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. Author manuscript; available in PMC: 2019 Jun 1.
Published in final edited form as: Am J Kidney Dis. 2018 Feb 23;71(6):772–782. doi: 10.1053/j.ajkd.2017.12.002

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

Jesse H Morris 1, Nicole M Bohm 2, Branden D Nemecek 3, Rachel Crawford 4, Denise Kelley 5, Bhavna Bhasin 6, Paul J Nietert 7, Juan Carlos Velez 8
PMCID: PMC5970971  NIHMSID: NIHMS932594  PMID: 29478867

Abstract

Background

Tolvaptan effectively corrects hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but undesired overcorrection can occur. We hypothesized that pre-therapy 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 (sNa) ≤ 130 mEq/L at 5 US hospitals.

Predictors

Demographic and laboratory parameters.

Outcomes

Rate of change in sNa.

Measurements

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

Results

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

Limitations

Lack of uniformity in serial sNa determinations and documentation of water intake.

Conclusions

Baseline sNa and BUN values are predictive of the rapidity of hyponatremia correction following tolvaptan in SIADH. We advise caution when dosing tolvaptan in patients with both low levels of sNa and BUN.

Keywords: overcorrection, tolvaptan, hyponatremia, serum sodium, kidney function, blood urea nitrogen (BUN), syndrome of inappropriate secretion of antidiuretic hormone (SIADH), congestive heart failure (CHF), osmolality, hypouremia

Overly rapid correction of chronic hyponatremia is an undesired event that can potentially lead to irreversible neurological damage resulting from brain dehydration due to an adaptive loss of intracellular osmoles in the brain of chronically hyponatremic individuals1,2. Cases of osmotic demyelination syndrome (ODS) have been reported in association with administration of hypertonic3–6 or isotonic saline7,8. Vasopressin receptor antagonists are now available to treat hyponatremia. Conivaptan, a non-selective V1a/V2 receptor antagonist, is available via intravenous route, and tolvaptan, a selective V2 receptor antagonist, is available as oral formulation9. 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 reported10, and cases in patients concomitantly treated with tolvaptan and hypertonic saline have been submitted to the US Food and Drug Administration11. 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 in response to tolvaptan than those with hypervolemic hyponatremia12. Overcorrection of hyponatremia has been reported in SIADH patients treated with tolvaptan13–15. Further illustrating this phenomenon, reports of requirement of administration of intravenous 5% dextrose in water following treatment with a vasopressin receptor antagonist in order to revert overcorrection of SIADH-induced hyponatremia have emerged14–16.

Herein, we sought to examine whether the baseline demographic, clinical or laboratorial 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 SIADH patients revealed a significant correlation between the rise in serum sodium and the levels of glomerular filtration rate (GFR) and blood urea nitrogen (BUN)16, we hypothesized that kidney function parameters may predict the magnitude of the rise in serum sodium concentration following administration of tolvaptan in SIADH patients.

Materials and 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 to the Declaration of Helsinki and was approved by the Institutional Review Board at the Medical University of South Carolina (MUSC) 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 MUSC. The patients were identified based on documentation of administration of tolvaptan during a hospitalization from a centralized pharmacy data warehouse at each participating institution. All data was de-identified, thus the need for informed consent was waived.

Study Population

The study population comprised of hospitalized adult subjects ≥ 18 years of age treated with an initial daily dose of 15 mg of tolvaptan. Eligible patients had a diagnosis of moderate to severe hypoosmolal hyponatremia, defined as serum sodium ≤ 130 mEq/L and serum osmolality ≤ 280 mOsm/kg, caused by either SIADH (defined as euvolemic hyponatremia with inappropriate urinary concentration, i.e., urine osmolality > 100 mOsm/kg and urine sodium > 20 mEq/L15–20), or by CHF (defined as hypervolemic hyponatremia with echocardiographic evidence of systolic or diastolic dysfunction and urine sodium < 20 mEq/L for those not taking diuretics). Each patient needed documented failure to correct hyponatremia despite ≥ 24 hours of free water restriction (≤ 1 liter daily). To reduce the risk for rapid correction, fluid restriction was discontinued at the time of initiation of tolvaptan. Exclusion criteria included initial daily dose of tolvaptan different than 15 mg (i.e., 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 dextrose 5% in water (D5W) solution, 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 onwards. The purpose of censoring data from the initiation of an intervention to slow the rate of correction and onwards was not to bias the results towards 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. Patients with hypervolemic hyponatremia from CHF were allowed to be on diuretics for inclusion.

