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

Familial renal glucosuria and a new drug for diabetes mellitus

The kidney contributes to glucose homeostasis by reabsorbing ~180 grams of glucose daily. Two sodium-coupled glucose transporters play an important role in this process, SGLT1 and SGLT2. Of these two, SGLT2 (encoded by the gene SLC5A2 on chromosome 16p11.2) is the transporter which is predominantly expressed in the luminal brush border of the proximal tubule (S1 segment) and mediates primarily renal glucose re-absorption.

Glucosuria, in the absence of diabetes mellitus, can occur in the setting of global dysfunction of the proximal tubule (PT), known as Renal Fanconi Syndrome. The latter is typically accompanied by excessive urinary excretion of amino acids, phosphate and bicarbonate. The occurrence of glucosuria in the absence of PT dysfunction and hyperglycemia is known as renal glucosuria or familial renal glucosuria (FRG) as it is recognized as an inherited disorder.

Patients with FRG have decreased renal tubular reabsorption of glucose from the urine in the absence of hyperglycemia or any other signs of tubular dysfunction. Glucosuria can range from 1 - 150 grams/1.73m2 per day. The majority of affected patients does not develop significant clinical problems and individuals are typically picked up during routine clinical tests. However, higher levels of glucosuria lead to osmotic diuresis and could cause volume contraction when access to fluid is limited.

Both, autosomal recessive and dominant pattern of inheritance for FRG have been reported. Mutations in SCL5A2 (encoding SGLT2) account for the majority if not all families with this condition. So far ~44 different mutations in 14 exons have been reported for FRG. Establishing a definite genotype-phenotype correlation has been difficult due to variable expressivity of SGLT2 and other genes that may have an overall impact on renal glucose reabsorption. In general, heterozygous mutations lead likely to mild glucosuria Here's a nice review.

In summary, FRG is a relatively benign condition nephrologists should be familiar with, especially with the availability of Dapagliflozin, a new drug for treatment of diabetes mellitus. First trials look promising since inhibiting SGLT2 appears effective and relatively safe.