Prescribing salt tablets for a patient with low sodium levels may sound like good sense, but clinicians considering it should examine the evidence first, according to Annabelle Warren, MBBS (Hons), BMedSc (Hons), FRACP.
At Kidney Week 2023 in Philadelphia last November, Dr. Warren, an endocrinologist at Austin Health and Alfred Health in Melbourne, Australia, took her audience of nephrologists on a tour of syndrome of inappropriate antidiuresis (SIAD), including the latest on outpatient diagnosis and treatment.
SIAD accounts for about 30% to 40% of hyponatremia cases and is essentially an issue of water excess related to inappropriate production of arginine vasopressin (AVP), Dr. Warren said. Formal diagnostic criteria for the syndrome include hyponatremia with a low serum osmolality (<275 mOsm/kg), inappropriate urine concentration (>100 mOsm), elevated urinary sodium level (>30 mmol/L), euvolemia, absence of adrenal insufficiency and untreated hypothyroidism, normal renal function, and absence of diuretic treatment.
"You need to exclude a number of other pathologies that could mimic [SIAD]..., although of course multiple conditions can coexist," Dr. Warren said.
In the office setting, in addition to taking a clinical history and getting an up-to-date medication list, physicians should first exclude severe symptoms, such as seizure, altered consciousness, and vomiting, that would indicate the need for hospitalization and urgent treatment with hypertonic saline, Dr. Warren said.
Relevant tests to establish the diagnosis include serum and urine sodium and osmolality, and serum glucose and lipids, since hyperglycemia and hyperlipidemia are the most common causes of nonhypotonic hyponatremia, she said.* She also noted that morning cortisol is a good screening test for adrenal insufficiency, which can be mistaken for SIAD; in one study, published in Clinical Endocrinology in 2016, approximately 4% of patients assumed to have SIAD actually had adrenal insufficiency, an important and readily treatable differential, instead.
One test that won't help is AVP or copeptin levels, Dr. Warren stressed: "AVP is raised in many different causes of hyponatremia, including dehydration and heart failure, so an AVP or copeptin level would not help you discriminate between SIAD and 'appropriate' antidiuresis."
After SIAD has been established, it's time to consider whether there is a potentially modifiable underlying cause, such as cancer (especially small-cell lung cancer), pulmonary disorders, central nervous system disorders, or medications, Dr. Warren said.† Transient stimuli such as pain and nausea can also prompt AVP release, although that's more common in hospitalized patients, she said.
Patients with no obvious underlying cause, especially if they are older, are considered to have idiopathic SIAD. "For completeness, there is a genetic form of SIAD, 'nephrogenic SIAD,' caused by activating mutation of the V2 receptor, but that's exceedingly rare," Dr. Warren said.
A CT of the brain and of the chest, potentially including the abdomen and pelvis, is recommended to help pin down any underlying cause if no explanation is apparent, Dr. Warren said, but the role of subsequent imaging is unclear. "If you have a young patient with otherwise unexplained SIAD, you may consider a [fluorodeoxyglucose-positron emission tomography] scan or other imaging, but that's not clearly evidence-based and will be on a case-by-case basis," she said. "And certainly in older patients, the likelihood [of an underlying cause] is lower and you may simply observe."
To manage SIAD, Dr. Warren said, "the basic principle, given we're dealing with water excess, is to stop more water going in—or promote water going out." The current U.S. and European guidelines on management of hyponatremia, which were published in 2013 in the American Journal of Medicine and in 2014 in the European Journal of Endocrinology, offer a useful starting point for discussion, despite being a decade old, she said.
"There's a consensus recommendation on fluid restriction as a first-line treatment, but for subsequent therapies, there's a little bit more discrepancy," Dr. Warren said.
Fluid restriction is free and easily accessible but relies on patient adherence and isn't always effective, she said, citing observational data suggesting a 50% response rate. A randomized trial published in the Journal of Clinical Endocrinology in 2020 assigned 46 outpatients with chronic SIAD to 1-L fluid restriction or usual care and found a statistically significant improvement in serum sodium levels, by 2 mmol/L, in the fluid restriction group at day four.
The trial also suggested that highly concentrated urine (urine osmolality >500 mOsml/L and urine sodium level >130 mmol/L) was the strongest predictor of a lack of response. "In fluid restriction, you're relying on output exceeding input. If your output is constrained with very concentrated urine, then no matter how long you fluid restrict, you're not really clearing the water," Dr. Warren explained. It can be useful to identify patients who are less likely to respond to fluid restriction so that second-line therapy can be considered earlier, she said.
One such therapy is tolvaptan, first evaluated in the SALT trial, published in the New England Journal of Medicine in 2006, which compared tolvaptan, 15 mg, with placebo in 448 patients with chronic hyponatremia, 24.6% of whom had SIAD. Sodium levels were statistically significantly improved with tolvaptan at day 4 and day 30, with a relatively low overcorrection rate of 1.7%.
However, among patients with SIAD, the overcorrection rate was higher, at 5.9%, and real-world data since then have indicated that it may be as high as 12% to 24%, "which is quite significant," Dr. Warren said. Some researchers have suggested that risk may be lower with a lower tolvaptan dose, 7.5 mg or 3.75 mg, but there are no clear trial data yet to support this, she noted. She is conducting a randomized controlled trial comparing fluid restriction with tolvaptan, 7.5 mg, in hospitalized patients with hyponatremia and hopes to have results to share later this year.
