Methotrexate Toxicity in a Patient With Renal Failure Despite a Normal Methotrexate Concentration: A Case Report and...

Methotrexate (MTX) is a folate antagonist widely used as a disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA), as well as in several malignancies and autoimmune disorders. Although low-dose MTX (5-20 mg/week) is generally considered safe, it has a narrow therapeutic index, and toxicity can occur even at therapeutic doses, particularly in high-risk patients. We describe a 58 year-old man with RA and chronic kidney disease (CKD) who presented with gastrointestinal symptoms, neurologic impairment, and a papulopustular rash. Laboratory evaluation revealed pancytopenia and acute kidney injury (AKI) superimposed on CKD. Despite a normal serum MTX level, clinical findings strongly suggested MTX toxicity. The patient received emergent hemodialysis, leucovorin rescue therapy, hematologic support, and intensive care management. Extensive investigations excluded alternative hematologic, infectious, and systemic causes. His clinical course was complicated by acute pancreatitis, and he ultimately died. This case emphasizes that serum MTX levels may not reliably predict toxicity in high-risk patients and underscores the importance of recognizing clinical signs and symptoms, promptly identifying early manifestations, discontinuing MTX, and initiating leucovorin rescue therapy.