Assessments

We collected demographic and clinical data at baseline and throughout the first 24 hours following administration of tolvaptan. Laboratory parameters included: serum creatinine, blood urea nitrogen, serum uric acid, serum potassium, serum sodium and osmolality, and urine sodium and osmolality. Baseline parameters were considered those obtained within 4 hours prior to the first administered dose of tolvaptan. Kidney function was estimated using the 4-variable IDMS-traceable Modification of Diet in Renal Disease (MDRD) Study equation21 or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation22. Medical records were manually reviewed to ascertain presumed etiology of hyponatremia and documentation of prior failure to correct hyponatremia with fluid restriction.

Study Endpoints

The primary endpoint was the absolute changes 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 > 12 mEq/L after 24 hours of therapy18. A more conservative definition of rapid correction (> 8 mEq/L in 24 hours) was also examined.

Statistical Analysis

Since as many as 10 serum sodium measurements were obtained on study subjects over the 24-hour time period (at baseline, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours), linear mixed effects models (LMEMs) were used to conduct multivariable repeated measures analyses20,21. The LMEMs allowed us to determine the extent to which any demographic, clinical, or laboratorial characteristics were independently associated with change from baseline in serum sodium during the 24-hour time period. They also allowed us to compare slope estimates over time between the 2 cohorts using a 2-sample t-test framework based on the slope estimates and their standard errors. The LMEMs incorporated random subject effects with an autoregressive covariance structure to account for within-subject correlation. Backwards model selection was used to identify the factors most strongly correlated with change in serum sodium. In addition, analyses were conducted to test whether there were any significant interactions between the identified factors and time.

In separate analyses, utilizing actual unadjusted data values, we performed Spearman correlations to assess the degree of association between change in serum sodium over 24 hours and the continuous variables at baseline. For categorical baseline variables, Wilcoxon rank sum tests were used. In addition, two-way analysis of variance (ANOVA) with post-test Tukey test were run to assess the effect of baseline serum sodium and BUN in the rise in serum sodium. BUN and serum sodium were chosen because of being the top performing parameters in the LMEMs-based analyses. The 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 v9.4 (Cary, NC). P values < 0.05 were deemed significant.

Results

Patient population

A total of 128 patients were identified, of which 52 were excluded based on the 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 lower than 15 mg (either 7.5 or 3.75 mg) (Figure S1) and 1 patient (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 SIADH patients entering the analyses. Similarly, 42 patients with hypervolemic hyponatremia were identified but 3 were excluded because of diagnosis of cirrhosis, resulting in 39 patients with CHF entering the analyses (Figure 1).

Figure 1.

Figure 1

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Flow chart illustrating the stepwise process followed for the selection of cases for inclusion in the study. SIADH = syndrome of inappropriate secretion of antidiuretic hormone, CHF = congestive heart failure.

Baseline characteristics

The SIADH and CHF cohort were similar in age, race and gender distribution, but body mass index (BMI) was significantly greater among CHF subjects (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, BUN, estimated GFR (eGFR), serum osmolality and urine sodium between groups (Table 1). No difference was found in urine osmolality or serum potassium. The cause of SIADH was attributed to malignancy in half of the cases, with lung cancer accounting for half of them. The remainder of SIADH cases were either drug-induced, post-operative, idiopathic, due to pulmonary disease (pneumonia, bronchiectasis) or due to a non-malignant lesion of the central nervous system (Table 2). All CHF patients were receiving loop diuretics.

Table 1.

