H.
      A general and simple method for obtaining R2 from generalized linear mixed-effects models.
      The LMEMs allowed us to determine the extent to which any demographic, clinical, or laboratory characteristics were independently associated with change from baseline in serum sodium concentration during the 24-hour period. They also allowed us to compare slope estimates over time between the 2 cohorts using a 2-sample t test framework based on slope estimates and their standard errors. LMEMs incorporated random participant effects with an autoregressive covariance structure to account for within-participant correlation. Backwards model selection was used to identify the factors most strongly correlated with change in serum sodium concentration. In addition, analyses were conducted to test whether there were significant interactions between the identified factors and time.
      In separate analyses, using actual unadjusted data values, we performed Spearman correlations to assess the degree of association between change in serum sodium concentration over 24 hours and the continuous variables at baseline. For categorical baseline variables, Wilcoxon rank sum tests were used. In addition, 2-way analysis of variance (ANOVA) with posttest Tukey test were run to assess the effect of baseline serum sodium and SUN concentration on the increase in serum sodium concentration. SUN and serum sodium were chosen because of being the top performing parameters in the LMEM-based analyses. ANOVA tests were intended to provide more clinically discernable output. Analyses were conducted separately on the SIADH and CHF cohorts.
      All analyses were performed using SAS, version 9.4 (SAS Institute). P < 0.05 was deemed significant.

      Results

      Patient Population

      A total of 128 patients were identified, of whom 52 were excluded based on criteria detailed in Methods. In particular, 8 patients were excluded because they did not receive a 15-mg initial dose of tolvaptan; 7 (6 SIADH and 1 CHF) were treated with a tolvaptan dose < 15 mg (either 7.5 or 3.75 mg; Fig S1), and 1 patient (with CHF) was treated with an initial 30-mg dose. After initial exclusions, we identified 34 patients with euvolemic hyponatremia from SIADH, but 6 were excluded from the analysis because of concomitant sodium-based treatment, resulting in 28 patients with SIADH entering the analyses. Similarly, 42 patients with hypervolemic hyponatremia were identified, but 3 were excluded because of a diagnosis of cirrhosis, resulting in 39 patients with CHF entering the analyses (Fig 1).
      Figure thumbnail gr1
      Figure 1Flow chart illustrates the stepwise process followed for the selection of cases for inclusion in the study. Abbreviations: CHF, congestive heart failure; IV, intravenous; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; sNa, serum sodium.

      Baseline Characteristics

      The SIADH and CHF cohorts were similar in age, race, and sex distribution, but body mass index was significantly greater among patients with CHF (25.7 and 30.0 kg/m2, respectively; P = 0.04). In terms of baseline laboratory data, serum sodium concentrations were comparable between groups (120.6 and 122.3 mEq/L for SIADH and CHF, respectively). As expected for each medical condition, there were differences in serum creatinine, SUN, estimated GFR (eGFR), serum osmolality, and urine sodium values between groups (Table 1). No difference was found in urine osmolality or serum potassium values. The cause of SIADH was attributed to malignancy in half the cases, with lung cancer accounting for half of them. The rest of the SIADH cases were either drug induced, postoperative, idiopathic, due to pulmonary disease (pneumonia or bronchiectasis), or due to a nonmalignant lesion of the central nervous system (Table 2). All patients with CHF were receiving loop diuretics.
      Table 1Baseline Characteristics of the Study Population
      SIADH Cohort (n = 28)CHF Cohort (n = 39)P
      Female sex13/28 (50%)17/39 (44%)0.9
      Race0.9
       White22/28 (79%)27/39 (69%)
       African American6/28 (21%)12/39 (31%)
      Age, y67.3 ± 15.362.0 ± 17.00.2
      Weight, kg74.0 ± 20.387.1 ± 32.00.06
      Body mass index, kg/m225.7 ± 4.830.0 ± 10.00.04
      Baseline laboratory data
       Serum sodium, mEq/L120.6 ± 5.2122.3 ± 3.80.1
       Serum osmolality, mOsm/kg251.8 ± 12.4260.8 ± 10.70.006
       Serum urea nitrogen, mg/dL12.2 ± 7.632.4 ± 20.1<0.001
       Serum creatinine, mg/dL0.76 ± 0.371.35 ± 0.72<0.001
       eGFRCKD-EPI, mL/min/1.73 m2120.0 ± 74.264.4 ± 28.1<0.001
       eGFRMDRD, mL/min/1.73 m292.8 ± 26.663.9 ± 25.4<0.001
       Serum uric acid, mg/dL2.8 ± 2.3
      Data available for only 10 patients.
      NA
       Serum potassium, mEq/L4.2 ± 0.64.2 ± 0.70.9
       Urine sodium, mEq/L88.4 ± 37.955.4 ± 24.1
      Data available for 24 patients.
      <0.001
       Urine osmolality, mOsm/kg480.6 ± 130.5426.3 ± 159.5
      Data available for 24 patients.
      0.3
      Note: Categorical values given as n/N (%); continuous values, as mean ± standard deviation.
      Abbreviations and definitions: CHF, congestive heart failure; eGFRCKD-EPI, glomerular filtration rate estimated using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation; eGFRMDRD, glomerular filtration rate estimated using the Modification of Diet in Renal Disease Study equation; NA, not available (values obtained in <10% of patients in the cohort); SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
      a Data available for only 10 patients.
      b Data available for 24 patients.
      Table 2Cause of SIADH in the Study Population
      Cause of SIADHn/N (%)
      Pulmonary9/28 (32%)
       Malignancy7/28 (25%)
       Nonmalignant2/28 (7%)
      Other malignancy6/28 (21%)
      Postoperative
      Nausea, pain.
      3/28 (11%)
      Drug induced
      Citalopram, ketorolac.
      2/28 (7%)
      Neurologic/central2/28 (7%)
      Idiopathic6/28 (21%)
      Abbreviation: SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
      a Nausea, pain.
      b Citalopram, ketorolac.

