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Low-Dose Methotrexate Safe, Possibly Protects Kidneys

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Low-dose methotrexate (LD-MTX), which is contraindicated in patients with advanced chronic kidney disease (CKD), is potentially reno-protective in patients with normal kidney function or mild-to-moderate CKD, according to a recent study.

The study, published in the Journal of the American Society of Nephrology, was a secondary analysis of the randomized Cardiovascular Inflammation Reduction Trial (CIRT), in which 4786 participants receive either LD-MTX (2391 patients) or placebo (2395 patients) in addition to 1 mg folic acid 6 days per week. The median follow-up was 23 months. The LD-MTX recipients had a 27% reduced risk of kidney adverse events (AEs) during safety laboratory monitoring compared with the placebo group. The LD-MTX group also experienced a smaller decline in estimated glomerular filtration rate (eGFR), with a difference in least-squares mean change of 0.93 mL/min/1.73 mfrom baseline to on-treatment visits.

“The intriguing finding that low-dose methotrexate may slow progression to chronic kidney disease deserves further study to replicate our findings and determine clinical significance,” said corresponding study author Jeffrey A. Sparks, MD, an assistant professor of medicine at Harvard Medical School and the Director of Immuno-Oncology and Autoimmunity at Brigham and Women’s Hospital in Boston, Massachusetts. “Future studies should further examine the role of inflammation and immune dysregulation in the pathogenesis of chronic kidney disease.”

Arshia Ghaffari, DO, MBA, director of dialysis services and associate chief of the Division of Nephrology and Hypertension at the University of Southern California’s Keck School of Medicine in Los Angeles, said the study findings are unexpected and intriguing. “While the study was not originally designed to study kidney-related outcomes, the possibility of the benefit of low-dose methotrexate is possible through a specific anti-inflammatory pathway,” Dr. Ghaffari said. “However, since these are surrogate kidney outcomes in this study, which was designed to study cardiovascular endpoints, we need to be cautious about the results.”

Based on these new findings, other measures of kidney function other than creatinine, such as cystatin C and 24-hour urine creatinine clearance, will need to be investigated. Dr. Ghaffari noted that the findings may be just an effect of artificial lowering of creatinine without actual kidney function improvement. “If this is confirmed, then a dedicated study should be undertaken with a protocol designed to study kidney-related outcomes, as opposed to surrogate outcomes that were studied in this study,” Dr. Ghaffari said.

There have been other anti-inflammatory, antioxidants, and antifibrotic agents studied in kidney disease with variable results. Dr. Ghaffari said there is a need to better understand which specific anti-inflammatory pathways are activated in certain types of kidney disease, such as diabetic kidney disease, hypertensive kidney disease, and specifically develop therapeutics that target those pathways. “This is an important clinical issue not so much because methotrexate is used so widely but if confirmed that methotrexate is protective in certain kidney conditions, it would open further discussion and studies for other anti-inflammatory medications in chronic kidney disease,” Dr. Ghaffari said.

Anthony J. Bleyer, MD, professor of nephrology and leader of the Rare Inherited Kidney Disease Team at Wake Forest School of Medicine in Winston-Salem, North Carolina, said the new findings point to a variety of possible future therapies, but more robust data are needed. “Patients on low-dose methotrexate had an increased risk of elevation of liver enzymes, reduction in white count, and a higher risk of non-basal-cell skin cancers,” Dr. Bleyer said. “There is a high toxicity from methotrexate in patients with advanced kidney disease. Thus, patients even on low-dose methotrexate with early CKD would need to have their labs monitored closely because the toxicity of methotrexate increases with worsening kidney function.”

Dr. Bleyer pointed out that sodium-glucose transport protein 2 inhibitors have recently entered clinical practice as a treatment for slowing progression of CKD, “and any new therapies would have to be evaluated with or compared to these agents.”

Arlene Chapman, MD, a professor of medicine and chief of the section of nephrology at the University of Chicago Medicine in Chicago, Illinois, cautioned that the latest findings only suggest a renoprotective effect of LD-MTX and are in no way confirmatory. “These analyses are promising, but very early. Other anti-inflammatory medications could be considered for this indication of a key role in disease progression.”


Sparks J, Vanni K, Sparks M, et al. Effect of low-dose methotrexate on estimated glomerular filtration rate and kidney adverse events: A randomized clinical trial. J Am Soc Nephrol. Published online September 22, 2021.  doi:10.1681/ASN.2021050598

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Schedule1 Oct 2023