Identification of Risk Factors in High-Dose Methotrexate-Induced Acute Kidney Injury in Childhood Acute Lymphoblastic Leukemia

Abstract

Aims: Although high-dose methotrexate (HDMTX) is an effective means for the treatment of acute lymphoblastic leukemia (ALL), the development of renal dysfunction remains a significant management challenge. This study aimed to identify the key factors in HDMTX-induced acute kidney injury (AKI) in childhood ALL. Methods: We retrospectively analyzed the clinical data in 1,329 courses of HDMTX treatment in 336 Chinese ALL children at the First Affiliated Hospital of Guangxi Medical University from September 2012 to November 2016. The clinical data were compared between the groups of children with development of AKI and those without. Risk factors were identified by multiple logistic regression analysis, and the diagnostic performance of plasma MTX concentration was evaluated by receiver operating characteristic (ROC) curve analysis. Results: AKI was observed in 88 patients (26.2%) and 104 courses (7.8%). Binary logistic regression revealed that age (OR 1.349; p = 0.005), first HDMTX course (OR 1.767; p = 0.013), MTX dose per body surface area (BSA; OR 1.944; p = 0.015), and baseline serum total protein (OR 0.929; p = 0.021) significantly correlated with AKI. The area under the ROC for 48-h plasma MTX concentration was 0.890 (95% CI 0.850–0.930), and sensitivity and specificity values of the cut-off value were 78.8 and 90.4%, respectively. Conclusion: Increasing age, higher MTX dose per BSA, lower baseline serum protein, and first HDMTX course were significant risk factors for developing HDMTX-induced AKI in childhood ALL. The threshold of 48-h MTX plasma concentration is valuable for the prediction of HDMTX-induced AKI.

<p>Development and Validation of UHPLC-MS/MS Assay for Therapeutic Drug Monitoring of High-dose Methotrexate in Children with Acute Lymphoblastic Leukemia</p>

“…Methotrexate (MTX) was a vital medication in treatment regimens for acute lymphoblastic leukemia (ALL) in children. [1][2][3][4] There were evidently individual differences in MTX plasma concentrations owing to large inter-individual variation in the absorption, distribution, metabolism, and excretion of MTX in the body. Therefore, individualized therapies were important for therapeutic dose adjustments.…”

“…The high-dose MTX (HD-MTX) (1-5 g/m 2 ) as a 24-h infusion, 1/6 of the high-dose MTX was infused in initial one hour and the rest of the dose at a constant rate in the remaining 23 h, based on HD-MTX treatment regimen. 1,2,5 MTX was mainly eliminated via the kidneys in vivo, and renal clearance was influenced by many prerequisites, especially dosage, individual differences, and urinary pH. 6,7 During HD-MTX administration, patients could achieve the cytotoxic benefits by avoiding overtreatment which may lead to acute renal function injury and tubular toxicity.…”

A Case of Methotrexate Neurotoxicity Presented as Status Epilepticus, Encephalopathy, and High Fever

“…High-dose MTX, defined as a dose of 500 mg/m 2 or higher, is used to treat a range of adult and childhood cancers including acute lymphoblastic leukemia, central nervous system lymphomas, leptomeningeal metastases, and osteosarcoma. 1-4…”

Metabolic underpinnings of leukemia pathology and treatment

“…Thus, MTX confers cytotoxicity by interfering with nucleic acid synthesis along with other molecular mechanisms. MTX is utilized in a variety of cancer types; however, adverse effects are common, and can include acute kidney injury, cognitive/memory impairment, leukoencephalopathy, and myelopathy. As MTX is the subject of at least hundreds of clinical trials, we will highlight here only several of the most recent developments regarding its role in the treatment of ALL with a particular focus on multiple metabolic manipulations used in conjunction.…”