      Response to Therapy

      Tolvaptan was effective in correcting hyponatremia. A more rapid and greater increase in serum sodium concentration was observed in patients with SIADH compared with patients with CHF, as shown by a steeper trajectory of serum sodium concentration increase during the first 24 hours of therapy (Fig 2A). For example, at 2 hours, LMEM slope estimates ± standard errors were 0.799 ± 0.203 and 0.174 ± 0.035 in the SIADH and CHF cohorts, respectively, a difference that was highly significant (P < 0.001). The mean increase in serum sodium concentration at 24 hours after initiation of tolvaptan therapy was greater for the SIADH cohort compared to the CHF group: 8.3 ± 6.3 mEq/L versus 5.0 ± 3.7 mEq/L (P = 0.03). Rapid correction of hyponatremia (>12 mEq/L in 24 hours) occurred in 25% of patients with SIADH versus 3% of those with CHF (P < 0.001; Fig 2B). Applying the more conservative definition of rapid correction (>8 mEq/L in 24 hours), we observed an incidence of 33% in patients with SIADH compared to 5% in those with CHF (P < 0.001; Fig 2B). No episode of ODS was documented.
      Figure thumbnail gr2
      Figure 2(A) Trajectories depict change in serum sodium concentration during the initial 24-hour period following tolvaptan administration in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH; black) and congestive heart failure (CHF; gray) cohorts. Dashed curves show trends based on the linear mixed-effects model adjusted predicted means in serum sodium measurements, whereas circular data markers show unadjusted mean values at each time point. Size of the marker is proportional to the sample size at each time point. ¥P < 0.0001 between slopes. (B) Treatment safety (unadjusted rates of rapid hyponatremia correction based on 2 alternate definitions) and treatment efficacy in the SIADH and CHF cohorts. ∗P < 0.001.
      Within the SIADH group, the underlying cause of SIADH did not seem to influence the rate of correction (Fig 3). Five (17.9%) patients with SIADH received intravenous D5W solution as an attempt to revert a rapid correction of hyponatremia (Fig S2). One of those patients received D5W solution 19 hours after tolvaptan administration, whereas the rest received D5W solution after the 24-hour mark. One patient also received 1 dose of oral desmopressin at the 38-hour mark. As per our methods, all serum sodium values obtained subsequent to either D5W solution or desmopressin administration were censored.
      Figure thumbnail gr3
      Figure 3Unadjusted maximum rate of increase in serum sodium concentration according to underlying cause of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) expressed in mEq/L/h and registered at either the first 8, 12, or 24 hours after tolvaptan administration. Dashed line denotes the maximum recommended rate of 0.5 mEq/L/h as reference. Abbreviation: CNS, central nervous system.

