ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO1875

Utility of Liquid Chromatography in Monitoring Methotrexate Levels After Glucarpidase for Methotrexate Toxicity

Session Information

Category: Onco-Nephrology

  • 1500 Onco-Nephrology

Authors

  • Parvathareddy, Vishnupriyadevi, Baylor College of Medicine, Houston, Texas, United States
  • Mukku, Venkata Kishore R., The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
  • Polani, Adnann Salim, Baylor College of Medicine, Houston, Texas, United States
  • Chen, Sheldon, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Introduction

Methotrexate (MTX) is an anti-metabolite with a 1,000-fold affinity for dihydrofolate reductase, competitively inhibiting the reduction of dihydrofolate to tetrahydrofolate that is needed for DNA/RNA and protein synthesis. High-dose MTX is defined as a dose higher than 500 mg/m2 and results in acute kidney injury in 2-12% of patients. Values above 10 μM at 24 h post-infusion confer a high risk for toxicity.

Case Description

A 61 y/o male with newly diagnosed primary CNS diffuse B cell lymphoma was admitted for De Angelis regimen which included MTX 3,500 mg/m2. His creatinine increased from 0.9 to 3.1 mg/dL despite concurrent hydration, urinary alkalinization, and leucovorin. MTX level was 89 at 24 h, confirming MTX toxicity. He then received a single dose of glucarpidase 50 U/kg IV. Plasma MTX levels remained high at 44, 41, and 14 on post-glucarpidase days 1, 2, and 3. In contrast, high-performance liquid chromatography (HPLC) measurement of MTX was below 0.05 on post-glucarpidase day 2, showing efficacy of glucarpidase in lowering MTX levels.

Discussion

After high-dose MTX, serum levels must be monitored to determine when to administer leucovorin and glucarpidase, a recombinant carboxypeptidase-G2 that cleaves MTX to inactive metabolites. Intrarenal MTX crystallization can 1) obstruct the tubules, 2) damage the tubular epithelium, and 3) vasoconstrict the afferent arterioles. Because volume depletion and acidic urine are major risk factors for AKI, hyperhydration and urine alkalinization are mandatory during high-dose MTX treatment.

Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop kidney dysfunction. A single dose of glucarpidase 50 U/kg IV reduces plasma MTX concentration by >97% within 15 mins. Liquid chromatographic measurement of MTX is recommended within 48 hours of glucarpidase administration, as the MTX metabolites 7-hydroxymethotrexate and 4-deoxy-4-amino N10 methylpteroic acid (DAMPA) cross react with standard immunoassays and falsely elevate the level. In our patient, the serum MTX levels were still elevated by immunoassay, while they were undetectable by liquid chromatography. We recommend using HPLC when available to confirm the lowering of MTX by glucarpidase.