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Glucarpidase for treatment of high-dose methotrexate toxicity
Shruti Gupta1,2,3, Sarah A Kaunfer1, Kevin L Chen4
1Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.
Abstract:
High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69-4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18-3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28-0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28-0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49-1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.
Insights
Glucarpidase administration significantly improved kidney recovery and reduced neutropenia and liver toxicity in patients with high-dose methotrexate-induced acute kidney injury (MTX-AKI). This enzyme may offer a valuable therapeutic option for managing MTX toxicity.
Area of Science:
- Oncology
- Nephrology
- Pharmacology
Background:
- High-dose methotrexate (MTX) therapy is associated with significant risks of acute kidney injury (AKI), neutropenia, and hepatotoxicity.
- Glucarpidase, an enzyme that cleaves MTX, has limited clinical data supporting its efficacy in mitigating MTX-related toxicities.
- Understanding the real-world effectiveness of glucarpidase in patients with MTX-induced AKI (MTX-AKI) is crucial for clinical decision-making.
Purpose of the Study:
- To evaluate the association between glucarpidase administration and clinical outcomes in adult patients experiencing MTX-AKI.
- To assess the impact of glucarpidase on kidney recovery, time to recovery, neutropenia, transaminitis, and mortality.
Main Methods:
- A sequential target trial emulation framework was employed using data from 28 US cancer centers.
- Multivariable logistic and Cox regression models were used to compare outcomes between patients who received glucarpidase within 4 days of MTX initiation and those who did not.
- The primary endpoint was kidney recovery at hospital discharge; secondary endpoints included time to recovery, neutropenia, transaminitis, and death.
Main Results:
- Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase.
- Glucarpidase receipt was associated with a 2.70-fold increased odds of kidney recovery (95% CI, 1.69-4.31) and faster time to recovery (aHR, 1.88; 95% CI, 1.18-3.33).
- Patients treated with glucarpidase also showed reduced risks of grade ≥2 neutropenia (aOR, 0.50; 95% CI, 0.28-0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28-0.91) on day 7, with no significant difference in time to death.
Conclusions:
- Glucarpidase administration appears to improve renal recovery and reduce extrarenal toxicities, such as neutropenia and transaminitis, in patients with MTX-AKI.
- These findings suggest glucarpidase may be a beneficial adjunctive therapy for managing high-dose methotrexate toxicity.
- Further prospective studies are warranted to confirm these benefits and establish optimal use guidelines.
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