      Correlations

      In the SIADH cohort, age and baseline values for serum sodium, serum osmolality, SUN, serum creatinine, eGFRMDRD, and eGFRCKD-EPI significantly correlated with the magnitude of increase in serum sodium concentration during the first 24 hours of therapy (Fig 4). Unlike those parameters, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either body weight, body mass index, or baseline urine sodium, urine osmolality, serum uric acid, or serum potassium value. In the CHF cohort, baseline serum sodium, serum osmolality, SUN, serum creatinine, and serum potassium values significantly correlated with the 24-hour increase in serum sodium concentration (Fig 5). Conversely, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either age, body weight, body mass index, or baseline urine sodium, urine osmolality, eGFRMDRD, and eGFRCKD-EPI values. Of note, the strength of the correlations was greater in the SIADH cohort. In particular, correlations (R values) for baseline serum sodium, serum osmolality, and SUN were −0.78, −0.77, and −0.76, respectively, whereas the strongest R value for the CHF cohort was −0.53 for baseline serum osmolality. For both cohorts, higher baseline SUN concentrations corresponded to lower predicted serum sodium concentrations at 24 hours; however, the slope reflecting this association was significantly (P < 0.001) steeper in the SIADH cohort compared to CHF (Fig S3).
      Figure thumbnail gr4
      Figure 4Representation of Spearman correlations between the magnitude of change in serum sodium concentration (in mEq/L) after 24 hours following tolvaptan therapy initiation and key baseline parameters in patients with syndrome of inappropriate secretion of antidiuretic hormone. Abbreviations: BMI, body mass index; Cr, creatinine; eGFR, estimated glomerular filtration rate; Osm, osmolality; SUN, serum urea nitrogen.
      Figure thumbnail gr5
      Figure 5Representation of Spearman correlations between the magnitude of change in serum sodium concentration (in mEq/L) after 24 hours following initiation of tolvaptan therapy and key baseline parameters in patients with congestive heart failure. Abbreviations: BMI, body mass index; Cr, creatinine; Osm, osmolality; SUN, serum urea nitrogen.
      Although the definition of SIADH requires preserved kidney function, 1 patient included in the SIADH group had a stable serum creatinine concentration of 2.0 mg/dL and serum sodium concentration was persistently within the reference range. Then the patient developed euvolemic hyponatremia (with urine sodium excretion of 81 mEq/L and urine osmolality of 299 mOsm/kg) along with lung metastasis secondary to renal cell carcinoma without a change in kidney function, strongly suggesting that hyponatremia was due to lung metastasis–induced SIADH. Upon removal of that patient from the analysis, correlations for baseline serum sodium or SUN concentration remained strong at −0.79 and −0.73, respectively.

      Predictors of Rapid Correction

      The ability of baseline clinical and laboratory parameters to predict the entire variation in serum sodium concentrations during the first 24 hours following tolvaptan administration was assessed by a multivariate LMEM taking into account all serum sodium values extracted throughout the first 24 hours. In the SIADH cohort, potentially significant main effects of serum sodium (P < 0.001) and SUN concentrations (P = 0.06) were identified as a result of the backwards selection process. The final resulting model that included these main effects and their interactions with time are presented in Table 3. For the CHF cohort, the final resulting model incorporated only linear effects of time and baseline SUN concentration (Table 3). When the SIADH model was applied to the CHF cohort, none of the model parameters were significant (all P > 0.05), indicating that the SIADH model is a poor fit to the CHF cohort.
      Table 3Results of the Multivariate Linear Mixed Effects Model Predicting the Magnitude of Change in Serum Sodium During the 24 Hours After Tolvaptan Therapy Initiation
      Effectβ Estimate
      The β estimate reflects the expected increase/decrease in serum sodium concentration associated with a 1-unit change in the effect of interest.
      β Standard ErrorP
      Final SIADH cohort model
       Baseline serum sodium−0.590.13<0.001
       Time (h)1.090.24<0.001
       Time2 (h2)−0.020.010.007
       Baseline SUN0.080.130.6
       Time × baseline SUN−0.020.010.01
      Final CHF cohort model
       Time (h)0.170.04<0.001
       Baseline SUN−0.070.030.01
      Abbreviations: CHF, congestive heart failure; SIADH, syndrome of inappropriate secretion of antidiuretic hormone; SUN, serum urea nitrogen.
      a The β estimate reflects the expected increase/decrease in serum sodium concentration associated with a 1-unit change in the effect of interest.
      Because baseline serum sodium and baseline SUN concentrations were the strongest predictors of the rapidity of hyponatremia correction in the SIADH cohort, these parameters were assessed against model-generated absolute change in serum sodium concentration over 24 hours. Changes were estimated at the 25th and 75th percentiles of the baseline serum sodium (118.5 and 124.5 mEq/L, respectively) and SUN concentrations (6.0 and 16.5 mg/dL, respectively), revealing a greater increase in serum sodium concentration for those with both values at the 25th percentile (Fig 6A). We then divided the SIADH cohort into 4 groups depending on being higher or lower than the median for baseline serum sodium and SUN concentrations. Four patients were excluded from this analysis due to lack of a 24-hour data point. Patients with low baseline serum sodium (≤121 mEq/L) and low baseline SUN concentrations (≤10 mg/dL) exhibited a significantly greater increase in serum sodium concentrations in 24 hours following tolvaptan administration, P < 0.05 (Fig 6B). Similar analyses were performed for the CHF cohort (Fig 7).
      Figure thumbnail gr6
      Figure 6Relationship between the magnitude of the initial 24-hour increase in serum sodium (sNa) concentration and baseline sNa concentration (in mEq/L) and serum urea nitrogen (SUN; in mg/dL) in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) cohort (n = 28). (A) The height of the bars represents the mixed-model-based–adjusted estimated mean 24-hour change in sNa concentration, and error bars reflect the standard error of the estimates. Changes were estimated at the 25th and 75th percentiles of baseline sNa (25th percentile = 118.5 mEq/L, 75th percentile = 124.5 mEq/L) and SUN concentrations (25th percentile = 6.0 mg/dL, 75th percentile = 16.5 mg/dL). (B) Baseline parameters were categorized according to the median as being higher or lower than the median (n = 24, missing 24-hour sNa in 4 patients) and unadjusted values are displayed. P value for 2-way analysis of variance was <0.0001. Posttest Tukey was performed to assess differences between groups; #P < 0.05; ˆP < 0.01; ∗P < 0.0001.
      Figure thumbnail gr7
      Figure 7Relationship between the magnitude of the initial 24-hour increase in serum sodium (sNa) concentration and baseline sNa values (in mEq/L) and serum urea nitrogen (SUN; in mg/dL) in the congestive heart failure (CHF) cohort (n = 39). (A) The height of the bars represents the mixed-model–based adjusted estimated mean 24-hour change in sNa concentration, and error bars reflect the standard error of the estimates. Changes were estimated at the 25th and 75th percentiles of baseline sNa (25th percentile = 120 mEq/L, 75th percentile = 124 mEq/L) and SUN concentrations (25th percentile = 14 mg/dL, 75th percentile = 46 mg/dL). (B) Baseline parameters were categorized according to the median as being higher or lower than the median (n = 29, missing 24-hour sNa in 10 patients), and unadjusted values are displayed. P value for 2-way analysis of variance was <0.05. Posttest Tukey was performed to assess differences between groups. #P < 0.05.

