Correspondence

Hyperkalemia Due to Nafamostat Mesylate

N Engl J Med 1995; 332:687March 9, 1995

Article

To the Editor:

Nafamostat mesylate (6-amidino-2-naphthyl p-guanidinobenzoate, dimethanesulfonate; molecular weight, 540) is a synthetic serine protease inhibitor that is widely used to treat acute pancreatitis in Japan.1 The drug and its metabolites reversibly inhibit amiloride-sensitive sodium conductance of renal cortical collecting ducts,2,3 thus impairing urinary potassium excretion. Hyperkalemia could therefore develop in patients receiving this drug.

We describe a 77-year-old man admitted to the hospital for acute pancreatitis in whom nafamostat mesylate therapy was associated with hyperkalemia. The patient was initially treated with intravenous fluids and a continuous infusion of nafamostat mesylate (150 mg per day). The intravenous fluid contained 30 to 50 mmol of potassium daily until day 10, when it was eliminated, and no oral potassium intake was allowed until the 18th hospital day. The patient's serum potassium concentration increased steadily from 4.2 mmol per liter initially to 6.3 mmol per liter on the ninth hospital day (Figure 1Figure 1Course of Hyperkalemia in a Patient with Acute Pancreatitis Treated with Nafamostat Mesylate at a Dose of 150 mg per Day.). At that time, the urinary potassium concentration was 15.5 mmol per liter; plasma renin activity, measured with the patient supine, was 2.9 ng per milliliter per hour (0.81 ng per liter per second; normal, 0.2 to 2.7 ng per milliliter per hour [0.06 to 0.75 ng per liter per second]); and the plasma aldosterone concentration was 8.0 ng per deciliter (222 pmol per liter; normal, 2 to 13 ng per deciliter [55 to 360 pmol per liter]). The patient's transtubular potassium gradient4 was 1.6, suggesting impaired urinary potassium excretion (the transtubular potassium gradient is greater than 7.0 in the presence of hyperkalemia in patients with normal renal function4). A tendency to lose salt was evident, because the rate of urinary sodium excretion was 100 to 180 mmol per day while the intake of sodium was 18 mmol per day. The patient also had mild renal dysfunction (creatinine clearance, 42 ml per minute) that did not change during his hospitalization. No other causes of hyperkalemia were found. After nafamostat mesylate was discontinued, the patient's serum potassium concentration returned to normal (4.3 mmol per liter) within two days, with a concomitant increase in the transtubular potassium gradient (to 5.3) and disappearance of the salt-losing tendency.

Nafamostat mesylate is rapidly metabolized to 6-amidino-2-naphthol and p-guanidinobenzoic acid, which are excreted in the urine. Examination of the patient's urine by high-performance liquid chromatography revealed high concentrations of 6-amidino-2-naphthol (3.0 × 10-⁵ M) and p-guanidinobenzoic acid (5.5 × 10-⁵ M), which were close to the concentrations of these compounds (10-⁴ M for 6-amidino-2-naphthol and 10-⁵ M for p-guanidinobenzoic acid) that inhibit amiloride-sensitive sodium conductance.3

Several drugs, including amiloride, triamterene, and trimethoprim,5 block sodium conductance in the cortical collecting ducts, leading to reversible hyperkalemia with a low transtubular potassium gradient, normal or high plasma aldosterone concentrations, and a mild salt-losing tendency. The present case report suggests that nafamostat mesylate also belongs to this group.

Hirochika Kitagawa, M.D.
Hangil Chang, M.D., Ph.D.
Toshiro Fujita, M.D.
University of Tokyo School of Medicine, Tokyo 112, Japan

5 References

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