Baseline characteristics of the study population

SIADH1 Cohort
(n = 28)		 CHF2 Cohort
(n = 39)		 P value
Female sex 13/28 (50%) 17/39 (44%) 0.9
Race 0.9
 Caucasian 22/28 (79%) 27/39 (69%)
 African American 6/28 (21%) 12/39 (31%)
Age (years) 67.3 ± 15.3 62.0 ± 17.0 0.2
Weight, kg 74.0 ± 20.3 87.1 ± 32.0 0.06
Body Mass Index, kg/m2 25.7 ± 4.8 30.0 ± 10.0 0.04
Baseline laboratory data
 Serum sodium (mEq/L) 120.6 ± 5.2 122.3 ± 3.8 0.1
 Serum osmolality (mOsm/kg) 251.8 ± 12.4 260.8 ± 10.7 0.006
 Serum urea nitrogen (mg/dL) 12.2 ± 7.6 32.4 ± 20.1 <0.001
 Serum creatinine (mg/dL) 0.76 ± 0.37 1.35 ± 0.72 <0.001
 eGFRCKD-EPI (mL/min/1.73 m2) 120.0 ± 74.2 64.4 ± 28.1 <0.001
 eGFRMDRD (mL/min/1.73 m2) 92.8 ± 26.6 63.9 ± 25.4 <0.001
 Serum uric acid (mg/dL) 2.8 ± 2.35 NA6
 Serum potassium (mEq/L) 4.2 ± 0.6 4.2 ± 0.7 0.9
 Urine sodium (mEq/L) 88.4 ± 37.9 55.4 ± 24.17 <0.001
 Urine osmolality (mOsm/kg) 480.6 ± 130.5 426.3 ± 159.57 0. 3
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Note: categorical values given as n/N (%); continuous values as mean +/− standard deviation.

1

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

2

Congestive Heart Failure

3

GFRCKD-EPI = glomerular filtration rate estimated by the CKD-EPI creatinine equation

4

GFRMDRD = glomerular filtration rate estimated by the MDRD Study equation

5

Data available only in 10 patients

6

NA = not available (values obtained in less than 10% of the patients in the cohort).

7

Data available in 24 patients.

Table 2.

Etiology of SIADH in the study population

Cause of SIADH1 n/N (%)
 Pulmonary 9/28 (32%)
  Malignancy 7/28 (25%)
  Non-malignant 2/28 (7%)
 Other Malignancy 6/28 (21%)
 Post-operative2 3/28 (11%)
 Drug-induced3 2/28 (7%)
 Neurological / Central 2/28 (7%)
 Idiopathic 6/28 (21%)
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1

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

2

Nausea, pain

3

Citalopram, ketorolac

Response to therapy

Tolvaptan was effective in correcting hyponatremia. A more rapid and greater increase in serum sodium was observed in SIADH patients compared to CHF patients, as shown by a steeper trajectory of serum sodium rise during the first 24 hours of therapy (Figure 2a). For example, at 2 hours, the 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 at 24 hours post-initiation of tolvaptan was greater for the SIADH cohort compared to that for the CHF group: 8.3 ± 6.3 mEq/L vs. 5.0 ± 3.7 mEq/L (p = 0.03). Rapid correction of hyponatremia (> 12 mEq/L in 24 hrs.) occurred in 25% of SIADH patients versus 3% in those with CHF (p < 0.001)(Figure 2b). Applying the more conservative definition of rapid correction (> 8 mEq/L in 24 hrs.) we observed an incidence of 33% in SIADH patients compared to 5% in those with CHF (p < 0.001)(Figure 2b). No episode of ODS was documented.

Figure 2.

Figure 2

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(A) Trajectories depicting the change in serum sodium during the initial 24 hour time period following administration of tolvaptan in the SIADH (black) and 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 correction of hyponatremia based on 2 alternate definitions) and treatment efficacy in the SIADH and CHF cohorts. *p < 0.001. SIADH = syndrome of inappropriate secretion of antidiuretic hormone, CHF = congestive heart failure.

Within the SIADH group, the underlying cause of SIADH did not seem to influence the rate of correction (Figure 3). Five (17.9%) patients with SIADH received intravenous D5W as an attempt to revert a rapid correction of hyponatremia (Figure S2). One of those patients received D5W 19 hours post-administration of tolvaptan, whereas the remainder received D5W 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 or desmopressin administration were censored.

Figure 3.

Figure 3

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Unadjusted maximum rate of rise in serum Na (sodium) according to underlying cause of SIADH expressed in mEq/L/hr and registered at either the first 8, 12 or 24 hrs after administration of tolvaptan. Dashed line denotes the maximum recommended rate of 0.5 mEq/L/hr as reference. SIADH = syndrome of inappropriate secretion of antidiuretic hormone, CNS = central nervous system.