      Discussion

      This study demonstrates that the rapidity of correction of hyponatremia due to SIADH with tolvaptan is significantly associated with lower serum sodium and lower SUN concentrations before initiation of therapy. Although the finding of a lower serum sodium concentration predicting larger increases in serum sodium concentrations is fairly intuitive and logical and has been previously reported,
      • Vaghasiya R.P.
      • DeVita M.V.
      • Michelis M.F.
      Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      • Gheorghiade M.
      • Konstam M.A.
      • Burnett Jr., J.C.
      • et al.
      Short term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
      • Hirai K.
      • Shimomura T.
      • Moriwaki H.
      • et al.
      Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment.
      the observation of a low baseline SUN concentration as predictor of rapid correction may represent a valuable novel tool for identification of patients at risk for overcorrection. When our cohort was divided according to baseline serum sodium and baseline SUN concentrations, those with both lower serum sodium and lower SUN concentrations carried higher risk for overly rapid correction. Thus, it seems prudent to recommend caution when prescribing tolvaptan in patients with SIADH presenting with both severe hyponatremia (ie, serum sodium ≤ 121 mEq/L) and low SUN concentrations (ie, ≤10 mg/dL). Notably, among patients with both baseline serum sodium concentration < 120 mEq/L and baseline SUN concentration < 6 mEq/L, 5 of 6 had an initial 24-hour increase > 12 mEq/L, and 6 of 6 had an initial 24-hour increase > 8 mEq/L. In such a patient population, a lower starting dose of 3.75 to 7.5 mg might be sufficient to adequately correct the hyponatremic state, with lesser risk for rapid correction.
      • Torres A.C.
      • Wickham E.P.
      • Biskobing D.M.
      Tolvaptan for the management of syndrome of inappropriate antidiuretic hormone secretion: lessons learned in titration of dose.
      • Kenz S.
      • Haas C.S.
      • Werth S.C.
      • Bohnet S.
      • Brabant G.
      High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (SIADH).
      • Tzoulis P.
      • Waung J.A.
      • Bagkeris E.
      • et al.
      Real-life experience of tolvaptan use in the treatment of severe hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion.
      • Sanchez-Sobrino P.
      • Fernandez Catalina P.
      • Lorenzo Solar M.
      • Rego Iraeta A.
      [Lower doses of tolvaptan in hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion.].
      Low SUN concentration or hypouremia is a well-recognized laboratory feature of SIADH.
      • Decaux G.
      • Musch W.
      Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone.
      • Decaux G.
      • Genette F.
      • Mockel J.
      Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone.
      • Musch W.
      • Decaux G.
      Utility and limitations of biochemical parameters in the evaluation of hyponatremia in the elderly.
      • Musch W.
      • Verfaillie L.
      • Decaux G.
      Age related increase in plasma urea level and decrease in fractional urea excretion: clinical application in SIADH.
      Typically, SUN concentration decreases around 3 to 10 mg/dL. However, some patients may present with SUN concentrations between 10 and 30 mg/dL.
      • Decaux G.
      • Musch W.
      Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone.
      Older patients may also present with higher SUN concentrations.
      • Sanchez-Sobrino P.
      • Fernandez Catalina P.
      • Lorenzo Solar M.
      • Rego Iraeta A.
      [Lower doses of tolvaptan in hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion.].
      Although the diagnostic utility of a low SUN concentration is established,
      • Irazabal M.V.
      • Torres V.E.
      • Hogan M.C.
      • et al.
      Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease.
      it had not been linked to prognosticate response to therapy. In agreement with this study, we previously reported a correlation of low SUN concentration with the magnitude of increase in serum sodium concentration in a cohort of 18 patients with SIADH treated with conivaptan.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      Furthermore, a recent study also found a correlation between increase in serum sodium and SUN concentrations during treatment with tolvaptan in a mixed group of critically ill patients.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      However, our study provides evidence of a numerically stronger correlation between low SUN concentration and the magnitude of the increase in serum sodium concentration in patients with SIADH with moderate to severe hyponatremia treated with tolvaptan and demonstrates the predictability of low baseline SUN concentration when added to baseline serum sodium concentration.
