Sparks JA, Vanni KMM, Sparks MA, et al. Effect of Low-Dose Methotrexate on eGFR and Kidney Adverse Events: A Randomized Clinical Trial. J Am Soc Nephrol. 2021 Sep 22. pii: ASN.2021050598. doi: 10.1681/ASN.2021050598. (Original study)

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 ?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 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.

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

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Nephrology 6 / 7
Endocrine 6 / 7
Internal Medicine 5 / 7
Comments from MORE raters

Endocrine rater

Unless we are going to treat CKD per se with methotrexate, this information will not be of much clinical interest to endocrinologists. The paper is of much more relevance to rheumatologists.

Family Medicine (FM)/General Practice (GP) rater

This is probably more relevant to specialists, but GPs are monitoring DMARDs more and the information here was useful for me.

Family Medicine (FM)/General Practice (GP) rater

This study is very interesting considering the eligibility criteria. These patients are at high risk of CKD progression, hence the safety of MTX is really important.

General Internal Medicine-Primary Care(US) rater

As a practicing physician, I find this topic highly relevant. The suggestion that LD-MTX is safe to use in patients with normal eGFR or mild-to-moderate CKD is beneficial especially when such dose is indicated in similar patients.

Nephrology rater

This secondary analysis of RCT looking at low dose oral methotrexate in patients with varying degrees of mild-to-moderate kidney disease (eGFR > 40 needed to enroll in trial) showed no renal toxicity from low dose methotrexate. In fact, eGFR was better in the methotrexate group versus placebo, and this hypothesis needs further investigation. This shows that methotrexate can be safely given in patients with mild-to-moderate kidney disease.

Nephrology rater

The study provided evidence of safety of low dose methotrexate among CKD patients. These data are important for the use of methotrexate especially in rheumatologist disease in patients with CKD.
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