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The relationship of homocysteine and its redox forms with renal toxicity after high-dose methotrexate treatment in patients with leukemia or lymphoma

Year: 2026

Type: article

Abstract: Background High-dose methotrexate (HD-MTX) chemotherapy inhibits dihydrofolate reductase, leading to impaired homocysteine metabolism, elevated levels, and associated clinical adverse reactions. Currently, studies often monitor total homocysteine (tHcy) levels, but its toxic mechanism remains unclear. Objectives Given the association between HD-MTX toxicity and oxidative stress, this study aimed to analyze the correlations between tHcy and its redox forms with liver/kidney function indicators, and to evaluate their discriminatory ability for hepatic and renal toxicity. Methods A total of 310 blood samples were collected from 89 patients (38 adults, 51 children) with leukemia or lymphoma treated with HD-MTX. Concentrations of tHcy, free reduced homocysteine (Hcy), free oxidized homocysteine (HHcy, homocystine), and the ratio of Hcy concentration to HHcy concentration (Hcy/HHcy) were measured at 42, 72, and 96 h post-chemotherapy. Generalized estimating equations (GEE) were used to assess associations between tHcy-related redox forms and liver/kidney function indicators, and to compare concentration differences between toxicity and non-toxicity groups. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the discriminatory ability of relevant indicators for HD-MTX-related toxicity. Results In pediatric patients, Hcy/HHcy was significantly negatively correlated with creatinine (CR) ( P < 0.028), and tHcy was significantly negatively correlated with alanine aminotransferase (ALT), total bilirubin (TB), and direct bilirubin (DB). No significant associations were observed in adult patients. Compared with the control group, the kidney injury group showed significant differences in Hcy and HHcy levels at 42 h ( P < 0.05), Hcy at 72 h, and HHcy at 96 h. No significant differences were observed in the liver injury group. HHcy, tHcy, and Hcy/HHcy at 42 h all demonstrated good discriminatory ability for kidney injury, with HHcy showing an AUC of 0.817 (95% CI: 0.702–0.932, P < 0.01). tHcy at 72 h and 96 h showed reverse discriminatory ability for liver and kidney injury. Conclusion Alterations in tHcy redox status after HD-MTX treatment, particularly changes in HHcy levels and the Hcy/HHcy, may be associated with renal function changes and may have potential value for identifying patients with HD-MTX-related nephrotoxicity.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1972047