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.

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 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.

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 m² (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 eGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m², 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.

These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.

晚期 CKD 禁用低剂量甲氨蝶呤 (LD-MTX)，但肾功能正常或轻度至中度 CKD 的肾脏安全性尚不清楚。

我们使用随机双盲、安慰剂对照的心血管炎症减少试验对 eGFR 和肾脏 AE 进行了二次分析。患有心血管疾病和糖尿病和/或代谢综合征的成年人被随机分配到口服 LD-MTX（目标剂量 15-20 毫克/周）或安慰剂组。所有参与者每周服用 6 天 1 毫克叶酸。排除标准包括全身性风湿病和肌酐清除率 <40 毫升/分钟。最小二乘均值在每次研究访问时计算基线的 eGFR；比较了 LD-MTX 和安慰剂之间 eGFR 的差异。我们使用 Cox 比例风险模型来比较 LD-MTX 与安慰剂的肾脏 AE 发生率。

共有 2391 名参与者被随机分配到 LD-MTX 组，2395 名参与者被随机分配到安慰剂组。基线时，平均年龄为 66 岁，19% 为女性，平均 eGFR 为 80.0 ml/min/1.73 m ²（54% 患有 2 期 CKD，18% 患有 3 期 CKD）。中位随访时间为 23 个月。LD-MTX 组的 eGFR 下降幅度低于安慰剂组（从基线到治疗就诊的最小二乘平均 eGFR 差异：0.93 ml/min 每 1.73 m ^2，95 % 置信区间 [95% CI]，0.45 至 1.40 , P <0.001)。LD-MTX 组有 138 例（发生率 [IR]，每 100 人年 2.97 例）肾脏 AE，安慰剂组有 184 例（IR，每 100 人年 3.99 例）（风险比 [HR] 0.73，95% 置信度）安全实验室监测期间的间隔 [95% CI]，0.59 至 0.91)。

这些结果证明了 LD-MTX 在基线时肾功能正常或轻度至中度 CKD 患者中的肾脏安全性。