Prevention and Treatment of Acute Kidney Injury Associated with High-Dose Methotrexate

Abstract

AKI is a rare but life-threatening complication of the administration of methotrexate (MTX) at high doses (≥1 g/m 2 ) for the treatment of solid or hematological malignancies. MTX overexposure can lead to MTX-AKI and subsequent higher risk of extrakidney toxicities, morbidity, and mortality. MTX-AKI can also lead to secondary CKD requiring a reduced dose or contraindication for subsequent MTX infusions, thus worsening the cancer-related prognosis. Treatment of MTX-AKI is mainly preventive, combining alkaline hyperhydration, withdrawal of all nephrotoxic agents and drugs that modulate the metabolism of MTX, metabolic salvage using leucovorin (folinic acid), and close monitoring of serum MTX and creatinine concentrations. Glucarpidase (carboxypeptidase-G2), a recombinant bacterial enzyme that hydrolyzes MTX into two noncytotoxic metabolites, should be considered for patients with MTX overexposure to prevent and lessen AKI and other potential toxicities. This article provides a comprehensive review of MTX metabolism, mechanisms and prevention of MTX-AKI, and its management.

Figure 1

Metabolism of MTX and prevention of kidney toxicity. CH2, methylene group; DAMPA, 2,4-diamino-N¹⁰-methylpteroic acid; DHFR, dihydrofolate reductase; dUMP, desoxyuridine monophosphate; FH2, dihydrofolic acid; FH4, tetrahydrofolic acid; GLU, glutamyl; MTX, methotrexate; PolyGlu, polyglutamyl derivatives of dihydrofolate reductase; TMP, thymidine monophosphate.

Figure 2

Prevention and treatment of AKI induced by HD-MTX. * and **The timing of MTX assessment and start of leucovorin will depend on the MTX regimen used.^, #Use of glucarpidase in patients with delayed clearance of MTX but no AKI is not universally recommended, but can be discussed in cases of very high blood concentrations of MTX or high risk of AKI (summary of product characteristics, 2024: https://www.ema.europa.eu/en/documents/product-information/voraxaze-epar-product-information_en.pdf). Given the lack of robust data in this setting, the decision mainly relies on clinical judgment. An online tool (https://mtxpk.org) can be used to identify patients with overt delayed MTX elimination. HD, high dose; NSAIDs, nonsteroidal anti-inflammatory drugs; PPIs, proton pump inhibitors; SCr, serum creatinine.