Effect of Low-Dose Methotrexate on eGFR and Kidney Adverse Events: A Randomized Clinical Trial

Significance Statement Methotrexate can lead to kidney injury at high doses for cancer and is contraindicated in advanced CKD. The effect of low-dose methotrexate (LD-MTX, ≤25 mg weekly) on eGFR and kidney adverse events (AEs) with normal kidney function or mild-to-moderate CKD is unclear. In this clinical trial that included 4786 adults with cardiovascular disease and no systemic rheumatic condition, participants randomized to LD-MTX had less decline in eGFR over 23-month median follow-up compared with placebo. Those randomized to LD-MTX had a 27% reduced rate of kidney AEs on safety laboratory monitoring compared with placebo. These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD. Background Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear. Methods We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15–20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean Δ eGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo. Results A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m 2 (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m 2 , 95% confidence interval [95% CI], 0.45 to 1.40, P <0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring. Conclusions These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.