Correlations

In the SIADH cohort, age and baseline values of serum sodium, serum osmolality, BUN, serum creatinine, eGFRMDRD and eGFRCKD-EPI significantly correlated with the magnitude of the rise in serum sodium during the first 24 hours of therapy (Figure 4). Unlike those parameters, no significant correlation was found between the initial 24-hour rise in serum sodium and either body weight, BMI or baseline value of urine sodium, urine osmolality, serum uric acid or serum potassium. In the CHF cohort, baseline value of serum sodium, serum osmolality, BUN, serum creatinine and serum potassium significantly correlated with the 24 hour rise in serum sodium (Figure 5). Conversely, no significant correlation was found between the initial 24-hour rise in serum sodium and either age, body weight, BMI or baseline value of urine sodium, urine osmolality, eGFRMDRD and eGFRCKD-EPI. Of note, the strength of the correlations were greater in the SIADH cohort. In particular, the correlations (R values) for baseline serum sodium, serum osmolality and BUN 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 BUN values corresponded to lower predicted serum sodium levels at 24 hours; however, the slope reflecting this association was significantly (p<0.001) steeper in the SIADH cohort compared to CHF (Figure S3).

Figure 4.

Figure 4

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Representation of Spearman’s correlations between the magnitude of change in serum sodium (in mEq/L) after24 hours following initiation of tolvaptan and key baseline parameters in patients with SIADH. BMI = body mass index, Na = sodium, Osm = osmolality, BUN = blood urea nitrogen, Cr = creatinine, eGFR = estimated glomerular filtration rate.

Figure 5.

Figure 5

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Representation of Spearman’s correlations between the magnitude of change in serum sodium (in mEq/L) after 24 hours following initiation of tolvaptan and key baseline parameters in patients with CHF. BMI = body mass index, Na = sodium, Osm = osmolality, BUN = blood urea nitrogen, Cr = creatinine, K = potassium.

While the definition of SIADH requires preserved kidney function, 1 patient included in the SIADH group had a stable serum creatinine of 2.0 mg/dL and serum sodium was persistently within the reference range. Then, the patient developed euvolemic hyponatremia (with urine sodium of 81 mEq/L and urine Osm 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, the correlations for baseline serum sodium or BUN remained strong, −0.79 and −0.73, respectively.

Predictors of rapid correction

The ability of baseline clinical and laboratorial parameters to predict the entire variation of serum sodium levels during the first 24 hours following administration of tolvaptan was assessed by a multivariate linear mixed effects model 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 BUN (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 BUN (Table 3). When the SIADH model was applied to the CHF cohort, none of the model parameters were significant (all p-values >0.05), indicating that the SIADH model is a poor fit to the CHF cohort.

Table 3.

Results of the multivariate linear mixed effects model predicting the magnitude of change in serum sodium during the 24 hours after initiation of tolvaptan therapy.

Effect Beta Estimate* Beta Standard Error P value
Final SIADH cohort model
 Baseline serum sodium − 0.59 0.13 <0.00 1
 Time (h) 1.09 0.24 <0.001
 Time2 (h2) −0.02 0.01 0.007
 Baseline SUN 0.08 0.13 0.6
 Time × Baseline SUN −0.02 0.01 0.01
Final CHF cohort model
 Time (h) 0.17 0.04 <0.0 01
 Baseline SUN −0.07 0.03 0.01
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*

The beta estimate reflects the expected increase/decrease in serum sodium associated with a 1-unit change in the effect of interest

1

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

2

Serum Urea Nitrogen

3

Congestive Heart Failure

Because baseline serum sodium and baseline BUN were the strongest predictors of the rapidity of correction of hyponatremia in the SIADH cohort, these parameters were assessed against model-generated absolute change in serum sodium over 24 hours. The changes were estimated at the 25th and 75th percentiles of the baseline serum sodium (118.5 and 124.5 mEq/L, respectively) and BUN (6.0 and 16.5 mg/dL, respectively) revealing greater rise in serum sodium for those with both values at the 25th percentile (Figure 6a). We then divided the SIADH cohort into 4 groups depending on being above or below the median for baseline serum sodium and BUN. Four patients were excluded for this analysis due to lack of a 24-hour data point. Patients with low baseline serum sodium (≤ 121 mEq/L) and low baseline BUN (≤ 10 mg/dL) exhibited a significantly greater increase in serum sodium in 24 hours following tolvaptan administration, p < 0.05 (Figure 6b). Similar analyses were performed for the CHF cohort (Figure 7).

Figure 6.

