Case Presentation: An 87-year-old woman presented with generalized malaise 3 days after starting Trimethoprim-Sulfamethoxazole (TMP-SMX) for treatment of a UTI. Admission vitals were within normal limits and examination was benign with a baseline mental status. Labs on arrival were notable for sodium of 120mmol/L, serum osmolality of 253mOsm/kg, potassium 4.3mmol/L, bicarbonate 18mmol/L, urine sodium of 34mmol/L and urine osmolality of 201mOsm/kg. Due to recent use of TMP-SMX and low bicarbonate, the patient was diagnosed with hyponatremia secondary to TMP-SMX induced salt wasting. TMP-SMX was held, 500mls of normal saline was given and normal diet encouraged. Serum sodium improved to 128mmol/L within 29 hours, with resolution of symptoms.
Discussion: TMP-SMX is a combination of a diaminopyrimidine and a sulfonamide which work together to inhibit bacterial folate metabolism (1). Hyponatremia is a known side effect. This is thought to occur by TMP-induced salt wasting as TMP is structurally similar to potassium-sparing diuretics like amiloride and triamterene which block the ENaC sodium channel in the distal nephron. This can cause hyponatremia due to natriuresis, hyperkalemia due to decreased potassium secretion in the distal tubules secondary to increased positive luminal charge from increased luminal sodium and metabolic acidosis through various not fully determined mechanisms (2, 3, 4, 5). Hyponatremia occurs in 72.3% of patients receiving >/=8mg/kg/day of TMP for 3 or more days and less commonly at lower doses, but serum sodium levels less than 125mmol/L only occur in 10.5% of patients (2, 6, 7). Risk factors include old age and concurrent diuretic use (3). Diagnosis of salt wasting nephropathy is difficult as urine studies show raised urine osmolality and sodium, similar to SIADH. However, it is key to quickly distinguish between these etiologies as salt wasting nephropathy requires saline containing fluid administration whereas SIADH requires fluid restriction (2, 3). Subtle differences between these two diagnoses are that salt wasting nephropathy is classically hypovolemic, and therefore can have raised renin, aldosterone and BUN:Cr ratios. Patients taking trimethoprim specifically can also have low bicarbonate or high potassium due to ENaC blockade. In contrast, SIADH is classically euvolemic, with normal bicarbonate and low potassium due to ADH escape via increased expression of ENaC channels and hyponatremia-stimulated increased aldosterone levels (3). Salt wasting nephropathy can also be suspected when management options aimed at SIADH, such as fluid restriction, fail.
Conclusions: TMP-SMX causes hyponatremia via a salt wasting nephropathy, which presents similarly to SIADH, but requires opposite treatment. Treatment of salt wasting nephropathy induced hyponatremia involves administration of saline containing fluids, whereas treatment of SIADH induced hyponatremia involves fluid restriction.Rapid identification is key for successful management since treating salt wasting nephropathy as SIADH can worsen hyponatremia and hypovolemia.