Potential risk factors for overcorrection are a lower initial serum sodium level, lower body mass index, and use of other concurrent therapies, Dr. Warren said. The FDA has recommended that tolvaptan be initiated in a hospital setting so that serum sodium levels can be monitored and rescue therapy can be given as needed. In addition, since tolvaptan is usually used for polycystic kidney disease at higher doses, which have revealed a potential risk of liver toxicity, the FDA currently recommends limiting treatment to 30 days. Cost can also be an issue, she noted.
Urea, which Dr. Warren said is probably the most popular SIAD therapy, is administered as a powder at a starting dose of 15 to 30 g/d and is typically used along with fluid restriction. "One of the concerns, however, is that it does have a bitter taste," she said. "There is a proprietary formulation that's available—it's premixed sachet with some flavoring agents—or if you're using compounded urea, then you can mix it with fruit juice for a delicious twist."
No randomized controlled trials have looked at urea for SIAD, she said, but an observational study published in the April 2019 Clinical Endocrinology found a mean increase of 6 mmol/L in serum sodium levels at day 4 of urea therapy among 56 inpatients whose SIAD did not respond to fluid restriction. "One other potential advantage of urea is perhaps a lower risk of overcorrection, anecdotally," Dr. Warren noted.
The use of urea has suggested another potential therapy. "We know that urea is a product of protein metabolism," Dr. Warren said, "so the genius idea is why not just give protein?" In a small proof-of-concept study published in the August 2023 European Journal of Endocrinology, 16 SIAD patients followed a diet that included 90 g of protein per day for a week, followed by a washout period, then 30 g of urea daily for another week.
After each treatment week, there was a mean increase of 2 mmol/L in serum sodium levels. "The actual number of patients who completed the study was very small, but it's a promising low-risk intervention that we may be able to offer patients," Dr. Warren said.
Early research has also indicated a potential role for sodium-glucose cotransporter-2 (SGLT-2) inhibitors, Dr. Warren said. In one randomized controlled trial involving 87 inpatients and published in the March 2020 Journal of the American Society of Nephrology, empagliflozin, 25 mg, was compared with placebo plus fluid restriction. The change in serum sodium level between the two groups was statistically significant, with a difference of 3 mmol/L.
Also, a smaller randomized crossover study in 14 outpatients with chronic hyponatremia found that mean serum sodium levels were 4.1 mmol/L higher in those who took empagliflozin versus placebo after one month. The latter trial, which was published in the February 2023 Journal of the American Society of Nephrology, also signaled potential for cognitive improvement, with higher Montreal Cognitive Assessment scores in the empagliflozin group.
Both studies together could provide "an early hint that there may be some clinical benefits [with SGLT-2s] to improving sodium, although that is far from established," Dr. Warren said.
She next discussed the intervention on which her views might be slightly controversial, she noted. "Salt tablets are a very popular treatment for hyponatremia, and intuitively, 'low sodium, more sodium' seems like a good idea," she said. "But of course, it's the water excess that we're trying to address, and in fact, we have very little evidence for salt tablets."
Most people eating Western diets have more than enough salt in their diet already, Dr. Warren said, consuming the equivalent of about 6 g a day. "Some people argue, well, you're not using salt tablets for the salt supplementation, you're using them for the osmotic draw, that extra salt load. And to that I say, urea has a much stronger solute load and is going to achieve that much more effectively."
To get a benefit similar to that with one 15-g dose of urea, a patient would need to take at least 10 salt tablets, Dr. Warren said. "Of course, urea is used at a dose of 30 grams, not 15 grams, commonly, so that's starting to look like 20 salt tablets a day, which is not sounding very appealing for your patient."
Only one randomized controlled trial, published in the August 2020 American Journal of Kidney Disease, has assessed salt tablets, in combination with furosemide, Dr. Warren said. Ninety-two inpatients with SIAD were assigned to fluid restriction alone, fluid restriction plus 20 to 40 mg of furosemide daily, and fluid restriction plus furosemide plus 3 g of salt tablets daily. No change in serum sodium level was seen among the groups. In addition, Dr. Warren noted, the group receiving all three therapies had a very high rate of adverse events, 20%, due primarily to severe hypokalemia and acute kidney injury.
"It's difficult to recommend sodium chloride supplementation and furosemide, despite its enduring popularity in some of the recommendations," Dr. Warren said. She added a couple of other agents that have fallen out of favor: "demeclocycline and lithium, which induce a nephrogenic diabetes insipidus, an AVP deficiency-like state, but also carry a high risk of adverse effects, including renal injury."
Dr. Warren concluded her talk by reaffirming that while fluid restriction is widely endorsed as first-line therapy, the choice among second-line therapies is less clear. Of those available, urea is currently preferred, although data from randomized controlled trials are lacking.
Meanwhile, "tolvaptan, while very effective, is perhaps too effective in many circumstances, but I personally believe it can be used safely with the right monitoring and interventions in place," she said. "One thing I will mention is that if tolvaptan does cause overcorrection of sodium, desmopressin will not be effective because of the receptor blockade. So if you did need to relower sodium, IV dextrose 5% is required."
The latest evidence also suggests that SGLT-2 inhibitors and a high-protein diet may have potential benefit and that salt tablets should be abandoned. "Salt tablets may perhaps have some effects, but only at a very high dose, so I'm hesitant to recommend them unless you don't have access to any of the other options," Dr. Warren said. "What we really need is comparative data between the second-line options to inform future guidelines."