Clinical Outcomes and Renal Recovery after Glucarpidase Rescue in High-Dose Methotrexate–Induced Acute Kidney Injury: A Systematic Review

 

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https://storage.unitedwebnetwork.com/files/1099/8a0f77cd3b21d0588de601a588f10558.pdf
Clinical Outcomes and Renal Recovery after Glucarpidase Rescue in High-Dose Methotrexate–Induced Acute Kidney Injury: A Systematic Review

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Andree
Kurniawan
Andree Kurniawan a125ee@yahoo.com Faculty of Medicine, Universitas Pelita Harapan Internal Medicine Tangerang Indonesia *
Angeline Tancherla angeline.tancherla@gmail.com Faculty of Medicine, Universitas Pelita Harapan Medicine Tangerang Indonesia -
Jeremia Siregar jeremia.siregar@uph.edu Faculty of Medicine, Universitas Pelita Harapan Internal Medicine Tangerang Indonesia -
Vidhia Umami vidhia.umami@yarsi.ac.id Medical Faculty Universitas YARSI Internal medicine Jakarta Indonesia -
Dina Nilasari deen_es@yahoo.com Siloam Hospitals Group Clinical research Jakarta Indonesia -
Margaret Merlyn Tjiang margaret_merlyn@yahoo.com aculty of Medicine, Universitas Pelita Harapan Internal Medicine Tangerang Indonesia -
Donnie Lumban Gaol donnie.gaol@UKI.ac.id Faculty of Medicine, Universtas Kristen Indonesia Internal Medicine Jakarta Indonesia -
Fernando Dharmaraja fd100601@gmail.com Faculty of Medicine, Universitas Pelita Harapan Medicine Tangerang Indonesia -
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High-dose methotrexate (HD-MTX) is a cornerstone in the treatment of hematologic malignancies and certain solid tumors, including osteosarcoma and germ cell tumors. However, HD-MTX can cause acute kidney injury (AKI) and delayed MTX clearance, leading to severe systemic toxicity. Glucarpidase (carboxypeptidase G2) is an enzymatic rescue therapy that rapidly hydrolyzes MTX into inactive metabolites. This systematic review aimed to evaluate the impact of glucarpidase on renal recovery and clinical outcomes in patients with HD-MTX–induced AKI or delayed MTX elimination.

PubMed, PMC, and Scopus were systematically searched for clinical studies assessing glucarpidase use in adults receiving HD-MTX for lymphoma, leukemia, central nervous system malignancies, osteosarcoma, or germ cell tumors who developed AKI or delayed MTX elimination. Eligible designs included cohort studies, clinical trials, and target trial emulations. AKI was predominantly defined using KDIGO or AKIN criteria, with renal recovery defined as improvement of serum creatinine to CTCAE grade 0–1 or near-baseline values. Data on MTX clearance, renal recovery, adverse events, and mortality were extracted and qualitatively synthesized due to heterogeneity across study designs and populations.

Nine studies (four cohorts, four clinical trials, and one target trial emulation) involving 3,179 patients were included. Glucarpidase doses (1,000–2,000 U or 50 U/kg) were typically administered within 24–72 hours after HD-MTX. Across studies, rapid MTX reduction (≥95%) occurred within 15–30 minutes, even with lower doses. Renal recovery (improvement of serum creatinine from CTCAE grade ≥2 to 0–1) was achieved in 64–93% of evaluable patients, with faster recovery in younger populations. Cohort data showed comparable recovery between glucarpidase and non-glucarpidase groups despite greater initial AKI severity in the treated cohort. Trials demonstrated sustained MTX reduction, minimal rebound, and favorable safety, while the target trial emulation suggested improved kidney recovery (OR 2.7, 95% CI 1.7–4.3) and reduced systemic toxicities. Most studies reported normalization or improvement of serum creatinine within 2–4 weeks after glucarpidase, with limited rebound in MTX levels. Adverse events were infrequent and mild, and no MTX-related deaths were reported. 

Glucarpidase provides rapid enzymatic reduction of MTX levels and facilitates renal function recovery in patients with HD-MTX–induced AKI. Its early use supports renal recovery, minimizes systemic toxicity, and allows safe continuation of chemotherapy. Further prospective studies are warranted to optimize timing, patient selection, and integration with renal replacement therapy in MTX-associated nephrotoxicity.

Kewords