      Twenty-five percent of patients in the SIADH cohort increased their serum sodium concentrations by >12 mEq/L during the first 24 hours of therapy and 33% did so by >8 mEq/L within the same period. This rate of overcorrection resembles the observed incidence of rapid correction previously reported in patients with SIADH treated with conivaptan.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      Other studies in tolvaptan-treated patients with SIADH reported only around a 6% to 11% incidence of rapid correction of hyponatremia.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      • Verbalis J.G.
      • Adler S.
      • Schrier R.W.
      Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion.
      • Greenberg A.
      • Verbalis J.G.
      • Amin A.N.
      • et al.
      Current treatment practice and outcomes. Report of the hyponatremia registry.
      In addition, the average 24-hour increase in serum sodium concentration of 8.3 mEq/L found in our study has been previously observed in patients with SIADH treated with vasopressin receptor antagonists,
      • Metzger B.L.
      • DeVita M.V.
      • Michelis M.F.
      Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia.
      • Zeltser D.
      • Rosansky S.
      • van Rensburg H.
      • Verbalis J.G.
      • Smith N.
      Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.
      whereas lesser average increases in serum sodium concentrations have been reported elsewhere.
      • Schrier R.W.
      • Gross P.
      • Gheorghiade M.
      • et al.
      Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
      • Verbalis J.G.
      Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis.
      The greater mean magnitude of increase in serum sodium concentration and higher rate of rapid correction of hyponatremia in our SIADH cohort likely corresponds to the lower mean baseline serum sodium concentration in our patients. In both SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2), mean baseline serum sodium concentration was ∼9 mEq/L above the mean baseline serum sodium concentration in our SIADH cohort. In agreement with our findings, other reports have described markedly steep improvements in serum sodium concentrations upon tolvaptan administration in patients with SIADH.
      • Vaghasiya R.P.
      • DeVita M.V.
      • Michelis M.F.
      Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
      • Umbrello M.
      • Mantovani E.S.
      • Formenti P.
      Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      • Kenz S.
      • Haas C.S.
      • Werth S.C.
      • Bohnet S.
      • Brabant G.
      High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (SIADH).
      • Tzoulis P.
      • Waung J.A.
      • Bagkeris E.
      • et al.
      Real-life experience of tolvaptan use in the treatment of severe hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion.
      Those brisk responses underscore the exquisite efficacy of tolvaptan in SIADH. Thus, careful identification of patients with SIADH who could exhibit a brisk response to tolvaptan is clinically important.
      SIADH leads to a state of increased total-body water.
      • Metzger B.L.
      • DeVita M.V.
      • Michelis M.F.
      Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia.
      As a result, there is an adaptive release of atrial natriuretic peptide that leads to an increase in GFR through opposition to mesangial cell contraction.
      • Appel R.G.
      • Wang J.
      • Simonson M.S.
      • Dunn M.J.
      A mechanism by which atrial natriuretic factor mediates its glomerular actions.
      • Cogan M.G.
      Atrial natriuretic factor can increase renal solute excretion primarily by raising glomerular filtration.
      • Cogan E.
      • Debieve M.F.
      • Pepersack T.
      • Abramow M.
      Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis.
      Following the increase in volemia and GFR, a reduction in proximal tubular reabsorption ensues.
      • Metzger B.L.
      • DeVita M.V.
      • Michelis M.F.
      Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia.
      • Cogan E.
      • Debieve M.F.
      • Pepersack T.
      • Abramow M.
      Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis.
      • Mathisen O.
      • Monclair T.
      • Kiil F.
      Factors limiting renal proximal tubular reabsorption at high glomerular filtration rate.
      Consequently, early nephron reabsorption of molecules such sodium, urea, and uric acid is significantly decreased in SIADH.
      • Decaux G.
      • Musch W.
      Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone.
      • Beck L.H.
      Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.
      • Prospert F.
      • Soupart A.
      • Brimioulle S.
      • Decaux G.
      Evidence of defective tubular reabsorption and normal secretion of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone.
      • Decaux G.
      • Prospert F.
      • Cauchie P.
      • Soupart A.
      Dissociation between uric acid and urea clearances in the syndrome of inappropriate secretion of antidiuretic hormone related to salt excretion.
      These phenomena are thought to contribute to the high urinary sodium, low SUN, and low serum uric acid concentrations observed in SIADH, although other unknown mechanisms could also be present. It is also known that direct effect of arginine vasopressin (AVP) on urea transporters could contribute to the tubular handling of urea, but a specific role of those transporters in SIADH has not been clearly elucidated.
