Identifying risk factors for methotrexate-induced acute kidney injury despite full prevention in patients with...

Primary central nervous system lymphoma (PCNSL) accounts for 3 % of all brain tumors worldwide and high-dose methotrexate (HD-MTX) is used as the frontline chemotherapy. Given the renal excretion of methotrexate, we aimed to identify risk factors for HD-MTX-induced acute kidney injury (AKI) in patients with PCNSL. A comprehensive retrospective cohort study was conducted on newly diagnosed PCNSL patients who received HD-MTX chemotherapy.

Baseline characteristics, comorbidities, and laboratory data were collected at diagnosis and prior to each chemotherapy cycle. Serum methotrexate levels were measured at 24-48, 48-72, and 72-96 h post-infusion. Generalized estimating equations were used to identify risk factors for AKI. Among 146 patients with PCNSL, 108 received HD-MTX-based regimens, comprising 576 treatment cycles.

Univariate analysis revealed that male gender, serum MTX levels ≥2 μmol/L at 48-72 h post-infusion, fluid accumulation in third spaces, low serum albumin, elevated blood urea nitrogen (BUN), and serum creatinine ≥2.0 mg/dL were all associated with increased AKI risk. In multivariate analysis, serum MTX levels ≥2 μmol/L and fluid accumulation in third spaces remained significant risk factors for AKI. Notably, none of the comorbidities were associated with the incidence of AKI.

These findings indicate that third-space fluid accumulation and elevated serum methotrexate levels at 48-72 h post-infusion are significant independent predictors of AKI in PCNSL patients receiving HD-MTX. We also developed a clinically applicable risk scoring system with strong predictive performance to support early identification and management of high-risk patients.