In the last couple of months there has been an outpouring of new hyponatremia data and resources. The first I want to discuss is data on the speed of sodium correction with tolvaptan.

Juan Carlos lead a group who looked at the speed of sodium rise with tolvaptan. The primary endpoint was the change in sodium at 24-hours in patients given 15 mg of tolvaptan.

All patients had to have failed fluid restriction to be included in the analysis.

For the purpose of the study, SIADH was defined as:

• serum sodium concentration ≤ 130 mEq/L
• serum osmolality ≤ 280mOsm/kg
• urine osmolality > 100 mOsm/ kg
• urine sodium excretion > 20 mEq/L

CHF induced hyponatremia was defined as:

• serum sodium concentration ≤ 130 mEq/L
• serum osmolality ≤ 280mOsm/kg
• echo- cardiographic evidence of systolic or diastolic dysfunction
• urine sodium excretion < 20 mEq/L (if not on diuretics)

All patients had to start with a tolvaptan dose of 15 mg.

The only other concurrent therapy allowed was fluid restriction. Patients who subsequently were started on D5 water, diuretics or salt tablets, had their data censored at the point where the additional therapies were added.

Diuretics are listed as an exclusion criteria but the CHF group were allowed to use them (an exclusion to the exclusion criteria). This is not well described in the methods.

After restricting the patients by their pre-specified exclusion criteria they had 28 patients with SIADH and 39 with CHF.

Table 1.

Remember how the urine sodium is supposed to be low in heart failure. Take a look at the elevated level found in this study. Conclusion: diuretics work. Also take a look at the low Bun and low uric acid in the SIADH group. These are really helpful in my experience at differentiating the cause in tricky cases.

Tolvaptan was much more effective in SIADH with an average change sodium of 0.80 mmol/L/hr versus 0.17 mmol/L/hr in CHF

Sodium went up by more than 12 mEq/L in 25% of patients with SIADH and 3% of patients with CHF.

Using linear mixed-effects models to conduct multivariable repeated-measures analysis the investigators found:

• In SIADH a lower serum sodium (<120 mmol/L) and lower serum urea (<6 mg/dL) were risk factors for rapid correction of sodium.
• In CHF, only serum urea was a risk factor for rapid correction

This is what these variables look like when mixed together (data for SIADH patients)

The discussion includes this tidbit where the investigators try to explain why there is a more dramatic response in SIADH than in CHF.

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.

I don’t find this argument convincing because kidney function was tested to see if it predicted response and though eGFR did correlate with response to tolvaptan in SIADH, it was not an independent predictor of response and was not a predictor of response at all in CHF.

In the SIADH cohort, age and baseline values for serum sodium, serum osmolality, SUN, serum creatinine, MDRD, and CKD-EPI significantly correlated with the magnitude of increase in serum sodium concentration during the first 24 hours of therapy. 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. 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, MDRD, and CKD-EPI values.

This article is accompanied by an editorial by NephMadness Selection Committee member Richard Sterns. He does a nice job describing why this rapid increase in sodium in SIADH show in Morris’ paper was not also seen in Schrier’s SALT 1 and 2 paper. In that phase 3 trial that lead to the approval of tolvaptan, there were 51 patients patients with SIADH, and only 3 of them corrected too fast. This is 6%, well below the 25% found in Morris’ study. Sterns points out the relatively high sodiums found in SALT study (no one below 120 and only 30 had a sodium below 130) as a likely explanation.

Sterns wraps up his editorial with a neat description of the pharmacokinetics of tolvaptan and arguing for dosing the drug at 3.75 mg and then repeating the dose as needed every 6 hours to titrate the change in the sodium level.  Clever.

The minimally effective tolvaptan plasma concentration to increase urine output is approx. 25 ng/mL, and maximal increases in output occur when tolvaptan concentrations exceed 100 ng/mL. Levels > 25 ng/mL are achieved by doses as low as 3.75 mg, but do not remain at this level for long because the half-life for this dose is a little more than 4 hours. A 15-mg dose achieves peak plasma concentra- tions well above 100 ng/mL in patients with SIADH, enough to sustain a maximum water diuresis for more than 4 hours. A maximum water diuresis can increase the serum sodium concentration by >2.5 mEq/L per hour, yet it is not clear why this would be desired.

The standard practice in the United States is to administer 15 mg of tolvaptan and then encourage water intake to offset the resulting variable (and often large) water losses. Considering the high price of the drug in the United States (w$300 per tablet), this practice is basically flushing money down the toilet…

…A much more desirable outcome in patients with severe hyponatremia would be a modest but sustained increase in urine volume with a resulting slow steady increase in serum sodium concentration. If urine volumes were less massive, free-water restriction could be continued to avoid unwanted exacerbation of hypona- tremia. Theoretically, the desired response could be achieved with initial doses of 3.75 mg, repeating or increasing the dose every 6 hours if necessary, based on results of urine output and/or serum sodium levels measured before each dose, until the target increase in serum sodium level for the day is achieved.

Another source of additional insight on the study is an interview by Tim Yau of Juan Carlos at AJKDbog.org.