Crystal-Clear Consequences: Trimethoprim-Sulfamethoxazole-Induced Nephrolithiasis

Introduction: Trimethoprim-sulfamethoxazole (TMP-SMX) has remained a widely used antibiotic since its introduction in the late 1960s. Sulfamethoxazole inhibits the synthesis of dihydrofolic acid, while trimethoprim blocks dihydrofolate reductase. In combination, they effectively prevent the formation of tetrahydrofolic acid, a critical cofactor for bacterial DNA synthesis. Over decades of clinical use, TMP-SMX’s adverse effects have been well documented, ranging from gastrointestinal upset to Stevens-Johnson syndrome. Renal-related adverse events include reduced tubular secretion of creatinine, life-threatening hyperkalemia, and hypersensitivity reactions such as acute interstitial nephritis. A much lesser-known complication is the development of kidney stones composed of N4-acetyl sulfamethoxazole. We present a case that illustrates this uncommon manifestation. Case Description: An elderly male with a history of benign prostatic hyperplasia (BPH) presented with acute renal failure due to a large burden of obstructing and non-obstructing renal calculi following a 6-week course of TMP-SMX for treatment of a periprosthetic joint infection. Imaging via renal ultrasound and CT revealed extensive calculi from the ureteropelvic junction to the bladder and mild left-sided hydronephrosis. He was treated conservatively with intravenous fluids and tamsulosin, resulting in the successful passage of multiple stones and return to baseline renal function. Stone analysis revealed 100% N4-acetyl sulfamethoxazole composition. Discussion: Although there are a handful of case reports linking TMP-SMX to kidney stone formation, the condition remains underrecognized. Risk factors proposed include prolonged antibiotic therapy, dehydration, low urinary pH, chronic hydronephrosis, and a history of calcium oxalate stones. Some have suggested that calcium oxalate stones may act as a nidus for the crystallization of sulfonamide metabolites. In this case, the patient had no prior history of nephrolithiasis and received a relatively short course of antibiotic therapy. However, BPH likely contributed by promoting urinary stasis, creating an environment conducive to precipitation of the drug’s poorly soluble metabolites. This case underscores the need for heightened awareness of sulfonamide crystalluria and stone formation—even in the absence of traditional risk factors—and prompts consideration of urinary flow dynamics as a key contributor.