Methotrexate nephrotoxicity: a pragmatic approach

High-dose methotrexate (HDMTX) is an integral component of treatment for multiple malignancies. However, preventive strategies often fail, resulting in renal impairment and delayed methotrexate elimination (DME), which increases the risk of systemic toxicity. This review aims to summarize past, current, and emerging strategies for the management of HDMTX-related toxicity.

Recent research has identified host genetic factors, hypoalbuminemia, and larger body surface area as contributors to DME. Animal studies have explored potential nephroprotective agents, including synthetic 1,3,4-oxadiazole (5b) and repurposed drugs such as empagliflozin and amlodipine. The preferred mitigation agent, glucarpidase, continues to demonstrate improved clinical and financial outcomes, with higher odds of renal recovery even at lower doses. Early therapeutic drug monitoring has shown promise as a biomarker for predicting acute kidney injury. In addition, the web-based clinical tool MTXPK.org now integrates population pharmacokinetic models with patient-specific data to guide interpretation and management of DME.

Identification of emerging risk factors, advances in pharmacogenomics, and timely methotrexate monitoring, combined with patient-specific pharmacokinetic modeling, underscore the importance of personalized therapeutic strategies to reduce renal toxicity and DME.