A rare case of pure N4-acetyl-sulfamethoxazole nephrolithiasis associated with trimethoprim-sulfamethoxazole treatment of pulmonary nocardiosis.

Trimethoprim-Sulfamethoxazole is a commonly used antibiotic for treatment of urinary tract infections, but also used to treat less common conditions such as pulmonary nocardiosis. N4-acetyl-sulfamethoxazole is the main active metabolite of Sulfamethoxazole. Pure stones of this compound are very rare with only a few cases documented in the literature. Here we present a case of a patient treated with long term trimethoprim-sulfamethoxazole therapy for pulmonary nocardiosis who developed pure N4-acetyl-sulfamethoxazole nephrolithiasis resulting in upper tract obstruction. This report provides an additional data point for this unique calculus etiology.

Introduction

Trimethoprim-sulfamethoxazole, or Bactrim, is a commonly used antibiotic for treatment of urinary tract infections. It is also commonly used to treat Nocardia infections. Less common are reports of nephrolithiasis consisting purely of N4-acetyl-sulfamethoxazole, the primary metabolite of trimethoprim-sulfamethoxazole. This is a case of a patient with a past medical history of Mantle Cell Lymphoma and T-cell Leukemia on Bactrim therapy for pulmonary nocardiosis who developed several pure N4-acetyl-sulfamethoxazole renal calculi causing right sided ureteral obstruction.

Case presentation

The patient is a 70-year-old male with a past medical history of Mantle Cell Lymphoma and T-cell Leukemia who had previously undergone bone marrow transplant. He later developed pulmonary nocardiosis for which he was started on trimethoprim-sulfamethoxazole (TMP-SMX) 800-160 mg, three pills, three times daily over a course of 6 months by his infectious disease specialist. He then presented to the emergency room with confusion following an unwitnessed fall at home. He had no prior history of nephrolithiasis, but during his hospitalization he developed renal colic with concurrent renal insufficiency.

He underwent non-contrast CT scan of the abdomen and pelvis demonstrating an obstructing proximal right ureteral calculus as well as several small, non-obstructing right renal calculi [Fig. 1]. The CT scan demonstrated 70 Hounsefield units at its maximum. Due to persistent pain and renal insufficiency, the patient required cystoscopy with placement of ureteral stent followed by interval ureteroscopy. During this ureteroscopy, several small, soft and dark-orange colored calculi were seen in the proximal ureter. These were removed with laser lithotripsy and basket retrieval which was somewhat difficult given a large amount of blood clot. There also appeared to be stone eroding into the wall of the ureter, which was very friable. The patient had a double-J ureteral stent placed, and was discharged home. Stone analysis showed 100% N4-acetyl-sulfamethoxazole.

Fig. 1

Preoperative imaging. A) Cross sectional and B) coronal non-contrast CT scan of abdomen and pelvis. Obstructing proximal right ureteral calculus as well as several small, non-obstructing right renal calculi.

Prior to stent removal, a repeat non-contrast CT scan showed calcifications around the proximal curl of the stent in the renal pelvis [Fig. 2]. When he presented to the clinic for stent removal two weeks postoperatively his stent was unretrievable due to calcification of the proximal curl, and he required formal cystoscopy/ureteroscopy and stent removal under general anesthesia. At the time of his repeat procedure, the proximal segment of the stent was indeed noted to be severely encrusted requiring extensive laser lithotripsy prior to successful removal of the stent. The patient was found to have a significantly larger stone burden than previously. Following successful stone treatment, a new double-J stent was placed, which was then removed in the office two days later without complication. The patient returned to his infectious disease specialist for adjustment of antibiotic regimen versus alternative measures such as alkalinization of urine or diuresis. Initially, the patient was started on sodium bicarbonate and potassium citrate for attempted alkalinization of his urine. However, he continues to have waxing and waning renal insufficiency, and was eventually converted from TMP-SMX to amoxicillin clavulanate for continued Nocardia treatment.

Fig. 2

Postoperative imaging. A) Coronal and B) cross-sectional non-contrast CT scan of abdomen and pelvis. A 4 mm calculus is present at the right ureteropelvic junction just inferior to the proximal pigtail loop of the stent. Subtle layering hyperdense material in the renal pelvis and lower pole right renal collecting system may be hemorrhage from recent intervention.

Discussion

Bactrim is a synthetic antibacterial combination of sulfamethoxazole and trimethoprim. The metabolism of sulfamethoxazole predominantly occurs in the liver by N4-acetylation. Both sulfamethoxazole and trimethoprim metabolites are primarily excreted through glomerular filtration and tubular secretion. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remainder excreted as N4-acetylated metabolite.

The initial generation of sulfonamides released in the 1930s were found to cause drug-induced crystal formation resulting in renal injury and/or obstruction. Since then, cases of sulfonamide-induced stone formation have notably decreased as sulfonamides have been developed with greater solubility, thus reducing crystallization and, with it, renal complications. Drug-induced kidney stones are a rare cause of all kidney stones, accounting for one to two percent. Sulfamethoxazole has low lithogenic potential given the losangic shape of the crystals, however, it is associated with crystallization, and rarely obstructive uropathy. Despite the rarity, there have been some documented cases of sulfonamide compounds provoking urolithiasis via intratubular crystallization.

This case report is unique for the purity of this rare stone etiology, N4-acetyl-sulfamethoxazole. This case is also notable for the negative history of nephrolithiasis in the patient. Siegel et al. described an elderly male who developed oliguria and had an obstructing 5 mm N4-acetyl-sulfamethoxazole stone, but their patient had a concurrent obstructing calcium oxalate stone in the contralateral ureter. Rince et al. described a case of a mixed stone with components of N4-acetyl-sulfamethoxazole, uric acid and calcium oxalate in a tetraplegic male following Bactrim treatment for persistent UTIs. Similarly, Roedel et al. described a staghorn obstructing calculus in an elderly woman with past medical history of nephrolithiasis on her fourth month of Bactrim treatment for Nocardia pneumonia. Unlike our patient, their patient had a known stone when starting Bactrim treatment and their stone's analysis revealed a mixed calculus constituent with a predominant N4-acetyl-sulfamethoxazole (80%) and the remaining components 20% being calcium oxalate and calcium phosphate carbonate. Their stone demonstrated a density of 194.46 Hounsfield units. Recently, DeMasi et al. describe a case of an 100% pure N4-acetyl-sulfamethoxazole obstructing ureteral calculi in an immunocompromised HIV patient on prophylactic Bactrim treatment. Our case further contributes to the limited reports of pure N4-acetyl-sulfamethoxazole stones in patients undergoing Bactrim therapy.

Conclusion

Pure N4-acetyl-sulfamethoxazole stones are exceptionally rare and have only been documented in a few case reports in patients receiving long term sulfonamides. This case provides an important reminder that although uncommon trimethoprim-sulfamethoxazole related stones can lead to significant morbidity and are one of the most serious consequences of sulfonamide treatment. Discontinuation of the offending agent and instead starting alternative antibiotics and treatment including alkalinization of the urine and diuresis can be considered for stone prevention and dissolution.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

None.