      • Sands J.M.
      Renal urea transporters.
      • Hoffert J.D.
      • Pisitkun T.
      • Saeed F.
      • Wilson J.L.
      • Knepper M.A.
      Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct.
      Collectively, it is not entirely clear why patients with SIADH with low SUN concentrations display an exquisite response to tolvaptan administration. A very low SUN concentration may reflect a greater degree of inappropriate AVP secretion, thereby leading to greater relative ability of V2 receptor blockade to affect tubular water handling. One study found a correlation between plasma AVP concentration and the magnitude of increase in serum sodium concentration.
      • Vaghasiya R.P.
      • DeVita M.V.
      • Michelis M.F.
      Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
      Alternatively, delivery of tolvaptan to its site of action at the basolateral membrane of the medullary collecting duct might be more effective in patients with a greater increase in total-body water and GFR and lower SUN concentration.
      As observed elsewhere, the magnitude of the increase in serum sodium concentration was greater for patients with SIADH than for those with CHF.
      • Schrier R.W.
      • Gross P.
      • Gheorghiade M.
      • et al.
      Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
      Our model did not offer a strong predictive index in patients with CHF. Interestingly, a recent study suggested that higher SUN concentration may correlate with a greater increase in serum sodium concentration, opposite to our findings.
      • Hirai K.
      • Shimomura T.
      • Moriwaki H.
      • et al.
      Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment.
      In contrast, a previous study also showed a correlation between lower SUN concentration and greater increase in serum sodium concentration in SIADH.
      • Velez J.C.
      • Dopson S.J.
      • Sanders D.S.
      • Delay T.A.
      • Arthur J.M.
      Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
      The remarkable differences in the pathogenesis of hyponatremia, effective circulatory volume, and distal delivery of water to the collecting duct between SIADH and CHF are likely to account for the difference in rapidity of response to tolvaptan. As seen in Table 1, average kidney function of patients with SIADH was significantly greater than that of patients with CHF. As shown in Figures 4 and 5, a total of 8 of 39 patients with CHF and 1 of 28 patients with SIADH had serum creatinine concentrations > 1.5 mg/dL. Thus, difference in kidney function may account for the observed difference in therapeutic response between the SIADH and CHF groups. Further, an elevated SUN concentration in CHF is a surrogate for avid proximal tubular reabsorption and low GFR, either of which would impair free water excretion in response to tolvaptan.
      Our study is not without limitations. Although fluid restriction was lifted before initiation of tolvaptan therapy in all patients, implementation of physician’s orders in a hospital setting, outside of a rigorous clinical trial, is subject to errors or delays. Due to the retrospective nature of our study, we were unable to accurately collect data for water intake in all patients in our cohort. Therefore, we cannot rule out the possibility that some patients remained under some degree of fluid restriction for several hours after the initiation of tolvaptan therapy, thereby increasing the risk for overcorrection of hyponatremia. Because we collected data from 5 centers, there was lack of uniformity in the number and frequency of serum sodium determinations. However, our data reflect actual medical practice. Furthermore, pooling data from 5 different hospitals in the United States increases the generalizability of our results. Therefore, we regard our findings as valuable and applicable to current practice. In addition, our sample size is relatively small. Thus, our data may not be fully representative of demographics and in-hospital practice patterns from other institutions. Nonetheless, baseline characteristics of our cohort are fairly representative of the SIADH population, notably the inclusion of lung cancer as the cause in 25% of patients.
      • Thajudeen B.
      • Salahudeen A.K.
      Role of tolvaptan in the management of hyponatremia in patients with lung and other cancers: current data and future perspectives.
      Although SUN concentration performed better than serum creatinine concentration and eGFR in our model, a larger sample size could reveal equal or superior predictability of standard measures of kidney function.
      In summary, we call for attention to tolvaptan dosing for patients with SIADH who present with severe hyponatremia and concomitant very low SUN concentrations. Our findings suggest that those patients can respond to an initial dose of 15 mg of tolvaptan very briskly and carry a risk for rapid correction of hyponatremia. The ability of lower initial tolvaptan doses to adequately treat hyponatremia with a lesser risk for rapid correction should be formally evaluated.

