Urea and Hyponatremia

Urea is a hyponatremia treatment long forgotten in the United States. Chronic SIADH is usually managed either by vaptans or a combination of fluid restriction, salt and furosemide. However, vaptans are very expensive and few patients can afford it. In a recent Belgian article, the use of urea as a comparable, cheaper alternative is being advocated.

What do we know about urea? It is a very cheap powder (< $0.50/30 gram) that works by increasing free water excretion through osmotic diuresis. Shown below is the solute excretion as a determinant of free water excretion.

Free water clearance = solute excretion/Uosm x (1 - Uosm/Posm)

Physiologically it makes sense, but does it really work? In this article, 13 patients with SIADH were tried on vaptans (satavaptan or tolvaptan) for 12 months. Then vaptans were discontinued for 8 days and urea was started after ensuring that their Na level came down. The result? It worked as well as vaptans! Side effects included hypernatremia and gastric irritation but no osmotic myelinolysis has been reported with urea. It does not cause volume overload (unlike salt), hypokalemia (unlike diuretics), or uremia. You will not become uremic even if your BUN is 100 after you take urea (but you will be urinating a lot!).

So why are we not using it? Are you a fan of bitter drinks? We know Belgians are (great beer there!). In Belgium, only about 15% of patients discontinue to take urea due to its taste. In Canada, Dr. Bichet tried it himself (mixed with orange juice) and wrote “it does not smell of anything but the bitterness is strong”. On this side of the border, Dr. Berl wrote that it is “rarely compatible with North American palate”.

That being said, it may be a time to use urea again as a comparable, cheaper alternative for hyponatremia treatment. Across the Pacific (in Japan) there is a proverb “good medicine tastes bitter”. 


Posted by Tomoki Tsukahara

Appropriate or inappropriate: stop guessing

In the evaluation of patients with hyponatremia (serum Na less than 135 mEq/L), differentiating hypovolemia from euvolemia is often challenging, particularly if the history and physical findings are unrevealing and frequently leads to misdiagnosis. This conundrum exists even for the nephrologists and often leads to guesswork. Measuring the antidiuretic hormone (AVP) levels is not helpful as most cases of hyponatremia have either appropriate or inappropriate elevation of AVP levels and despite frequent reliance on central venous pressure (CVP) measurements to determine the volume status, they are rarely measured in hypovolemic or euvolemic states and their accuracy is debatable.

Reliance on the urine biochemical parameters therefore becomes necessary. Urine electrolytes particularly low urine sodium (less than 30 mEq/L) is often used to distinguish these two conditions but can be misleading, as up to 30% patients with hypovolemia may have elevated urine sodium and on the flip side, up to 40% SIADH patients may have low urine sodium (low salt intake). A recent CJASN review of SAIDH nicely covers this. Urine osmolality is often elevated (greater than 100mosm/kg) and does not distinguish hypovolemia from euvolemia. Recent studies have therefore suggested that a combined use of urine sodium (UNa), fractional excretion of sodium (FENa) and fractional excretion of urea (FEUrea) would best help in differentiating these two states (diuretic use, renal failure, hypocortisolism and hypothyroidism excluded).

1) In patients with adequate urine flow (urine/plasma Cr less than140), a UNa less than 30, FENa less than 0.5% and FEUrea less than 55% indicates hypovolemia.

2) In patients with low urine flow (urine/plasma Cr greater than 140) an even lower FENa (less than 0.15%) and FEUrea (less than 45%) are recommended to capture all the cases of hypovolemia.
Low serum uric acid levels (less than 4mg/dL) and increased fractional excretion of uric acid (greater than 12%) are also useful in differentiating SIADH from hypovolemia, major exception being salt wasting syndromes (click here for review or here for a discussion about CSW vs. RSW). In these patients, unlike SIADH, correction of hyponatremia does not lead to improvement of hypouricemia and uricosuria, likely due to persistent proximal tubular defect causing impairment of uric acid absorption. Phosphaturia (FEPO4 greater than 20%), for the same reason also favors salt wasting, at least initially. Moreover, the plasma renin activity and plasma aldosterone levels are elevated in salt wasting but low in SIADH.

Although the interesting findings in these studies need further validation, they offer a completely different perspective and help us move away from complete reliance on assessment of volume status to make a correct diagnosis of hyponatremia, an exercise that often involves guesswork. Hopefully, the next time when we encounter hyponatremia, this new approach would help us to stop guessing.

Viresh Mohanlal, MD.

Ecstasy-Induced Hyponatremia

The recreational drug ecstasy (MDMA) is known to result in hyponatremia--which has been reported to result in seizures and death--has a multifactorial mechanism which is interesting.

MDMA is associated with elevated ADH levels. In addition, individuals who take ecstasy are often encouraged to drink large amounts of water to "dilute" out the drug for concerns regarding drug testing, and their may even be an increased thirst drive in addition to this.