Figure 6

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Relationship between the magnitude of the initial 24-hour rise in serum sodium (Na) and the baseline values of serum Na (sNa, in mEq/L) and blood urea nitrogen (BUN, in mg/dL) in the SIADH cohort (n = 28). (a) The heights of the bars represent the mixed model-based adjusted estimated mean 24-hour change in serum Na (sNa), and the error bars reflect the standard error of the estimates. The changes were estimated at the 25th and 75th percentiles of the baseline sNa (25th percentile = 118.5 mEq/L, 75th percentile = 124.5 mEq/L) and BUN (25th percentile = 6.0 mg/dL, 75th percentile = 16.5 mg/dL). (b) Baseline parameters were categorized according to the median as being above or below the median (n = 24, missing 24-hour serum Na in 4 patients) and unadjusted values are displayed. P value for two-way analysis of variance (ANOVA) was < 0.0001. Post-test Tukey was performed to assess differences between groups; # p < 0.05; ˆ p < 0.01; * p < 0.0001.

Figure 7.

Figure 7

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Relationship between the magnitude of the initial 24-hour rise in serum sodium (Na) and the baseline values of serum Na (sNa, in mEq/L) and blood urea nitrogen (BUN, in mg/dL) in the CHF cohort (n = 39). (a) The heights of the bars represent the mixed model-based adjusted estimated mean 24-hour change in serum Na (sNa), and the error bars reflect the standard error of the estimates. The changes were estimated at the 25th and 75th percentiles of the baseline sNa (25th percentile = 120 mEq/L, 75th percentile = 124 mEq/L) and BUN (25th percentile = 14 mg/dL, 75th percentile = 46 mg/dL). (b) Baseline parameters were categorized according to the median as being above or below the median (n = 29, missing 24-hour serum Na in 10 patients), and unadjusted values are displayed. P value for two-way analysis of variance (ANOVA) was < 0.05. Post-test 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 a lower serum sodium concentration and a lower BUN value prior to initiation of therapy. While the finding of a lower serum sodium predicting larger increases in serum sodium is fairly intuitive and logical and has been previously reported14,15,25,26, the observation of a low baseline BUN 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 BUN, those with both lower serum sodium and lower BUN carried the higher risk for overly rapid correction. Thus, seems prudent to recommend caution when prescribing tolvaptan in SIADH patients presenting with both severe hyponatremia (i.e., serum sodium ≤ 121 mEq/L) and low BUN (i.e., ≤ 10 mg/dL). Notably, among patients with both baseline serum sodium < 120 mEq/L and baseline BUN < 6 mEq/L, 5 out of 6 had an initial 24-hour rise > 12 mEq/L, and 6 out of 6 had an initial 24-hr rise > 8 mEq/L. In such patient population, a lower starting dose of 3.75 – 7.5 mg might be sufficient to adequately correct the hyponatremic state, with a lesser risk for rapid correction13,27–29.

Low level of BUN concentration or hypouremia is a well-recognized laboratory feature of SIADH17,30–32. Typically, the value of BUN falls around 3 – 10 mg/dL. However, some patients may present with BUN between 10 and 30 mg/dL17. Older subjects may also present with higher BUN (29). Although the diagnostic utility of low BUN is established33, it had not been linked to prognosticate response to therapy. In agreement with this study, we previously reported a correlation of low BUN with the magnitude of rise in serum sodium in a cohort of 18 SIADH patients treated with conivaptan16. Furthermore, a recent study also found a correlation between rise in serum sodium and BUN during treatment with tolvaptan in a mixed group of critically ill patients15. However, our study provides evidence of a numerically stronger correlation between low BUN and the magnitude of the rise in serum sodium in SIADH patients with moderate to severe hyponatremia treated with tolvaptan and demonstrates predictability of low baseline BUN when added to baseline serum sodium.

Twenty-five percent of patients in the SIADH cohort increased their serum sodium concentration by more than 12 mEq/L during the first 24 hours of therapy and 33% did so by more than 8 mEq/L within the same time period. This rate of overcorrection resembles the observed incidence of rapid correction previously reported in SIADH patients treated with conivaptan16. Other studies in tolvaptan-treated SIADH patients reported only around 6 – 11% incidence of rapid correction of hyponatremia15,20,34. In addition, the average 24-hour rise in serum sodium of 8.3 mEq/L found in our study has been previously observed in SIADH subjects treated with vasopressin receptor antagonists35,36, whereas lesser average increases in serum sodium have been reported elsewhere12,37. The greater mean magnitude of rise in serum sodium 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), the mean baseline serum sodium was approximately 9 mEq/L above the mean baseline serum sodium in our SIADH cohort. In agreement with our findings, other reports have described markedly steep improvements in serum sodium upon administration of tolvaptan in SIADH patients14–16,27,28. Those brisk responses underscore the exquisite efficacy of tolvaptan in SIADH. Thus, careful identification of patients with SIADH that could exhibit a brisk response to tolvaptan is clinically important.