      Supplementary Material

      • Supplementary Figure S2 (PDF)

        Change in serum sodium over time in 5 SIADH patients who received either IV dextrose 5% water or desmopressin as an attempt to arrest a rapid rise in serum sodium.

      References

        • Norenberg M.D.
        Central pontine myelinolysis: historical and mechanistic considerations.
        Metab Brain Dis. 2010; 25: 97-106
        • Sterns R.H.
        • Riggs J.E.
        • Schocet S.S.
        Osmotic demyelination syndrome following correction of hyponatremia.
        N Engl J Med. 1986; 314: 1535-1542
        • Brunner J.E.
        • Redmond J.M.
        • Haggar A.M.
        • Kruger D.F.
        • Elias S.B.
        Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: a prospective magnetic resonance imaging study.
        Ann Neurol. 1990; 27: 61-66
        • Kleinschmidt-Demasters B.
        • Norenberg M.
        Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis.
        Science. 1981; 211: 1068-1080
        • Norenberg M.D.
        • Papendick R.E.
        Chronicity of hyponatremia as a factor in experimental myelinolysis.
        Ann Neurol. 1984; 15: 544-547
        • Verbalis J.G.
        • Martinez A.J.
        Neurological and neuropathological sequelae of correction of chronic hyponatremia.
        Kidney Int. 1991; 39: 1274-1282
        • Corona G.
        • Simonetti L.
        • Giuliani C.
        • Sforza A.
        • Peri A.
        A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum.
        BMC Endocr Disord. 2014; 14
        • Ellis S.J.
        Extrapontine myelinolysis after correction of chronic hyponatraemia with isotonic saline.
        Br J Clin Pract. 1995; 49: 49-50
        • Jovanovich A.J.
        • Berl T.
        Where vaptans do and do not fit in the treatment of hyponatremia.
        Kidney Int. 2013; 83: 563-567
        • Malhotra I.
        • Gopinath S.
        • Janga K.C.
        • Greenberg S.
        • Sharma S.K.
        • Tarkovsky R.
        Unpredictable nature of tolvaptan in treatment of hypervolemic hyponatremia: case review on role of vaptans.
        Case Rep Endocrinol. 2014; https://doi.org/10.1155/2014/807054
      1. US Food & Drug Administration, US Department of Health and Human Services. Samsca (tolvaptan) tablets. September 28, 2011. www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/022275s003ltr.pdf. Accessed March 14, 2017.