SIADH leads to a state of increased total body water35. As a result, there is an adaptive release of atrial natriuretic peptide that leads to an increase in GFR through opposition to mesangial cell contraction38–40. Following the increase in volemia and GFR, a reduction in proximal tubular reabsorption ensues35,40–41. Consequently, early nephron reabsorption of molecules like sodium, urea and uric acid is significantly decreased in SIADH17,42–44. These phenomena are thought to contribute to the high urinary sodium, low BUN and low serum uric acid levels 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 elucidated45,46. Collectively, it is not entirely clear why SIADH patients with low BUN display an exquisite response to administration of tolvaptan. A very low BUN may reflect a greater degree of inappropriate secretion of AVP, thereby leading to greater relative ability of blockade of V2 receptors to impact tubular water handling. One study found a correlation between plasma AVP concentration and the magnitude of rise in serum sodium14. Alternatively, the 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 BUN concentration.

As observed elsewhere, the magnitude of the rise in serum sodium was greater for SIADH patients than for those with CHF12. Our model did not offer a strong predictive index in CHF patients. Interestingly, a recent study suggested that higher BUN may correlate with a greater rise in serum sodium, opposite to our findings26. In contrast, a previous study also showed a correlation between lower BUN and greater rise in serum sodium in SIADH16. 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, the average kidney function of the SIADH patients was significantly greater than that of the CHF patients. As shown in Figures 4 and 5, 8 of the 39 patients with CHF and 1 of the 28 patients with SIADH had a serum creatinine greater than 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, elevated BUN 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 prior to 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 of intake of water in all the 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, thereby increasing the risk of 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 reflects actual medical practice. Furthermore, pooling data from 5 different hospitals in 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, the baseline characteristics of our cohort are fairly representative of the SIADH population, notably the inclusion of lung cancer as the etiology in 25% of the patients47. While BUN performed better than serum creatinine 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 the dosing of tolvaptan for patients with SIADH who present with severe hyponatremia and concomitant very low BUN. 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 doses of tolvaptan to adequately treat hyponatremia with a lesser risk of a rapid correction should be formally evaluated.

Supplementary Material

1

Figure S1: Change in serum sodium over time in 6 SIADH patients treated with a tolvaptan dose < 15 mg.

2

Figure S2: 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.

3

Figure S3: Model-predicted serum sodium–adjusted value at 24 h after initiation of tolvaptan at various levels of baseline SUN for the SIADH and CHF cohorts.

Acknowledgments

P.J.N.’s time on this project was funded by the National Institutes of Health (National Center for Advancing Translational Science grant number UL1TR001450, and National Institute of General Medical Sciences grant number U54-GM104941). The funders did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Authors’ Contributions: Research idea and study design: JHM, NMB, JCV; data acquisition: NMB, BDN, RC, DK, BB; data analysis/interpretation: JHM, JCV; statistical analysis: PJN; supervision or mentorship: JCV. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Financial Disclosure: J.C.V is a member of the speaker bureau for Otsuka Pharmaceuticals and has participated as advisory board panelist and a member of a speaker bureau for Mallinckrodt Pharmaceuticals. The remaining authors declare that they have no other relevant financial interests.

Prior Presentation: Portions of this work were presented as a poster during the proceedings of Kidney Week, November 15–20, 2016, Chicago, Illinois, U.S.A.

Peer Review: Received April 26, 2017. Evaluated by two external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

Figure S1: Change in serum sodium over time in 6 SIADH patients treated with a tolvaptan dose < 15 mg.

NIHMS932594-supplement-1.pdf (53.7KB, pdf)
2

Figure S2: 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.

NIHMS932594-supplement-2.pdf (52.1KB, pdf)
3

Figure S3: Model-predicted serum sodium–adjusted value at 24 h after initiation of tolvaptan at various levels of baseline SUN for the SIADH and CHF cohorts.

NIHMS932594-supplement-3.pdf (56.8KB, pdf)

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