        • Schrier R.W.
        • Gross P.
        • Gheorghiade M.
        • et al.
        Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
        N Engl J Med. 2006; 355: 2099-2112
        • Torres A.C.
        • Wickham E.P.
        • Biskobing D.M.
        Tolvaptan for the management of syndrome of inappropriate antidiuretic hormone secretion: lessons learned in titration of dose.
        Endocr Pract. 2011; 17: 97-100
        • Vaghasiya R.P.
        • DeVita M.V.
        • Michelis M.F.
        Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.
        Int Urol Nephrol. 2012; 44: 865-871
        • Umbrello M.
        • Mantovani E.S.
        • Formenti P.
        Tolvaptan for hyponatremia with preserved sodium pool in critically ill patients.
        Ann Intensive Care. 2016; 6: 1-9
        • Velez J.C.
        • Dopson S.J.
        • Sanders D.S.
        • Delay T.A.
        • Arthur J.M.
        Intravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience.
        Nephrol Dial Transplant. 2010; 25: 1524-1531
        • Decaux G.
        • Musch W.
        Clinical laboratory evaluation of the syndrome of inappropriate secretion of antidiuretic hormone.
        Clin J Am Soc Nephrol. 2008; 3: 1175-1184
        • Rose B.D.
        • Post T.W.
        Clinical Physiology of Acid-Base and Electrolyte Disorders.
        5th ed. McGraw-Hill, New York, NY2001: 703-709
        • Segal M.S.
        • Wingo C.S.
        Disorders of water balance.
        in: Wilcox C.S. Tischer C.C. Handbook of Nephrology & Hypertension. 6th ed. Lippincott Williams & Wilkins, Philadelphia, PA2009: 109
        • Verbalis J.G.
        • Adler S.
        • Schrier R.W.
        Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion.
        Eur J Endocrinol. 2011; 164: 725-732
        • Levey A.S.
        • Coresh J.
        • Greene T.
        • et al.
        Using standardized serum creatinine values in the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate.
        Ann Intern Med. 2006; 145: 247-254
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Fitzmaurice G.M.
        • Laird N.M.
        • Ware J.H.
        Applied Longitudinal Analysis.
        2nd ed. John Wiley & Sons, Inc, New York, NY2004
        • Nakagawa S.
        • Schielzeth H.
        A general and simple method for obtaining R2 from generalized linear mixed-effects models.
        Methods Ecol Evol. 2013; 4: 133-142
        • Gheorghiade M.
        • Konstam M.A.
        • Burnett Jr., J.C.
        • et al.
        Short term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials.
        JAMA. 2007; 297: 1332-1343
        • Hirai K.
        • Shimomura T.
        • Moriwaki H.
        • et al.
        Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment.
        Eur J Clin Pharmacol. 2016; 72: 1177-1183
        • Kenz S.
        • Haas C.S.
        • Werth S.C.
        • Bohnet S.
        • Brabant G.
        High sensitivity to tolvaptan in paraneoplastic syndrome of inappropriate ADH secretion (SIADH).
        Ann Oncol. 2011; 22: 2696
        • Tzoulis P.
        • Waung J.A.
        • Bagkeris E.
        • et al.
        Real-life experience of tolvaptan use in the treatment of severe hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion.
        Clin Endocrinol. 2016; 84: 620-626
        • Sanchez-Sobrino P.
        • Fernandez Catalina P.
        • Lorenzo Solar M.
        • Rego Iraeta A.
        [Lower doses of tolvaptan in hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion.].
        Med Clin (Barc). 2015; 145 ([Article in Spanish]): 138-139
        • Decaux G.
        • Genette F.
        • Mockel J.
        Hypouremia in the syndrome of inappropriate secretion of antidiuretic hormone.
        Ann Intern Med. 1980; 93: 716-717
        • Musch W.
        • Decaux G.
        Utility and limitations of biochemical parameters in the evaluation of hyponatremia in the elderly.
        Int Urol Nephrol. 2001; 32: 475-493
        • Musch W.
        • Verfaillie L.
        • Decaux G.
        Age related increase in plasma urea level and decrease in fractional urea excretion: clinical application in SIADH.
        Clin J Am Soc Nephrol. 2006; 1: 909-914
        • Irazabal M.V.
        • Torres V.E.
        • Hogan M.C.
        • et al.
        Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease.
        Kidney Int. 2011; 80: 295-301
        • Greenberg A.
        • Verbalis J.G.
        • Amin A.N.
        • et al.
        Current treatment practice and outcomes. Report of the hyponatremia registry.
        Kidney Int. 2015; 88: 167-177
        • Metzger B.L.
        • DeVita M.V.
        • Michelis M.F.
        Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia.
        Int Urol Nephrol. 2008; 40: 725-730
        • Zeltser D.
        • Rosansky S.
        • van Rensburg H.
        • Verbalis J.G.
        • Smith N.
        Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia.
        Am J Nephrol. 2007; 27: 447-457
        • Verbalis J.G.
        Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis.
        Am J Physiol. 1994; 267: 1617-1625
        • Appel R.G.
        • Wang J.
        • Simonson M.S.
        • Dunn M.J.
        A mechanism by which atrial natriuretic factor mediates its glomerular actions.
        Am J Physiol. 1986; 251: 1036-1042
        • Cogan M.G.
        Atrial natriuretic factor can increase renal solute excretion primarily by raising glomerular filtration.
        Am J Physiol. 1986; 250: 710-714
        • Cogan E.
        • Debieve M.F.
        • Pepersack T.
        • Abramow M.
        Natriuresis and atrial natriuretic factor secretion during inappropriate antidiuresis.
        Am J Med. 1988; 84: 409-418
        • Mathisen O.
        • Monclair T.
        • Kiil F.
        Factors limiting renal proximal tubular reabsorption at high glomerular filtration rate.
        Scand J Clin Lab Invest. 1978; 38: 573-579
        • Beck L.H.
        Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone.
        N Engl J Med. 1979; 301: 528-530
        • Prospert F.
        • Soupart A.
        • Brimioulle S.
        • Decaux G.
        Evidence of defective tubular reabsorption and normal secretion of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone.
        Nephron. 1993; 64: 189-192
        • Decaux G.
        • Prospert F.
        • Cauchie P.
        • Soupart A.
        Dissociation between uric acid and urea clearances in the syndrome of inappropriate secretion of antidiuretic hormone related to salt excretion.
        Clin Sci (Lond). 1990; 78: 451-455
        • Sands J.M.
        Renal urea transporters.
        Curr Opin Nephrol Hypertens. 2004; 13: 525-532
        • Hoffert J.D.
        • Pisitkun T.
        • Saeed F.
        • Wilson J.L.
        • Knepper M.A.
        Global analysis of the effects of the V2 receptor antagonist satavaptan on protein phosphorylation in collecting duct.
        Am J Physiol Renal Physiol. 2014; 306: 410-421
        • Thajudeen B.
        • Salahudeen A.K.
        Role of tolvaptan in the management of hyponatremia in patients with lung and other cancers: current data and future perspectives.
        Cancer Manag Res. 2016; 22: 105-114

      Linked Article

      • Tolvaptan for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone: Is the Dose Too High?
        American Journal of Kidney DiseasesVol. 71Issue 6
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          What could be more logical than treating hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) with an inhibitor of antidiuretic hormone? After many years of searching for this magic bullet, 2 vasopressin antagonists (vaptans), tolvaptan and conivaptan, became available for use in the United States.1 However, a decade after their approval by the US Food and Drug Administration, they are still used infrequently in hospitalized patients.
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